TW202417627A - Anti-c5 antibody/c5 irna co-formulations and combination therapies - Google Patents

Abstract

The present disclosure provides a co-formulation that includes an antibody that binds specifically to C5 and a C5 iRNA which is a glycoconjugate that includes a ligand having terminal N-Acetylgalactosamine (GalNAc) residues and/or N-acetylglucosamine (GlcNAc) residues. Methods for reducing degradation of glycoconjugate RNA by beta-hexosaminidase enzyme are also provided. The present disclosure also includes methods for treating or preventing a C5-associated disease or disorder by administering one or more doses of an anti-C5 antibody or antigen-binding fragment thereof in combination with one or more doses of a C5 iRNA; preferably wherein the anti-C5 antibody or fragment and the C5 iRNA are in a co-formulation. The present disclosure also includes dosing regimens for treating C5-associated disease or disorder with a combination of anti-C5 antibody and C5 iRNA in subjects that either are treatment naive or are switching from a previous C5 inhibitor therapy.

Description

Anti-C5 antibody/C5 IRNA co-formulations and combination therapy

This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/381,450, filed on October 28, 2022; U.S. Provisional Patent Application No. 63/382,087, filed on November 2, 2022; U.S. Provisional Patent Application No. 63/382,264, filed on November 3, 2022; U.S. Provisional Patent Application No. 63/383,442, filed on November 11, 2022; U.S. Provisional Patent Application No. 63/385,9 09, filed on December 2, 2022; U.S. Provisional Patent Application No. 63/386,787, filed on December 9, 2022; U.S. Provisional Patent Application No. 63/495,767, filed on April 12, 2023; U.S. Provisional Patent Application No. 63/498,112, filed on April 25, 2023; and U.S. Provisional Patent Application No. 63/505,011, filed on May 30, 2023; each of which is incorporated herein by reference in its entirety.

The sequence listing for this application is submitted electronically in ASCII format, with the file name "11282seqlist", the creation date of which is October 28, 2022, and the size is 112 Kb. The submitted sequence listing is part of the specification and is incorporated herein by reference in its entirety.

The field of the invention relates to co-formulations and combination therapies comprising RNA and antibodies or antigen-binding fragments thereof, and methods for stabilizing RNA in compositions comprising β-hexosaminidase.

The complement component C5 is the target of many rare diseases, including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, neuromyelitis optica, and generalized myasthenia gravis. For example, uncontrolled complement activation in PNH patients leads to the major clinical manifestation of chronic hemolysis and an increased risk of thromboembolism, resulting in target organ damage and death.

Complement 5 is a recognized target for the treatment of complement-mediated diseases such as generalized myasthenia gravis (gMG), established after the approval of eculizumab (Ecu) for the treatment of patients with gMG. Monotherapy with the anti-C5 antibody pozelimab has been shown to effectively block C5 activity in another disease that is highly sensitive to complement-mediated effects, paroxysmal nocturnal hemoglobinuria (PNH).

In order to provide rapid and dramatic disease suppression and to obtain complete and uninterrupted C5 inhibition throughout the C5 inhibitor dosing interval, a substantial level of tonic suppression is required. Current C5 inhibitor monotherapy does not achieve a sufficient level of suppression.

C5-targeted therapies for PNH, such as Eculizumab and Ravulizumab (Soliris and Ultomiris, Alexion Pharmaceuticals), have been shown to be effective. However, in rare cases, Eculizumab and Ravulizumab are ineffective due to polymorphic variants in the gene encoding C5, such that the C5 protein is not bound by Eculizumab or Ravulizumab (Nishimura et al ., Genetic variants in C5 and poor response to Eculizumab. N Engl J Med 2014; 370(7):632-639). In addition, treatment is cumbersome because the drugs are usually administered long-term by IV infusion Q2W or Q8W, respectively, to maintain efficacy. In addition, breakthrough hemolysis due to incomplete C5 inhibition has been reported in up to 20% of patients receiving eculizumab at the labeled maintenance dose (900 mg Q2W IV) requiring significant dose increases or dosing frequency (Peffault de Latour et al ., Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving Eculizumab. Blood 2015; 125(5):775-783) (Hillmen et al ., Long-term safety and efficacy of sustained Eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2013; 162(1):62-73). Although regulatory approval for ravulizumab provides for an IV dosing frequency of Q8W, some patients still experience hemolytic breakthrough (Lee et al ., Ravulizumab (ALXN1210) vs Eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood 2019; 133(6):530-539).

In a phase 2 study (R3918-PNH-1852) of patients with PNH who had not received prior therapy, a 30 mg/kg IV loading dose followed by 800 mg SC weekly was effective in reducing serum LDH to <1.5 × ULN in all patients and <1.0 ULN in the majority of patients. However, this regimen represents a relatively high dose of a biologic.

The need for such high anti-C5 mAb doses is due to the need for 100% inhibition, which is achieved in the setting of complete target engagement (Peffault de Latour, 2015) and high levels of C5, and to the fact that in order to achieve 100% inhibition on a population basis, it is necessary to account for inter- and intra-patient variability in C5 concentrations as well as for enhanced complement activation (which may occur during intercurrent illness).

Cemdisiran is a synthetic small interfering RNA (siRNA) that targets C5 messenger RNA (mRNA) and is covalently linked to a tritentaneous N-acetylgalactosamine (GalNAc) ligand. Cemdisiran is designed to inhibit hepatic production of C5 protein when administered by SC injection. C5 is encoded by a single gene and is primarily expressed and secreted by hepatocytes. Through the RNA interference pathway, cemdisiran causes C5 mRNA to be degraded by RNase, thereby reducing C5 protein production and resulting in lower circulating C5 protein levels. Cemdisiran monotherapy has been found to be insufficiently effective as a single-agent treatment for PNH. Badri et al., Clin Pharmacokinet. 2021;60(3):365-78-Epub 2020/10/14.

Combination of pasirizumab and cemdisiran therapy is difficult in patients who have already received another anti-C5 antibody therapy, such as ravulizumab or eculizumab. In patients who switch from a previous anti-C5 antibody to another anti-C5 antibody, there is a risk of adverse reactions (e.g., serum sickness-like reactions, rash) due to C5 binding to two non-competitive C5 mAb antibodies to form a drug-target-drug (DTD) complex (Röth et al. , The SMART Anti-hC5 Antibody (SKY59/RO7112689) Shows Good Safety and Efficacy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). Blood 2018; 132(Suppl 1):535; U.S. Patent Publication US2009/0220508).

There were two arms in the COMMODORE-1 clinical trial in which patients were treated with either the anti-C5 antibody crovalimab or eculizumab during a 24-week primary treatment period. After the primary treatment period, patients receiving eculizumab had the option to switch to crovalimab. Sixteen percent of patients who switched from eculizumab experienced type 3 hypersensitivity (T3H) reactions. T3H reactions and injection-related reactions were not applicable to the eculizumab arm because they are related to DTD complex formation and subcutaneous administration, respectively, which are unique to the crovalimab arm. Scheinberg et al ., Phase III Randomized, Multicenter, Open-Label Commodore 1 Trial: Comparison of Crovalimab vs Eculizumab in Complement Inhibitor-Experienced Patients With Paroxysmal Nocturnal Hemoglobinuria, European Hematology Association, Frankfurt, Germany; Virtual (Hybrid) 09 June 2023.

The experiments showed that the antibody with the sequence of eculizumab and paslimab combined was able to form a high molecular weight heterocomplex with C5.

Furthermore, it is difficult to synthesize antibodies (such as paslimab) and iRNAs (such as cemdisiran) into a single formulation. These molecules are significantly different chemically, and forming a stable formulation containing both presents significant technical hurdles.

The present invention includes a co-formulation comprising a C5 iRNA bound to a ligand comprising one or more terminal amino sugars (such as N-acetylgalactosamine (GalNAc) and/or N-acetylglucosamine (GlcNAc) residues); an antibody or antigen-binding fragment thereof that specifically binds to C5 (anti-C5) and is isolated from a mammalian host cell; having a pH greater than or less than about 6; and a pharmaceutically acceptable carrier. For example, in one embodiment of the present invention, the co-formulation comprises C5 iRNA; an antibody or antigen-binding fragment thereof that specifically binds to C5; a buffer (e.g., a histidine-based buffer, a citrate-based buffer, a phosphate-based buffer, and/or an acetate-based buffer, e.g., at a concentration of about 10-35, 35-45, 20-50, 20, 25, 30, 35, 40, 45, or 50 mM); stabilizers (e.g., polyols, sugars, trehalose, sorbitol, mannitol, taurine, propanesulfonic acid, L-proline, sucrose, glycerol, threitol, maltitol, polyethylene glycol (PEG) and/or PEG3350; for example, at a concentration of about 0.8-3.6, 0.8, 0.9, 1.0, 1.25, 1.50, 2.0, 2.25, 2.50, 2.75, 3.00, 3.1, 3.2, 3.3, 3.4, 3.5 or 3.6%) (w/v)); viscosity reducers, and non-ionic surfactants (e.g., polyoxyethylene glycol alkyl ethers; glucoside alkyl ethers; polyoxyethylene glycol octylphenol ethers; polyoxyethylene glycol alkylphenol ethers; glycerol alkyl esters; polyoxyethylene glycol sorbitan alkyl esters; sorbitan alkyl esters; block copolymers of polypropylene glycol; block copolymers of polyethylene glycol; polysorbates, octaethylene glycol monododecyl ether; pentaethylene glycol monododecyl ether; polyoxypropylene glycol alkyl ethers; decyl glucoside, lauryl glucoside, octyl glucoside; triton X-100; nonoxynol-9; glyceryl laurate; cocamide MEA, cocamide DEA, dodecyl dimethylamine oxide; poloxamer; polyethoxylated tallow amine (PPOEA); polysorbate-20 (PS20) and/or polysorbate-80 (PS80); for example, at a concentration of about 0.025, 0.05, 0.075, 0.1, 0.125, 0.15, 0.175% (w/v)), and a pH greater than or less than about 6 (e.g., within 0.5 of not less than 6.0).

In one embodiment of the present invention, the viscosity reducing agent (e.g., dicarboxylic acid, inorganic salt, citrate, xanthine, adipic acid; NaCl; caffeine; triethyl citrate, amino acids, (D- or L-) arginine, L-arginine HCl, (D- or L-) alanine, (D- or L-) histidine, proline, (D- or L-) valeric acid, glycine, (D- or L-) serine, (D- or L-) phenylalanine, (D- or L-) lysine and (D- or L-) glutamine, and salts thereof; pyridoxamine; L-ornithine; thiamine phosphate chloride dihydrate, benzenesulfonic acid and/or pyridoxine; for example, at a concentration of about 20-140, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135 or 140 mM), each at a concentration of about 5 mM to about 100 mM (e.g., 50-75 mM). If the viscosity reducer is an amino acid, it may be its L-enantiomer or its D-enantiomer. The viscosity reducer may be a conjugated base of an acid specified herein or a salt thereof. In one embodiment of the invention, the co-formulation is characterized in that the anti-C5 antibody or antigen-binding fragment has a purity of about 96% or more as assessed by size exclusion analysis after about 1 month at 2-8°C; and/or the C5 iRNA has a purity of about 94% or more as assessed by anion exchange analysis after about 1 month at 2-8°C. In one embodiment of the invention, the co-formulation has a C5 iRNA and an anti-C5 antibody or antigen-binding fragment at a mg/mL concentration ratio of 1:1; and optionally, a viscosity reducing agent, which is arginine, adipate, NaCl, lysine, aspartic acid, proline, histidine, caffeine, phenylalanine and/or triethyl citrate, for example, at a concentration of about 75 mM arginine, 75 mM adipate, 75 mM NaCl, 75 mM lysine, 75 mM aspartic acid, 75 mM proline, 50 mM histidine (wherein, if the buffer is histidine-based, the total histidine concentration of the co-formulation is 50 mM), 50 mM caffeine, 50 mM phenylalanine and/or 75 In one embodiment of the invention, the co-formulation has a C5 iRNA and an anti-C5 antibody or antigen-binding fragment at a mg/mL concentration ratio of 1:2; and optionally, a viscosity reducing agent such as arginine, adipate, NaCl, lysine and/or aspartic acid, for example, at a concentration of about 75 mM arginine, 75 mM adipate, 75 mM NaCl, 75 mM lysine and/or 75 mM aspartic acid.

In one embodiment of the present invention, the co-formulation includes an antibody or antigen-binding fragment thereof that specifically binds to C5 (anti-C5), comprising: a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 2, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 10; a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 18, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 26; a NO:34, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:42; a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:50, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:58; a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:66, and a LCVR comprising a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:67; NO:74; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:82, and a LCVR comprising LCDR1, LCDR2 and LCDR3 comprising the amino acid sequence of SEQ ID NO:90; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:98, and a LCVR comprising LCDR1, LCDR2 and LCDR3 comprising the amino acid sequence of SEQ ID NO:106; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:110; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:111; a LCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:112; a LCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:113; a LCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:114; a LCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:115; a LCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:116 NO:98, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:114; a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:122, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:106; a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:98, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:114; a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:122, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:106 NO:130; a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:138, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:106; a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:146, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:106; a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:146, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:106; a NO: 122, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 130; a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 114; a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: NO:130; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:138, and a LCVR comprising LCDR1, LCDR2 and LCDR3 comprising the amino acid sequence of SEQ ID NO:130; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:154, and a LCVR comprising LCDR1, LCDR2 and LCDR3 comprising the amino acid sequence of SEQ ID NO:162; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:164; a LCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:165; a LCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:166; a LCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:167; a LCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:168; a LCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:169; a LCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:170 NO: 170, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 178; a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 186, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 194; a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 202, and a LCVR comprising a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 194; NO:210; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:218, and a LCVR comprising LCDR1, LCDR2 and LCDR3 comprising the amino acid sequence of SEQ ID NO:226; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:234, and a LCVR comprising LCDR1, LCDR2 and LCDR3 comprising the amino acid sequence of SEQ ID NO:242; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:244; a LCVR comprising LCDR1, LCDR2 and LCDR3 comprising the amino acid sequence of SEQ ID NO:245; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:246. NO:250, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:258; a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:266, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:258; a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:274, and a LCVR comprising a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:280. NO:282; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:290, and a LCVR comprising LCDR1, LCDR2 and LCDR3 comprising the amino acid sequence of SEQ ID NO:298; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:306, and a LCVR comprising LCDR1, LCDR2 and LCDR3 comprising the amino acid sequence of SEQ ID NO:314; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:315; a HCVR comprising HCDR1, HCDR2 and HCDR3 comprising the amino acid sequence of SEQ ID NO:320 NO:322, and a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO:322, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO:330; and/or a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO:338, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO:346. For example, in one embodiment of the present invention, an antibody or antigen-binding fragment thereof that specifically binds to C5 (anti-C5) comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 4, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 6, and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 8, and the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 14, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 16; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 20, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 22, and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 24, and the light chain variable region comprises SEQ ID NO: 13. The invention further comprises a LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 28, a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 30, and a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 32; the heavy chain variable region comprises a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 36, a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 38, and a HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 40; the light chain variable region comprises a LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 44, a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 46, and a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 48; the heavy chain variable region comprises a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 52, a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 54, and a HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 56; the light chain variable region comprises a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 54, a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 56 The invention further comprises a LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 60, a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 62, and a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 64; the heavy chain variable region comprises a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 68, a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 70, and a HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 72; the light chain variable region comprises a LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 76, a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 78, and a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 80; the heavy chain variable region comprises a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 84, a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 86, and a HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 88; the light chain variable region comprises a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 84, a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 86, and a HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 88. NO: 92, LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 94, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 94, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 96; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 100, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 102, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 104, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 110, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 112; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 100, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 102, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 104, the light chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 110, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 112 The invention further comprises a LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 116, a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 118, and a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 120; the heavy chain variable region comprises a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 124, a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 126, and a HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 128; the light chain variable region comprises a LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108, a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 110, and a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 112; the heavy chain variable region comprises a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 100, a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 102, and a HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 104; the light chain variable region comprises a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 106, a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 107, and a HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 108; The invention further comprises a LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 132, a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 134, and a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 136; the heavy chain variable region comprises a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 140, a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 142, and a HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 144; the light chain variable region comprises a LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108, a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 110, and a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 112; the heavy chain variable region comprises a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 148, a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 150, and a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: NO: 152, the light chain variable region comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 108, LCDR2 comprising the amino acid sequence of SEQ ID NO: 110, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 112; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 124, HCDR2 comprising the amino acid sequence of SEQ ID NO: 126, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 128, the light chain variable region comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 132, LCDR2 comprising the amino acid sequence of SEQ ID NO: 134, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 136; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 148, HCDR2 comprising the amino acid sequence of SEQ ID NO: 150, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 1 The light chain variable region comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 116, LCDR2 comprising the amino acid sequence of SEQ ID NO: 118, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 120; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 148, HCDR2 comprising the amino acid sequence of SEQ ID NO: 150, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 152; the light chain variable region comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 132, LCDR2 comprising the amino acid sequence of SEQ ID NO: 134, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 136; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 140, LCDR2 comprising the amino acid sequence of SEQ ID NO: 151, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 153. The light chain variable region comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 132, LCDR2 comprising the amino acid sequence of SEQ ID NO: 134, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 136; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 156, HCDR2 comprising the amino acid sequence of SEQ ID NO: 158, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 160; the light chain variable region comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 164, LCDR2 comprising the amino acid sequence of SEQ ID NO: 166, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 168; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 172, LCDR2 comprising SEQ ID NO: 174, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 176. The invention relates to an antibody comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 174, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 176, a light chain variable region comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 180, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 182, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 184; a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 188, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 190, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 192; a light chain variable region comprising a LCDR1 comprising the amino acid sequence of SEQ ID NO: 196, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 198, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 200; a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence of SEQ ID NO: 196, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 198, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 200. NO: 204, HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 206, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 208, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 212, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 214, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 216; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 220, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 222, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 224, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 228, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 230, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 232; the heavy chain variable region comprises SEQ ID NO: 234. The invention further comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 236, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 238, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 240, the light chain variable region comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 244, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 246, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 248; the heavy chain variable region comprises a HCDR1 comprising the amino acid sequence of SEQ ID NO: 252, a HCDR2 comprising the amino acid sequence of SEQ ID NO: 254, and a HCDR3 comprising the amino acid sequence of SEQ ID NO: 256, the light chain variable region comprises a LCDR1 comprising the amino acid sequence of SEQ ID NO: 260, a LCDR2 comprising the amino acid sequence of SEQ ID NO: 262, and a LCDR3 comprising the amino acid sequence of SEQ ID NO: 268. NO: 264; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 268, HCDR2 comprising the amino acid sequence of SEQ ID NO: 270, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 272; the light chain variable region comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 260, LCDR2 comprising the amino acid sequence of SEQ ID NO: 262, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 264; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 276, HCDR2 comprising the amino acid sequence of SEQ ID NO: 278, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 280; the light chain variable region comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 284, LCDR2 comprising the amino acid sequence of SEQ ID NO: 286, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 284. the heavy chain variable region comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 292, HCDR2 comprising the amino acid sequence of SEQ ID NO: 294, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 296; the light chain variable region comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 300, LCDR2 comprising the amino acid sequence of SEQ ID NO: 302, and LCDR3 comprising the amino acid sequence of SEQ ID NO: 304; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence of SEQ ID NO: 308, HCDR2 comprising the amino acid sequence of SEQ ID NO: 310, and HCDR3 comprising the amino acid sequence of SEQ ID NO: 312; the light chain variable region comprises LCDR1 comprising the amino acid sequence of SEQ ID NO: 316, and LCDR2 comprising the amino acid sequence of SEQ ID NO: 317. NO: 318, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 320, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 320; the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 324, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 326, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 328, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 332, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 334, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 336; or the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 340, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 342, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 344, the light chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 345 LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 348, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 350, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 352. In one embodiment of the present invention, an antibody or antigen-binding fragment thereof that specifically binds to C5 (anti-C5) comprises a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 2, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 10; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 18, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 26; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 34, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 42; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 50, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 58; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 66, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 74; NO: 82, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 90; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 98, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 106; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 98, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 114; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 122, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 106; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 98, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 130; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 138, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: NO: 106; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 146, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 106; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 122, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 130; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 146, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 114; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 146, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 130; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 138, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 130; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 138 NO: 154, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 162; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 170, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 178; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 186, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 194; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 202, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 210; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 218, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 226; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 234, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 242; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 250, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 258; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 266, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 258; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 274, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 282; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 290, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 298; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 306, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 314; a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 320 NO: 322, a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 330, or a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 338, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 346. For example, in one embodiment of the present invention, the co-formulation includes about 90 to about 275 mg/ml; or about 90; 91; 92; 93; 94; 95; 96; 97; 98; 99; 100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 147 7; 148; 149; 150; 151; 152; 153; 154; 155; 156; 157; 158; 159; 160; 161; 162; 163; 164; 165; 166; 167; 168; 169; 170; 171; 172; 173; 174; 175; 176; 177; 178; 179; 180; 181; 182; 183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 211, 220, 242, or 274 mg/mL; or at least about 150 mg/ml, at least about 175 mg/ml, at least about 200 mg/ml, at least about 211 mg/ml, at least about 220 mg/ml, at least about 242 mg/ml or at least about 274 mg/ml of an antibody or antigen-binding fragment that specifically binds to C5 (anti-C5).

In one embodiment of the invention, the co-formulation includes a C5 iRNA, which is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises a complementary region comprising at least 17 consecutive nucleotides that differ from the nucleotide sequence of 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 364) by no more than 3 nucleotides, and wherein the dsRNA agent comprises at least one modified nucleotide. In one embodiment of the invention, the co-formulation comprises a C5 iRNA, which is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO: 406) and the antisense strand comprises 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO: 369), wherein a, g, c and u are 2'-0-methyl (2'-OMe) A, G, C and U, respectively; Af, Gf, Cf and Uf are 2'-fluoro A, G, C and U, respectively; dT is a deoxythymidine nucleotide; s is a phosphorothioate linkage; and wherein the sense strand is joined to a ligand at the 3'-end (e.g., wherein the C5 iRNA is Cemdisiran). In one embodiment of the invention, the co-formulation includes a C5 iRNA that is Cemdisiran and one or more of Cemdisiran Impure 1, Cemdisiran Impure 2, and Cemdisiran Impure 3 discussed herein. In one embodiment of the invention, the C5 iRNA is present at a concentration of about 20-100, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 130, 140, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 2 350, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg/ml.

In one embodiment of the present invention, the co-formulation is characterized by a viscosity of < 30 cP at 20°C; and/or an osmotic pressure of 240-450 mOsm/kg; for example, a viscosity of ≦20 cP at 20°C.

The present invention includes co-formulations containing any of the following: Bi-stranded C5 iRNA; and Anti-C5 antibody or antigen-binding fragment thereof, pH above or below 6.0 (different by at least 0.5); C5 iRNA, Anti-C5 antibody or antigen-binding fragment thereof, Buffer, Viscosity reducer, Stabilizer, and Non-ionic surfactant; C5 iRNA, Anti-C5 antibody or antigen-binding fragment thereof, Histidine-based buffer, L-arginine, Stabilizer, and Non-ionic surfactant; C5 iRNA, Anti-C5 antibody or antigen-binding fragment thereof, Histidine-based buffer, L-arginine, Sugar or polyol, and nonionic surfactant; Cemdisiran, Pazelimumab, a histidine-based buffer, L-arginine, a stabilizer, and a nonionic surfactant, pH about 6.5; Cemdisiran, Pazelimumab, a histidine-based buffer, L-arginine, sucrose, and polysorbate 80, pH about 6.5; 100 (±10) mg/mL C5 iRNA, 100 (±10) mg/mL anti-C5 antibody or antigen-binding fragment thereof, 50 (±5) mM viscosity reducer, 10 (±1) mM buffer, 1.0 (±0.1)% stabilizer, 0.075 (±0.0075)% non-ionic surfactant, pH 6.5; 75 (±7.5) mg/mL C5 iRNA, 150 (±15) mg/mL anti-C5 antibody or its antigen-binding fragment, 75 (±7.5) mM viscosity reducer, 15 (±1.5) mM buffer, 1.5(±0.15)% stabilizer, 0.1125 (±0.01125)% non-ionic surfactant, pH 6.5; 50 (±5) mg/mL C5 iRNA, 100 (±10) mg/mL anti-C5 antibody or its antigen-binding fragment, 75 mM (±7.5) viscosity reducer, 15 (±1.5) mM buffer, 1.5 (±0.15)% stabilizer, 0.1125 (±0.01125)% non-ionic surfactant; pH 6.5; 50 (±5) mg/mL C5 iRNA, 100 (±10) mg/mL anti-C5 antibody or antigen-binding fragment thereof, 75 (±7.5) mM viscosity reducer, 35 (±3.5) mM buffer, 1.5 (±0.15)% stabilizer, 0.1125 (±0.01125)% non-ionic surfactant, pH 6.5; 100 (±10) mg/mL C5 iRNA, 100 (±10) mg/mL anti-C5 antibody or its antigen-binding fragment, 50 (±5) mM viscosity reducer, 30 (±3) mM buffer, 1 (±0.1)% stabilizer, 0.075 (±0.0075)% non-ionic surfactant, pH 6.5; 50 (±5) mg/mL C5 iRNA, 100 (±10) mg/mL anti-C5 antibody or its antigen-binding fragment, 90 (±9) mM viscosity reducer, 30 (±3) mM buffer, 1 (±0.1)% stabilizer, 0.075 (±0.0075)% non-ionic surfactant, pH 6.5; 100 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 50 mM L-arginine, 30 mM histidine-based buffer, 1% (w/v) sucrose, 0.075% (w/v) PS80, pH 6.5; 50 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 90 mM L-arginine, 30 mM histidine-based buffer, 1% (w/v) sucrose, 0.075% (w/v) PS80, pH 6.5; 100 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 50 mM L-arginine, 10 mM Histidine-based buffer, 1.0% sucrose, 0.075% PS80, pH 6.5; 75 mg/mL Cemdisiran, 150 mg/mL Paselimab, 75 mM L-arginine, 15 mM Histidine-based buffer, 1.5% sucrose, 0.1125% PS80, pH 6.5; 50 mg/mL Cemdisiran, 100 mg/mL Paselimab, 75 mM L-arginine, 15 mM Histidine-based buffer, 1.5% sucrose, 0.1125% PS80, pH 6.5; 50 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 75 mM L-arginine, 35 mM histidine-based buffer, 1.5% sucrose, 0.1125% PS80, pH 6.5; 100 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 50 mM L-arginine, 30 mM histidine-based buffer, 1% sucrose, 0.075% PS80, pH 6.5; 50 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 90 mM L-arginine, 30 mM histidine-based buffer, 1% sucrose, 0.075% PS80, pH 6.5; further comprising GalNAc and/or GlcNAc as appropriate; 120 mg/mL C5 iRNA, 120 mg/mL anti-C5 antibody or antigen-binding fragment, viscosity reducer; 15 mM histidine, pH 6.2; 75 mg/mL C5 iRNA, 150 mg/mL anti-C5 antibody or antigen-binding fragment, viscosity reducer; 15 mM histidine, pH 6.2; 120 mg/mL C5 iRNA, 120 mg/mL anti-C5 antibody or antigen-binding fragment, 15 mM histidine, pH 6.2; 75 mg/mL C5 iRNA, 150 mg/mL anti-C5 antibody or antigen-binding fragment, 15 mM histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 15 mM Histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM Arginine, 15 mM Histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM Adipate, 15 mM Histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM Sodium Chloride, 15 mM Histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM Sodium Chloride, 15 mM Histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM lysine, 15 mM histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM aspartic acid, 15 mM histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM proline, 15 mM histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 50 mM histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 50 mM caffeine, 15 mM histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 50 mM Phenylalanine, 15 mM Histidine, pH 6.2 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 50 mM Triethyl Citrate, 15 mM Histidine, pH 6.2; 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 15 mM Histidine, pH 6.2; 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 75 mM Arginine, 15 mM Histidine, pH 6.2; 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 75 mM Arginine, 15 mM Histidine, pH 6.2; 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 75 mM adipate, 15 mM histidine, pH 6.2; 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 75 mM NaCl, 15 mM histidine, pH 6.2; 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 75 mM lysine, 15 mM histidine, pH 6.2; or 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 75 mM aspartic acid, 15 mM histidine, pH 6.2.

The present invention includes a co-formulation comprising a C5 iRNA, which is Cemdisiran; an antibody or antigen-binding fragment, which is Pasirimab; a viscosity reducer, which is L-arginine; a buffer, which is a histidine-based buffer; a stabilizer, which is sucrose; a non-ionic surfactant, which is polysorbate 80; and a pH of about 6.5.

In one embodiment of the invention, the co-formulation comprises a C5 iRNA conjugated to a ligand comprising one or more terminal N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc) residues; has a pH of not less than about 6 to about 0.5; and/or a pH of about 6.5.

In one embodiment of the invention, the co-formulation is characterized by one or more of the following: comprising β-hexosaminidase; comprising an antibody or antigen-binding fragment thereof expressed and isolated from a mammalian host cell containing β-hexosaminidase; comprising an antibody or antigen-binding fragment thereof expressed and isolated from a Chinese hamster ovary cell; comprising no more than about 1% Cemdisiran impurity 1 relative to total Cemdisiran; comprising not less than about 80% Cemdisiran relative to total Cemdisiran after storage at 2-8°C for 2 years; having about 91% Cemdisiran before storage (at t=0); having not less than about 80% Cemdisiran after storage at 2-8°C for 1, 1½, 2, 2½ or 3 years; having about 80% to about 91% Cemdisiran; Cemdisiran purity (%) was approximately 90.5% according to dIPRP at t=0, 91.1% after 1 month at 2-8°C; 90.8% after 3 months at 2-8°C; 90% after 6 months at 2-8°C; 88.8% after 9 months at 2-8°C; 88.7% after 12 months at 2-8°C; 89% after 18 months at 2-8°C; and/or 89.4% after 24 months at 2-8°C; Cemdisiran purity (%) was approximately 90.5% according to dIPRP at t=0, 91.1% after 1 month at 2-8°C; 90.8% after 3 months at 2-8°C; 90% after 6 months at 2-8°C; 88.8% after 9 months at 2-8°C; 88.7% after 12 months at 2-8°C; 89% after 18 months at 2-8°C; and/or 89.4% after 24 months at 2-8°C. The purity of siran (%) was about 90.8%, 90.6% after 1 month storage at 2-8℃; 90.5% after 3 months storage at 2-8℃; 89.4% after 6 months storage at 2-8℃; 88.3% after 9 months storage at 2-8℃; 87.8% after 12 months storage at 2-8℃; 87.8% after 18 months storage at 2-8℃; and/or 89.4% after 24 months storage at 2-8℃; Cemdisiran single strand purity (%) was about 90.5% according to dIPRP at t=0; at 25℃ and 60% 90.2% after 1 month storage at 25℃ and 60% RH; 87.8% after 3 months storage at 25℃ and 60% RH; 85.1% after 6 months storage at 25℃ and 60% RH; 90% after 0.5 month storage at 40℃ and 75% RH; 88.9% after 1 month storage at 40℃ and 75% RH; 85.8% after 3 months storage at 40℃ and 75% RH; The purity (%) of Cemdisiran according to dIPRP at t=0 was about 90.8%, 88.8% after 1 month storage at 25℃ and 60% RH; 85.9% after 3 months storage at 25℃ and 60% RH; 82.3% after 6 months storage at 40℃ and 75% RH; 88.9% after 0.5 month storage at 40°C and 75% RH; 87.3% after 1 month storage at 40°C and 75% RH; 82.3% after 3 months storage at 40°C and 75% RH; about 90.9% purity (%) of Cemdisiran according to dIPRP at t=0; about 90.1% after 1 month storage at 25°C and 60% RH; about 90.9% after 3 months storage at 25°C and 60% RH; about 90.4% after 6 months storage at 25°C and 60% RH; about 89.9% after 0.5 month storage at 40°C and 75% RH; about 89.7% after 1 month storage at 40°C and 75% RH; and/or about 90.1% after 1 month storage at 40°C and 75% RH. 89.5% after 3 months storage at 40°C, 75% RH; about 89.6% after 1 month storage at 40°C, 75% RH; and/or about 89.1% after 3 months storage at 40°C, 75% RH; about 90.5% after t=0 according to dIPRP; about 90.8% after 3 months storage at 25°C, 60% RH; about 90.3% after 6 months storage at 25°C, 60% RH; about 89.5% after 0.5 month storage at 40°C, 75% RH; about 89.6% after 1 month storage at 40°C, 75% RH; and/or about 89.1% after 3 months storage at 40°C, 75% RH; about 90.5% after t=0 according to dIPRP; about 90.6% after 3 months storage at 25°C, 60% RH; and about 90.8% after 3 months storage at 25°C, 60% RH; and about 90.8% after 6 months storage at 25°C, 60% RH; and about 90.3% after 6 months storage at 25°C, 60% RH; and about 90.5% after 0.5 month storage at 40°C, 75% RH; and about 90.6% after 1 month storage at 40°C, 75% RH; and about 90.8% after 3 months storage at 40°C, 75% RH; and about 90.8% after 3 months storage at 25°C, 60% RH; and about 90.8% after 3 months storage at 25°C, 60% RH; and about 90.8% after 6 months storage at RH for 1 month; 90.8% for 3 months at 25°C, 60% RH; 90.4% for 6 months at 25°C, 60% RH; 90.1% for 0.5 month at 40°C, 75% RH; 89.6% for 1 month at 40°C, 75% RH; and/or 89.9% for 3 months at 40°C, 75% RH; and/or 91.1% for Cemdisiran purity (%) according to dIPRP at t=0; 90% for 1 month at 25°C, 60% RH; 91% for 3 months at 25°C, 60% RH; and 91.6% for 40°C, 75% RH at t=0. RH for 6 months; about 90% after storage at 40℃, 75% RH for 0.5 month; about 89.7% after storage at 40℃, 75% RH for 1 month; and/or about 89.9% after storage at 40℃, 75% RH for 3 months. In one embodiment of the invention, the co-formulation is characterized by one or more of the following: a molar ratio of no more than about 2.1 parts per million (ppm) of β-hexosaminidase to antibody or antigen-binding fragment; including no more than about 0.170 micrograms/ml β-hexosaminidase, including no more than about 0.04 micrograms/ml β-hexosaminidase; and/or about 0.04; 0.05; 0.06; 0.06; 0.0605; 0.0605; 0.0605; 0.063; 0.07; 0.07; 0.0765; 0.078; 0.08; 0.14; 0.141; 0.15; 0.1525; 0.166; or 0.17 micrograms/ml β-hexosaminidase; or no more than any of these concentrations.

The invention also includes methods of administering a co-formulation as described herein to a subject, the method comprising introducing the co-formulation into the subject, such as by injecting the co-formulation into the subject; for example, by intramuscular, subcutaneous, intravenous, intraocular and/or intravitreal injection.

The invention also includes methods for treating or preventing a C5-related disease or condition in a subject in need thereof (C5-related diseases or conditions are, for example, conditions of inappropriate or undesirable complement activation; complications of hemodialysis; lung diseases or conditions; neurological diseases; parasitic diseases; post-ischemic reperfusion conditions; proteinuric kidney diseases; nephropathy; adult respiratory distress syndrome; adult respiratory distress syndrome (ARDS); age-related macular degeneration (AMD); allergies; Alport syndrome; Alzheimer's disease; autoimmune diseases or; immune complex disorders; inflammatory disorders; eye diseases; organic dust disease (organic dust disease) disease); vascular thrombosis and protein-deficient enteropathy); asthma; asthma; atherosclerosis; bronchoconstriction; bullous pemphigoid; C3 glomerulopathy; capillary leak syndrome; CHAPLE disease (CD55 deficiency with overactivation of complements; chemical injury caused by irritating gases and/or chemicals; chronic obstructive pulmonary disease (COPD); complement activation caused by burns; complement activation caused by frostbite; complement activation caused by obesity; Sepsis-induced complement activation; Crohn's disease; diabetes; diabetic macular edema (DME); diabetic nephropathy; diabetic retinopathy; dry AMD; dyspnea; emphysema; epilepsy; fibrosis; geographic atrophy (GA); glomerulopathy; Goodpasture's syndrome; Guillain-Barré syndrome; hemolytic anemia; hemoptysis; hereditary vascular edema; hyperacute allograft rejection; allergic pneumonitis; immune complex-associated inflammation; infectious diseases; autologous Inflammation in immune diseases; hereditary CD59 deficiency; injury caused by inert dusts and/or minerals; IL-2-induced toxicity during interleukin-2 therapy; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative nephritis; mesenteric artery reperfusion after aortic reconstruction; multiple sclerosis; myasthenia gravis; myocardial infarction; neuromyelitis optica; ocular angiogenesis; Parkinson's disease; pneumonia; progressive renal failure; eczema; pulmonary embolism and infarction; pulmonary fibrosis; pulmonary vasculitis; kidney ischemia; renal ischemia-reperfusion injury; rheumatoid arthritis; schizophrenia; SLE nephritis; smoke injury; stroke; systemic inflammatory response to post-pump syndrome caused by cardiopulmonary bypass or renal bypass; systemic lupus erythematosus (SLE); thermal injury; traumatic brain injury; uveitis; vasculitis; wet AMD; paroxysmal nocturnal hemoglobinuria (PNH); and/or xenograft rejection), the method comprising treating an individual in need thereof with an effective amount of a co-formulation as described herein. In one embodiment of the invention, one or more additional therapeutic agents are administered to a subject, such as, for example, androgens, anticoagulants, anti-inflammatory drugs, antihypertensives, immunosuppressants, fibrinolytics, lipid-lowering agents, anti-CD20 agents, anti-TNFα agents, C3 inhibitors, antithrombotics, corticosteroids, nonsteroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, inhibitors of hydroxymethylglutaryl CoA reductase, anti-epileptics, warfarin, aspirin, heparin, phenindione, fondaparinux, x), idraparinux, and thrombin inhibitors (such as argatroban, lepirudin, bivalirudin, dabigatran, vincristine, cyclosporine A, methotrexate, ancrod, epsilon-aminocaproic acid, anticytosine-a1, prostacyclin, defibrotide, rituximab, infliximab, and/or magnesium sulfate).

The present invention provides a method for increasing RNA stability or reducing β-hexosaminidase activity in a composition, wherein the composition comprises RNA bound to a ligand and β-hexosaminidase, wherein the ligand comprises one or more terminal N-acetylgalactosamine (GalNAc) residues and/or N-acetylglucosamine (GlcNAc) residues; the method comprises (i) adding GalNAc and/or GlcNAc to the composition, and/or (ii) increasing or decreasing the pH of the composition relative to about 6; for example, wherein the composition comprises RNA, which is C5 iRNA; an antibody or antigen-binding fragment thereof expressed and isolated from a mammalian host cell containing β-hexosaminidase (e.g., Chinese hamster ovary (CHO) cell); and optionally a buffer; a viscosity reducer; a stabilizer; and a non-ionic surfactant. In one embodiment of the present invention, the RNA is a double-stranded RNA, optionally comprising an overhang of 1 or 2 nucleotides at one or both ends, for example, wherein the RNA is chemically synthesized.

The invention includes methods of making co-formulations comprising combining an RNAi with an antibody or antigen binding fragment, and (i) adding GalNAc to the co-formulation and/or (ii) adjusting the pH of the co-formulation to about 6 or below about 6. Co-formulations (products that form part of the methods of the invention) constitute part of the invention.

The present invention provides a method for administering an antibody or antigen-binding fragment thereof that specifically binds to C5 (anti-C5) and a C5 iRNA to an individual, comprising introducing the antibody or fragment and the iRNA into the individual. In one embodiment of the present invention, the antibody or fragment and the iRNA are introduced by subcutaneous injection or intravenous infusion of a co-formulation comprising the antibody or fragment and the iRNA; or by subcutaneous injection or intravenous infusion of a separate formulation each comprising the antibody or fragment or the iRNA.

The present invention provides a method for treating or preventing a C5-related disease or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to C5 and a C5 iRNA (they are in a single co-formulation or in separate formulations). In one embodiment of the present invention, the method further comprises administering to the individual one or more initial intravenous or subcutaneous loading doses of the antibody or antigen-binding fragment and/or iRNA. For example, in one embodiment of the invention, the method comprises administering one or more doses of the following: (1) about 400 mg of an anti-C5 antibody or antigen-binding fragment; (2) about 200 mg of a C5 iRNA; for example, administering about 400 mg of an anti-C5 antibody or antigen-binding fragment about every 2, 3, or 4 weeks (±3); and administering about 200 mg of a C5 iRNA about every 4 weeks (±3 days). In one embodiment of the present invention, the method comprises (i) subcutaneously administering about 400 mg of an anti-C5 antibody or antigen-binding fragment about every 2 weeks (±3, 4, 5, 6, or 7 days), and subcutaneously administering about 200 mg of a C5 iRNA about every 4 weeks (±3, 4, 5, 6, or 7 days); (ii) subcutaneously administering about 400 mg of an anti-C5 antibody or antigen-binding fragment about every 4 weeks (±3, 4, 5, 6, or 7 days), and subcutaneously administering about 200 mg of a C5 iRNA every 4 weeks (±3, 4, 5, 6, or 7 days); (iii) an intravenous loading dose of an anti-C5 antibody or antigen-binding fragment, subcutaneously administering about 400 mg of an anti-C5 antibody or antigen-binding fragment, and subcutaneously administering about 200 mg of a C5 iRNA. iRNA; and then, approximately every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, subcutaneously administering about 400 mg of an anti-C5 antibody or antigen-binding fragment and subcutaneously administering about 200 mg of a C5 iRNA; (iv) an intravenous loading dose of about 30 or 60 mg/kg of an anti-C5 antibody or antigen-binding fragment, subcutaneously administering about 400 mg of an anti-C5 antibody or antigen-binding fragment, and subcutaneously administering about 200 mg of a C5 iRNA; and then, approximately every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, subcutaneously administering about 400 mg of an anti-C5 antibody or antigen-binding fragment and subcutaneously administering about 200 mg of a C5 iRNA; (v) approximately 30 or 60 mg/kg of an intravenous loading dose of mg/kg intravenous loading dose of anti-C5 antibody or antigen-binding fragment, followed by one or more weekly subcutaneous doses of about 800 mg of anti-C5 antibody or antigen-binding fragment, and then, as appropriate, about 400 mg of anti-C5 antibody or antigen-binding fragment and about 200 mg of C5 iRNA subcutaneously administered after a 1-week period; and then, about 400 mg of anti-C5 antibody or antigen-binding fragment and about 200 mg of C5 iRNA subcutaneously administered about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter; (vi) (a) intravenous administration of one dose of eculizumab and subcutaneous administration of about 200 mg of C5 iRNA; (b) up to about 14 days (±3, 4, 5, 6, or 7 days) later, a dose of eculizumab; and (c) about another 14 or 15 days (±3, 4, 5, 6, or 7 days) later, intravenous administration of 30 or 60 mg/kg body weight of anti-C5 antibody or antigen-binding fragment, subcutaneous administration of about 400 mg of anti-C5 antibody or antigen-binding fragment, and subcutaneous administration of about 200 mg of C5 iRNA, and (d) about every 4 weeks (±3, 4, 5, 6, or 7 days) thereafter, subcutaneous administration of a dose of about 400 mg of anti-C5 antibody or antigen-binding fragment and subcutaneous administration of about 200 mg of C5 iRNA; or (vii) (a) about 200 mg SC dose of C5 iRNA; (b) about 28 days (±3, 4, 5, 6, or 7 days) later, a 30 or 60 mg/kg IV loading dose of the anti-C5 antibody or antigen-binding fragment, a 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment, and a 200 mg SC dose of the C5 iRNA; and (c) about 29 days (±3, 4, 5, 6, or 7 days) later and about every 4 weeks (±3, 4, 5, 6, or 7 days) thereafter, a 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment and a 200 mg SC dose of the C5 iRNA; or (viii) (a) about 4 weeks (±3, 4, 5, 6, or 7 days) after administration of ravlizumab, a 200 mg SC dose of C5 iRNA; (b) approximately another 28 days (±3, 4, 5, 6, or 7 days) later, a 30 or 60 mg/kg IV loading dose of the anti-C5 antibody or antigen-binding fragment, a 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment, and a 200 mg SC dose of the C5 iRNA; and (c) approximately another 29 days (±3, 4, 5, 6, or 7 days) later and approximately every 4 weeks (±3, 4, 5, 6, or 7 days) thereafter, a 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment and a 200 mg SC dose of the C5 iRNA. In one embodiment of the present invention, an anti-C5 antibody or antigen-binding fragment and a C5 iRNA are administered subcutaneously about every 4 weeks (±3, 4, 5, 6, or 7 days) as a single injection of a co-formulation comprising an anti-C5 antibody or antigen-binding fragment and a C5 iRNA; and an anti-C5 antibody or antigen-binding fragment is administered subcutaneously again about every 4 weeks (±3, 4, 5, 6, or 7 days); and an anti-C5 antibody or antigen-binding fragment and a C5 iRNA are administered subcutaneously about every 4 weeks (±3, 4, 5, 6, or 7 days) as separate injections of separate formulations, wherein one formulation comprises an anti-C5 antibody or antigen-binding fragment and the other formulation comprises C5 iRNA; and about every 4 weeks (±3, 4, 5, 6 or 7 days) the anti-C5 antibody or antigen-binding fragment is subcutaneously administered; about every 4 weeks (±3, 4, 5, 6 or 7 days) the anti-C5 antibody or antigen-binding fragment and C5 iRNA are subcutaneously administered as a single injection of a co-formulation comprising the anti-C5 antibody or antigen-binding fragment and C5 iRNA; and about every 2 weeks (±3, 4, 5, 6 or 7 days) the anti-C5 antibody or antigen-binding fragment is subcutaneously administered again; and/or about every 4 weeks (±3, 4, 5, 6 or 7 days) the anti-C5 antibody or antigen-binding fragment and C5 iRNA are subcutaneously administered as separate injections of separate formulations, wherein one formulation comprises the anti-C5 antibody or antigen-binding fragment and the other formulation comprises C5 iRNA; and anti-C5 antibody or antigen-binding fragment is subcutaneously injected approximately every 2 weeks (±3, 4, 5, 6 or 7 days).

In one embodiment of the invention, the subject has previously been treated with ravlizumab (e.g., intravenously or subcutaneously) and/or eculizumab (e.g., intravenously, e.g., 900 mg intravenously); and/or pazelimab monotherapy. In one embodiment of the invention, the subject has not been treated with a complement inhibitor.

The present invention includes a method for treating or preventing a C5-related disease or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the individual has previously received eculizumab, wherein the individual: (i) is administered a dose of eculizumab intravenously and 200 mg of C5 iRNA subcutaneously; (ii) up to about 14 days (±3, 4, 5, 6, or 7 days) later (about day 15) a dose of eculizumab; (iii) about 14 or 15 days (±3, 4, 5, 6, or 7 days) later (about day 29), the anti-C5 antibody or antigen-binding fragment thereof is administered intravenously at a dose of about 60 mg/kg body weight, and about 400 mg/kg of C5 iRNA is administered subcutaneously; mg of anti-C5 antibody or antigen-binding fragment and about 200 mg of C5 iRNA subcutaneously; and (iv) starting about 28 days (±3, 4, 5, 6, or 7 days) later (about day 57) and about every about 28 days (±3, 4, 5, 6, or 7 days) thereafter, about 400 mg of anti-C5 antibody or antigen-binding fragment and about 200 mg of C5 iRNA subcutaneously administered.

The present invention provides a method for treating or preventing a C5-related disease or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the individual has previously received revlizumab, wherein the individual: (i) is administered a SC dose of about 200 mg of C5 iRNA about 28 days (±3, 4, 5, 6, or 7 days) after the last administration of revlizumab; (ii) is administered a SC dose of about 60 mg/kg of anti-C5 antibody or antigen-binding fragment thereof, a SC dose of about 400 mg of anti-C5 antibody or antigen-binding fragment thereof, and a SC dose of about 200 mg of C5 iRNA about 28 days (±3, 4, 5, 6, or 7 days) after the last administration of revlizumab (about day 29); iRNA; (iii) starting about 28 days (±3, 4, 5, 6, or 7 days) later (about day 57) and about every about 28 days (±3, 4, 5, 6, or 7 days) thereafter, administering about 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and about 200 mg SC dose of C5 iRNA.

The present invention provides a method for treating or preventing a C5-related disease or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the individual has not previously received or has not recently received complement inhibitor therapy, wherein the individual is (i) administered an intravenous dose of about 30 mg/kg of the anti-C5 antibody or antigen-binding fragment, a subcutaneous (SC) dose of the antibody or fragment, and a 200 mg SC dose of the C5 iRNA on about day 1; and (ii) beginning about day 28 (±3, 4, 5, 6, or 7 days) later and about every 4 weeks (±3, 4, 5, 6, or 7 days) thereafter, administered about 400 mg SC of the anti-C5 antibody or antigen-binding fragment and about 200 mg SC of the C5 iRNA. C5 iRNA for SC.

The present invention provides a method for treating or preventing a C5-related disease or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-C5 antibody or an antigen-binding fragment thereof and a C5 iRNA, wherein the individual has previously received monotherapy with the anti-C5 antibody or antigen-binding fragment, and (i) administering about 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment and about 200 mg SC dose of C5 starting about 7 to 8 days (±3 days) after the last dose of anti-C5 antibody or antigen-binding fragment monotherapy or when the next dose of monotherapy is due and about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter. iRNA; or (ii) starting about 7 to 8 days (±3 days) after the last dose of anti-C5 antibody or antigen-binding fragment monotherapy or when the next dose of monotherapy is due: about 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and another dose about every 2 weeks (±3, 4, 5, 6, or 7 days) thereafter; and about 200 mg SC dose of C5 iRNA and another dose about every 4 weeks (±3, 4, 5, 6, or 7 days) thereafter.

The present invention further provides a method for treating or preventing a C5-related disease or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the individual has received one or more doses of a non-competitive anti-C5 antibody or antigen-binding fragment (N/C Ab) (e.g., wherein the individual has a detectable blood level of N/C Ab at the start of treatment): (1) a dose of C5 iRNA and non-competitive antibody or fragment on the day the N/C Ab dose expires; (2) a dose of non-competitive anti-C5 antibody or antigen-binding fragment on the day the dose expires; (3) after about 1-2 half-lives of the N/C Ab, a 60 mg/kg IV loading dose of paszelimumab, a 400 mg IV loading dose of paszelimumab, and a 500 mg IV loading dose of paszelimumab. SC and Cemdisiran 200 mg SC; (4) starting 4 weeks later, Pazelimumab 400 mg SC Q4W and Cemdisiran 200 mg SC Q4W; or (1) after about 1-2 half-lives from the last dose of the noncompetitive anti-C5 antibody or antigen-binding fragment, a dose of C5 iRNA; (2) after an additional about 1-2 half-lives of the N/C Ab, a Pazelimumab 60 mg/kg IV loading dose, Pazelimumab 400 mg SC, and Cemdisiran 200 mg SC; and (3) starting 4 weeks later, Pazelimumab 400 mg SC Q4W and Cemdisiran 200 mg SC Q4W. In one embodiment of the present invention, the C5 iRNA is Cemdisiran; the anti-C5 antibody or antigen-binding fragment thereof is Pasirimab; the non-competitive anti-C5 antibody or antigen-binding fragment is Eculizumab; the non-competitive anti-C5 antibody or antigen-binding fragment is Ravelizumab; the half-life of the non-competitive antibody is about 11 days; and/or the half-life of the non-competitive antibody is about 32 days.

In one embodiment of the present invention, during treatment, the subject achieves or achieves and maintains one or more of the following: stable hemoglobin; no red blood cell transfusion; hemoglobin does not decrease by ≧2 g/dL; no breakthrough hemolysis occurs; the CH50 level in the blood is completely suppressed relative to the baseline (0 kIU/L) before treatment and/or during any breakthrough hemolysis event; lack of adverse events during treatment; fatigue is improved compared to before treatment; FACIT-fatigue score is improved by ＞5 points compared to before treatment; improvement according to the European Physical Functioning Scale compared to before treatment; European; organization for Research and Treatment of Cancer: Quality-of-Life Questionnaire; core 30 items, EORTC The physical function scores of the QLQ-C30) were improved; the GHS/QoL (Global Health Status/QOL Scale (GHS)) was improved compared with before treatment; the lactate dehydrogenase (LDH) content was reduced compared with before treatment; compared with LDH ≦ 1.5 × upper limit of normal (ULN) before treatment, LDH ≦ 1.0 × ULN; decreased blood bilirubin compared to before treatment; decreased reticulocyte count compared to before treatment; decreased alternative pathway hemolytic activity assay (AH50) compared to before treatment; decreased PNH erythrocytes and/or granulocytes compared to before treatment; improved fatigue, shortness of breath, muscle weakness, headache, abdominal pain, back/leg pain, chest discomfort, difficulty sleeping, difficulty thinking clearly, and/or difficulty swallowing compared to before treatment; improved renal function as measured by estimated glomerular filtration rate (eGFR) compared to before treatment; decreased blood free hemoglobin compared to before treatment; decreased blood total C5 compared to before treatment; PNH strains (PNH) compared to before treatment clone size; and/or an increase in haptoglobin relative to pre-treatment levels.

In one embodiment of the invention, the C5-related disease or condition is a condition in which complement activation is inappropriate or undesirable; hemodialysis complications; lung diseases or conditions; neurological diseases; parasitic diseases; ischemic reperfusion conditions; proteinuric kidney diseases; nephropathy; adult respiratory distress syndrome; adult respiratory distress syndrome (ARDS); age-related macular degeneration (AMD); allergies; Alport syndrome; Alzheimer's disease; autoimmune diseases or; immune complex disorders; inflammatory disorders; ocular diseases; organic dust diseases; vasculothrombosis and protein-deficient enteropathy) ; Asthma; Asthma; Atherosclerosis; Bronchoconstriction; Bullous pemphigoid; C3 glomerulopathy; Capillary leak syndrome; CHAPLE disease (CD55 deficiency with complement overactivation; Chemical injury caused by irritants and/or chemicals; Chronic obstructive pulmonary disease (COPD); Complement activation caused by burns; Complement activation caused by frozen sores; Complement activation caused by obesity; Complement activation caused by sepsis; Crohn's disease; Diabetes mellitus; Diabetic macular edema (DME); Diabetic nephropathy; Diabetic retinopathy; Dry AMD; Dyspnea; Emphysema ; epilepsy; fibrosis; geographic atrophy (GA); glomerulopathy; Goodpasture's syndrome; Guillain-Barré syndrome; hemolytic anemia; hemoptysis; hereditary vascular edema; hyperacute allograft rejection; allergic pneumonitis; immune complex-associated inflammation; infectious diseases; inflammation in autoimmune diseases; hereditary CD59 deficiency; injury caused by inert dust and/or mineral substances; IL-2-induced toxicity during interleukin-2 therapy; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative nephritis; enteric artery reperfusion after aortic reconstruction; multiple sclerosis myasthenia gravis; myocardial infarction; neuromyelitis optica; ocular angiogenesis; Parkinson's disease; pneumonia; progressive renal failure; eczema; pulmonary embolism and infarction; pulmonary fibrosis; pulmonary vasculitis; renal ischemia; renal ischemia-reperfusion injury; rheumatoid arthritis; schizophrenia; systemic lupus erythematosus nephritis; smoke injury; stroke; systemic inflammatory response to post-pump syndrome with cardiopulmonary bypass or renal bypass; systemic lupus erythematosus (SLE); thermal injury; traumatic encephalopathy; uveitis; vasculitis; wet AMD; paroxysmal nocturnal hemoglobinuria (PNH); and/or xenograft rejection.

In one embodiment of the present invention, C5 iRNA and anti-C5 antibody or antigen-binding fragment are co-formulated as a co-formulation, and both the antibody or fragment and C5 iRNA are administered by a single injection of the co-formulation.

In one embodiment of the present invention, the pH of the co-formulation is about 6.5. In one embodiment of the present invention, the C5 iRNA and the anti-C5 antibody or antigen-binding fragment are co-formulated as a co-formulation comprising 100 mg/ml Cemdisiran and 100 mg/ml Paslimab; or 50 mg/ml Cemdisiran and 100 mg/ml Paslimab.

In one embodiment of the present invention, the co-formulation includes Cemdisiran; Paszelimumab, which is expressed and isolated by mammalian host cells comprising β-hexosaminidase; a buffer; a viscosity reducer; a stabilizer; a non-ionic surfactant and, optionally, a viscosity reducer; and a pH of about 6.5.

In one embodiment of the invention, subcutaneous injections are administered using a prefilled syringe or autoinjector.

In one embodiment of the present invention, the individual suffers from aplastic anemia and/or myelodysplastic syndrome.

In one embodiment of the invention, the subject has previously received or further comprises administering to the subject: one or more subcutaneous or intravenous pazelimumab; one or more 400 mg subcutaneous pazelimumab and 200 mg subcutaneous cemdisiran before (as appropriate, any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days before), after or during administration of: mg subcutaneous dose of pasorizumab; one or more subcutaneous or intravenous doses of anti-C5 antibody or antigen-binding fragment; one or more subcutaneous or intravenous doses of eculizumab; one or more subcutaneous or intravenous doses of ravulizumab; one or more subcutaneous or intravenous doses of cemdisiran; one or more subcutaneous or intravenous doses of C5 iRNA; one or more subcutaneous doses of 800 mg pasorizumab; one or more subcutaneous doses of 800 mg anti-C5 antibody or antigen-binding fragment; one or more intravenous doses of 30 mg/kg body weight pasorizumab; one or more intravenous doses of 30 mg/kg body weight of an anti-C5 antibody or antigen-binding fragment; one or more intravenous doses of about 60 mg/kg body weight of paslimab; one or more intravenous doses of about 60 mg/kg body weight of an anti-C5 antibody or antigen-binding fragment; one or more subcutaneous doses of about 800 mg of paslimab; one or more subcutaneous doses of about 800 mg of an anti-C5 antibody or antigen-binding fragment; one intravenous dose of about 60 mg/kg body weight of paslimab, followed by one or more subcutaneous doses of about 800 mg of paslimab; one intravenous dose of about 60 mg/kg body weight of an anti-C5 antibody or antigen-binding fragment, followed by one or more subcutaneous doses of about 800 mg of mg of anti-C5 antibody or antigen-binding fragment; one or more intravenous doses of eculizumab ≥ 300, ≥ 600, ≥ 900 or ≥ 1200 mg; one or more subcutaneous doses of cemdisiran 200 mg; and/or one or more subcutaneous doses of C5 iRNA 200 mg.

In one embodiment of the present invention, intravenous administration of anti-C5 antibody or antigen-binding fragment is separated from subcutaneous administration of anti-C5 antibody or antigen-binding fragment or C5 iRNA by about 30 minutes; subcutaneous administration of anti-C5 antibody or antigen-binding fragment and C5 iRNA is followed by an observation period of about 30 minutes, 1 hour or 2 hours; and/or subcutaneous administration of C5 iRNA is followed by an observation period of about 30 minutes, 1 hour or 2 hours.

In one embodiment of the invention, the subject receives intensified treatment further comprising one or more 30 mg/kg IV doses of an anti-C5 antibody or antigen-binding fragment if the subject exhibits one or more of the following criteria: breakthrough hemolysis not due to complement activation conditions; and/or an increase in LDH ≧2 x ULN due to complement activation conditions.

In one embodiment of the invention, an individual is given a boost therapy if the individual exhibits one or more of the following criteria: breakthrough hemolysis not due to a complement activation condition; and/or an increase in LDH ≧2×ULN due to a complement activation condition, wherein: (1) if the individual has received a treatment regimen comprising subcutaneous administration of about 400 mg of an anti-C5 antibody or antigen binding fragment approximately every 4 weeks (±3, 4, 5, 6, or 7 days) and subcutaneous administration of about 200 mg of a C5 iRNA approximately every 4 weeks (±3, 4, 5, 6, or 7 days); a single 30 mg/kg IV dose of the anti-C5 antibody or antigen binding fragment is administered on the day of the boost, and subcutaneous administration of about 400 mg of a C5 iRNA approximately every 2 weeks (±3, 4, 5, 6, or 7 days) starting on the day of the boost; mg of anti-C5 antibody or antigen-binding fragment and a booster regimen of about 200 mg of C5 iRNA administered subcutaneously about every 4 weeks (±3, 4, 5, 6, or 7 days); or (2) if the individual has received a treatment regimen comprising about 400 mg of anti-C5 antibody or antigen-binding fragment administered subcutaneously about every 2 weeks (±3, 4, 5, 6, or 7 days) and about 200 mg of C5 iRNA administered subcutaneously about every 4 weeks (±3, 4, 5, 6, or 7 days); then administer a single 30 mg/kg IV dose of anti-C5 antibody or antigen-binding fragment on the day of the booster, and restart the regimen comprising about 400 mg of anti-C5 antibody or antigen-binding fragment administered subcutaneously about every 2 weeks (±3, 4, 5, 6, or 7 days) mg of anti-C5 antibody or antigen-binding fragment and about 200 mg of C5 iRNA administered subcutaneously about every 4 weeks (± 3, 4, 5, 6 or 7 days).

In one embodiment of the invention, the anti-C5 antibody or antigen-binding fragment or Pasqualizumab is expressed in mammalian host cells (e.g., Chinese hamster ovary cells), and the iRNA or Cemdisiran is chemically synthesized.

In one embodiment of the invention, an anti-C5 antibody or antigen-binding fragment and a C5 iRNA are co-formulated as a co-formulation comprising a molar ratio of no more than about 2.1 parts per million (ppm) of β-hexosaminidase to the antibody or antigen-binding fragment; including no more than about 0.170 micrograms/ml β-hexosaminidase, including no more than about 0.04 micrograms/ml β-hexosaminidase; and/or about 0.04; 0.05; 0.06; 0.0605; 0.063; 0.07; 0.0765; 0.078; 0.08; 0.14; 0.141; 0.15; 0.1525; 0.166; or 0.17 micrograms/ml β-hexosaminidase; or no more than any of these concentrations.

In one embodiment of the present invention, the anti-C5 antibody or antigen-binding fragment thereof is (1) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 2, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 10; (2) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 18, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 26; (3) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 34, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: (4) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:50, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:58; (5) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:66, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:74; (6) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:50, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:58; NO:82, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:90; (7) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:98, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:106; (8) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:98, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:106. NO:114; (9) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:122, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:106; (10) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:98, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:130; (11) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:124, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:130. NO: 138, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 106; (12) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 106; (13) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 122, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: NO: 130; (14) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 114; (15) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 130; (16) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 130; NO: 138, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 130; (17) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 154, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 162; (18) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 170, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: NO: 178; (19) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 186, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 194; (20) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 202, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 210; (21) a HCVR comprising SEQ ID NO: 186; and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 194. NO: 218, and a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 226, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence set forth in SEQ ID NO: 229; (22) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 234, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence set forth in SEQ ID NO: 242; (23) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence set forth in SEQ ID NO: 250, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence set forth in SEQ ID NO: NO: 258; (24) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 266, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 258; (25) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 274, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 282; (26) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 266, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 258. NO: 290, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 298; (27) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 306, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 314; (28) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 322, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: NO: 330; and/or (29) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 338, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 346.

In one embodiment of the present invention, the C5 iRNA comprises an RNA strand that complements an mRNA transcribed from the sense strand DNA sequence of the C5 gene AAGCAAGATATTTTTATAATA (nucleotides 782-802 of SEQ ID NO: 360). In one embodiment of the present invention, the C5 iRNA is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises a complementary region comprising at least 17 consecutive nucleotides that differ from the nucleotide sequence of 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 364) by no more than 3 nucleotides, and wherein the dsRNA agent comprises at least one modified nucleotide. In one embodiment of the present invention, the C5 iRNA is a double-stranded RNA (dsRNA) agent comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO: 406) and the antisense strand comprises 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO: 369), wherein a, g, c and u are 2'-0-methyl (2'-OMe) A, G, C and U, respectively; Af, Gf, Cf and Uf are 2'-fluoro A, G, C and U, respectively; dT is a deoxythymidine nucleotide; s is a phosphorothioate linkage; and wherein the sense strand is bound to a ligand at the 3' end. .

In one embodiment of the present invention, C5 iRNA and an antibody or antigen-binding fragment thereof that specifically binds to C5 are in the form of a co-formulation as specifically described herein.

In one embodiment of the present invention, wherein the C5 iRNA and the anti-C5 antibody or antigen-binding fragment thereof are in the form of a single co-formulation, when administered subcutaneously, the co-formulation is administered in one or two or more (e.g., two ) injections.

Preferably, the C5 iRNA is Cemdisiran; and/or the anti-C5 antibody or antigen-binding fragment thereof is Pasirimab.

Although combining two C5 inhibitor treatments with complementary mechanisms of action (paslimab and cemdisiran) could offer the advantage of complete inhibition of the C5 pathway at (relatively) low C5 expression levels, various technical challenges had to be overcome to achieve a dosing regimen and delivery vehicle that was appropriate for the agents.

The superior C5 inhibition provided by the compositions and methods of the present invention allows for the need for less paslimab, which in turn results in a reduced SC volume of antibody injection, reduced dosing frequency, a wider range of combined drug administration than paslimab monotherapy, and reduced likelihood of injection site reactions. In patients requiring prolonged and chronic dosing, the combination has the potential to improve compliance and quality of life compared to paslimab monotherapy, while providing maximal inhibition of C5 activity in a greater percentage of patients than eculizumab treatment. In addition, as discussed herein, the dosing regimens of the present invention avoid the risk of adverse events due to the formation of large drug-target-drug complexes (e.g., eculizumab-C5-paslimab). Co-formulation of the two agents also provides the convenience of administering both agents together with a single subcutaneous injection.

The present invention provides a stable co-formulation comprising an antibody or antigen-binding fragment thereof (e.g., Paseritumab) and a C5 iRNA (e.g., Cemdisiran). Co-formulation of antibodies expressed from mammalian host cells and iRNA molecules bound to ligands having terminal N-acetylgalactosamine (GalNAc) and/or N-acetylglucosamine (GlcNAc) represents a technical challenge. A small amount of enzyme (β-hexosaminidase) from such host cells that often contaminates antibody preparations has been shown to catalyze the removal of the terminal GalNAc residue from such iRNA ligands. The present invention provides stable co-formulations comprising such antibodies and iRNA molecules that overcome this problem, for example by adjusting the pH relative to 6 (e.g., 6.5), adding GalNAc and/or GlcNAc; and/or adding arginine (e.g., L-arginine, such as L-arginine HCl).

In the method of the present invention, the administration of anti-C5 antibodies and C5 iRNA is designed to rapidly and continuously suppress C5 concentrations to a pharmacologically inactive level. Typically, relatively high doses of anti-C5 monotherapy are required for PNH patients. The need for such high anti-C5 mAb doses is driven by two factors. First, the high C5 content requires 100% inhibition, which can only be achieved with complete target engagement (Peffault de Latour R et al ., Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Blood 2015; 125(5):775-83); and second, to achieve 100% inhibition on a population basis, the inter- and intra-patient variability in C5 concentrations and the presence of enhanced complement activation (which may occur in inter-complication disease) can be exploited. The combination of paszelimumab and cemdisiran achieves high complement inhibition with relatively low doses of antibody. Combining pazelimab and cemdisiran also has the advantage of achieving low tonic content with less pazelimab administered (relative to pazelimab monotherapy), resulting in a smaller SC volume injected, less frequent dosing, a wider dosing range for the combination than pazelimab monotherapy, and a reduced potential for injection site reactions.

The present invention includes dosing regimens for switching from a previous anti-C5 antibody therapy (e.g., eculizumab or ravelizumab) to a C5 iRNA + anti-C5 antibody or antigen-binding fragment thereof therapy of the present invention (e.g., paslimab + cemdisiran). Paslimab has been shown to bind C5 non-competitively with antibodies having the amino acid sequence of eculizumab (eculizumab*), and thus has the potential to form heterocomplexes, including large DTD immune complexes, such as in patients who are switched from eculizumab to paslimab treatment. Large DTD immune complexes are known to cause adverse events, such as serum sickness-like reactions, rash. The dosing regimens of the present invention are designed to reduce the risk of DTD complex formation and the occurrence of such adverse events. Antigen Binding Proteins

As used herein, the term "antibody" refers to an immunoglobulin molecule (e.g., IgG) comprising four polypeptide chains (two heavy chains (HC) and two light chains (LC)) interconnected by disulfide bonds, such as H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P 8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; korolizumab; eculizumab, tesidolumab, mubodina, or ravulizumab; preferably pazelimumab. In one embodiment of the present invention, each antibody heavy chain (HC) comprises a heavy chain variable region ("HCVR" or " _VH ") (e.g., SEQ ID NO: 2; 18; 34; 50; 66; 82; 98; 98; 122; 98; 138; 146; 122; 146; 146; 138; 154; 170; 186; 202; 218; 234; 250; 266; 274; 290; 306; 322; or 338; or variants thereof) and a heavy chain constant region; and each antibody light chain (LC) comprises a light chain variable region ("LCVR" or " _VL ") (e.g., SEQ ID NO: NO: 10; 26; 42; 58; 74; 90; 106; 114; 106; 130; 106; 106; 130; 114; 130; 130; 162; 178; 194; 210; 226; 242; 258; 282; 298; 314; 330; or 346; or its variants) and a light chain constant region (CL). _{The VH} and _VL regions can be further divided into highly variable regions, called complementary determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). Each _VH and _VL contains three CDRs and four FRs. Preferably, the antibodies or antigen-binding fragments thereof in the co-formulations of the invention are expressed and isolated from mammalian host cells, such as Chinese hamster ovary (CHO) cells.

Antibodies as described herein include, for example, monoclonal antibodies, recombinant antibodies, chimeric antibodies, human and/or humanized antibodies.

In one embodiment of the present invention, the amino acid assignment for each framework or CDR domain is according to the following definitions: Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, et al. , (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al. , (1987) J Mol. Biol. 196:901-917 or Chothia, et al. , (1989) Nature 342:878-883. Thus, the present invention includes antibodies and antigen-binding fragments comprising the CDRs of _VH and the CDRs of _VL , wherein _VH and _VL comprise the amino acid sequences as set forth herein (or variants thereof), wherein the CDRs are defined according to Kabat and/or Chothia.

In one embodiment of the present invention, the anti-C5 antigen-binding protein (e.g., antibody or antigen-binding fragment) comprises a heavy chain constant domain, such as a heavy chain constant domain of type IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g., IgG1, IgG2, IgG3 and IgG4 (e.g., comprising S228P and/or S108P mutations)) or IgM. In one embodiment of the present invention, the antigen-binding protein (e.g., antibody or antigen-binding fragment) comprises a light chain constant domain, such as a light chain constant domain of type kappa or lambda. The present invention includes antigen binding proteins comprising the variable domains disclosed herein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12166P11; H4H12166P12; H4H12166P13; H4H12166P14; H4H12166P15; H4H12166P16; H4H12166P17; H4H12166P18; H4H12166P19; H4H12166P10; H4H12166P1 2167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; korolizumab; eculizumab, tertulumab, mubodina or ravlizumab; preferably pazelimumab), which is linked to the heavy chain constant domain and/or the light chain constant domain, for example as shown above.

"Isolated" antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof), polypeptides, polynucleotides, and vectors are at least partially free of other biomolecules from the cells or cell cultures in which they are produced. Such biomolecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other materials (such as cell debris and growth medium). Isolated antigen-binding proteins may further be at least partially free of expression system components, such as biomolecules from host cells or their growth medium. In general, the term "isolated" is not intended to refer to the complete absence of such biomolecules (e.g., small or trace amounts of impurities that may remain) or the absence of water, buffers or salts, or components of pharmaceutical formulations that include antigen-binding proteins (e.g., antibodies or antigen-binding fragments).

In one embodiment of the present invention, an antibody or antigen-binding fragment thereof that specifically binds to a complement factor 5 (C5) protein interacts with one or more amino acids contained in NMATGMDSW (SEQ ID NO: 353) (or at least 1, 2, 3, 4 or 5 amino acids thereof); or WEVHLVPRRKQLQFALPDSL (SEQ ID NO: 354) (or at least 1, 2, 3, 4 or 5 amino acids thereof) as determined by hydrogen/deuterium exchange. In one embodiment of the present invention, an antibody or antigen-binding fragment thereof that specifically binds to a complement factor 5 (C5) protein interacts with one or more amino acids contained in the alpha chain and/or beta chain of C5 as determined by hydrogen/deuterium exchange. For example, in one embodiment of the invention, the antibody or antigen-binding fragment does not interact with amino acids of the C5a hypersensitive toxin region of C5 as determined by hydrogen/deuterium exchange. In one embodiment of the invention, an antibody or antigen-binding fragment thereof that specifically binds to complement factor 5 (C5) protein interacts with an amino acid sequence selected from the group consisting of: (a) NMATGMDSW (SEQ ID NO: 353); (b) ATGMDSW (SEQ ID NO: 355); (c) WEVHLVPRRKQLQ (SEQ ID NO: 356); (d) WEVHLVPRRKQLQFALPDSL (SEQ ID NO: 354); and (e) LVPRRKQLQ (SEQ ID NO: 357).

Listed below are the sequences of anti-C5 antibodies and antigen-binding fragments thereof that may be included in co-formulations. Table A. Anti -C5 Antibody Chain Amino Acid Sequences * Antibody nomenclature SEQ ID NO HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 H2M11683N 2 4 6 8 10 12 14 16 H2M11686N 18 20 twenty two twenty four 26 28 30 32 H4H12159P 34 36 38 40 42 44 46 48 H4H12161P 50 52 54 56 58 60 62 64 H4H12163P 66 68 70 72 74 76 78 80 H4H12164P 82 84 86 88 90 92 94 96 H4H12166P 98 100 102 104 106 108 110 112 H4H12166P2 98 100 102 104 114 116 118 120 H4H12166P3 122 124 126 128 106 108 110 112 H4H12166P4 98 100 102 104 130 132 134 136 H4H12166P5 138 140 142 144 106 108 110 112 H4H12166P6 146 148 150 152 106 108 110 112 H4H12166P7 122 124 126 128 130 132 134 136 H4H12166P8 146 148 150 152 114 116 118 120 H4H12166P9 146 148 150 152 130 132 134 136 H4H12166P10 138 140 142 144 130 132 134 136 H4H12167P 154 156 158 160 162 164 166 168 H4H12168P 170 172 174 176 178 180 182 184 H4H12169P 186 188 190 192 194 196 198 200 H4H12170P 202 204 206 208 210 212 214 216 H4H12171P 218 220 222 224 226 228 230 232 H4H12175P 234 236 238 240 242 244 246 248 H4H12176P2 250 252 254 256 258 260 262 264 H4H12177P2 266 268 270 272 258 260 262 264 H4H12183P2 274 276 278 280 282 284 286 288 H2M11682N 290 292 294 296 298 300 302 304 H2M11684N 306 308 310 312 314 316 318 320 H2M11694N 322 324 326 328 330 332 334 336 H2M11695N 338 340 342 344 346 348 350 352 *Antibodies and fragments may include one or more variants of the sequence. See WO 2017/218515

The polynucleotides encoding the chains shown in Table A are listed below in Table B. Table B. Anti -C5 Antibody Chain Nucleotide Sequences * Antibody nomenclature SEQ ID NO HCVR HCDR1 HCDR2 HCDR3 LCVR LCDR1 LCDR2 LCDR3 H2M11683N 1 3 5 7 9 11 13 15 H2M11686N 17 19 twenty one twenty three 25 27 29 31 H4H12159P 33 35 37 39 41 43 45 47 H4H12161P 49 51 53 55 57 59 61 63 H4H12163P 65 67 69 71 73 75 77 79 H4H12164P 81 83 85 87 89 91 93 95 H4H12166P 97 99 101 103 105 107 109 111 H4H12166P2 97 99 101 103 113 115 117 119 H4H12166P3 121 123 125 127 105 107 109 111 H4H12166P4 97 99 101 103 129 131 133 135 H4H12166P5 137 139 141 143 105 107 109 111 H4H12166P6 145 147 149 151 105 107 109 111 H4H12166P7 121 123 125 127 129 131 133 135 H4H12166P8 145 147 149 151 113 115 117 119 H4H12166P9 145 147 149 151 129 131 133 135 H4H12166P10 137 139 141 143 129 131 133 135 H4H12167P 153 155 157 159 161 163 165 167 H4H12168P 169 171 173 175 177 179 181 183 H4H12169P 185 187 189 191 193 195 197 199 H4H12170P 201 203 205 207 209 211 213 215 H4H12171P 217 219 221 223 225 227 229 231 H4H12175P 233 235 237 239 241 243 245 247 H4H12176P2 249 251 253 255 257 259 261 263 H4H12177P2 265 267 269 271 257 259 261 263 H4H12183P2 273 275 277 279 281 283 285 287 H2M11682N 289 291 293 295 297 299 301 303 H2M11684N 305 307 309 311 313 315 317 319 H2M11694N 321 323 325 327 329 331 333 335 H2M11695N 337 339 341 343 345 347 349 351 *Antibodies and fragments may include one or more variants of the sequence. See WO 2017/218515

In one embodiment of the present invention, an antibody or antigen-binding fragment thereof that specifically binds to C5 in the form of a co-formulation of the present invention comprises: (1) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 2 (or a variant thereof), and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 10 (or a variant thereof); (2) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 18 (or a variant thereof), and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 26 (or a variant thereof); (3) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 34 (or a variant thereof), and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 42 (or a variant thereof); (4) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 50 (or a variant thereof), and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 58 (or a variant thereof); (5) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 66 (or a variant thereof), and LCVR, comprising LCVR LCVR comprises an amino acid sequence as shown in SEQ ID NO: 74 (or a variant thereof); (6) HCVR comprising an HCDR1, HCDR2 and HCDR3 of an HCVR, an amino acid sequence as shown in SEQ ID NO: 82 (or a variant thereof); and LCVR comprising an LCDR1, LCDR2 and LCDR3 of an LCVR, an amino acid sequence as shown in SEQ ID NO: 90 (or a variant thereof); (7) HCVR comprising an HCDR1, HCDR2 and HCDR3 of an HCVR, an amino acid sequence as shown in SEQ ID NO: 98 (or a variant thereof); and LCVR comprising an LCDR1, LCDR2 and LCDR3 of an LCVR, an amino acid sequence as shown in SEQ ID NO: 106 (or a variant thereof); (8) HCVR comprising an HCDR1, HCDR2 and HCDR3 of an HCVR, an amino acid sequence as shown in SEQ ID NO: 106 (or a variant thereof); NO: 98 amino acid sequence (or its variant), and LCVR, which comprises LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprises the amino acid sequence shown in SEQ ID NO: 114 (or its variant); (9) HCVR, which comprises HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprises the amino acid sequence shown in SEQ ID NO: 122 (or its variant), and LCVR, which comprises LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprises the amino acid sequence shown in SEQ ID NO: 106 (or its variant); (10) HCVR, which comprises HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprises the amino acid sequence shown in SEQ ID NO: 98 (or its variant), and LCVR, which comprises LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprises the amino acid sequence shown in SEQ ID NO: NO: 130 (or a variant thereof); (11) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 138 (or a variant thereof), and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 106 (or a variant thereof); (12) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 146 (or a variant thereof), and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 106 (or a variant thereof); (13) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: NO: 122 amino acid sequence (or its variant), and LCVR, which comprises LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprises the amino acid sequence shown in SEQ ID NO: 130 (or its variant); (14) HCVR, which comprises HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprises the amino acid sequence shown in SEQ ID NO: 146 (or its variant), and LCVR, which comprises LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprises the amino acid sequence shown in SEQ ID NO: 114 (or its variant); (15) HCVR, which comprises HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprises the amino acid sequence shown in SEQ ID NO: 146 (or its variant), and LCVR, which comprises LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprises the amino acid sequence shown in SEQ ID NO: 146 (or its variant), and LCVR, which comprises LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprises the amino acid sequence shown in SEQ ID NO: NO: 130 (or a variant thereof); (16) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence of SEQ ID NO: 138, and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence of SEQ ID NO: 130 (or a variant thereof); (17) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence of SEQ ID NO: 154 (or a variant thereof), and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence of SEQ ID NO: 162 (or a variant thereof); (18) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence of SEQ ID NO: 170 (or a variant thereof), and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 178 (or a variant thereof); (19) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 186 (or a variant thereof), and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 194 (or a variant thereof); (20) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 202 (or a variant thereof), and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 210 (or a variant thereof); (21) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 218 (or a variant thereof), and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 226 (or a variant thereof); (22) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 234 (or a variant thereof), and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 242 (or a variant thereof); (23) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 250 (or a variant thereof), and LCVR, comprising LCVR LCDR1, LCDR2 and LCDR3 of HCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 258 (or a variant thereof); (24) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 266 (or a variant thereof), and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 258 (or a variant thereof); (25) HCVR, comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 274 (or a variant thereof), and LCVR, comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 282 (or a variant thereof); (26) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 290 (or a variant thereof), and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 298 (or a variant thereof); (27) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 306 (or a variant thereof), and LCVR comprising LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 314 (or a variant thereof); (28) HCVR comprising HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 322 (or a variant thereof), and LCVR comprising LCVR LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 330 (or a variant thereof); and/or (29) HCVR, which comprises HCDR1, HCDR2 and HCDR3 of HCVR, HCVR comprising the amino acid sequence shown in SEQ ID NO: 338 (or a variant thereof), and LCVR, which comprises LCDR1, LCDR2 and LCDR3 of LCVR, LCVR comprising the amino acid sequence shown in SEQ ID NO: 346 (or a variant thereof).

In one embodiment of the present invention, the antibody or antigen-binding fragment thereof that specifically binds to C5 in the form of a co-formulation of the present invention comprises: (a) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 4 (or a variant thereof), a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 6 (or a variant thereof), a HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 8 (or a variant thereof), and a light chain variable region comprising a LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 12 (or a variant thereof), a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 14 (or a variant thereof), a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 16 (or a variant thereof); (b) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 20 (or a variant thereof), a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 21 (or a variant thereof), a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 23 (or a variant thereof); NO: 22 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 24 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 28 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 30 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 32 (or a variant thereof); (c) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 36 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 38 (or a variant thereof), HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 40 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 44 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 30 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 32 (or a variant thereof); NO: 46 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 48 (or a variant thereof); (d) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 52 (or a variant thereof), a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 54 (or a variant thereof), and a HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 56 (or a variant thereof); and a light chain variable region comprising a LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 60 (or a variant thereof), a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 62 (or a variant thereof), and a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 64 (or a variant thereof); (e) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 68 (or a variant thereof), a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 69 (or a variant thereof), and a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 70 (or a variant thereof). NO: 70 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 72 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 76 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 78 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 80 (or a variant thereof); (f) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 84 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 86 (or a variant thereof), HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 88 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 92 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 98 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 100 (or a variant thereof); NO: 94 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 96 (or a variant thereof); (h) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 100 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 102 (or a variant thereof), HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 104 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 110 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 112 (or a variant thereof); (j) a heavy chain variable region comprising NO: 100 (or a variant thereof), HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 102 (or a variant thereof), HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 104 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 116 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 118 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 120 (or a variant thereof); (k) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 124 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 126 (or a variant thereof), HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 128 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 110 (or a variant thereof), and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 112 (or a variant thereof); (m) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 100 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 102 (or a variant thereof), and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 104 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 134 (or a variant thereof), and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 116 (or a variant thereof). NO: 136 (or a variant thereof); (n) a heavy chain variable region comprising a HCDR1 comprising an amino acid sequence shown in SEQ ID NO: 140 (or a variant thereof), a HCDR2 comprising an amino acid sequence shown in SEQ ID NO: 142 (or a variant thereof), a HCDR3 comprising an amino acid sequence shown in SEQ ID NO: 144 (or a variant thereof), and a light chain variable region comprising a LCDR1 comprising an amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof), a LCDR2 comprising an amino acid sequence shown in SEQ ID NO: 110 (or a variant thereof), a LCDR3 comprising an amino acid sequence shown in SEQ ID NO: 112 (or a variant thereof); (p) a heavy chain variable region comprising a HCDR1 comprising an amino acid sequence shown in SEQ ID NO: 148 (or a variant thereof), a HCDR2 comprising an amino acid sequence shown in SEQ ID NO: 142 (or a variant thereof), a HCDR3 comprising an amino acid sequence shown in SEQ ID NO: 144 (or a variant thereof), NO: 150 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 152 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 110 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 112 (or a variant thereof); (q) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 124 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 126 (or a variant thereof), HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 128 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 110 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 112 (or a variant thereof); NO: 132 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 134 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 136 (or a variant thereof); (r) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 148 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 150 (or a variant thereof), HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 152 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 116 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 118 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 120 (or a variant thereof); (s) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 148 (or a variant thereof), a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 150 (or a variant thereof), a HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 152 (or a variant thereof), and a light chain variable region comprising a LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof), a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 134 (or a variant thereof), a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 136 (or a variant thereof); (t) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 140 (or a variant thereof), a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 142 (or a variant thereof), a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 137 (or a variant thereof); NO: 144 (or a variant thereof), and a light chain variable region comprising a LCDR1 comprising an amino acid sequence shown in SEQ ID NO: 132 (or a variant thereof), a LCDR2 comprising an amino acid sequence shown in SEQ ID NO: 134 (or a variant thereof), and a LCDR3 comprising an amino acid sequence shown in SEQ ID NO: 136 (or a variant thereof); (u) a heavy chain variable region comprising a HCDR1 comprising an amino acid sequence shown in SEQ ID NO: 156 (or a variant thereof), a HCDR2 comprising an amino acid sequence shown in SEQ ID NO: 158 (or a variant thereof), and a HCDR3 comprising an amino acid sequence shown in SEQ ID NO: 160 (or a variant thereof), and a light chain variable region comprising a LCDR1 comprising an amino acid sequence shown in SEQ ID NO: 164 (or a variant thereof), a LCDR2 comprising an amino acid sequence shown in SEQ ID NO: 165 (or a variant thereof), and a LCDR3 comprising an amino acid sequence shown in SEQ ID NO: 167 (or a variant thereof). NO: 166 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 168 (or a variant thereof); (v) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 172 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 174 (or a variant thereof), HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 176 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 180 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 182 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 184 (or a variant thereof); (w) a heavy chain variable region comprising NO: 188 (or a variant thereof), HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 190 (or a variant thereof), HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 192 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 196 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 198 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 200 (or a variant thereof); (x) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 204 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 206 (or a variant thereof), HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 208 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 212 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 214 (or a variant thereof), and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 216 (or a variant thereof); (y) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 220 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 222 (or a variant thereof), and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 224 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 228 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 230 (or a variant thereof), and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 236 (or a variant thereof). NO: 232 (or a variant thereof); (z) a heavy chain variable region comprising a HCDR1 comprising an amino acid sequence shown in SEQ ID NO: 236 (or a variant thereof), a HCDR2 comprising an amino acid sequence shown in SEQ ID NO: 238 (or a variant thereof), a HCDR3 comprising an amino acid sequence shown in SEQ ID NO: 240 (or a variant thereof), and a light chain variable region comprising a LCDR1 comprising an amino acid sequence shown in SEQ ID NO: 244 (or a variant thereof), a LCDR2 comprising an amino acid sequence shown in SEQ ID NO: 246 (or a variant thereof), a LCDR3 comprising an amino acid sequence shown in SEQ ID NO: 248 (or a variant thereof); (aa) a heavy chain variable region comprising a HCDR1 comprising an amino acid sequence shown in SEQ ID NO: 252 (or a variant thereof), a HCDR2 comprising an amino acid sequence shown in SEQ ID NO: 258 (or a variant thereof), NO: 254 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 256 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 260 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 264 (or a variant thereof); a heavy chain variable region comprising HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 268 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 270 (or a variant thereof), HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 272 (or a variant thereof), and a light chain variable region comprising NO: 260 (or a variant thereof), LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 262 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 264 (or a variant thereof); (ac) a heavy chain variable region comprising HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 276 (or a variant thereof), HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 278 (or a variant thereof), HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 280 (or a variant thereof), and a light chain variable region comprising LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 284 (or a variant thereof), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 286 (or a variant thereof), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 288 (or a variant thereof); (ad) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 292 (or a variant thereof), a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 294 (or a variant thereof), a HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 296 (or a variant thereof), and a light chain variable region comprising a LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 300 (or a variant thereof), a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 302 (or a variant thereof), a LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 304 (or a variant thereof); (ae) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 308 (or a variant thereof), a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 310 (or a variant thereof), a NO: 312 (or a variant thereof), and a light chain variable region comprising a LCDR1 comprising an amino acid sequence shown in SEQ ID NO: 316 (or a variant thereof), a LCDR2 comprising an amino acid sequence shown in SEQ ID NO: 318 (or a variant thereof), and a LCDR3 comprising an amino acid sequence shown in SEQ ID NO: 320 (or a variant thereof); (af) a heavy chain variable region comprising a HCDR1 comprising an amino acid sequence shown in SEQ ID NO: 324 (or a variant thereof), a HCDR2 comprising an amino acid sequence shown in SEQ ID NO: 326 (or a variant thereof), and a HCDR3 comprising an amino acid sequence shown in SEQ ID NO: 328 (or a variant thereof), and a light chain variable region comprising a LCDR1 comprising an amino acid sequence shown in SEQ ID NO: 332 (or a variant thereof), a LCDR2 comprising an amino acid sequence shown in SEQ ID NO: 334 (or a variant thereof), and a LCDR3 comprising an amino acid sequence shown in SEQ ID NO: 335 (or a variant thereof). NO: 334 (or its variant), LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 334 (or its variant), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 336 (or its variant); and/or (ag) a heavy chain variable region comprising a HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 340 (or its variant), a HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 342 (or its variant), HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 344 (or its variant), and a light chain variable region comprising a LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 348 (or its variant), a LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 350 (or its variant), LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 352 (or its variant).

In one embodiment of the present invention, the antibody or antigen-binding fragment thereof that specifically binds to C5 in the form of a co-formulation of the present invention comprises: (i) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 2 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 10 (or its variant); (ii) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 18 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 26 (or its variant); (iii) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 34 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 42 (or its variant); (iv) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 51 (or its variant); NO:50 containing the amino acid sequence (or its variant), and containing the light chain variable region of the amino acid sequence (or its variant) shown in SEQ ID NO:58; (v) containing the amino acid sequence (or its variant) shown in SEQ ID NO:66 containing the heavy chain variable region, and containing the amino acid sequence (or its variant) shown in SEQ ID NO:74 containing the light chain variable region; (vi) containing the amino acid sequence (or its variant) shown in SEQ ID NO:82 containing the heavy chain variable region, and containing the amino acid sequence (or its variant) shown in SEQ ID NO:90 containing the light chain variable region; (vii) containing the amino acid sequence (or its variant) shown in SEQ ID NO:98 containing the heavy chain variable region, and containing the amino acid sequence (or its variant) shown in SEQ ID NO:106 containing the light chain variable region; (viii) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 98 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 114 (or its variant); (ix) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 122 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 106 (or its variant); (x) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 98 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 130 (or its variant); (xi) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 138 (or its variant), and a light chain variable region comprising SEQ ID NO: 106 (or its variant); (xii) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 146 (or its variant), and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 106 (or its variant); (xiii) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 122 (or its variant), and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 130 (or its variant); (xiv) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 146 (or its variant), and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 114 (or its variant); (xv) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 122 (or its variant), and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 130 (or its variant); NO: 146 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 130 (or its variant); (xvi) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 138 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 130 (or its variant); (xvii) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 154 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 162 (or its variant); (xviii) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 170 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 171 (or its variant); NO: 178 (or its variant); (xix) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 186 (or its variant), and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 194 (or its variant); (xx) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 202 (or its variant), and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 210 (or its variant); (xxi) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 218 (or its variant), and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 226 (or its variant); (xxii) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 203 (or its variant), and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 217 (or its variant); NO: 234 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 242 (or its variant); (xxiii) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 250 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 258 (or its variant); (xxiv) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 266 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 258 (or its variant); (xxv) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 274 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 280 (or its variant); NO: 282 (or its variant); (xxvi) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 290 (or its variant), and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 298 (or its variant); (xxvii) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 306 (or its variant), and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 314 (or its variant); (xxviii) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 322 (or its variant), and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 330 (or its variant); and/or (xxix) A heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 306 (or its variant), and A light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 314 (or its variant); A heavy chain variable region comprising the amino acid sequence shown in NO: 338 (or its variant), and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 346 (or its variant).

In one embodiment of the present invention, the antibody or antigen-binding fragment thereof that specifically binds to C5 in the form of a co-formulation of the present invention comprises a heavy chain comprising the following amino acid sequence: A light chain containing the following amino acid sequence: ; Such antibodies may be referred to herein as pazelimab or REGN3918.

Unless otherwise stated elsewhere, "H2M11683N";"H2M11686N;H4H12159P";"H4H12161P";"H4H12163P";"H4H12164P";"H4H12166P";"H4H12166P2";"H4H12166P3";"H4H12166P4";"H4H12166P5";"H4H12166P6";"H4H12166P7";"H4H12166P8";"H4H12166P9";"H4H12166P10";"H4H12167P";"H4H12168P";"H4H1"H4H12170P";"H4H12171P";"H4H12175P";"H4H12176P2";"H4H12177P2";"H4H12183P2";"H2M11682N";"H2M11684N";"H2M11694N"; or "H2M11695N" refers to an anti-C5 antigen-binding protein that specifically binds to C5, such as an antibody or an antigen-binding fragment thereof (including a multispecific antigen-binding protein), which comprises an immunoglobulin heavy chain or variable region (V _{H )} corresponding to the amino acid sequence shown in Table A herein or in Table 1 of WO2017/218515 for the following specific examples. ): H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H 12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; or H2M11695N (e.g., SEQ ID NO: 2; 18; 34; 50; 66; 82; 98; 98; 122; 98; 138; 146; 122; 146; 146; 138; 154; 170; 186; 202; 218; 234; 250; 266; 274; 290; 306; 322; or 338) (or variants thereof), and/or an immunoglobulin light chain or variable region thereof (V _{L ...} ): H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H 12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; or H2M11695N (e.g., SEQ ID NO: 10; 26; 42; 58; 74; 90; 106; 114; 106; 130; 106; 106; 130; 114; 130; 130; 162; 178; 194; 210; 226; 242; 258; 282; 298; 314; 330; or 346) (or variants thereof); and/or a heavy chain or _VH comprising its CDRs (CDR-H1 (or variants thereof), CDR-H2 (or variants thereof), and CDR-H3 (or variants thereof)), and/or a light chain or VL comprising its _CDRs (CDR-L1 (or variants thereof), CDR-L2 (or variants thereof), and CDR-L3 (or variants thereof)). In one embodiment of the invention, _VH is linked to an IgG heavy chain constant domain (e.g., IgG1 or IgG4 (e.g., IgG4 (S228P mutant))) and/or _VL is linked to a Lamdara or Kappa light chain constant domain.

An "anti-C5" antibody or antigen-binding fragment or an antibody or antigen-binding fragment that "specifically binds" to C5 binds to human C5 with a _KD of at least 1 nM (i.e., an affinity of 1 nM or greater), such as about 0.1 or 0.2 nM. Interfering RNA (iRNA)

The present invention provides a co-formulation comprising: an anti-C5 antibody or an antigen-binding fragment thereof (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12166P11; 12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; korolizumab; eculizumab, tertulumab, mubodina, or ravulizumab; preferably pazelimumab); and iRNAs that affect RNA-induced silencing complexes (RNA-induced The invention relates to a method for affecting the cleavage of RNA transcripts (C5 iRNA) of the C5 gene mediated by an RNA-induced silencing complex (RISC), such as Cemdisiran (e.g., Cemdisiran/Paslimab). The C5 gene may be in a cell, such as a cell in an individual (e.g., a human). The invention provides an iRNA agent incorporated into the co-formulation of the invention, which affects the cleavage of RNA transcripts (C5 iRNA) of the complement component C5 gene mediated by an RNA-induced silencing complex (RISC).

Cemdisiran is a chemically synthesized double-stranded oligonucleotide sugar conjugate covalently linked to a ligand containing three GalNAc residues to facilitate targeted delivery to the liver. See, e.g., Figure 1. All nucleosides are modified with 2'-deoxy, 2'-methoxy, or 2'-fluoro groups and linked via 3' to 5' phosphodiester bonds to form the sugar-phosphate backbone of the oligonucleotide.

The sense strand (A-125167) contains 21 nucleotides, while the antisense strand (A-125647) contains 25 nucleotides. The 3' end of the sense strand is bound to a triantennary GalNAc moiety (called L96) via a phosphodiester bond.

The antisense strand (A-125647) contains four phosphorothioate linkages, with two consecutive phosphorothioate linkages at the 3' end and two consecutive phosphorothioate linkages at the 5' end. The sense strand (A-125167) contains two phosphorothioate linkages at the 5' end. The 21 nucleotides of the sense strand hybridize with the 21 complementary nucleotides of the antisense strand to form a 21 nucleotide base pair double helix with four base overhangs at the 3' end of the antisense strand. The bases involved in the base pair formation are attached to the central point. Cemdisiran is preferably in salt form, such as Na ⁺ salt form, but the present invention includes embodiments comprising Cemdisiran in free acid form as well as in other salt forms (such as ^Ca2+ salt).

When the RNAi concentration in a composition (such as the co-formulations of the present invention) is expressed herein as mass/volume (e.g., mg/ml), the RNAi is in salt form or free acid form. Preferably, when referring to Cemdisiran itself, Cemdisiran is in salt form, preferably Na ⁺ salt form. Due to the net negatively charged ribonucleotide phosphate backbone, Na ⁺ counterions are present. The amount of Cemdisiran free acid form can be obtained by multiplying the concentration of Cemdisiran Na ⁺ salt form by 0.9443.

The structure of Cemdisiran Sodium (ALN-62643) is shown below, with A-125167 located at the top (5'-3') and A-125647 located at the bottom (3'-5'): Af, Gf and Uf = 2'-F ribonucleosides Am, Cm and Um - 2'-OMe ribonucleosides dT = thymidine S = phosphorothioate L96 is .

C5 iRNAs that can be incorporated into the co-formulations of the invention include RNA strands (e.g., antisense strands) having a region of about 30 nucleotides or less in length, such as at least 15, 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23 or 21-22 nucleotides, which region is substantially complementary to at least a portion of the mRNA transcript of the C5 gene.

In one embodiment of the present invention, the C5 iRNA is a glycoconjugate comprising a double-stranded RNA complementary to a region of C5, wherein the region of C5 is bound (e.g., via a linker) to a terminal mono-, bi-, or tri-antennary N-acetylgalactosamine (GalNAc) group, preferably tri-antennary N-acetylgalactosamine.

In one embodiment of the present invention, the iRNA agent that can be incorporated into the co-formulation of the present invention includes a single-stranded RNA that interacts with a target RNA sequence (e.g., a C5 target mRNA sequence) to guide the cleavage of the target RNA. Without wishing to be bound by theory, it is believed that the long double-stranded RNA introduced into the cell is broken down into siRNA by a type III nuclease called Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer, a ribonuclease-III-like enzyme, processes dsRNA into short interfering RNAs of 19-23 base pairs with a characteristic two-base 3' overhang (Bernstein, et al. , (2001) Nature 409:363). The siRNA is then incorporated into the RNA-induced silencing complex (RISC), where one or more helicases unwind the siRNA duplex, allowing the complementary antisense strand to guide target recognition (Nykanen, et al. , (2001) Cell 107:309). After binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al. , (2001) Genes Dev. 15:188). Thus, in one aspect, the present invention relates to a single-stranded RNA (siRNA) generated within a cell that promotes RISC complex formation to achieve silencing of a target gene (i.e., C5 gene). Therefore, the term "siRNA" is also used herein to refer to the iRNA as described above.

In another embodiment, the iRNA agent that can be incorporated into the co-formulation of the present invention may be a single-stranded siRNA that is introduced into a cell or organism to inhibit a target mRNA. The single-stranded iRNA agent binds to the RISC endonuclease Argonaute 2, which in turn cleaves the target mRNA. Single-stranded siRNAs are typically 15-30 nucleotides and are chemically modified. The design and testing of single-stranded siRNAs are described in U.S. Patent No. 8,101,348 and Lima et al. , (2012) Cell 150: 883-894, each of which is incorporated herein by reference in its entirety. Any antisense nucleotide sequence described herein can be used as a single-stranded siRNA as described herein or as chemically modified by the method described in Lima et al. , (2012) Cell 150: 883-894.

In another embodiment, the iRNA used in the compositions, uses and methods of the invention is a double-stranded RNA and is referred to herein as a "double-stranded iRNA agent," "double-stranded RNA (dsRNA) molecule," "dsRNA agent," or "dsRNA." The term "dsRNA" refers to a complex of ribonucleic acid molecules having a double helical structure comprising two antiparallel and substantially complementary nucleic acid strands, referred to as having "sense" and "antisense" orientations relative to the target RNA (i.e., C5 gene). In some embodiments of the invention, the double-stranded RNA (dsRNA) triggers degradation of the target RNA (e.g., mRNA) by a post-transcriptional gene silencing mechanism referred to herein as RNA interference or iRNA.

In one embodiment of the present invention, the iRNA is a double-stranded ribonucleic acid (dsRNA), wherein the dsRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises nucleotides (e.g., at least 15 consecutive nucleotides) that differ from the nucleotide sequence of C5 (underlined open reading frame) by no more than 3 nucleotides: (SEQ ID NO: 360), and the antisense strand comprises nucleotides that differ by no more than 3 nucleotides (e.g., at least 15 consecutive nucleotides) from the following nucleotide sequence: (SEQ ID NO: 361).

In one embodiment of the present invention, the C5 iRNA (e.g., dsRNA) is characterized by the following structure: Wherein X is 2'-deoxy-2'-fluoro, X is 2'-O-methyl, and Z is thymidine. =For R1- R-for See International Nonproprietary Names for Pharmaceutical Substances (INN) (Proposed INN: List 114), WHO Drug Information, Vol. 29, No. 4, 2015.

The present invention includes iRNAs that can be incorporated into co-formulations of the present invention, which are double-stranded ribonucleic acid (dsRNA) agents (e.g., having a complementary region of 19-23 nucleotides in length and/or a strand length of no more than 30 nucleotides) for inhibiting the expression of complement component C5, wherein the dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a complementary region comprising at least 17 consecutive nucleotides that differ from the nucleotide sequence of 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 364) by no more than 3 nucleotides, wherein one or more of the dsRNA nucleotides are modified. The dsRNA agent may include at least one modified nucleotide, e.g., modified with a 2'-deoxy, 2'-methoxy, and/or 2'-fluoro group; e.g., wherein substantially all of the nucleotides of the sense strand and the antisense strand are modified nucleotides. Additionally, the sense strand can be conjugated to a ligand attached at the 3' end, e.g., terminally modified via a trianthracn GalNAc moiety.

Modified nucleotides that can be incorporated into dsRNA include 3'-terminal deoxythymine (dT) nucleotides, 2'-O-methyl modified nucleotides, 2'-fluoro modified nucleotides, 2'-deoxy modified nucleotides, locked nucleotides, abasic nucleotides, 2'-amine modified nucleotides, 2'-alkyl modified nucleotides, morpholino nucleotides, phosphoamidates, nucleotides containing unnatural bases, nucleotides containing 5'-phosphorothioate groups, and terminal nucleotides linked to cholesterol derivatives or dodecanoic acid didecylamide groups. dsRNA may include phosphorothioate and/or methylphosphonate internucleotide linkages.

dsRNA is double-stranded, but may include one or more overhangs, such as at the 3' end of one or more strands (eg, an overhang of 2 or more nucleotides).

The double-stranded RNA of the present invention may include a ligand (e.g., a N-acetylgalactosamine (GalNAc) derivative ). In one embodiment of the present invention, the ligand is bound to the 3' end of the sense strand of the dsRNA.

In one aspect, the invention provides a double-stranded ribonucleic acid (dsRNA) agent for inhibiting complement component C5 expression, which can be incorporated into a co-formulation of the invention, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence 5'-AAGCAAGAUAUUUUUUAUAAUA-3' (SEQ ID NO: 365), and wherein the antisense strand comprises the nucleotide sequence 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 364), e.g., wherein one or more dsRNA nucleotides are modified; e.g., modified with 2'-deoxy, 2'-methoxy and/or 2'-fluoro groups and/or terminally modified with a triantennary GalNAc moiety. In one embodiment, the dsRNA agent comprises at least one modified nucleotide, as described herein.

In one aspect, the invention provides a double-stranded iRNA agent that can be incorporated into a co-formulation of the invention for inhibiting the expression of complement component C5, wherein the double-stranded iRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 consecutive nucleotides that differ from the nucleotide sequence of SEQ ID NO: 365 by no more than 3 nucleotides, and the antisense strand comprises at least 15 consecutive nucleotides that differ from the nucleotide sequence of SEQ ID NO: 364 by no more than 3 nucleotides, wherein substantially all nucleotides of the sense strand and substantially all nucleotides of the antisense strand are modified nucleotides, and wherein the sense strand is bound to a ligand attached to the 3' end. In one embodiment, the dsRNA agent comprises at least one modified nucleotide, as described herein.

In one embodiment, substantially all nucleotides of the sense strand are modified nucleotides selected from the group consisting of 2'-O-methyl modification, 2'-fluoro modification, and 3'-terminal deoxythymine (dT) nucleotides. In another embodiment, substantially all nucleotides of the antisense strand are modified nucleotides selected from the group consisting of 2'-O-methyl modification, 2'-fluoro modification, and 3'-terminal deoxythymine (dT) nucleotides. In another embodiment, the modified nucleotides are a short sequence of deoxythymine (dT) nucleotides. In another embodiment, the sense strand comprises two phosphorothioate internucleotide linkages at the 5'-end. In one embodiment, the antisense strand comprises two phosphorothioate internucleotide linkages at the 5'-end and two phosphorothioate internucleotide linkages at the 3'-end. In yet another embodiment, the sense strand is conjugated to one or more GalNAc derivatives attached at the 3' end via a branched bivalent or trivalent linker.

In one embodiment, at least one of the modified nucleotides is selected from 3'-terminal deoxythymine (dT) nucleotides, 2'-O-methyl modified nucleotides, 2'-fluorine modified nucleotides, 2'-deoxy modified nucleotides, locked nucleotides, basic nucleotides, 2'-amine modified nucleotides, 2'-alkyl modified nucleotides, morpholino nucleotides, phosphamides, nucleotides containing unnatural bases, nucleotides containing 5'-thiophosphate groups, and terminal nucleotides linked to a cholesterol derivative or dodecanoic acid didecylamide group.

In another embodiment, the modified nucleotide comprises a short sequence of 3'-terminal deoxythymidine (dT) nucleotides.

In one embodiment, the length of the complementary region is at least 17 nucleotides. In another embodiment, the length of the complementary region is between 19 and 21 nucleotides. In one embodiment, the length of the complementary region is 19 nucleotides. In one embodiment, the length of each strand is no more than 30 nucleotides. In one embodiment, at least one strand comprises a 3' overhang of at least 1 nucleotide. In another embodiment, at least one strand comprises a 3' overhang of at least 2 nucleotides. In one embodiment, the dsRNA agent further comprises a ligand. In one embodiment, the ligand is bound to the 3' end of the sense strand of the dsRNA agent. In one embodiment, the ligand is an N-acetylgalactosamine (GalNAc) derivative. In one embodiment, the ligand is .

In one embodiment, the dsRNA agent is conjugated to a ligand as shown below And, wherein X is O or S. In one embodiment, X is O.

In one embodiment of the invention, the C5 iRNA comprises an RNA strand complementary to the mRNA transcribed from the sense strand DNA sequence AAGCAAGATATTTTTATAATA of the C5 gene, for example, wherein the iRNA is a dsRNA comprising another hybrid RNA strand.

In another aspect, the present invention provides a double-stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of complement component C5, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence 5'-AAGCAAGAUAUUUUUUAUAAUA-3' (SEQ ID NO: 366), and wherein the antisense strand comprises the nucleotide sequence 5'-UAUUAUAAAAAUAUCUUGCUUUUdTdT-3' (SEQ ID NO: 367).

In another aspect, the present invention provides a double-stranded ribonucleic acid (dsRNA) agent for inhibiting the expression of complement component C5, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence asasGfcAfaGfaUfAfUfuUfuuAfuAfauaL96 (SEQ ID NO: 368), and wherein the antisense strand comprises the nucleotide sequence usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT (SEQ ID NO: 369).

In one embodiment of the invention, the sense strand or antisense strand of the dsRNA that can be included in the co-formulation of the invention comprises a sequence selected from the group consisting of: A-118320, A-118321, A-118316, A-118317, A-118332, A-118333, A-118396, A-118397, A-118386, A-118387, A-118312, A-118313, A-118324, A-118325, A-119324, A-119325, A-119332, A-119333, A-119328, A-119329, A-119322, A-119323, A-119324, A-119325, A-119334, A-119335, A-119330, A-119331, A-119326, A-119327, A-125167, A-125173, A-125647, A-125157, A-125173 and A-125127. In one embodiment, the dsRNA agent comprises at least one modified nucleotide. Table C. Sense RNA strand and antisense RNA strand of C5 dsRNA ( unmodified and modified strands are shown ) A-118320 (SEQ ID NO: 370) Sense strand aagcaagaua uuuuuauaau a AfaGfcAfaGfaUfAfUfuUfuUfaUfaAfuAfL96 A-118321 antisense strand (SEQ ID NO: 371) uauuauaaaa auaucuugcu uuu uAfuUfaUfaAfaAfauaUfcUfuGfcUfusUfsu A-118316 sense strand (SEQ ID NO: 372) gacaaaauaa cucacuauaa u GfaCfaAfaAfuAfAfCfuCfaCfuAfuAfaUfL96 A-118317 antisense strand (SEQ ID NO: 373) auuauaguga guuauuuugu caa aUfuAfuAfgUfgAfguuAfuUfuUfgUfcsAfsa A-118332 sense strand (SEQ ID NO: 374) aggauuuuga guguaaaagg a AfgGfaUfuUfuGfAfGfuGfuAfaAfaGfgAfL96 A-118333 antisense strand (SEQ ID NO: 375) uccuuuuaca cucaaaaucc uuu A-118396 sense strand (SEQ ID NO: 376) guuccggaua uuugaacuuu u GfuUfcCfgGfaUfAfUfuUfgAfaCfuUfuUfL96 A-118397 antisense strand (SEQ ID NO: 377) aaaaguucaa auauccggaa ccg aAfaAfgUfuCfaAfauaUfcCfgGfaAfcsCfsg A-118386 sense strand (SEQ ID NO: 378) cagaucaaac acaauuucag u CfaGfaUfcAfaAfCfAfcAfaUfuUfcAfgUfL96 A-118387 antisense strand (SEQ ID NO: 379) acugaaauug uguuugaucu gca aCfuGfaAfaUfuGfuguUfuGfaUfcUfgsCfsa A-118312 sense strand (SEQ ID NO: 380) ugacaaaaua acucacuaua a UfgAfcAfaAfaUfAfAfcUfcAfcUfaUfaAfL96 A-118313 antisense strand (SEQ ID NO: 381) uuauagugag uuauuuuguc aau uUfaUfaGfuGfaGfuuaUfuUfuGfuCfasAfsu A-118324 sense strand (SEQ ID NO: 382) auuuaaacaa caaguaccuu u AfuUfuAfaAfcAfAfCfaAfgUfaCfcUfuUfL96 A-118325 antisense strand (SEQ ID NO: 383) aaagguacuu guuguuuaaa ucu AfuUfuAfaAfcAfAfCfaAfgUfaCfcUfuUfL96 A-119324 sense strand (SEQ ID NO: 384) gacaaaauaa cucacuauaa u AfuUfuAfaAfcAfAfCfaAfgUfaCfcUfuUfL96 A-119325 antisense strand (SEQ ID NO: 385) auuauaguga guuauuuugu caa asUfsuAfuAfgUfgAfguuAfuUfuUfgUfcsasa A-119332 sense strand (SEQ ID NO: 386) cagaucaaac acaauuucag u CfsasGfaUfcAfaAfCfAfcAfaUfuUfcAfgUfL96 A-119333 antisense strand (SEQ ID NO: 387) acugaaauug uguuugaucu gca asCfsuGfaAfaUfuGfuguUfuGfaUfcUfgscsa A-119328 sense strand (SEQ ID NO: 388) auuuaaacaa caaguaccuu u AfsusUfuAfaAfcAfAfCfaAfgUfaCfcUfuUfL96 A-119329 antisense strand (SEQ ID NO: 389) aaagguacuu guuguuuaaa ucu asAfsaGfgUfaCfuUfguuGfuUfuAfaAfusesu A-119322 sense strand (SEQ ID NO: 390) ugacaaaaua acucacuaua a UfsgsAfcAfaAfaUfAfAfcUfcAfcUfaUfaAfL96 A-119323 antisense strand (SEQ ID NO: 391) uuauagugag uuauuuuguc aau A-119324 sense strand (SEQ ID NO: 392) gacaaaauaa cucacuauaa u GfsasCfaAfaAfuAfAfCfuCfaCfuAfuAfaUfL96 A-119325 antisense strand (SEQ ID NO: 393) auuauagugaguuauuuugucaa asUfsuAfuAfgUfgAfguuAfuUfuUfgUfcsasa A-119334 sense strand (SEQ ID NO: 394) guuccggaua uuugaacuuu u GfsusUfcCfgGfaUfAfUfuUfgAfaCfuUfuUfL96 A-119335 antisense strand (SEQ ID NO: 395) aaaaguucaa auauccggaa ccg asAfsaAfgUfuCfaAfauaUfcCfgGfaAfesesg A-119330 sense strand (SEQ ID NO: 396) ugcagaucaa acacaauuuc a UfsgsCfaGfaUfcAfAfAfcAfcAfaUfuUfcAfL96 A-119331 antisense strand (SEQ ID NO: 397) ugaaauugug uuugaucugc aga usGfsaAfaUfuGfuGfuuuGfaUfcUfgCfasgsa A-119326 sense strand (SEQ ID NO: 398) aagcaagaua uuuuuauaau a AfsasGfcAfaGfaUfAfUfuUfuUfaUfaAfuAfL96 A-119327 antisense strand (SEQ ID NO: 399) uauuauaaaa auaucuugcu uuu usAfsuUfaUfaAfaAfauaUfcUfuGfcUfususu A-125167 sense strand (SEQ ID NO: 400) aagcaagaua uuuuuauaau a asasGfcAfaGfaUfAfUfuUfuuAfuAfauaL96 A-125173 antisense strand (SEQ ID NO: 401) uauuauaaaa auaucuugcu uuutt usAfsUfuAfuAfAfaAfauaUfcUfuGfcuususudTdT A-125647 antisense strand (SEQ ID NO: 402) uauuauaaaa auaucuugcu uuutt usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT A-125157 sense strand (SEQ ID NO: 403) aagcaagaua uuuuuauaau a asasGfcAfaGfaUfAfUfuUfuuAfuaAfuaL96 A-125173 antisense strand (SEQ ID NO: 404) uauuauaaaa auaucuugcu uuutt usAfsUfuAfuAfAfaAfauaUfcUfuGfcuususudTdT A-125127 sense strand (SEQ ID NO: 405) aagcaagaua uuuuuauaau a asasgcaagaUfaUfuuuuauaauaL96 Among them, A=adenosine-3'-phosphateAf=2'-fluoroadenosine-3'-phosphateAfs=2'-fluoroadenosine-3'-thiophosphateAs=adenosine-3'-thiophosphateC=cytidine-3'-phosphateCf=2'-fluorocytidine-3'-phosphateCfs=2'-fluorocytidine-3'-thiophosphateCs=cytidine-3'-thiophosphateG=guanosine-3'-phosphateGf=2'-fluoroguanosine-3'-phosphateGfs=2'-fluoroguanosine-3'-thiophosphateGs= Guanosine-3'-phosphorothioate Ｔ=5'-methyluridine-3'-phosphate Tf=2'-fluoro-5-methyluridine-3'-phosphate Tfs=2'-fluoro-5-methyluridine-3'-phosphorothioate Ts=5-methyluridine-3'-phosphorothioate U=uridine-3'-phosphate Uf=2'-fluorouridine-3'-phosphate Ufs=2'-fluorouridine-3'-phosphorothioate Us=uridine-3'-phosphorothioate N=any nucleotide (G, A, C, T or U) a=2'-0-methyladenosine-3'-phosphateas=2'-0-methyladenosine-3'-phosphorothioatec=2'-0-methylcytidine-3'-phosphatecs=2'-0-methylcytidine-3'-phosphorothioateg=2'-0-methylguanosine-3'-phosphategs=2'-0-methylguanosine-3'-phosphorothioatet=2'-0-methyl-5-methyluridine-3'-phosphatets=2'-0-methyl-5-methyluridine-3'-phosphorothioateu=2'-0-methyluridine-3'-phosphateus=2'-0-methyluridine-3'-phosphorothioates=phosphorothioate linkageL96=N-[(GalNAc-alkyl)-amidodecanoyl)]-4-hydroxyprolinolHyp-(GalNAc-alkyl) ₃ (dt)=deoxythymidine

In one embodiment of the invention, the dsRNA comprises two of the following paired strands: A-118320 & A-118321 A-118316 & A-118317 A-118332 & A-118333 A-118396 & A-118397 A-118386 & A-118387 A-118312 & A-118313 A-118324 & A-118325 A-119324 & A-119325 A-119332 & A-119333 A-119328 & A-119329 A-119322 & A-119323 A-119324 & A-119325 A-119334 & A-119335 A-119330 & A-119331 A-119326 & A-119327 A-125167 & A-125173 or A-125647 A-125157 & A-125173 or A-125647 A-125127 & A-125173 or A-125647

In one embodiment of the present invention, C5 iRNA (eg, Cemdisiran) comprises one or more galactosamines (eg, 3), such as represented by the following structure: Wherein the wavy double helix-like structure represents the RNA portion of the molecule and X is O or X is S; for example, However, in one embodiment of the present invention, the co-formulation of the present invention further comprises a degradation product represented by one or more of the following structures (the wavy line represents a double-stranded RNA structure): (Cemdisiran Impurities 1) (Cemdisiran Impurities 2) (Cemdisiran impurity 3); which lacks 1, 2 or 3 terminal N-acetylgalactosamine (GalNAc).

The iRNA of the invention may be chemically linked via the RNA portion of the molecule to one or more ligands, moieties or binding agents that enhance the activity, cellular distribution or cellular uptake of the iRNA. Such moieties include, but are not limited to, lipid moieties such as cholesterol moieties (Letsinger et al. , Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556), cholic acid (Manoharan et al. , Biorg. Med. Chem. Let., 1994, 4: 1053-1060), thioethers (e.g., benzyl-S-tritylthiol) (Manoharan et al. , Ann. NY Acad. Sci., 1992, 660: 306-309; Manoharan et al. , Biorg. Med. Chem. Let., 1993, 3: 2765-2770), thiocholesterols (Oberhauser et al. , Nucl. Acids Res., 1992, 20:533-538), aliphatic chains (e.g., dodecanediol or undecyl residue) (Saison-Behmoaras et al. , EMBO J, 1991, 10:1111-1118; Kabanov et al. , FEBS Lett., 1990, 259:327-330; Svinarchuk et al. , Biochimie, 1993, 75:49-54), phospholipids (e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycerol-3-phosphonate) (Manoharan et al. , Tetrahedron Lett., 1995, 36:3651-3654; Shea et al. , Nucl. Acids Res., 1990, 18:3777-3783), polyamines or polyethylene glycol chains (Manoharan et al. , Nucleosides & Nucleotides, 1995, 14:969-973), or adamantane acetic acid (Manoharan et al. , Tetrahedron Lett., 1995, 36:3651-3654), a palmityl moiety (Mishra et al. , Biochim. Biophys. Acta, 1995, 1264:229-237), or an octadecylamine or hexylamino-carbonyloxycholesterol moiety (Crooke et al. , J. Pharmacol. Exp. Ther., 1996, 277:923-937).

The ligand may be a carbohydrate. Carbohydrate-bound RNA facilitates in vivo delivery of nucleic acids. As used herein, a "carbohydrate" ligand refers to a carbohydrate itself consisting of one or more monosaccharide units having at least 6 carbon atoms (may be linear, branched, or cyclic) plus oxygen, nitrogen, or sulfur bonded to each carbon atom; or a compound having as part of it a carbohydrate moiety consisting of one or more monosaccharide units having at least six carbon atoms (may be linear, branched, or cyclic) plus oxygen, nitrogen, or sulfur bonded to each carbon atom. Representative carbohydrates include sugars (monosaccharides, disaccharides, trisaccharides, and oligosaccharides containing about 4, 5, 6, 7, 8, or 9 monosaccharide units) and polysaccharides such as starch, glycogen, cellulose, and polysaccharides. Specific monosaccharides include sugars of C5 and above (eg, C5, C6, C7, or C8); disaccharides and trisaccharides include sugars having two or three monosaccharide units (eg, C5, C6, C7, or C8).

In one embodiment, the carbohydrate conjugate used in the compositions and methods of the present invention is a monosaccharide. In one embodiment, the monosaccharide is N-acetylgalactosamine, such as ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;or , when one of X or Y is an oligonucleotide, the other is hydrogen.

In some embodiments, the conjugates or ligands described herein can be attached to the iRNA oligonucleotide using a variety of cleavable or non-cleavable linkers. The term "linker" or "linking group" refers to an organic moiety that connects two parts of a compound (e.g., covalently attaches two parts of a compound). Linkers typically include direct bonds or atoms (such as oxygen or sulfur), units (such as NR8, C(O), C(O)NH, SO, SO ₂ , SO ₂ NH or an atomic chain), such as but not limited to substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl, heterocycloalkenyl, heterocycloalkynyl, aryl, heteroaryl, heterocyclo, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocycloalkyl, alkylheterocycloalkenyl, alkylheterocycloalkynyl, alkenylheterocycloalkyl, alkenylheterocycloalkenyl, alkenylheterocycloalkynyl, alkynylheterocycloalkyl, alkynylheterocycloalkenyl, alkynylheterocycloalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylheteroaryl, wherein one or more methylene groups may be replaced by O, S, S(O), SO ₂ , N(R8), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic interrupted or terminated; wherein R8 is hydrogen, acyl, aliphatic or substituted aliphatic. In one embodiment, the linker has about 1-24 atoms, 2-24, 3-24, 4-24, 5-24, 6-24, 6-18, 7-18, 8-18 atoms, 7-17, 8-17, 6-16, 7-16 or 8-16 atoms. The linker may include a redox cleavable linking group, a phosphate-based cleavable linking group, an acid-cleavable linking group, an ester-based linking group and/or a peptide-based cleavage group. Where x=1-30 and y=1-15; , where y=1-30 and y=1-15; , where x=0-30 and y=1-15; , where x=0-30, y=1-15 and z=1-20; , where x=1-30, y=1-15 and z=1-20; , wherein x=1-30, y=1-15 and z=1-20; when one of X or Y is an oligonucleotide, the other is hydrogen. In certain embodiments of the compositions and methods of the present invention, the ligand is one or more GalNAc (N-acetylgalactosamine) derivatives attached via a bivalent or trivalent branched linker. Co-formulations

The present invention provides pharmaceutical (preferably aqueous) co-formulations comprising a pharmaceutically acceptable carrier and different components (i) an anti-C5 antibody or an antigen-binding fragment thereof (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12166P11; H4H12166P12; H4H12166P13; H4H12166P14; H4H12166P15; H4H12166P16; H4H12166P17; H4H12166P18; H4H12166P19; H4H12166P20; H4H12166P30; H4H12166P40; H4H12166P50; H4H12166P60; H4H12166P70; H4H12166P80; H4H12166P1 4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; korolizumab; eculizumab, tertulumab, mubodina or ravulizumab; preferably pazelimumab), and (ii) C5 iRNA, preferably a glycoconjugate such as cemdisiran.

Co-formulations may be designated in the form of: Antibody/iRNA; for example, "Paslimumab/Cemdisiran" or "Cemdisiran/Paslimumab" refers to a co-formulation of the invention comprising Paslimumab and Cemdisiran.

As used herein, co-formulation or pharmaceutical co-formulation refers to a formulation comprising an anti-C5 antigen binding protein (e.g., an antibody or an antigen binding fragment thereof), a C5 iRNA, and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers include, for example, one or more excipients. In one embodiment of the present invention, the co-formulation of the present invention is aqueous, i.e., comprises water.

Pharmaceutical formulations comprising anti-C5 antigen binding proteins can be prepared by mixing the antigen binding protein with one or more excipients (see, e.g., Hardman et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY).

The present invention provides a method for preparing a co-formulation, comprising combining C5 iRNA (e.g., Cemdisiran or its Na ⁺ salt; for example, wherein the C5 iRNA is reduced from its freeze-dried composition with water); an antibody or an antigen-binding fragment thereof that specifically binds to C5 (e.g., Paseritumab); a buffer (e.g., histidine); a viscosity reducer (e.g., L-arginine); a stabilizer (e.g., sucrose); and a non-ionic surfactant (e.g., polysorbate 80), and optionally adjusting the pH of the co-formulation to greater than or less than about 6 (e.g., about 6.5±0.2); and optionally sterile filtering the co-formulation.

The present invention provides methods for making the co-formulations of the present invention, comprising combining RNAi (e.g., Cemdisiran) with an antibody or antigen-binding fragment (e.g., Paslimumab) (e.g., which includes a detectable β-hexosaminidase contaminant), and (i) adding GalNAc to the co-formulation and/or (ii) adjusting the pH of the co-formulation to about 6 or below about 6 (e.g., within 0.5). In one embodiment of the present invention, other excipients, such as buffers, viscosity reducers, stabilizers, and/or surfactants are also combined. The co-formulations (e.g., Cemdisiran/Paslimumab) produced by such methods are part of the present invention. In one embodiment of the invention, the antibody or fragment that is combined with other components is initially in a batch that includes a β-hexosaminidase contaminant and is diluted by a factor of 0.25, 0.5 or 0.75 when incorporated into the co-formulation.

A variety of viscosity reducers are known in the art for use with co-formulations. A viscosity reducer is an agent that can reduce the viscosity of a formulation. A viscosity reducer can also act as a tensile agent to adjust the osmotic pressure of a co-formulation. Such viscosity reducers include adipic acid; amino acids or salts thereof; (D- or L-) arginine; L-arginine HCl; (D- or L-) alanine; benzenesulfonic acid; caffeine; dicarboxylic acids; esters of citric acid; (D- or L-) glutamine; glycine; (D- or L-) histidine; inorganic salts; L-ornithine; (D- or L-) lysine; proline; (D- or L-) phenylalanine; (D- or L-) serine; NaCl; pyridoxamine; pyridoxine; thiamine phosphate chloride dihydrate; triethyl citrate; (D- or L-) valeric acid; and/or xanthine. In one embodiment of the present invention, the amino acid is an L-amino acid, such as L-arginine. L-arginine can act as a tensiometer, stabilizer and viscosity reducer. Arginine HCl can reduce the degradation of Cemdisiran and form a near isotonic solution.

Stabilizers include agents such as sugars or polyols that help reduce degradation, such as aggregation, of, for example, antibodies or antigen-binding fragments. Polyols are sugar alcohols with multiple hydroxyl groups. Stabilizers include sugars or polyols, such as trehalose, sorbitol, mannitol, taurine, propanesulfonic acid, L-proline, sucrose, glycerol, threitol, maltitol, and/or polyethylene glycol (PEG; such as PEG3350).

Nonionic surfactants contain molecules with uncharged head groups. Nonionic surfactants include those containing polyoxyethylene moieties; desorbitan; polyoxyethylene glycol alkyl ethers, such as octaethylene glycol monododecyl ether; pentaethylene glycol monododecyl ether; polyoxypropylene glycol alkyl ethers; glucoside alkyl ethers, such as decyl glucoside, lauryl glucoside, octyl glucoside; polyoxyethylene glycol octylphenol ethers, such as triton X-100; polyoxyethylene glycol alkylphenol ethers, such as nonoxynol-9; glyceryl alkyl esters, such as glyceryl laurate; polyoxyethylene glycol dehydrated sorbitan alkyl esters, such as polysorbate; dehydrated sorbitan alkyl esters, such as span; cocamide MEA, cocamide DEA, dodecyl dimethylamine oxide; block copolymers of polyethylene glycol and polypropylene glycol, such as poloxamer; and polyethoxylated tallow amine (PPOEA); poloxamer 188, polyethylene glycol 3350, polyethylene glycol (e.g., PEG3350) or polysorbate (such as polysorbate 80 (PS80) or polysorbate 20 (PS20)). In one embodiment of the present invention, the non-ionic detergent is polysorbate 20 (PS20) or polysorbate 80 (PS80).

A buffer is a mixture of a weak acid and its conjugated base and vice versa, which resists changes in its pH, thereby keeping the pH at a nearly constant value. A variety of buffers can be used in the co-formulations of the present invention, such as histidine-based buffers, phosphate buffers or citrate buffers. Histidine-based buffers are buffers containing histidine. Examples of histidine buffers include histidine chloride, histidine hydrochloride, histidine acetate, histidine phosphate and histidine sulfate.

The invention encompasses co-formulations having any of the specifically recited components (e.g., in the specifically recited concentrations), but wherein the pH of the co-formulation is about 6.5.

In one embodiment of the invention, the co-formulation contains impure β-hexosaminidase, e.g., in an amount of about 0.04 to about 0.17 μg/ml, e.g., when the pH of the co-formulation is less than about 6 or greater than about 6 (e.g., differs by at least 0.5), e.g., 6.5.

For example, the invention includes pharmaceutical co-formulations (e.g., Cemdisiran/Paslimab) comprising: • One or more C5 iRNAs, e.g., as described herein (e.g., Cemdisiran, preferably in Na ⁺ form), e.g., at a concentration of about 20-100, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 mg/ml 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395 or 400 mg/ml); wherein the free acid form content can be increased by adding Na ⁺ form concentration multiplied by 0.9443; • one or more anti-C5 antibodies or antigen-binding fragments thereof (e.g., paslimumab), e.g., at a concentration of about 90 to about 275 mg/ml (e.g. about 90; 91; 92; 93; 94; 95; 96; 97; 98; 99; 100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 147; 7; 148; 149; 150; 151; 152; 153; 154; 155; 156; 157; 158; 159; 160; 161; 162; 163; 164; 165; 167; 168; 169; 170; 171; 172; 173; 174; 175; 176; 177; 178; 179; 180; 181; 182; 183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 211, 220, 242, 274 • a viscosity reducer, such as L-arginine (e.g., L-arginine HCl) (e.g., at a concentration of about 40-140 mM, such as about 50 mM or 90 mM); (e.g. 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96 , 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, or 140 mM); • stabilizers, such as sugars or polyols (e.g., at a concentration of about 0.8 to about 3.6% (w/v), such as about 1%) (e.g., 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6% (w/v)); • non-ionic surfactants, such as polysorbate 80 (PS80) or polysorbate 20 (PS20) (e.g., at a concentration of about 0.025 to about 0.2% (w/v), such as about 0.075% (w/v) a buffer, such as a histidine-based buffer (e.g., at a concentration of about 10 to about 50 mM, such as about 30 mM (e.g., 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47; 48; 49; or 50 mM)); and having a pH of about 5.5 to about 7.0, such as about 6.5; or not less than 0.5 of pH 6.0.

In one embodiment of the invention, a co-formulation (e.g., Cemdisiran/Paslimab) comprises (e.g., such as with detectable β-hexosaminidase, as discussed herein): a double-stranded C5 iRNA conjugated to a tritantral GalNAc moiety; and an anti-C5 antibody or an antigen-binding fragment thereof expressed and isolated by a mammalian host cell comprising β-hexosaminidase, at a pH above or below (different by at least 0.5) 6.0; C5 iRNA (e.g., which is conjugated to a tritantral GalNAc moiety), an anti-C5 antibody or an antigen-binding fragment thereof (e.g., which is expressed and isolated by a mammalian host cell comprising β-hexosaminidase), a buffer, a viscosity reducer, a stabilizer, and a non-ionic surfactant; C5 iRNA (e.g., which is conjugated to a triantennary GalNAc moiety), an anti-C5 antibody or an antigen-binding fragment thereof (e.g., which is expressed and isolated by a mammalian host cell comprising β-hexosaminidase), a histidine-based buffer, L-arginine, a stabilizer, and a non-ionic surfactant; C5 iRNA (e.g., which is conjugated to a triantennary GalNAc moiety), an anti-C5 antibody or an antigen-binding fragment thereof (e.g., which is expressed and isolated by a mammalian host cell comprising β-hexosaminidase), a histidine-based buffer, L-arginine, a sugar or polyol, and a non-ionic surfactant; Cemdisiran, Pazelimumab (e.g., expressed and isolated by mammalian host cells comprising β-hexosaminidase), a histidine-based buffer, L-arginine, a stabilizer, and a non-ionic surfactant, pH about 6.5; Cemdisiran, Pazelimumab (e.g., expressed and isolated by mammalian host cells comprising β-hexosaminidase), a histidine-based buffer, L-arginine, sucrose, and polysorbate 80, pH about 6.5; 100 (±10) mg/mL C5 iRNA, such as Cemdisiran (Na ⁺ form), 100 (±10) mg/mL anti-C5 antibody or antigen-binding fragment thereof, such as paslimumab (e.g., which is expressed and isolated by mammalian host cells comprising β-hexosaminidase), 50 (±10) mM viscosity reducer, such as L-arginine (e.g., L-arginine HCl), 10 (±2) mM buffer, such as histidine-based buffer, 1.0 (±0.2)% stabilizer, such as sucrose, 0.075 (±0.00375)% non-ionic surfactant, such as PS80, pH 6.5; 75 (±7.5) mg/mL C5 iRNA, such as Cemdisiran (Na ⁺ form), 150 (±15) mg/mL anti-C5 antibody or antigen-binding fragment thereof, such as paslimumab (e.g., which is expressed and isolated by mammalian host cells comprising β-hexosaminidase), 75 (±15) mM viscosity reducer, such as L-arginine (e.g., L-arginine HCl), 15 (±3) mM buffer, such as a histidine-based buffer, 1.5 (±0.3)% stabilizer, such as sucrose, 0.1125 (±0.056)% non-ionic surfactant, such as PS80, pH 6.5; 50 (±5) mg/mL C5 iRNA, such as Cemdisiran (Na ⁺ form), 100 (±10) mg/mL anti-C5 antibody or antigen-binding fragment thereof, such as paslimumab (e.g., which is expressed and isolated by mammalian host cells comprising β-hexosaminidase), 75 mM (±15) viscosity reducer, such as L-arginine (e.g., L-arginine HCl), 15 (±3) mM buffer, such as a histidine-based buffer, 1.5 (±0.3)% stabilizer, such as sucrose, 0.1125 (±0.056)% non-ionic surfactant, such as PS80; pH 6.5; 50 (±5) mg/mL C5 iRNA, such as Cemdisiran (Na ⁺ form), 100 (±10) mg/mL anti-C5 antibody or antigen-binding fragment thereof, such as paslimumab (e.g., which is expressed and isolated by mammalian host cells comprising β-hexosaminidase), 75 (±15) mM viscosity reducer, such as L-arginine (e.g., L-arginine HCl), 35 (±7) mM buffer, such as a histidine-based buffer, 1.5 (±0.3)% stabilizer, such as sucrose, 0.1125 (±0.056)% non-ionic surfactant, such as PS80, pH 6.5; 100 (±10) mg/mL C5 iRNA, such as Cemdisiran (Na ⁺ form), 100 (±10) mg/mL anti-C5 antibody or antigen-binding fragment thereof, such as paslimumab (e.g., which is expressed and isolated by mammalian host cells comprising β-hexosaminidase), 50 (±10) mM viscosity reducer, such as L-arginine (e.g., L-arginine HCl), 30 (±6) mM buffer, such as histidine-based buffer, 1 (±0.2)% stabilizer, such as sucrose, 0.075 (±0.00375)% non-ionic surfactant, such as PS80, pH 6.5; 50 (±5) mg/mL C5 iRNA, such as Cemdisiran (Na ⁺ form), 100 (±10) mg/mL anti-C5 antibody or antigen-binding fragment thereof, such as paslimumab (e.g., expressed and isolated by mammalian host cells comprising β-hexosaminidase), 90 (±18) mM viscosity reducer, such as L-arginine (e.g., L-arginine HCl), 30 (±6) mM buffer, such as a histidine-based buffer, 1 (±0.2)% stabilizer, such as sucrose, 0.075 (±0.00375)% non-ionic surfactant, such as PS80, pH 6.5; 100 mg/mL Cemdisiran (Na ⁺ form), 100 mg/mL paslimumab, 50 mM L-arginine (e.g., L-arginine HCl), 30 mM histidine-based buffer, 1% (w/v) sucrose, 0.075% (w/v) PS80, pH 6.5; 50 mg/mL Cemdisiran (Na ⁺ form), 100 mg/mL Paselimab, 90 mM L-arginine (e.g., L-arginine HCl), 30 mM histidine-based buffer, 1% (w/v) sucrose, 0.075% (w/v) PS80, pH 6.5; 100 mg/mL Cemdisiran (Na ⁺ form), 100 mg/mL Paselimab, 50 mM L-arginine (e.g., L-arginine HCl), 10 mM histidine-based buffer, 1.0% Sucrose, 0.075% PS80, pH 6.5; 75 mg/mL Cemdisiran (Na ⁺ form), 150 mg/mL Paselimab, 75 mM L-arginine (e.g., L-arginine HCl), 15 mM histidine-based buffer, 1.5% Sucrose, 0.1125% PS80, pH 6.5; 50 mg/mL Cemdisiran (Na ⁺ form), 100 mg/mL Paselimab, 75 mM L-arginine (e.g., L-arginine HCl), 15 mM histidine-based buffer, 1.5% Sucrose, 0.1125% PS80; pH 6.5; 50 mg/mL Cemdisiran (Na ⁺ form), 100 mg/mL Pazelimumab, 75 mM L-arginine (e.g., L-arginine HCl), 35 mM histidine-based buffer, 1.5% sucrose, 0.1125% PS80, pH 6.5; 100 mg/mL Cemdisiran (Na ⁺ form), 100 mg/mL Pazelimumab, 50 mM L-arginine (e.g., L-arginine HCl), 30 mM histidine-based buffer, 1% sucrose, 0.075% PS80, pH 6.5; 47.2 mg/mL Cemdisiran (free acid form (FAF)) molecule, which may be in any salt form, such as Na ⁺ , 100 mg/mL Pazelimumab, 30 mM histidine, 90 mM L-arginine, 1% (w/v) sucrose, 0.075% (w/v) polysorbate 80 (e.g., super refined grade (SR)), pH 6.5 50 mg/mL Cemdisiran (Na ⁺ form), 100 mg/mL Paszelimumab, 90 mM L-arginine (e.g., L-arginine HCl), 30 mM buffer, such as a histidine-based buffer, 1% stabilizer, such as sucrose, 0.075% PS80, pH 6.5; Optionally, any of the co-formulations described herein further comprises GalNAc or GlcNAc, e.g., about 5% (w/v).

In one embodiment of the invention, the co-formulations of the invention include antibodies and iRNAs in combination with an additional therapeutic agent, such as, for example, anticoagulants, warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux, thrombin inhibitors, argatroban, lepirudin, bivalirudin, dabigatran, anti-inflammatory drugs, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), antihypertensives. , angiotensin converting enzyme inhibitors, immunosuppressants, vincristine, cyclosporine A or methotrexate, the fibrinolytic agent ancrod, E-aminocaproic acid, anticytosine-a1, prostacyclin, defibrotide, lipid-lowering agents, inhibitors of hydroxymethylglutaryl CoA reductase, anti-CD20 agents, rituximab, anti-TNFα agents, infliximab, anti-epileptic agents, magnesium sulfate, C3 inhibitors, and/or antithrombotic agents.

The term "combined with" means providing a co-formulation with (2) one or more additional therapeutic agents (such as methotrexate), which can be formulated as a single composition, for example, for simultaneous delivery, or separately formulated as two or more compositions (e.g., a kit including each component, for example, wherein the other therapeutic agent is in a different formulation). The components administered in combination with each other can be administered to the subject at the same time as the other components or at a different time; for example, each administration can be administered simultaneously (e.g., administered together in a single composition or administered substantially simultaneously during the same administration period), or non-simultaneously at one or more intervals within a given period of time. In addition, the different components administered in combination with each other can be administered to the subject by the same or different routes. Thus, the invention includes co-formulations in combination with another therapeutic agent, and methods of treating or preventing a C5-related disease or disorder (e.g., PNH, MG, or CHAPLE) in a subject by administering to a subject in need thereof a co-formulation of the invention in combination with another therapeutic agent.

The present invention includes co-formulations described herein, wherein the concentration of the antibody and/or iRNA is ±10% of the indicated value; the concentration of the surfactant is ±50% of the indicated value; and/or the concentration or pH of any other excipient (e.g., viscosity reducer, buffer, stabilizer) is ±20% of the indicated value.

In one embodiment of the present invention, the co-formulation of the present invention, • comprises about 0.04 to 0.17 micrograms/ml of β-hexosaminidase (e.g., about 0.04; 0.05; 0.06; 0.06; 0.0605; 0.0605; 0.0605; 0.063; 0.07; 0.07; 0.0765; 0.078; 0.08; 0.14; 0.141; 0.15; 0.1525; 0.166; or 0.17 micrograms/mL (or not more than this amount)); • is a transparent to slightly opalescent liquid; • is substantially free of visible particles; • is colorless to yellow; • Characterized by a ratio of Cemdisiran concentration: Pazerimab concentration of about 1:1, 1:2, 1:3, 1:4, 1:5 or 2:3, e.g. wherein the viscosity is less than about 20 cP or less than about 30 cP at 20°C; • Viscosity < 30 cP (at 20°C) (e.g. about 6, 10, 20 or 30 cP); • Osmotic pressure of 266-706 • a density of about 1.1 or 1.061 g/ml; • a pH of about 6.5 ± 0.2; • a pH above 6, compared to a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml; • a pH of about 1.1 or 1.061 g/ml 6. Cemdisiran degradation at 40°C, 25°C and 2-8°C was significantly reduced; • Cemdisiran purity (%) was about 90.5% according to dIPRP at t=0; 91.1% after 1 month storage at 2-8°C; 90.8% after 3 months storage at 2-8°C; 90% after 6 months storage at 2-8°C; 88.8% after 9 months storage at 2-8°C; 88.7% after 12 months storage at 2-8°C; 89% after 18 months storage at 2-8°C; 89.4% after 24 months storage at 2-8°C; and/or 87.4% after 36 months storage at 2-8°C, for example, wherein the co-formulation is liquid (aqueous) during storage and includes 100 mg/ml Cemdisiran and 100 mg/ml paszelimumab (e.g., at pH 6.0); e.g., wherein the co-formulation comprises about 60.5 ng/ml β-hex; • Exhibits a Cemdisiran purity (%) of approximately 90.8% according to dIPRP at t=0; 90.6% after 1 month of storage at 2-8°C; 90.5% after 3 months of storage at 2-8°C; 89.4% after 6 months of storage at 2-8°C; 88.3% after 9 months of storage at 2-8°C; 87.8% after 12 months of storage at 2-8°C; 87.8% after 18 months of storage at 2-8°C; and/or 87.4% after 24 months of storage at 2-8°C and/or approximately 85.4% after 36 months of storage at 2-8°C, e.g., wherein the co-formulation is liquid (aqueous) during storage and comprises 75 mg/ml Cemdisiran and 150 mg/ml Paszelimumab (e.g., at pH 6.0); for example, wherein the co-formulation includes about 60.5 ng/ml β-hex; • exhibits a single strand purity (%) of Cemdisiran of about 90.5% at t=0 according to dIPRP; 90.2% after 1 month storage at 25°C and 60% RH (relative humidity); 87.8% after 3 months storage at 25°C and 60% RH; 85.1% after 6 months storage at 25°C and 60% RH; 90% after 0.5 month storage at 40°C and 75% RH; 88.9% after 1 month storage at 40°C and 75% RH; 85.8% after 3 months storage at 40°C and 75% RH; for example, wherein the co-formulation is liquid (aqueous) during storage and includes 100 mg/ml Cemdisiran and 100 mg/ml Paszelimab (e.g., at pH 6.0); for example, wherein the co-formulation includes about 60.5 ng/ml β-hex; • After about 48 hours of stirring, the purity (%) of Cemdisiran per dIPRP is about 91.4%, and/or after about 4 freeze-thaw cycles is about 90.7%, for example, wherein the co-formulation is liquid (aqueous) and includes 100 mg/ml Cemdisiran and 100 mg/ml Paszelimab (e.g., at pH 6.0); • The purity (%) of Cemdisiran per dIPRP is about 90.8% at t=0; 88.8% after 1 month storage at 25°C and 60% RH ... 85.9% after 3 months storage at 25°C and 60% RH; 82.3% after 6 months storage at 25°C and 60% RH; 88.9% after 0.5 month storage at 40°C and 75% RH; 87.3% after 1 month storage at 40°C and 75% RH; 82.3% after 3 months storage at 40°C and 75% RH; for example, wherein the co-formulation is liquid (aqueous) during storage and comprises 75 mg/ml Cemdisiran and 150 mg/ml Paszelimumab (e.g., at pH 6.0); for example, wherein the co-formulation comprises about 60.5 or 91 ng/ml β-hex; • exhibits a Cemdisiran purity (%) of about 90.7% according to dIPRP after about 48 hours of agitation and/or about 91.2% after about 4 freeze-thaw cycles, for example, wherein the co-formulation is liquid (aqueous) and comprises 75 mg/ml Cemdisiran and 150 mg/ml Pasqualizumab (e.g., at pH 6.0); • An increase in detectable high molecular weight species (HMW species) of no more than (e.g., within 5%) between 0.050, 0.075, 0.100, 0.125, 0.150, 0.175, or 0.200% after agitation at 250 rpm on an orbital shaker for 48 hours in the presence of 0.025% non-ionic surfactant (e.g., polysorbate 80) (w/v) non-ionic surfactant; for example, wherein the co-formulation includes 50 or 100 mg/mL Cemdisiran and 100 mg/mL Paselimab, such as 100 mg/mL Cemdisiran, 100 mg/mL Paselimab, 50 mM Arginine HCl, 30 mM Histidine, 1% Sucrose, X% PS80, pH 6.5, or 50 mg/mL Cemdisiran, 100 mg/mL Paselimab, 90 mM Arginine HCl, 30 mM Histidine, 1% Sucrose, X% PS80, pH 6.5 (wherein X is about 0.025% to about 0.2% (w/v), such as 0.075%); • exhibits a Cemdisiran purity (%) of about 90.9% according to dIPRP at t=0; at 25°C, 60% about 90.1% after storage at 25°C, 60% RH for 1 month; about 90.9% after storage at 25°C, 60% RH for 3 months; about 90.4% after storage at 25°C, 60% RH for 6 months; about 89.9% after storage at 40°C, 75% RH for 0.5 month; about 89.7% after storage at 40°C, 75% RH for 1 month; and/or about 89.5% after storage at 40°C, 75% RH for 3 months; for example, wherein the co-formulation is liquid (aqueous) during storage and contains 50 mg/ml Cemdisiran and 100 mg/ml Paslimab (pH 6.0 with 5% GlcNAc); for example, wherein the co-formulation includes about 78 ng/ml β-hex; • Cemdisiran purity (%) exhibited by dIPRP at t=0 was about 90.8%; about 90.2% after 1 month storage at 25°C, 60% RH; about 90.8% after 3 months storage at 25°C, 60% RH; about 90.3% after 6 months storage at 25°C, 60% RH; about 89.5% after 0.5 month storage at 40°C, 75% RH; about 89.6% after 1 month storage at 40°C, 75% RH; about 89.1% after 3 months storage at 40°C, 75% RH; for example, wherein the co-formulation is liquid (aqueous) during storage and contains 50 mg/ml Cemdisiran and 100 mg/ml Paszelimumab (pH 6.0 with 5% GalNAc); for example, wherein the co-formulation includes about 78 ng/ml β-hex; • exhibits a Cemdisiran purity (%) of about 90.5% at t=0 according to dIPRP; about 89.9% after 1 month storage at 25°C, 60% RH; about 90.8% after 3 months storage at 25°C, 60% RH; about 90.4% after 6 months storage at 25°C, 60% RH; about 90.1% after 0.5 month storage at 40°C, 75% RH; about 89.6% after 1 month storage at 40°C, 75% RH; about 89.9% after 3 months storage at 40°C, 75% RH; for example, wherein the co-formulation is liquid (aqueous) during storage and contains 100 mg/ml Cemdisiran and 100 mg/ml paszelimumab (pH 6.0 with 5% GalNAc); for example, wherein the co-formulation includes about 78 ng/ml β-hex; and/or • Cemdisiran purity (%) exhibited by dIPRP at t=0 was about 91.1%; about 90% after 1 month storage at 25°C, 60% RH; about 91% after 3 months storage at 25°C, 60% RH; about 90.7% after 6 months storage at 25°C, 60% RH; about 90% after 0.5 month storage at 40°C, 75% RH; about 89.7% after 1 month storage at 40°C, 75% RH; about 91.7 ...90.7% after 1 month storage at 40°C, 75% RH; about 90.7% after 1 month storage at 40°C, 75% RH; about 90.7% after 1 month storage at 40°C, 75% RH; about 90.7% after 1 month storage at 40°C, 75% RH. about 89.9% after 3 months storage at RH; for example, wherein the co-formulation is liquid (aqueous) during storage and contains 100 mg/ml Cemdisiran and 100 mg/ml Paszelimumab (pH 6.0 with 5% GalNAc); for example, wherein the co-formulation includes about 78 ng/ml β-hex; Combination therapy dosing regimen of anti -C5 and C5 iRNA

The invention includes methods comprising administering an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA (e.g., in the form of a co-formulation comprising the antibody or fragment and the iRNA (e.g., as described herein), to a subject in need thereof who has a disease, disorder or condition associated with C5, in an amount and frequency that achieves a safe and effective therapeutic response (combination therapy of the invention)).

In one embodiment, the invention relates to the administration of one or more anti-C5 antibodies or antigen-binding fragments thereof (e.g., Paseritumab) in combination with one or more C5 iRNAs (e.g., Cemdisiran). Preferably, the administration is in a co-formulation of the invention (as discussed herein), e.g., 100:100 or 50:100.

In general, co-formulations comprising Cemdisiran and Pazelimumab may be referred to herein in the following form: 100: 100, 75: 150, or 50: 100. In such notation, when referring to such co-formulations, the first number represents mg/ml of Cemdisiran and the second number represents mg/ml of Pazelimumab.

A "dosing regimen" or "combination therapy dosing regimen" refers to a method for treating or preventing a disease or disorder or condition associated with C5 (preferably PNH) which comprises administering an amount of the combination therapy of the invention at a frequency as discussed herein.

For example, the present invention encompasses methods of administering an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, comprising introducing the agents into an individual's body, e.g., by injection (e.g., by subcutaneous injection or intravenous infusion), e.g., according to any of the dosing regimens discussed herein, wherein the dosing regimen schedule is, for example, about 400 mg of an anti-C5 antibody or antigen-binding fragment (e.g., Paslimumab) subcutaneously administered approximately every 2-4 weeks (±3, 4, 5, 6, or 7 days) and about 200 mg of an iRNA (e.g., Cemdisiran) subcutaneously administered approximately every 4 weeks (±3, 4, 5, 6, or 7 days).

Therefore, the present invention provides a method for treating or preventing a C5-related disease or condition (e.g., dry AMD or MG; preferably PNH) in an individual in need thereof, comprising administering an anti-C5 antibody or antigen-binding fragment thereof ("anti-C5 Ab") and a C5 iRNA to the individual as follows: (i) one or more doses of about 400 mg of anti-C5 Ab (e.g., Paselimab) subcutaneously, and about 200 mg of C5 iRNA (e.g., Cemdisiran) subcutaneously; (ii) about 400 mg of anti-C5 Ab (e.g., Paselimab) subcutaneously approximately every 2 weeks, and about 200 mg of C5 iRNA (e.g., Cemdisiran) subcutaneously approximately every 4 weeks (Q4W). Preferably, a single injection of a co-formulation comprising anti-C5 Ab and C5 iRNA is administered every 4 weeks (Q4W), and a separate additional injection of anti-C5 Ab instead of C5 iRNA is administered every two weeks (Q2W); (iii) about 400 mg of anti-C5 Ab (e.g., Pazlimab) is administered subcutaneously about every 4 weeks, and about 200 mg of C5 iRNA (e.g., Cemdisiran) is administered subcutaneously about every 4 weeks, preferably a single injection of a co-formulation comprising anti-C5 Ab and C5 iRNA about every 4 weeks; or (iv) about 400 mg of anti-C5 Ab (e.g., Pazlimab) and about 200 mg of C5 iRNA (e.g., Cemdisiran) are administered subcutaneously about every 4 weeks in a 50:100 co-formulation.

In one embodiment of the invention, a subject is simultaneously administered: • about 400 mg of an anti-C5 antibody or antigen-binding fragment (e.g., Paslimab) subcutaneously approximately every 2-4 weeks (±3, 4, 5, 6, or 7 days); and • about 200 mg of an iRNA (e.g., Cemdisiran) subcutaneously approximately every 2-4 weeks (e.g., 4 weeks) (±3, 4, 5, 6, or 7 days).

The present invention also includes embodiments in which the following are administered to an individual simultaneously: • About 400 mg of anti-C5 antibody or antigen-binding fragment is administered subcutaneously approximately every 2 weeks (±3, 4, 5, 6 or 7 days); and • A dose of 200 mg of C5 iRNA is administered subcutaneously every 4 weeks (±3, 4, 5, 6 or 7 days).

The invention also includes embodiments in which the subject is simultaneously administered: • about 400 mg of an anti-C5 antibody or antigen-binding fragment subcutaneously about every 4 weeks (±3, 4, 5, 6, or 7 days); and • a 200 mg dose of C5 iRNA subcutaneously administered every 4 weeks (±3, 4, 5, 6, or 7 days). Switching from Paszelimab Monotherapy

For example, as described herein, for an individual who has previously received pasorimab monotherapy, a dosing regimen comprising anti-C5 and C5 iRNA (e.g., for the treatment of a C5-related disease or disorder or condition, such as PNH) may be referred to herein as a "pasorimab monotherapy switch" regimen.

In one embodiment of the invention, the regimen is as follows: On day 1 (7 to 8 days after the last dose of paslimab monotherapy), or when the next dose of paslimab monotherapy is due, the individual begins to receive (1) paslimab 400 mg SC and cemdisiran 200 mg SC Q4W every 4 weeks (Q4W); or (2) paslimab 400 mg SC and cemdisiran 200 mg SC Q4W every 2 weeks (Q2W).

Pazelimab monotherapy includes treatment with pazelimab as the sole C5-specific inhibitor or more specifically an anti-C5 antibody or antigen-binding fragment (e.g., without concurrent use of pazelimab and eculizumab) for the treatment of a disease or disorder or condition associated with C5 (preferably PNH). In one embodiment of the invention, prior to receiving a combination therapy as discussed herein, SC 400 mg of an anti-C5 antibody or antigen-binding fragment about every 2, 3, or 4 weeks, and SC about 400 mg of a C5 iRNA about every 4 weeks, the individual has received a dosing regimen according to the following: (i) one or more doses of about 30 mg/kg of antigen-binding protein intravenously (IV); then (ii) one or more doses (e.g., weekly) of about 800 mg of pasorizumab subcutaneously (SC); for example, wherein the individual has PNH; or, (a) one or more doses, preferably only one dose, of about 30 mg/kg of pasorizumab intravenously (IV); then (b) one or more doses (e.g., weekly) of 10 mg/kg of pazelimab [may be referred to as the maintenance phase], For example, where the individual has CHAPLE Or, (a) one or more doses, preferably only one dose, of about 30 mg/kg of pazelimab intravenously (IV); and (b) one or more doses (e.g., weekly) of pazelimab subcutaneously (SC) according to the following: - body weight (BW) < about 10 kg: about 125 mg; - BW≧10 kg and < about 20 kg: about 200 mg; - BW≧20 kg and < about 40 kg: about 350 mg; - BW≧40 kg and < about 60 kg: about 500 mg; and - BW≧60 kg: about 800 mg; [may be referred to as the maintenance phase] For example, where the individual has CHAPLE; Wherein, the subject has received one or more such doses and is switched to the combination therapy at any point (e.g., from a maintenance period). In one embodiment of the invention, the subject begins receiving the combination of anti-C5 and C5 iRNA on the day when the next dose of paslimab monotherapy is due, and also stops the monotherapy at that time. For example, a combination in which an individual switches from pazelimumab monotherapy and receives a first dose after receiving: (i) one or more doses of about 800 mg of pazelimumab subcutaneously (SC); (ii) one or more doses of about 30 mg/kg of pazelimumab intravenously (IV); (iii) one or more doses of about 125 mg of pazelimumab subcutaneously (SC); (iv) one or more doses of about 200 mg of pazelimumab subcutaneously (SC); (v) one or more doses of about: 350 mg of pazelimumab subcutaneously (SC); (vi) one or more doses of about: 500 mg of pazelimumab subcutaneously (SC); (vii) one or more doses of about 800 mg of pazelimumab subcutaneously (SC); (viii) one or more doses of 10 mg/kg paszelimumab subcutaneously (SC), For example, wherein the first dose of the combination is received on a date that is about 1 week after the dose labeled (i), (ii), (iii), (iv), (v), (vi), (vii), or (viii) is due or the last dose of paszelimumab monotherapy was received.

In one embodiment of the invention, a subcutaneous monotherapy dose of paslimumab is administered in a formulation comprising about: • 161-274 mg/ml or more paslimumab, and • a pharmaceutically acceptable carrier comprising: a buffer; L-arginine; water; and optionally an oligosaccharide (e.g., sucrose, mannitol, dextrose, glycerol, TMAO (trimethylamine N-oxide), trehalose, ethylene glycol, glycine betaine, xylitol or sorbitol); and optionally a non-ionic detergent (e.g., polysorbate-20, polysorbate-80), pH is at most about 5.8, 6.1, or 5.5-6.1; and the viscosity at 20°C is about 6.8, about 9.6, about 11.9, about 13.2, about 16.7, about 20.6, about 33.0, about 48.4, about 13.2-16.7, or about 6.8-48.4. The intravenous dose of paszelimumab monotherapy can be administered after the formulation is introduced into an intravenous aqueous solution (e.g., 0.9% saline).

Treatment-naive or sclerostin inhibitor-naive patients have never or have not recently (e.g., not within the last 1, 2, 3, 4, 5, or 6 months or not within at least about 4 or 5 half-lives of the last sclerostin inhibitor they received) received sclerostin inhibitor therapy (e.g., eculizumab, ravulizumab, paslimab).

In one embodiment of the invention, a C5-related disease or disorder or condition (preferably PNH) in a subject not treated with a complement inhibitor is treated by a method comprising administering: • Day 1: Pazelimumab as a single loading dose of 30 mg/kg intravenously (IV) and (e.g., followed by a delay of at least about 30 minutes, as appropriate) 400 mg subcutaneously (SC), and Cemdisiran 200 mg SC (combination maintenance dose); • Starting on Day 29: Pazelimumab 400 mg SC every 4 weeks (q4W) and Cemdisiran 200 mg SC q4W (e.g., as a Cemdisiran/Pazelimumab co-formulation).

In one embodiment of the invention, a C5-related disease or disorder or condition (preferably PNH) is treated in a subject not treated with a complement inhibitor by a method comprising administering: (i) a single loading dose of about 30 mg/kg intravenous (IV) anti-C5 antibody or antigen-binding fragment (preferably paslimab) on about day 1, followed by about 400 mg subcutaneous (SC) anti-C5 antibody or fragment and about 200 mg SC of C5 iRNA (preferably Cemdisiran); and (ii) starting on about day 29, about 400 mg SC dose of anti-C5 antibody or fragment Q4W and about 200 mg SC dose of C5 iRNA Q4W.

During a switch from eculizumab or ravelizumab to a therapy containing an anti-C5 Ab (e.g., pazelimab) and a C5 iRNA (e.g., cemdisiran), an additional dose of pazelimab (e.g., a dose of 30 or 60 mg/kg IV) may be administered, for example, in cases where potential adverse events (AEs) due to large drug-target-drug (DTD) immune complexes are suspected or have occurred and/or if systemic corticosteroids are administered for type III hypersensitivity reactions. This additional dose will establish conditions of pazelimab excess in the circulation, thereby minimizing the risk of further immune complex formation. Switching from eculizumab therapy

For example, a dosing regimen for an individual who has previously received eculizumab as described herein may be referred to herein as an "eculizumab switch" regimen. Preferably, the individual is being treated for a disease or disorder or condition associated with C5, such as PNH.

In one embodiment of the present invention, the eculizumab switching regimen has the following lead-in loading phase and switching phase:

Initially, subjects continued to receive background therapy with eculizumab at their usual dose/frequency, and cemdisiran was introduced alone as follows: • On Day 1 (the subject's scheduled eculizumab dosing day): cemdisiran 200 mg SC and eculizumab ≥ 900 mg IV (the subject's usual dose). NOTE: Eculizumab may be administered up to 2 days after Cemdisiran if not administered with Cemdisiran on Day 1; • On Day 15 (±2 days), for subjects receiving eculizumab q14 days (labeled dosing schedule): labeled eculizumab dose [for subjects receiving eculizumab more frequently than q14 days: patients dose within 2 days of their usual scheduled dose]; Switching • On Day 29 (Week 4 or when next dose of eculizumab is due or 2 weeks later or approximately 1-2 half-lives of eculizumab): Pazelimab 60 mg/kg IV loading dose, and (e.g., followed by a delay of at least about 30 minutes as appropriate) Pazelimab 400 mg SC and Cemdisiran 200 mg SC (e.g., as a Cemdisiran/Pazelimab co-formulation); and • Starting from Day 57 (Week 8; or 4 weeks later): Pazelimab 400 mg SC and Cemdisiran 200 mg SC q4W maintenance regimen (±7 days) (e.g., as a Cemdisiran/Pazelimab co-formulation) [may be referred to as the maintenance period]

In one embodiment of the invention, the half-life of eculizumab (e.g., in an individual with PNH) is about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days, for example, about 11 days (Wijnsma et al ., Pharmacology, Pharmacokinetics and Pharmacodynamics of Eculizumab, and Possibilities for an Individualized Approach to Eculizumab. Clin Pharmacokinet. 2019 Jul;58(7):859-874; Al-Ani et al ., Eculizumab in the management of paroxysmal nocturnal hemoglobinuria: patient selection and special considerations. Ther Clin Risk Manag. 2016 Aug 1;12:1161-70).

In one embodiment of the present invention, the dosing regimen comprises: (i) an initial dose (on day 1; e.g., on the day or up to 2 days before the next dose of eculizumab is due) of intravenous administration of eculizumab (at the individual's usual dose, e.g., ≧ about 900 mg) and subcutaneous administration of about 200 mg of C5 iRNA; (ii) a second dose of eculizumab up to about 14 days (±2 days) later (at the individual's usual dose, e.g., ≧ about 900 mg); (iii) on about day 29 (week 4): intravenous (IV) administration of anti-C5 Ab at a dose of about 60 mg/kg, followed by subcutaneous administration of anti-C5 Ab at a dose of about 400 mg and subcutaneous administration of C5 iRNA at a dose of about 200 mg; and (iv) On day 57 (week 8) and thereafter, anti-C5 Ab is administered subcutaneously at a dose of about 400 mg approximately every 4 weeks (±3, 4, 5, 6, or 7 days), and C5 iRNA is administered subcutaneously at a dose of about 200 mg approximately every 4 weeks (±3, 4, 5, 6, or 7 days).

The prescribed dosing regimen for treatment of PNH with eculizumab (e.g., for individuals 18 years of age or older) is as follows: • 600 mg weekly for the first 4 weeks, followed by • a fifth dose of 900 mg 1 week later, followed by • 900 mg every 2 weeks thereafter.

The dosing regimen for treating aHUS with eculizumab is as follows: • 900 mg weekly for the first 4 weeks, followed by • a fifth dose of 1200 mg 1 week later, followed by • 1200 mg every 2 weeks thereafter.

Eculizumab is prescribed for the treatment of generalized myasthenia gravis or neuromyelitis optica spectrum as follows: • 900 mg weekly for the first 4 weeks, followed by • a fifth dose of 1200 mg 1 week later, followed by • 1200 mg every 2 weeks thereafter. See Soliris® Prescribing Information. In one embodiment of the invention, the individual has previously received treatment with eculizumab for at least 12 weeks.

In one embodiment of the invention, eculizumab is administered to a subject in an amount taken from a pharmaceutical formulation comprising 300 mg of eculizumab, polysorbate 80 (6.6 mg) (plant source), sodium chloride (263.1 mg), sodium dihydrogen phosphate (53.4 mg), sodium dihydrogen phosphate (13.8 mg), and Water for Injection, USP, pH 7, in a volume of 30 mL. See Soliris® Prescribing Information. Switching from Ravelizumab Therapy

For example, a dosing regimen for an individual who has previously received Ravelizumab as described herein may be referred to herein as a "Ravelizumab switch" regimen. Preferably, the individual is being treated for a disease or disorder or condition associated with C5, such as PNH.

In one embodiment of the invention, the Revlizumab switching regimen is as follows: • On Day 1 (4 weeks after the last Revlizumab administration): Cemdisiran 200 mg SC; • On Day 29 or 4 weeks later or 1-2 half-lives of Revlizumab: Pazelimab 60 mg/kg single IV loading dose, and (e.g., followed by a delay of at least about 30 minutes as appropriate) Pazelimab 400 mg SC and Cemdisiran 200 mg SC (e.g., as a Cemdisiran/Pazelimab co-formulation); and • Starting on Day 57 or 4 weeks later or 1-2 half-lives of Revlizumab: start Pazelimab 400 mg SC q4W and Cemdisiran 200 mg SC (e.g. as a Cemdisiran/Pazerimab co-formulation) q4W maintenance regimen.

In one embodiment of the invention, the half-life of ravulizumab (e.g., in an individual with PNH) is about 32 days (Stern et al ., Ravulizumab: a novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria. Ther Adv Hematol. 2019 Sep 10;10:2040620719874728；Lee et al ., Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb 7;133(6):530-539；Lee et al ., Immediate, complete, and sustained inhibition of C5 with ALXN1210 reduces complement-mediated hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH): interim analysis of a dose-escalation study [abstract]. Blood. 2016;128(22). Abstract 2428).

In one embodiment of the invention, a subject is treated for a C5-related disease or disorder or condition (preferably PNH) wherein the subject has previously received Ravelizumab (e.g., according to a prescribed dosing regimen) and is switching to a treatment regimen using a different anti-C5 antibody or antigen-binding fragment (anti-C5 Ab) (preferably Pasirimab) and C5 iRNA (C5 iRNA) (preferably Cemdisiran) by administering: (i) C5 iRNA 200 mg SC on Day 1 (e.g., 4 weeks (±7 days) or 26 days (±7 days) or 27 days (±7 days) or 28 days (±7 days) after the last administration of Ravelizumab); (ii) a single IV loading dose of 60 mg/kg anti-C5 antibody on approximately Day 29. This IV loading dose may be followed by a 30-minute observation period. The IV dose is followed by an additional loading dose of anti-C5 Ab 400 mg SC and C5 iRNA 200 mg SC; (iii) on approximately day 57, a maintenance regimen of anti-C5 Ab 400 mg SC and C5 iRNA 200 mg SC is initiated, which may be followed by, (iv) approximately every 4 weeks thereafter.

The loading dose of ravulizumab on day 1 can be determined based on the patient's body weight (≥40 kg to <60 kg, 2400 mg IV; ≥60 kg to <100 kg, 2700 mg IV; ≥100 kg, 3000 mg IV). The first maintenance dose, administered 2 weeks after the loading dose, is as follows: (≥40 kg to <60 kg, 3000 mg IV; ≥60 kg to <100 kg, 3300 mg IV; ≥100 kg, 3600 mg IV). Thereafter, the maintenance dose should be administered IV Q8W (±7 days).

In adult patients weighing 40 kg or more with PNH or aHUS, for example, the subcutaneous maintenance dose of ravlizumab is 490 mg once weekly. The subcutaneous dosing schedule allows for occasional deviations of ± 1 day from the scheduled dosing day, but subsequent doses should be administered according to the original schedule.

The dosing regimen for ravulizumab in the treatment of PNH is as follows: • Patients weighing 5 to less than 10 kg, a loading dose of 600 mg, and a maintenance dose of 300 mg every 4 weeks; • Patients weighing 10 to less than 20 kg, a loading dose of 600 mg, and a maintenance dose of 600 mg every 4 weeks; • Patients weighing 20 to less than 30 kg, a loading dose of 900 mg, and a maintenance dose of 2,100 mg every 8 weeks; • Patients weighing 30 to less than 40 kg, a loading dose of 1200 mg, and a maintenance dose of 2,700 mg every 8 weeks; • Patients weighing 40 to less than 60 kg, a loading dose of 2,400 mg, and a maintenance dose of 3,000 mg every 8 weeks. mg maintenance dose; • Patients weighing 60 to less than 100 kg, a loading dose of 2,700 mg, and a maintenance dose of 3,300 mg every 8 weeks; and • Patients weighing 100 kg or more, a loading dose of 3,000 mg, and a maintenance dose of 3,600 mg every 8 weeks. See Ultomiris® Prescribing Information.

In adult patients with PNH who weigh 40 kg or more, the subcutaneous revlizumab maintenance dose may be 490 mg once weekly. Patients who are not currently receiving revlizumab or eculizumab and weigh ≥40 kg at the start of treatment may initiate subcutaneous doses of revlizumab approximately 2 weeks after the intravenous revlizumab loading dose. Patients who are currently being treated with eculizumab and weigh ≥40 kg at the time of the next scheduled eculizumab dose may initiate subcutaneous doses of revlizumab approximately 2 weeks after the intravenous revlizumab loading dose. Patients currently treated with intravenous (IV) revlizumab may initiate subcutaneous revlizumab approximately 8 weeks after the last IV maintenance dose of revlizumab. In one embodiment of the invention, the individual has previously received revlizumab for at least 24 weeks. Table C. Summary of Eculizumab and Revlizumab Switching Regimens Patients switching from eculizumab Patients switching from ravulizumab Day 1 of conversion Introducing Cemdisiran: 200 mg SC alone vs. eculizumab IV* Ravelizumab IV at the indicated weight-based dose Day 15 ( Week 2 ) Eculizumab IV Day 29 ( Week 4 ) Pazelimumab 60 mg/kg IV loading dose, followed by Pazelimumab 400 mg SC and Cemdisiran 200 mg SC on the same day, and thereafter Pazelimumab 400 mg SC and Cemdisiran 200 mg SC Q4W Introducing Cemdisiran: Cemdisiran 200 mg SC Day 57 ( Week 8 ) (See above) Pazelimumab 60 mg/kg IV loading dose, followed by Pazelimumab 400 mg SC and Cemdisiran 200 mg SC on the same day, and thereafter Pazelimumab 400 mg SC and Cemdisiran 200 mg SC Q4W * For example, 900 mg of eculizumab (IV)

As discussed, the subject may have previously received pazelimab monotherapy, e.g., at a dose of about 800 mg subcutaneously (SC) every 1, 2, 3, or 4 weeks (which may have been preceded by a loading dose of pazelimab, e.g., intravenously), or revlizumab or eculizumab, e.g., according to a prescribed dosing regimen. Patients who have previously received pazelimab monotherapy, revlizumab, or eculizumab may be at any stage of the antibody dosing regimen prior to switching to a combination therapy of the invention. For example, the subject may have received one or more loading doses and/or one or more maintenance doses of eculizumab. In one embodiment of the invention, when the subject is switched from eculizumab or ravulizumab or another anti-C5 antibody or antigen-binding fragment thereof, the subject receives an intravenous loading dose of paszelimab (e.g., 30 mg/kg or 60 mg/kg) and/or a single SC dose of cemdisiran (e.g., 200 mg) prior to or on the same day as starting treatment with a monthly regimen of 400 mg paszelimab and 200 mg cemdisiran. The switching period reduces the risk of large DTD (drug-target-drug) immune complex formation of eculizumab-C5-pazelimab during the switch from eculizumab to the pazelimab + cemdisiran combination or reduces the risk of immune complex formation of revulizumab-C5-pazelimab during the switch from ravelizumab to the pazelimab + cemdisiran combination.

In cases where potential adverse events [AEs] are suspected to be due to large DTD (drug-target-drug) immune complexes and/or systemic corticosteroids are administered for type III hypersensitivity reactions, an additional dose of anti-C5 antibody or antigen-binding fragment (preferably depazelimab) at approximately 30 mg/kg IV may be included. This additional dose may establish conditions of excess depazelimab in the circulation, thereby minimizing the risk of further immune complex formation.

Therefore, the present invention includes a method for treating or preventing a C5-related disease or condition (preferably PNH) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of Pazelimumab and a C5 iRNA (preferably Cemdisiran), wherein the individual has previously received a regimen comprising an antibody or antigen-binding fragment thereof that does not compete with Pazelimumab for binding to C5 (a non-competitive antibody or antigen-binding fragment thereof (N/C Ab), such as eculizumab or ravulizumab), wherein the individual is administered: (i) an intravenous loading dose of Pazelimumab (e.g., 60 mg/kg or 30 mg/kg), and a dose of Pazelimumab 400 mg SC Q4W and Cemdisiran 200 mg SC Q4W; then (2) Starting approximately 4 weeks thereafter (and continuing every 4 weeks thereafter), pazelimumab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W; or (1) One dose of C5 iRNA (e.g., 200 mg SC) approximately 4 weeks after a dose of N/C Ab has been administered and before an intravenous loading dose of pazelimumab (e.g., 60 mg/kg or 30 mg/kg), and one dose of pazelimumab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W; then (2) Starting approximately 4 weeks thereafter (and continuing every 4 weeks thereafter), pazelimumab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W; or (1) On the day the N/C Ab dose expires, a dose of C5 iRNA (e.g., Cemdisiran) and a noncompetitive antibody or fragment (N/C Ab); (2) On the day the dose expires, the next dose of N/C Ab; (3) After approximately 1-2 half-lives of the N/C Ab or when the next dose of N/C Ab expires, a 60 mg/kg IV loading dose of Pazelimumab, and 400 mg SC Pazelimumab and 200 mg SC Cemdisiran; (4) Starting 4 weeks thereafter (and continuing every 4 weeks thereafter), 400 mg SC Pazelimumab and 200 mg SC Cemdisiran Q4W; Or (1) On the day the N/C Ab dose expires, the next dose of N/C Ab; (2) On the day the N/C Ab dose expires, the next dose of N/C Ab; (3) After approximately 1-2 half-lives of the N/C Ab or when the next dose of N/C Ab expires, a 60 mg/kg IV loading dose of Pazelimumab, and 400 mg SC Pazelimumab and 200 mg SC Cemdisiran Q4W; (4) Starting 4 weeks thereafter (and continuing every 4 weeks thereafter), 400 mg SC Pazelimumab and 200 mg SC Cemdisiran Q4W; Ab approximately 1-2 half-lives from the last dose; or on the day the next dose of N/C Ab is due; or after half the interval between doses of N/C Ab, a dose of C5 iRNA; (2) approximately another 1-2 half-lives of N/C Ab, a loading dose of 60 mg/kg IV of pazerimab, 400 mg SC of pazerimab, and 200 mg SC of cemdisiran; and (3) beginning 4 weeks thereafter (and continuing every 4 weeks thereafter), 400 mg SC of pazerimab Q4W and 200 mg SC of cemdisiran Q4W.

In general, the non-repeated initial dose or doses may be referred to as the "loading" dose, and the repeated subsequent doses may be referred to as the "maintenance" dose.

A dosing regimen comprising monthly doses of an anti-C5 antibody or antigen-binding fragment thereof (e.g., Pasqualizumab; e.g., about 400 mg) and a C5 iRNA (e.g., Cemdisiran; e.g., about 200 mg) can be referred to as a q4w or Q4W regimen.

A dosing regimen comprising a 2-week dose (e.g., about 400 mg) of an anti-C5 antibody or antigen-binding fragment thereof and a monthly dose (e.g., about 200 mg) of C5 iRNA can be referred to as a q2w or Q2W regimen.

In one embodiment of the present invention, the term "4 weeks" or "month" refers to about 28, 29 or 30 days (± 3, 4, 5, 6 or 7 days).

In one embodiment of the present invention, the term "2 weeks" refers to about 14 days (± 3, 4, 5, 6 or 7 days).

Anti-C5 antibody or antigen-binding fragment thereof 400 mg SC Q4W refers to subcutaneous administration of about 400 mg of the antibody or fragment (e.g., paslimab) approximately monthly, 4 weeks, or 28 days (± 3, 4, 5, 6, or 7 days).

Anti-C5 antibody or antigen-binding fragment thereof 400 mg SC Q2W refers to subcutaneous administration of about 400 mg of the antibody or fragment (e.g., paslimab) approximately every 2 weeks or 14 days (± 3, 4, 5, 6, or 7 days).

C5 iRNA 200 mg SC Q4W refers to 200 mg of iRNA (eg, Cemdisiran) administered subcutaneously approximately every 4 weeks or 28 days (± 3, 4, 5, 6, or 7 days).

As indicated herein, any dosing event (e.g., where multiple doses of a drug are involved) may be followed by an observation period of 30 minutes to 2 hours after the last dose, or any longer at the discretion of the treating physician, without adverse events being likely to occur. Typically, when an individual receives an intravenous dose and one or more subcutaneous doses on a particular day, the intravenous dose is administered first; however, the scope of the invention includes embodiments in which the doses are administered in any order, such as SC then IV then SC.

In one embodiment of the invention, an individual receiving a combination therapy of an anti-C5 Ab and a C5 iRNA achieves or achieves and maintains one or more of the following while receiving treatment: • Hemoglobin stabilization; • No red blood cell transfusion; • No accumulation of detectable and/or clinically significant amounts of a drug-target-drug complex (e.g., paslimab-C5-paslimab); • No accumulation of detectable and/or clinically significant amounts of an eculizumab-C5-paslimab complex, for example if the individual is switched from eculizumab treatment to the combination therapy; • No adverse events due to large DTD complexes, such as rash, fever, malaise, rash, or polyarthritis were experienced; • No decrease in hemoglobin ≧2 g/dL; • No breakthrough hemolysis; CH50 levels in the blood were completely suppressed relative to baseline before treatment and/or during any breakthrough hemolysis events; • Fatigue improved relative to before treatment; • FACIT-fatigue score improved by >5 points relative to before treatment; • Physical functioning score on the European was improved; • EORTC QLQ-C30: Quality of Life Questionnaire; relative to before treatment, core 30 items (EORTC QLQ-C30); • GHS/QoL (global health status/QOL scale (GHS)) improved relative to before treatment; • Lactate dehydrogenase (LDH) decreased relative to before treatment; • Relative to before treatment, LDH reaches ≤1.5 × upper limit of normal (ULN); • Achieve and maintain LDH ≤1.0 × ULN; • Relative to before treatment, blood bilirubin level decreases; • Relative to before treatment, reticulocyte count decreases; • Relative to before treatment, alternative pathway hemolytic activity assay (AH50) decreases; • Relative to before treatment, PNH erythrocytes and/or granulocytes decrease; • Relative to before treatment, fatigue, shortness of breath, muscle weakness, headache, abdominal pain, back/leg pain, chest discomfort, difficulty sleeping, difficulty thinking clearly and/or difficulty swallowing are improved; • Relative to before treatment, renal function measured by estimated glomerular filtration rate (eGFR) is improved; • A decrease in free hemoglobin in the blood compared to before treatment; and/or • An increase in hemoglobin levels compared to before treatment.

In one embodiment of the present invention, an individual receiving a combination therapy of anti-C5 Ab and C5 iRNA achieves or achieves and maintains one or more of the following while receiving treatment: • For example, by about 2 weeks after the start of treatment, when the q4w regimen is used, the FACIT-fatigue score gain is about 13; or when the q2w regimen is used, the gain is about 11; • For example, by about 4 weeks after the start of treatment, when the q4w regimen is used, the FACIT-fatigue score gain is about 8; or when the q2w regimen is used, the gain is about 8; • For example, by about 8 weeks after the start of treatment, when the q4w regimen is used, the FACIT-fatigue score gain is about 11; or when the q2w regimen is used, the gain is about 7; • For example, by about 12 weeks after the start of treatment, the FACIT-fatigue score gain was about 11 with the q4w regimen, or about 8 with the q2w regimen; • For example, by about 16 weeks after the start of treatment, the FACIT-fatigue score gain was about 12 with the q4w regimen, or about 9 with the q2w regimen; • For example, by about 20 weeks after the start of treatment, the FACIT-fatigue score gain was about 11 with the q4w regimen, or about 4 with the q2w regimen; • For example, by about 24 weeks after the start of treatment, the FACIT-fatigue score gain was about 12 with the q4w regimen, or about 11 with the q2w regimen; • For example, by about 28 weeks after the start of treatment, the FACIT-fatigue score gain was about 11 when the q4w regimen was used, or about 9 when the q2w regimen was used; • For example, at about 2 weeks after the start of treatment, the EORTC-QLQ-C30 physical function score gain was about 23 when the q4w regimen was used, or about 14 when the q2w regimen was used; • For example, at about 4 weeks after the start of treatment, the EORTC-QLQ-C30 physical function score gain was about 19 when the q4w regimen was used, or about 13 when the q2w regimen was used; • For example, at about 8 weeks after the start of treatment, the EORTC-QLQ-C30 physical function score gain was about 22 when the q4w regimen was used, or about 14 when the q2w regimen was used; • For example, at about 12 weeks after the start of treatment, when the q4w regimen is adopted, the EORTC-QLQ-C30 physical function score gain is about 20, or when the q2w regimen is adopted, the gain is about 17; • For example, at about 16 weeks after the start of treatment, when the q4w regimen is adopted, the EORTC-QLQ-C30 physical function score gain is about 19, or when the q2w regimen is adopted, the gain is about 14; • For example, at about 20 weeks after the start of treatment, when the q4w regimen is adopted, the EORTC-QLQ-C30 physical function score gain is about 23, or when the q2w regimen is adopted, the gain is about 11; • For example, at about 24 weeks after the start of treatment, when the q4w regimen is used, the EORTC-QLQ-C30 physical function score gain is about 20, or when the q2w regimen is used, the gain is about 15; • For example, at about 28 weeks after the start of treatment, when the q4w regimen is used, the EORTC-QLQ-C30 physical function score gain is about 24, or when the q2w regimen is used, the gain is about 20; • For example, as of about 2 weeks after the start of treatment, when the q4w regimen is used, the EORTC-QLQ-C30 GHS/QoL score gain is about 15, or when the q2w regimen is used, the gain is about 14; • For example, as of about 4 weeks after the start of treatment, when the q4w regimen is used, the EORTC-QLQ-C30 The GHS/QoL score gain is about 10, or about 15 when the q2w regimen is adopted; • For example, by about 8 weeks after the start of treatment, when the q4w regimen is adopted, the EORTC-QLQ-C30 GHS/QoL score gain is about 9, or when the q2w regimen is adopted, the gain is about 9; • For example, by about 12 weeks after the start of treatment, when the q4w regimen is adopted, the EORTC-QLQ-C30 GHS/QoL score gain is about 11, or when the q2w regimen is adopted, the gain is about 12; • For example, by about 16 weeks after the start of treatment, when the q4w regimen is adopted, the EORTC-QLQ-C30 GHS/QoL score gain is about 12, or when the q2w regimen is adopted, the gain is about 8; • For example, by about 20 weeks after the start of treatment, the EORTC-QLQ-C30 GHS/QoL score gain was about 17 when the q4w regimen was used, or about 6 when the q2w regimen was used; • For example, by about 24 weeks after the start of treatment, the EORTC-QLQ-C30 GHS/QoL score gain was about 15 when the q4w regimen was used, or about 13 when the q2w regimen was used; • For example, by about 28 weeks after the start of treatment, the EORTC-QLQ-C30 GHS/QoL score gain was about 14 when the q4w regimen was used, or about 13 when the q2w regimen was used; • For example, by week 2 after the start of treatment, for example, when the q4w regimen was used, the FACIT-Fatigue score was about 45 (±4), or, for example, when the q2w regimen is used, the score is 43 (±8); • For example, as of week 4 after the start of treatment, for example, when the q4w regimen is used, the FACIT-fatigue score is about 40 (±11), or, for example, when the q2w regimen is used, the score is 40 (±10); • For example, as of week 8 after the start of treatment, for example, when the q4w regimen is used, the FACIT-fatigue score is about 43 (±7), or, for example, when the q2w regimen is used, the score is 39 (±11); • For example, as of week 12 after the start of treatment, for example, when the q4w regimen is used, the FACIT-fatigue score is about 44 (±7), or, for example, when the q2w regimen is used, the score is 40 (±9); • For example, by week 16 after the start of treatment, for example, when the q4w regimen is used, the FACIT-fatigue score is about 44 (±5), or, for example, when the q2w regimen is used, the score is 41 (±11); • For example, by week 20 after the start of treatment, for example, when the q4w regimen is used, the FACIT-fatigue score is about 43 (±7), or, for example, when the q2w regimen is used, the score is 37 (±13); • For example, by week 24 after the start of treatment, for example, when the q4w regimen is used, the FACIT-fatigue score is about 44 (±7), or, for example, when the q2w regimen is used, the score is 43 (±9); • For example, by week 28 after the start of treatment, for example, when the q4w regimen is used, the FACIT-fatigue score is about 44 (±7), or, for example, when the q2w regimen is adopted, the score is 42 (±10); • For example, as of the 2nd week after the start of treatment, for example, when the q4w regimen is adopted, the EORTC-QLQ-C30 physical function score is about 94 (±9), or, for example, when the q2w regimen is adopted, the score is 85 (±19); • For example, as of the 4th week after the start of treatment, for example, when the q4w regimen is adopted, the EORTC-QLQ-C30 physical function score is about 90 (±9), or, for example, when the q2w regimen is adopted, the score is 84 (±19); • For example, as of the 8th week after the start of treatment, for example, when the q4w regimen is adopted, the EORTC-QLQ-C30 physical function score is about 93 (±7), or, for example, when the q2w regimen is adopted, the score is 84 (±19); • For example, as of week 12 after the start of treatment, for example, when the q4w regimen is adopted, the EORTC-QLQ-C30 physical function score is about 91 (±9), or, for example, when the q2w regimen is adopted, the score is 88 (±16); • For example, as of week 16 after the start of treatment, for example, when the q4w regimen is adopted, the EORTC-QLQ-C30 physical function score is about 90.0 (±9.6), or, for example, when the q2w regimen is adopted, the score is 85.0 (±19.9); • For example, as of week 20 after the start of treatment, for example, when the q4w regimen is adopted, the EORTC-QLQ-C30 physical function score is about 94 (±8), or, for example, when the q2w regimen is adopted, the score is 82 (±19); • For example, as of week 24 after the start of treatment, the EORTC-QLQ-C30 physical function score is about 91 (±9) when the q4w regimen is used, or, for example, 86 (±19) when the q2w regimen is used; • For example, as of week 28 after the start of treatment, the EORTC-QLQ-C30 physical function score is about 95 (±6) when the q4w regimen is used, or, for example, 91 (±17) when the q2w regimen is used; • For example, as of week 2 after the start of treatment, the EORTC-QLQ-C30 GHS/QoL score is about 76 (±18) when the q4w regimen is used, or, for example, 75 (±17) when the q2w regimen is used; • For example, as of week 4 after the start of treatment, an EORTC-QLQ-C30 GHS/QoL score of about 71 (±26) when using a q4w regimen, or, for example, a score of 76 (±23) when using a q2w regimen; • For example, as of week 8 after the start of treatment, an EORTC-QLQ-C30 GHS/QoL score of about 69 (±21) when using a q4w regimen, or, for example, a score of 70 (±26) when using a q2w regimen; • For example, as of week 12 after the start of treatment, an EORTC-QLQ-C30 GHS/QoL score of about 72 (±15) when using a q4w regimen, or, for example, a score of 73 (±20) when using a q2w regimen; • For example, as of week 16 after the start of treatment, an EORTC-QLQ-C30 GHS/QoL score of about 72 (±22) when using a q4w regimen, or, for example, a score of 69 (±29) when using a q2w regimen; • For example, as of week 20 after the start of treatment, an EORTC-QLQ-C30 GHS/QoL score of about 77 (±20) when using a q4w regimen, or, for example, a score of 67 (±25) when using a q2w regimen; • For example, as of week 24 after the start of treatment, an EORTC-QLQ-C30 GHS/QoL score of about 76 (±19.0) when using a q4w regimen, or, for example, a score of 74 (±29) when using a q2w regimen; and/or • For example, by week 28 after the start of treatment, for example, when the q4w regimen is used, the EORTC-QLQ-C30 GHS/QoL score is about 75 (±17), or for example, when the q2w regimen is used, the score is 74 (±24). Achieving a specified score or score improvement (e.g., EORTC-QLQ-C30 GHS/QoL score; EORTC-QLQ-C30 physical function score or FACIT-fatigue score) includes embodiments in which the individual condition is measured, for example, according to a relevant questionnaire or scale; and embodiments in which, although not measured by a questionnaire or scale, the individual condition would achieve such a score or improvement if measured by a questionnaire or scale.

In one embodiment of the invention, while being treated with the combination therapy of the invention, a red blood cell (RBC) transfusion may be administered to an individual, for example, as follows: If the hemoglobin level is ≦9 g/dL and the new onset or signs or symptoms of anemia worsen to a severity that necessitates transfusion, then transfuse red blood cells; or If the hemoglobin level is ≦7 g/dL, then transfuse red blood cells with or without signs or symptoms of anemia.

In one embodiment of the invention, a subject receiving a combination therapy of the invention receives "intensified" therapy, e.g., if the subject develops breakthrough hemolysis that is not due to a complement activation condition (e.g., an intercurrent infection) and/or if the subject develops a persistently inadequate LDH response (i.e., LDH>1.5 x ULN) (e.g., in 2 consecutive measurements spanning at least about 2 weeks). In addition to the doses specified in the combination therapies discussed herein, the boost therapy further comprises one or more doses of an anti-C5 antibody or antigen-binding fragment (preferably Pazelimab) and/or a C5 iRNA (preferably Cemdisiran), for example, • For subjects receiving Pazelimab 400 mg SC Q4W (±3, 4, 5, 6, or 7 days) and Cemdisiran 200 mg SC Q4W (±3, 4, 5, 6, or 7 days), the subject receives a single dose of 30 mg/kg Pazelimab intravenously (IV) on the day of the boost, and a boosted regimen of Pazelimab 400 mg Q2W (±3, 4, 5, 6, or 7 days) with Cemdisiran 200 mg Q4W (±3, 4, 5, 6, or 7 days) starting on the day of the boost. •For subjects receiving Pazelimumab 400 mg SC Q2W (±3, 4, 5, 6, or 7 days) and Cemdisiran 200 mg SC Q4W (±3, 4, 5, 6, or 7 days), subjects received a single dose of Pazelimumab 30 mg/kg IV on the day of the boost and restarted the combination of Pazelimumab 400 mg Q2W (±3, 4, 5, 6, or 7 days) and Cemdisiran 200 mg Q4W (±3, 4, 5, 6, or 7 days) starting on the day of the boost.

In one embodiment of the invention, an individual receiving intensive therapy (e.g., undergoing an eculizumab switch regimen) (preferably for the treatment of PNH) receives 30 mg/kg paszelimab IV starting on the day of initiation (e.g., which may start on day 57), in addition to a maintenance regimen (a shortened dosing schedule of paszelimab 400 mg SC Q2W (±3, 4, 5, 6, or 7 days) with cemdisiran 200 mg SC Q4W (±3, 4, 5, 6, or 7 days)), e.g., for a period of 32 weeks starting on the day of initiation.

In some embodiments, the disclosed combination therapy comprises administering one or more doses of an anti-C5 antibody or antigen-binding fragment thereof to a subject in need thereof four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently as long as a therapeutic response is achieved. In one embodiment, a disclosed anti-C5 antibody or antigen-binding fragment thereof (e.g., paslimab) is administered to a subject once every two weeks or once every four weeks.

As used herein, the term "in combination with" means that the anti-C5 antibody or antigen-binding fragment thereof is administered before, after, or simultaneously with the C5 iRNA. This term includes sequential or simultaneous administration of the anti-C5 antibody or antigen-binding fragment thereof and the C5 iRNA.

In some embodiments, when the anti-C5 antibody or antigen-binding fragment thereof is administered “before” C5 iRNA, the anti-C5 antibody or antigen-binding fragment thereof can be administered more than 12 weeks, about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, about 1 week, about 150 hours, about 100 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the C5 iRNA.

In some embodiments, when the anti-C5 antibody or antigen-binding fragment thereof is administered "after" C5 iRNA, the anti-C5 antibody or antigen-binding fragment thereof can be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 5 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, or more than 12 weeks after administration of the C5 iRNA.

As used herein, "simultaneous" administration means that the anti-C5 antibody or antigen-binding fragment thereof (e.g., Paseritumab) and C5 iRNA (e.g., Cemdisiran) are administered to a subject in a single dosage form (e.g., co-formulated), or in separate dosage forms administered to a subject during the same treatment period, preferably within about 1 hour or 2 hours or 30 minutes or less (i.e., before, after, or at the same time), such as about 15 minutes or less, or about 5 minutes or less. If administered in separate dosage forms, each dosage form can be administered via the same route (e.g., intravenous, subcutaneous, etc.); alternatively, each dosage form can be administered via different routes. In any case, for the purposes of the present invention, administration of the components in a single dosage form, in separate dosage forms by the same route, or in separate dosage forms by different routes is considered to be administered "simultaneously." In one embodiment of the present invention, a subcutaneous dose of an anti-C5 antibody or antigen-binding fragment and a C5 iRNA are administered simultaneously by injection into different arms.

As used herein, "sequential" administration means that each dose of a selected treatment is administered to a subject at different time points, e.g., on different days separated by a predetermined interval, e.g., hours, days, weeks, or months. For illustration, sequential administration may include administration of an initial dose of an anti-C5 antibody or antigen-binding fragment thereof (or C5 iRNA), followed by one or more second doses of a C5 iRNA (or an anti-C5 antibody or antigen-binding fragment thereof), and optionally one or more third doses of an anti-C5 antibody or antigen-binding fragment thereof (or C5 iRNA). For illustration, sequential administration may include administering to a subject an initial dose of an anti-C5 antibody or an antigen-binding fragment thereof (or C5 iRNA), followed by one or more second doses of a C5 iRNA (or an anti-C5 antibody or an antigen-binding fragment thereof), and optionally, one or more third doses of a C5 iRNA (or an anti-C5 antibody or an antigen-binding fragment thereof).

As used herein, an "initial,""secondary," and "tertiary" dose refers to the temporal order of administration. Thus, an "initial" dose is the dose administered at the beginning of a treatment regimen (also called a "baseline dose"); a "secondary" dose is administered after the initial dose; and a "tertiary" dose is administered after the second dose. The initial, second, and third doses may all contain the same amount of the selected treatment or may contain different amounts of the selected treatment. Treatment and Administration

The co-formulations and/or combination therapies of the present invention (e.g., Cemdisiran/Paslimab) can be used to treat or prevent diseases or disorders or conditions associated with C5, comprising the step of administering a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment and a C5 iRNA (preferably in a co-formulation), for example, by a parenteral route, such as intramuscular (IM), subcutaneous (SC), intravenous (IV) or intravitreal (IVT) or intraocular injection. Preferably, about 400 mg of the antibody (preferably Paslimab) is administered every about 2-4 (e.g., 2, 3 or 4) weeks, and about 200 mg of the iRNA (preferably Cemdisiran) is administered about every 4 weeks.

In some embodiments, the disclosed co-formulations and/or combination therapies (e.g., Cemdisiran/Pasirimab) can be used to treat or prevent myasthenia gravis (MG), such as a 100:100 co-formulation. Signs and symptoms of MG include, but are not limited to, weakness of the eye muscles (ocular weakness), drooping of one or both eyelids (ptosis), blurred vision or double vision (diplopia), changes in facial expression, difficulty swallowing, shortness of breath, speech problems (dysarthria), weakness in the arms, hands, fingers, legs, and/or neck. Sometimes the severe weakness of myasthenia gravis can lead to respiratory failure. Thus, the present invention includes methods for treating or preventing MG in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a co-formulation of the invention (e.g., by SC, IM, or IV injection).

In some embodiments, the co-formulations and/or combination therapies disclosed herein (e.g., Cemdisiran/Paslimumab) can be used to treat or prevent atypical hemolytic uremic syndrome (aHUS). Signs and symptoms of aHUS include, but are not limited to, platelet activation, hemolysis, systemic thrombotic microangiopathy (formation of blood clots in small blood vessels throughout the body) leading to stroke, heart attack, kidney failure and/or death, end-stage kidney disease, permanent kidney damage, abdominal pain, mental confusion, edema, fatigue, nausea/vomiting, diarrhea, and microangiopathic anemia. Thus, the present invention includes methods for treating or preventing aHUS in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a co-formulation of the invention (eg, by SC, IM, or IV injection).

In some embodiments, the disclosed co-formulations and/or combination therapies (e.g., Cemdisiran/Paslimab) can be used to treat or prevent paroxysmal nocturnal hemoglobinuria (PNH), such as a 50:100 co-formulation. Signs and symptoms of PNH include, but are not limited to, red blood cell destruction, thrombosis (including deep venous thrombosis, pulmonary embolism), intravascular hemolytic anemia, red urine, anemia symptoms (such as fatigue, shortness of breath, and palpitations), abdominal pain, and difficulty swallowing. Thus, the present invention includes methods for treating or preventing PNH in an individual in need thereof, comprising the step of administering to the individual a therapeutically effective amount of a co-formulation of the invention (e.g., by SC, IM, or IV injection).

In some embodiments, the disclosed co-formulations and/or combination therapies can be used to treat PNH patients (including PNH patients who have been switched from paslimab monotherapy) by, for example, controlling hemolysis without any breakthrough hemolytic events, achieving hemoglobin stabilization, and/or maintaining LDH normalization for a period of time (e.g., at least 28 weeks). In some embodiments, the disclosed co-formulations and/or combination therapies can be used to treat PNH patients (including PNH patients who have been switched from paslimab monotherapy) by, for example, improving patient fatigue, improving global health status (GHS)/quality of life (QoL), and/or improving physical function compared to baseline.

In some embodiments, the disclosed co-formulations and/or combination therapies (e.g., Cemdisiran/Pasirimab) are useful for treating or preventing CHAPLE disease (CD55 deficiency with complement overactivation, angiopathic thrombosis, and protein-losing enteropathy). CHAPLE disease is characterized by symptoms such as inflammatory bowel disease, protein-losing enteropathy (which may be associated with hypoalbuminemia), hypogammaglobulinemia, intestinal lymphangiectasia, and/or thrombotic events. Thus, the present invention includes methods for treating or preventing CHAPLE in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a co-formulation of the invention (e.g., by SC, IM, or IV injection).

In some embodiments, the disclosed co-formulations and/or combination therapies (e.g., Cemdisiran/Paslimab) can be used to treat or prevent (including reducing or eliminating signs or symptoms thereof, or reducing complement activation associated therewith) a disease or disorder or condition associated with C5, such as a disorder of inappropriate or undesirable complement activation; systemic inflammatory response to post-pump syndrome caused by cardiopulmonary bypass or renal bypass; neurological disease; renal disease; hemodialysis complications; inflammatory disease; inflammation of autoimmune disease; heat injury; immune complex disorder; autoimmune disease or proteinuric nephropathy. Thus, the invention includes methods for treating or preventing any of these disorders in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a co-formulation of the invention (e.g., by SC, IM, or intravenous administration).

In some embodiments, the disclosed co-formulations and/or combination therapies (e.g., Cemdisiran/Pasirimab) can be used to treat or prevent (including reducing or eliminating its signs or symptoms, or reducing its associated complement activation) diseases or disorders or conditions associated with C5, such as burn-induced complement activation; hereditary CD59 deficiency; renal ischemia ; postischemia-reperfusion condition; adult respiratory distress syndrome; Alport syndrome; Alzheimer's disease; atherosclerosis; bullous pemphigoid; C3 glomerulopathy; capillary leak syndrome; Crohn's disease; diabetes mellitus; diabetic nephropathy; epilepsy; glomerulopathy; Guillain-Barré syndrome; hemolytic anemia; hyperacute allograft rejection reactions; infectious diseases; IL-2-induced toxicity during interleukin-2 therapy; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative nephritis; mesenteric artery reperfusion after aortic reconstruction; multiple sclerosis; myasthenia gravis; myocardial infarction; neuromyelitis optica; obesity-induced activation of tonic bodies; Parkinson's disease; progressive renal failure; eczema; renal ischemia-reperfusion Injection injury; rheumatoid arthritis; schizophrenia; SLE nephritis; stroke; systemic lupus erythematosus (SLE); traumatic brain injury; vasculitis; xenograft rejection; CHAPLE disease/syndrome (CD55 deficiency with complement overactivation, vasculothrombosis and PLE); complement activation caused by cryoinjury; complement activation caused by sepsis. Thus, the present invention includes methods for treating or preventing any such condition or disease in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a co-formulation of the present invention (e.g., by SC, IM or IV injection).

In some embodiments, the disclosed co-formulations and/or combination therapies (e.g., Cemdisiran/Paslimab) of the invention can be used to treat or prevent (including reducing or eliminating the signs or symptoms thereof, or reducing the complement activation associated therewith) diseases or disorders or conditions associated with C5, such as lung diseases or disorders, such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolism and infarction, pneumonia, fibrosis , injury caused by inert dusts and minerals (e.g., silica, coal dust, caladium, and asbestos), pulmonary fibrosis, organic dust disease, chemical injury (due to irritant gases and chemicals such as chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burns or frostbite), asthma, allergies, bronchoconstriction, allergic pneumonitis, parasitic diseases, Goodpasture's syndrome, pulmonary vasculitis, hereditary vascular edema, or immune complex-related inflammation. Thus, the present invention includes methods for treating or preventing any such condition or disease in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a co-formulation of the present invention (e.g., by SC, IM, or IV injection).

In some embodiments, the disclosed co-formulations and/or combination therapies (e.g., Cemdisiran/Paslimab) of the invention are useful for treating or preventing (including reducing or eliminating signs or symptoms thereof, or reducing complement activation associated therewith) diseases or disorders or conditions associated with C5, which are ocular diseases such as age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy, ocular angiogenesis (ocular neovascularization affecting choroidal, corneal or retinal tissue), geographic atrophy (GA), uveitis, and neuromyelitis optica. The co-formulations of the invention are useful for treating or ameliorating at least one sign and/or symptom of dry AMD or wet AMD. Thus, the present invention includes methods for treating or preventing any such condition or disease in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a co-formulation of the present invention (e.g., parenterally; or preferably by intraocular or intravitreal injection).

"Treat" or "treating" means administering a co-formulation of the invention (e.g., Cemdisiran/Paslimab) to a subject suffering from a disease, disorder or condition associated with C5 such that one or more signs or symptoms thereof are reduced or eliminated in the subject, such as by reducing complement activation associated therewith.

In co-formulations for treating a disease, disorder or condition associated with C5, a therapeutically effective dose or amount of the anti-C5 antibody and C5 iRNA is each in the range of about 10-800 mg, administered once every 1, 2, 3, 4, 5, 6, 7 or 8 weeks.

Individual or patient (used interchangeably herein) refers to a mammal, preferably a human. In one embodiment of the invention, the individual suffers from a disease or disorder or condition associated with C5, such as PNH or MG or aHUS or CHAPLE. In one embodiment of the invention, the individual is or has previously received a therapeutic agent for the treatment of the disease or condition (e.g., a complement inhibitor, such as korolimab; eculizumab, tesidorumab, mubodina and/or ravlizumab), and then switched to the co-formulation and/or combination therapy of the present invention, which includes a different agent (e.g., Cemdisiran/Pasirimab). In one embodiment of the invention, the subject is "treatment naive" (never previously received a complement inhibitor), or has not recently received a complement inhibitor (e.g., within 1, 2, 3, 4, 5, or 6 months). In one embodiment of the invention, the subject has been diagnosed with paroxysmal nocturnal hemoglobinuria, which has been confirmed by experience with high sensitivity flow cytometry. In one embodiment of the invention, the subject's lactate dehydrogenase is at least 1.5 x ULN (upper limit of normal). Sahin et al. , Pesg PNH diagnosis, follow-up and treatment guidelines. Am J Blood Res 2016; 6(2):19-27. In one embodiment of the present invention, the individual or patient does not have any one or more of the following characteristics: • Bone marrow transplant or organ transplant experience • Weight <40 kg • Any 2 of the following 3 abnormalities: a. Peripheral blood absolute neutrophil count (ANC) <500/μL [<0.5 × 10 ⁹ /L]; or b. Peripheral blood platelet count <20,000/μL; or c. Peripheral blood reticulocyte count abnormal, defined as <20,000/μL or <1% • Experienced hypocellular bone marrow with age-adjusted bone marrow cellularity and/or bone marrow cellularity ≤ 25% • No documented meningococcal vaccination • Inability to take antibiotics to prevent meningococcal disease • Any active ongoing infection or recent infection requiring systemic treatment with antibiotics, antivirals, or antifungals within 2 weeks • Systemic fungal disease or unresolved tuberculosis (TB), or History of active or latent tuberculosis infection (LTBI) • Positive hepatitis B surface antigen or hepatitis C virus RNA • History of human immunodeficiency virus (HIV) infection • SARS-CoV-2 infection • Genetic complement deficiency • History of active, uncontrolled, persistent systemic autoimmune disease • History of cirrhosis, or liver disease with evidence of current liver impairment, or ALT or AST (Not related to PNH) greater than 3 × ULN •eGFR <30 mL/min/1.73m ² (based on the Chronic Kidney Disease-Epidemiology Collaboration 2009 [CKD-EPI]) •Anticipated need for major surgery •Cancer within the past 5 years other than adequately treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma in situ •Allergy to pasirimab, cemdisiran •Documented functional or anatomic asplenia •Pregnant or breastfeeding women •Women of childbearing potential who are unwilling to use highly effective contraception •Not vaccinated against Streptococcus pneumoniae and/or Haemophilus influenzae type b.

In one embodiment of the invention, the individual is receiving or has received a blood transfusion.

In one embodiment of the invention, a subject receiving a co-formulation of the invention for treatment of a disease, disorder or condition associated with C5 achieves intravascular hemolysis or a decrease in blood lactate dehydrogenase (LDH) levels and/or a reduction in the need for blood transfusions compared to before the start of treatment.

The present invention also provides an injection device comprising a co-formulation of the present invention (e.g., Cemdisiran/Paslimab). An injection device is a device for introducing a substance into a patient via a non-parenteral route (e.g., intramuscular, subcutaneous, intravitreal, intraocular, or intravenous). For example, the injection device may be a syringe (e.g., a prefilled or autoinjector), which includes, for example, a barrel or cartridge for containing a fluid to be injected (e.g., a co-formulation), a needle for puncturing the skin and/or a blood vessel to inject the fluid; and a plunger for pushing the fluid out of the barrel and through the needle hole. In one embodiment of the present invention, the injection device comprising the co-formulation is suitable for subcutaneous, intravitreal, or intravenous (IV) injection. Such a device includes a co-formulation in a cannula or trocar/needle, which can be attached to a tube, which can be attached to a bag or reservoir for containing a fluid (e.g., saline; or lactated Ringer's solution containing NaCl, sodium lactate, KCl, _CaCl2 , and optionally dextrose, introduced into the patient's body through the cannula or trocar/needle).

In one embodiment of the invention, once the trocar and cannula are inserted into a vein of a subject and the trocar is removed from the inserted cannula, the co-formulation can be introduced into the device. The IV device can be inserted, for example, into a peripheral vein (e.g., in the hand or arm); into the upper or lower venous vein, or into the right atrium of the heart (e.g., a central IV); or into the subclavian, internal jugular, or femoral veins and advanced, for example, toward the heart until it reaches the upper venous vein or right atrium (e.g., a central venous line).

In one embodiment of the invention, the injection device is an autoinjector; a jet syringe or an external infusion pump. A jet syringe uses a high-pressure narrow fluid jet to penetrate the epidermis and introduce the co-formulation into the patient's body. An external infusion pump is a medical device that delivers the co-formulation into the patient's body in controlled amounts. The external infusion pump may be electrically or mechanically driven. Different pumps operate in different ways, for example, a syringe pump contains the fluid in a reservoir in the syringe, and a movable piston controls the fluid delivery, and an elastomeric pump maintains the fluid in a stretchable balloon reservoir, and the pressure from the elastic wall of the balloon drives the fluid delivery. In a peristaltic pump, a set of rollers compresses a section of tubing, pushing the fluid forward. In a multi-channel pump, fluid can be delivered from multiple reservoirs at multiple rates. β -Hexosaminidase (Beta-Hex)

The present invention provides methods for reducing the level of β-hexosaminidase activity in a composition, such as a pharmaceutical co-formulation, for example, a co-formulation comprising a molecule that is a substrate for the enzyme (e.g., an antibody or an antigen-binding fragment thereof) and an iRNA, the antibody or antigen-binding fragment thereof being, for example, H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H 4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; korolizumab; eculizumab, tertulumab, mubodina or ravlizumab; preferably pazelimumab), which is isolated from a mammalian host cell and includes β-hexosaminidase (β The invention relates to a ligand comprising a β-hexase contaminant; and the iRNA comprises a ligand having one or more terminal GalNAc and/or GlcNAc residues, which are substrates for β-hex. Generally, β-hexosaminidase is present in a small amount or trace amount, and it still exists with the antibody or antigen-binding fragment after being separated from the host cell and/or the host cell growth medium.

There is evidence that the amount of β-hex in an antibody composition depends on the specific antibody. Most antibodies tested exhibit <2 ppm β-hex. Pazelimumab has been observed to have somewhat higher β-hex levels than many other antibodies tested. However, the purification procedure may also affect the extent to which β-hex levels vary from antibody to antibody.

In one embodiment of the invention, the β-hex is Chinese hamster β-hex. In one embodiment of the invention, the β-hex is characterized as a mammalian β-hex, such as mouse or human β-hex. In one embodiment of the invention, the β-hex may be fungal, such as from yeast (such as Candida albicans or Pichia pastoris (such as Pichia pastoris)).

In one embodiment of the present invention, the antibody or fragment specifically binds to C5, tumor necrosis factor α, PD-1, PD-L1, VEGF, VEGF receptor, HER2, CTLA4, leptin receptor, CD3, CD28, CD20, IL-23 and/or EGFR. In one embodiment of the present invention, the iRNA binds to a polynucleotide encoding any one of these genes.

The present invention includes co-formulations that preferably contain no detectable β-hex. However, included within the scope of the invention are co-formulations (e.g., Cemdisiran/Paslimumab): • comprising no more than about 0.170 micrograms/ml β-hex, for example, about 0.04; 0.05; 0.06; 0.06; 0.0605; 0.0605; 0.0605; 0.063; 0.07; 0.07; 0.0765; 0.078; 0.08; 0.14; 0.141; 0.15; 0.1525; 0.166; or 0.17; or no more than any of these concentrations; • comprising a β-hex to antibody molar ratio of no more than about 2, 1.9, 1.65, 1.75, 1, 0.9, 0.8, 0.75, 0.7 or 0.5 parts per million (ppm); • comprising no more than about 1% Cemdisiran impurity 1 (e.g., about 0.2, 0.4, 0.6, 0.8, 0.9 or 1%); • when stored at 40°C (e.g., in a co-formulation comprising about 100 mg/ml Paszelimumab and about 100 mg/ml Cemdisiran), the percentage of Cemdisiran impurities 1, 2 and 3 relative to total Cemdisiran (Cemdisiran + any Cemdisiran impurities) at initial storage exhibits an increase over time characterized by the formula 0.9 + 3.84 (number of months of storage) ^1/2 or 0.9 + 2.84 (number of months of storage) ^1/2 , for example, wherein the percentage of impurities is measured according to dlPRP (denatured ion pair reversed phase chromatography); • When stored at 40°C (e.g., in a co-formulation comprising about 100 mg/ml Pasirimab and about 50 mg/ml Cemdisiran), the percentage of Cemdisiran impurities 1, 2 and 3 relative to total Cemdisiran (Cemdisiran + any Cemdisiran impurities) at initial storage exhibits an increase with time, characterized by the formula 0.8 + 4.79 (number of months of storage) ^1/2 or 0.9 + 3.30 (number of months of storage) ^1/2 ; • Before storage (t=0), about 91% Cemdisiran; • After storage at 2-8°C for 1, 1½, 2, 2½ or 3 years, not less than about 80% Cemdisiran; and/or • About 80% to about 91% Cemdisiran.

In humans, lysosomal β-hexosaminidase catalyzes the hydrolysis of β-glycosidically linked N-acetylglucosamine (GlcNAc) and N-acetylglucosamine (GalNAc) residues at the non-reducing end of a number of glycoconjugates (which may be referred to herein as molecules bound to a ligand containing one or more terminal GlcNAc or GalNAc residues). Three different isoforms of the dimeric enzyme are known: β-hexosaminidase A (HexA), representing a heterodimer of non-covalently linked α and β chains, and the homodimeric isozymes β-hexosaminidase B (HexB, ββ) and β-hexosaminidase S (HexS, αα). β-Hexosaminidase is particularly important for the lysosomal breakdown of glycosphingolipids, important membrane components on the surface of eukaryotic cells. See Wendeler & Sandhoff, Hexosaminidase assays, Glycoconj J (2009) 26:945-952.

Assays for β-hexosaminidase are commercially available. See β-Hexosaminidase Activity Assay, Tribioscience (Sunnyvale, CA). For example, the colorimetric assay measures the conversion of p-nitrophenyl N-acetyl-β-D-glucosamine to N-acetyl-D-glucosamine and p-nitrophenol, which can be measured at absorbance (OD 405 nm).

The optimal pH for β-hexosaminidase activity for Cemdisiran was measured to be about 6. Therefore, this activity can be reduced by changing the pH to values above or below 6 (e.g., 6.5). A pH above 6 will make Cemdisiran more stable; however, in co-formulations, such as antibodies to Paselimab, increasing the pH will result in an increase in the Area 1/% of acidic charge species of the antibody. Some co-formulations of the present invention have been formulated to achieve a balance of conditions that stabilize Cemdisiran while still maintaining the stability of Paselimab.

The present invention includes methods for reducing β-hexosaminidase activity in a composition that is hostile to double-stranded RNA (dsRNA) substrates (e.g., comprising terminal GalNAc, such as Cemdisiran), comprising adjusting the pH to a value above or below about 6, such as to a value above 0.5 to reach 6.

β-hexosaminidase activity has also been shown to be reduced in the presence of N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc). The present invention includes methods for reducing β-hexosaminidase activity in a composition that is not favorable for double-stranded RNA (dsRNA) substrates (e.g., including terminal GalNAc, such as Cemdisiran), comprising adding N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc) to the composition. For example, about 5% (w/v) GlcNAc and/or GalNAc can be added. Examples

These examples are intended to illustrate the present invention and not to limit it. The compositions and methods (including dosing regimens) shown in the examples constitute a part of the present invention. Example 1 : Quantification of β -hexosaminidase host cell protein impurities by UPLC-SRM-MS/MS

In this example, the host cell protein β-hexosaminidase, a process-related impurity in the preparation of the paszelimab antibody, was accurately and absolutely quantified. Materials

Recombinant β-hexosaminidase protein and antibody drug substance were produced in-house. Tris-HCl, tris(2-carboxyethyl)phosphine (TCEP HCl), iodoacetamide (IAM), and formic acid (FA) were from Thermo Fisher Scientific (Waltham, MA). Sequencing-grade modified trypsin was from Promega (Madison, WI). LC/MS-grade acetonitrile (containing 0.1% FA) and water (containing 0.1% FA) were purchased from Fisher Scientific (USA). Milli-Q water used in the experiments was generated. Methods

β-hexosaminidase ("β-hex") calibration standards were prepared by serial dilution of recombinant β-hex spiked with 5 mg/mL paszelimab antibody drug substance without β-hex. β-hex standards were prepared at 3.3, 8.2, 20.5, 51.2, 128, 320, and 800 ppm (on a molar basis). Quality controls were prepared at 3.3, 7.5, 173, 588, and 800 ppm (on a molar basis).

20 µL of β-hex calibration standards, controls, and samples were transferred to a 96-well plate and concentrated to dryness using a sample concentrator. The dried protein was then briefly mixed in a denaturing and reducing solution (8 M urea and 10 mM TCEP-HCl) for reduction and incubated at 56°C for 30 minutes with shaking. After cooling, the mixture was alkylated in 10 mM IAM at room temperature for 30 minutes in the dark. After alkylation, 10 µg of trypsin was added to the mixture (trypsin to substrate ratio of 1:10) and incubated at 37°C with shaking overnight. At the end of digestion, 10% FA was added to quench the reaction.

The digested peptide mixture was injected into a liquid chromatography instrument (Agilent 1290 Infinity II LC Systems) coupled to an Agilent 6495B Triple Quadrupole mass spectrometer for MRM analysis. Separation was performed by reversed phase liquid chromatography using an ACQUITY UPLC BEH130 C18 column (2.1 × 50 mm, 1.7 μm; Waters). Mobile phase A was 0.1% FA/water, and mobile phase B was 0.1% FA/acetonitrile. The initial gradient started with 3% B for 0.5 min, then increased to 35% B in 10 min, followed by elution with 90% B for 2.4 min, and equilibration with 3% B for 2.4 min. The flow rate used in the gradient was 0.4 mL/min. An Agilent Jet Stream electrospray ionization (AJS ESI source) was used with heated nitrogen as sheath gas and drying gas (400 °C and 180 °C, respectively) at a flow rate of 12 L/min. The MS was operated in positive mode with a capillary voltage of 3000 V, a nozzle voltage of 300 V, and a nebulizer pressure of 35 psi. Preselected mass-to-charge ratios (m/z) of β-hex peptide progenitor and product ion pairs were fragmented with optimized collision energies and detected in the mass spectrometer. The LC/MS system was operated using an Agilent MassHunter Workstation Data Acquisition 6400 Series Triple Quadrupole version B.10.0. Data analysis was performed using Agilent MassHunter Quantitative Analysis version B.09.00. Analysis Performance Summary

This analysis was performed in 5 mg/mL β-hex-free antibody drug substance and over the range of 3.3-800.0 ppm (on a molar basis). Five samples of known concentration (LLOQ, LQC, MQC, HQC, and ULOQ) were always prepared in triplicate to allow for evaluation during analytical development. Inter-assay accuracy and precision met the QC acceptance criteria (±25% for LLOQ and ±20% for other QCs), but one LQC (14/15 of the Day 1 QCs) failed in terms of accuracy (Table 1-2). Intra-assay accuracy and precision were calculated based on triplicate QC analyses performed on Day 2 in a single set of experiments rather than duplicate preparations. Intra-assay accuracy and precision met the acceptance criteria for all QCs (Table 1-3). The mass-to-charge ratio of the quantifier target peptide ("TLDMAFNK"; m/z shift: 505.9 > 796.7) is specific for β-hex in the analytical matrix and other components that may be present in the digestion buffer. Dilution linearity evaluated using spiked standards showed that Beta-hex recoveries were linear at 5, 10, 50, 100, 150, and 218 mg/mL antibody matrix (Figure 16). An analytical calibration curve was constructed over the range of 3.3-800.0 ppm with a weighting of 1/×2 to construct a relative response-standard concentration relationship for β-hex (Figure 15). Four QCs (LQC, MQC, HQC, and ULOQ) were evaluated for interference with cemdisiran spiked up to 5 mg/mL (1:1 mAb:Cemdisiran ratio), and 92% (11/12) of the QCs met the acceptance criteria (Table 1-4). Instrument reproducibility testing showed that the instrument injection and detector were reproducible for repeated sample injections (Table 1-5). Freeze-thaw stability testing using the QCs demonstrated that the samples remained stable after 3 freeze-thaw cycles (Table 1-6). The processed samples were shown to be stable for up to 48 hours at 4°C in an autosampler (Table 1-7). In summary, all evaluation parameters met the acceptance criteria (Table 1-1). β-hex measurement of pazelimumab batches

Eleven lots of Pazelimab were analyzed for β-hex content by SRM-LC-MS/MS analysis (see Methods section). The β-hex abundance in Pazelimab Lot A, Lot B, and Lot 1 (282-332 ng/mL) was at least 2-fold higher than that in Lot 2, Lot C, Lot D, Lot 4, Lot E, Lot F, Lot 3, and Lot G material (120-156 ng/mL). See Figure 14 for the β-hex content measured in different lots. Table 1-1. Summary of analytical performance Evaluation parameters and acceptance criteria result Analysis scope 5 mg/mL mAb matrix (ULOQ-LLOQ) 800.0-3.3 ppm (mole) Inter-analyst accuracy Accuracy % 80-120% (LLOQ 75-125%) 84-114% (one LQC failed; overall 93% QC passed) Inter-assay precision CV% ≦ 20% (LLOQ ≦ 25%) 2.3-14.5% Intra-analytical accuracy Accuracy % 80-120% (LLOQ 75-125%) 84-113% Intra-analytical precision CV% ≦ 20% (LLOQ ≦ 25%) 1.6-10.7% Selective Blank analysis matrix BLQ Blank digestion buffer Cemdisiran (5 mg/mL) BLQ BLQ Interference ( up to 5 mg/mL Cemdisiran ; mAb:Cemdisiran ratio = 1:1) Accuracy% 80-120% (LQC, MQC, HQC, ULOQ) CV% ≦ 20% (LQC, MQC, HQC, ULOQ) 98-112% (one ULOQ failed, overall 92% QC passed) 0.1-8.7% Remains Blank buffer after ULOQ BLQ Instrument reproducibility ( injector and detector) Accuracy % 80-120% (LLOQ 75-125%) 85-112% CV% ≦ 20% (LLOQ ≦ 25%) 1.2-10.7% Stability of processed samples (48 hrs) Accuracy % 80-20% (LLOQ 75-125%) 84-118% CV% ≦ 20% (LLOQ ≦ 25%) 3.5-11.0% Sample freeze-thaw stability (3 cycles) Accuracy % 80-120% (LLOQ 75-125%) 83-105% CV% ≦ 20% (LLOQ ≦ 25%) 1.9-11.5% Table 1-2. Inter-analyst accuracy and precision QC (N=3) Accuracy(%) CV (%) Day 1 Day 2 LLOQ 97 84 7.7 LLOQ 97 87 LLOQ 100 102 LQC 91 105 14.5 LQC 68 102 LQC 93 100 MQC 102 99 3.0 MQC 94 96 MQC 97 97 HQC 107 89 6.8 HQC 95 96 HQC 92 91 ULOQ 110 107 2.3 ULOQ 109 113 ULOQ 114 110 Table 1-3. Intra-analytical accuracy and precision QC (N=3) Accuracy(%) CV (%) LLOQ 84 10.7 LLOQ 87 LLOQ 102 LQC 105 2.8 LQC 102 LQC 100 MQC 99 1.6 MQC 96 MQC 97 HQC 89 4.2 HQC 96 HQC 91 ULOQ 107 2.6 ULOQ 113 ULOQ 110 Table 1-4. Instrument reproducibility ( injector and detector ) QC Accuracy(%) CV (%) LLOQ - Injection 1 102 3.1 LLOQ – Injection 2 101 LLOQ – Injection 3 96 LQC – Injection 1 100 10.7 LQC – Injection 2 106 LQC – Injection 3 85 MQC – Injection 1 97 2.8 MQC – Injection 2 92 MQC – Injection 3 96 HQC – Injection 1 91 1.8 HQC – Injection 2 91 HQC – Injection 3 94 ULOQ – Injection 1 110 1.2 ULOQ – Injection 2 112 ULOQ – Injection 3 110 Table 1-5. Interference effects: (1 : 1 mAb : Cemdisiran ratio ) QC (N=3) Accuracy(%) CV (%) 5 mg/mL mAb 5 mg/mL mAb + 5 mg/mL Cemdisiran LQC 101 98 6.5 LQC 116 105 LQC 107 101 MQC 110 110 1.0 MQC 111 110 MQC 109 108 HQC 111 108 4.9 HQC 115 102 HQC 116 108 ULOQ 114 111 3.8 ULOQ 115 112 ULOQ 117 123 Table 1-6. Stability of treated samples (48 hours ) QC (N=3) Accuracy(%) CV (%) LLOQ 84 11.0 LLOQ 87 LLOQ 102 LLOQ-48 110 LLOQ-48 109 LLOQ-48 102 LQC 105 6.5 LQC 102 LQC 100 LQC-48 92 LQC-48 105 LQC-48 91 MQC 99 3.5 MQC 96 MQC 97 MQC-48 104 MQC-48 103 MQC-48 102 HQC 89 5.2 HQC 96 HQC 91 HQC-48 100 HQC-48 102 HQC-48 97 ULOQ 107 3.7 ULOQ 113 ULOQ 110 ULOQ-48 116 ULOQ-48 117 ULOQ-48 118 Table 1-7. Freeze-thaw stability (3 cycles ) QC Accuracy(%) CV (%) Fresh(N=3) 3x FT (N=1) LLOQ 83 85 11.5 LLOQ 102 LLOQ 102 LQC 89 90 7.6 LQC 105 LQC 93 MQC 97 92 3.0 MQC 99 MQC 96 HQC 100 99 1.9 HQC 96 HQC 99 ULOQ 101 97 3.2 ULOQ 103 ULOQ 97 Case 2 : Cemdisiran + Pazelimumab Stability Study

An investigational study was initiated for the long-term, accelerated and pressure stability of co-formulations of Cemdisiran and Pasqualimumab in a single formulation. Co-formulations were manufactured and Cemdisiran was reconstituted in WFI (Water for Injection).

The glass vials were filled with filtered co-formulations (100:100 or 75:150 Cemdisiran mg/mL: Paselimab (mg/mL)). The 100:100 co-formulation contained 100 mg/mL Cemdisiran, 100 mg/mL Paselimab, 10 mM histidine, 50 mM arginine hydrochloride, 0.075% (w/v) polysorbate 80, 1% (w/v) sucrose, pH 6.0. The 75:150 co-formulation contained 75 mg/mL Cemdisiran, 150 mg/mL Paselimab, 15 mM histidine, 75 mM arginine hydrochloride, 0.1125% (w/v) polysorbate 80, 1.5% (w/v) sucrose, pH 6.0.

A liquid formulation containing cemdisiran alone (100 mg/mL cemdisiran in 50 mM Arg HCl, 10 mM His, 1% sucrose, 0.075% PS80, pH 6) was also prepared and used as a control in this study.

Long-term, accelerated, and stress stability studies. A summary of the long-term, accelerated, and stress stability conditions is presented in Table 2-1. Table 2-1. Stability studies for the initial feasibility assessment of Cemdisiran + Pasqualimab Long- ^term stabilitya Container / Seal Storage temperature Storage length ( months ) Glass bottle with elastic stopper 5℃ 0, 1, 3, 6, 9, 12, 18, 24, and 36 Acceleration and pressure stability Cultivation temperature Cultivation length 25℃/60%RH 0, 1, 3, and 6 months 40℃/75%RH 0, 0.5, 1, and 3 months Stability to freeze-thaw and stirring condition Pressure duration Freeze-thaw (-30℃ to RT) 0 and 4 cycles Agitation (250 rpm on orbital shaker) 0 and 48 hours

Results (Pazelimab: 24 months storage at 5°C ) . After 24 months at 5°C, no significant changes in the physical or chemical stability of Pazelimab in the co-formulations were observed for any of the monitored attributes (see Tables 2-2 and 2-3).

Results (Pazelimab: 3-6 months at 25°C or 40°C). After storage at 25°C/60% RH and 40°C/75% RH, the stability of pazelimab in liquid formulations changed significantly (e.g., formation of HMW and charge variants) (see Tables 2-4 and 2-5) similar to that of liquid formulations of pazelimab alone (data not shown).

Results (Cemdisiran: stored at 5°C, 25°C or 40°C). Cemdisiran purity (based on dIPRP) decreased in both co-formulations (100:100 and 75:100) at 5°C and 25°C/60% RH and 40°C/75% RH (see Tables 2-2 to 2-5, Figures 2 and 3). However, no significant changes in the physical or chemical stability of the Cemdisiran control formulation were observed for any of the monitored attributes after 3 months at 40°C/75% RH (Table 2-6 and Figure 3).

The chromatogram of the dIPRP analysis of the sample at 40℃/75% RH for 3 months is shown in Figure 4. The purity decreased due to the decrease in the sense peak and the increase in two impurities (#1 and #2). Table 2-2. Stability of 100 mg/mL Cemdisiran and 100 mg/mL Paszelimab Liquid Drug Products after Storage at 5 ℃ (Lot 2) Preparation 100 mg/mL Cemdisiran , 100 mg/mL Paszelimumab, 10 mM Histidine, 50 mM Arginine HCl, 0.075% (w/v) Polysorbate 80 , 1% (w/v) Sucrose, pH 6.0 analyze Storage length ( months ) t=0 1 3 6 9 12 18 twenty four 36 Color and ^appearance pass through pass through pass through pass through pass through pass through pass through pass through pass through pH 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 ^Particle analysis by MFIb (#/mL) ≧ 10µm 38 14 41 165 35 twenty two NR 16 16 ≧ 25µm 8 3 twenty four 17 19 5 NR 3 5 Purity of Cemdisiran according to dIPRP (%) 90.5 91.1 90.8 90.0 88.8 88.7 89.0 89.4 87.4 Total impurities 1, 2 and 3 according to dIPRP (%) ^c 1.0 0.9 1.4 1.7 2.0 2.4 2.9 3.3 4.8 Purity of Pazelimumab by SE-FLR-UPLC (%) HMW 1.0 0.9 0.9 1.1 1.2 1.4 1.4 1.3 1.6 Main Peak 98.3 98.4 98.4 98.0 98.4 98.0 97.8 98.2 97.4 LMW 0.7 0.7 0.7 0.9 0.4 0.7 0.8 0.6 0.9 Analysis of charge variants of pazelimab based on iCIEFd ^(%) Area 1 28.6 28.2 28.6 29.9 30.1 30.8 32.0 29.0 31.0 Area 2 56.2 57.2 55.7 57.1 57.8 57.3 55.7 58.1 56.6 Area 3 15.2 14.6 15.7 13.0 12.1 11.8 12.3 12.9 12.5 Relative efficacy of pazelimab (%) 101 103 105 NR NR 85 NR 105 118 a The sample was evaluated by color and visual appearance if it was clear to slightly opalescent, contained essentially no visible particles, and was colorless to yellow. b Silicone oil droplets and bubbles were removed by removing particles with an aspect ratio ≤ 0.85. c Impurities 1, 2, and 3 were generated by the loss of 1, 2, and 3 N-acetylgalactosamine (GalNAc). d Region 1 corresponds to acidic materials eluting before the main peak, region 2 corresponds to the main peak, and region 3 corresponds to alkaline materials eluting after the main peak. dIPRP, denaturing ion pair reversed phase; DP, drug product; FDS, formulated drug substance; FLR, fluorescence; HMW, high molecular weight; iCIEF, imaged capillary isoelectric focusing; LMW, low molecular weight; microfluidic imaging; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography Table 2-3. Stability of 75 mg/mL Cemdisiran and 150 mg/mL Paszelimumab liquid drug products after storage at 5 °C (Lot 2) Preparation 75 mg/mL Cemdisiran , 150 mg/mL Paszelimumab, 15 mM Histidine, 75 mM Arginine HCl, 0.1125% (w/v) Polysorbate 80 , 1.5% (w/v) Sucrose, pH 6.0 analyze Storage length ( months ) t=0 1 3 6 9 12 18 twenty four 36 Color and ^appearance pass through pass through pass through pass through pass through pass through pass through pass through pass through pH 6.0 6.0 6.0 6.0 6.0 6.0 5.9 6.0 5.9 ^Particle analysis by MFIb (#/mL) ≧ 10µm 19 19 63 76 8 5 NR 19 5 ≧ 25µm 5 5 27 17 0 3 NR 5 0 Purity of Cemdisiran according to dIPRP (%) 90.8 90.6 90.5 89.4 88.3 87.8 87.8 87.4 85.4 Total impurities 1, 2 and 3 according to dIPRP (%) ^c 1.1 1.3 1.7 2.4 2.8 3.4 4.2 4.7 6.6 Purity of Pazelimumab by SE-FLR-UPLC (%) HMW 0.9 0.9 1.0 1.0 1.2 1.3 1.2 1.2 1.5 Main Peak 98.4 98.4 98.3 98.3 98.3 98.1 98.2 98.2 97.7 LMW 0.7 0.7 0.7 0.7 0.5 0.6 0.6 0.6 0.8 Analysis of charge variants of pazelimab based on iCIEFd ^(%) Area 1 28.1 28.7 28.8 30.2 31.1 30.5 32.1 30.1 30.2 Area 2 56.3 55.7 55.9 57.6 57.0 57.1 53.7 55.1 55.0 Area 3 15.5 15.6 15.3 12.2 11.9 12.4 14.2 14.8 14.8 Relative efficacy of pazelimab (%) 90 103 114 NR NR 99 NR 92 93 a The sample was evaluated by color and visual appearance if it was clear to slightly opalescent, contained essentially no visible particles, and was colorless to yellow. b Silicone oil droplets and bubbles were removed by removing particles with an aspect ratio ≤ 0.85. c Impurities 1, 2, and 3 were generated by the loss of 1, 2, and 3 N-acetylgalactosamine (GalNAc). d Region 1 corresponds to acidic materials eluting before the main peak, region 2 corresponds to the main peak, and region 3 corresponds to alkaline materials eluting after the main peak. dIPRP, denaturing ion pair reversed phase; DP, drug product; FDS, formulated drug substance; FLR, fluorescence; HMW, high molecular weight; iCIEF, imaged capillary isoelectric focusing; LMW, low molecular weight; microfluidic imaging; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography Table 2-4. Stability of 100 mg/mL Cemdisiran and 100 mg/mL Paszelimab liquid drug products after storage at 25 °C /60%RH and 40 °C /75%RH (Lot 2) Preparation 100 mg/mL Cemdisiran , 100 mg/mL Paszelimumab, 10 mM Histidine, 50 mM Arginine HCl, 0.075% (w/v) Polysorbate 80 , 1% (w/v) Sucrose, pH 6.0 analyze Storage length ( months ) t=0 25 ℃ /60%RH 40 ℃ /75%RH 1 3 6 0.5 1 3 Color and ^appearance pass through pass through pass through pass through pass through pass through pass through pH 6.0 6.0 6.0 6.0 6.0 6.0 6.0 ^Particle analysis by MFIb (#/mL) ≧ 10µm 38 14 twenty four 28 30 52 twenty two ≧ 25µm 8 3 16 6 14 11 11 Purity of Cemdisiran according to dIPRP (%) 90.5 90.2 87.8 85.1 90.0 88.9 85.8 Total impurities 1, 2 and 3 according to dIPRP (%) ^c 1.0 2.2 4.2 6.1 2.4 3.5 6.2 Purity of Pazelimumab by SE-FLR-UPLC (%) HMW 1.0 1.2 1.4 1.8 2.0 3.0 8.5 Main Peak 98.3 98.1 97.9 97.3 97.2 96.1 90.2 LMW 0.7 0.7 0.7 0.9 0.7 0.9 1.3 Analysis of charge variants of pazelimab based on iCIEFd ⁽ %) Area 1 28.6 29.1 34.4 39.7 32.8 40.4 64.5 Area 2 56.2 53.5 51.7 46.6 48.4 43.0 25.5 Area 3 15.2 17.4 13.9 13.7 18.8 16.6 10.0 Relative efficacy of pazelimab (%) 101 NR NR NR NR 91 85 a The sample was evaluated by color and visual appearance if it was clear to slightly opalescent, contained essentially no visible particles, and was colorless to yellow. b Silicone oil droplets and bubbles were removed by removing particles with an aspect ratio ≤ 0.85. c Impurities 1, 2, and 3 were generated by the loss of 1, 2, and 3 N-acetylgalactosamine (GalNAc). d Region 1 corresponds to acidic materials eluting before the main peak, region 2 corresponds to the main peak, and region 3 corresponds to alkaline materials eluting after the main peak. dIPRP, denaturing ion pair reversed phase; FLR, fluorescence; HMW, high molecular weight; iCIEF, imaged capillary isoelectric focusing; LMW, low molecular weight; microfluidic imaging; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography Table 2-5. Stability of 75 mg/mL Cemdisiran and 150 mg/mL Paszelimumab liquid drug products after storage at 25 °C /60%RH and 40 °C /75%RH (Lot 2) Preparation 75 mg/mL Cemdisiran , 150 mg/mL Paszelimumab, 15 mM Histidine, 75 mM Arginine HCl, 0.1125% (w/v) Polysorbate 80 , 1.5% (w/v) Sucrose, pH 6.0 analyze Storage length ( months ) t=0 25 ℃ /60%RH 40 ℃ /75%RH 1 3 6 0.5 1 3 Color and ^appearance pass through pass through pass through pass through pass through pass through pass through Turbidity (OD increase at 405 nm) 0.00 0.00 0.00 0.00 0.00 0.00 0.01 pH 6.0 6.0 6.0 6.0 6.0 6.0 6.0 ^Particle analysis by MFIb (#/mL) ≧ 10µm 19 11 0 33 31 8 8 ≧ 25µm 5 0 0 5 0 0 3 Purity of Cemdisiran according to dIPRP (%) 90.8 88.8 85.9 82.3 88.9 87.3 82.3 Total impurities 1, 2 and 3 according to dIPRP (%) ^c 1.1 3.1 6.0 8.8 3.4 5.2 9.7 Total Pazelimumab Recovered (%) 100 99 99 99 99 98 94 Purity of Pazelimumab by SE-FLR-UPLC (%) HMW 0.9 1.2 1.4 1.8 2.0 3.1 9.1 Main Peak 98.4 98.1 97.8 97.5 97.2 95.9 89.5 LMW 0.7 0.7 0.8 0.8 0.8 1.0 1.4 Analysis of charge variants of pazelimab based on iCIEFc ^{( %)} Area 1 28.1 28.2 33.5 38.7 32.1 40.5 63.3 Area 2 56.3 54.0 50.5 45.2 48.9 40.7 25.0 Area 3 15.5 17.9 16.0 16.1 19.0 18.9 11.7 Relative efficacy of pazelimab (%) 90 NR NR NR NR 103 104 a The sample was evaluated by color and visual appearance if it was clear to slightly opalescent, contained essentially no visible particles, and was colorless to yellow. b Silicone oil droplets and bubbles were removed by removing particles with an aspect ratio ≤ 0.85. c Impurities 1, 2, and 3 were generated by the loss of 1, 2, and 3 N-acetylgalactosamine (GalNAc). d Region 1 corresponds to acidic materials eluting before the main peak, region 2 corresponds to the main peak, and region 3 corresponds to alkaline materials eluting after the main peak. dIPRP, denaturing ion pair reversed phase; FLR, fluorescence; HMW, high molecular weight; iCIEF, imaging capillary isoelectric focusing; LMW, low molecular weight; microfluidic imaging; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography Table 2-6. Stability of 100 mg/mL Cemdisiran liquid drug product after storage at 40 °C /75%RH Preparation 100 mg/mL Cemdisiran , 10 mM histidine, 50 mM arginine hydrochloride, 0.075% (w/v) polysorbate 80 , 1% (w/v) sucrose, pH 6.0 analyze Storage length ( months ) t=0 40 ℃ /75%RH 0.5 1 3 Color and ^appearance pass through pass through pass through pass through pH 6.1 6.2 6.1 6.1 ^Particle analysis by MFIb (#/mL) ≧ 10µm twenty two 5 5 106 ≧ 25µm 5 3 5 27 Purity of Cemdisiran according to dIPRP (%) 91.3 91.2 91.9 91.3 Total impurities 1, 2 and 3 according to dIPRP (%) ^c 0.6 0.6 0.6 0.7 a Assessed by color and visual appearance if the sample is clear to slightly opalescent, contains essentially no visible particles, and is colorless to yellow. b Silicone oil droplets and bubbles were removed by removing particles with an aspect ratio ≤ 0.85. c Impurities 1, 2, and 3 are due to the loss of 1, 2, and 3 N-acetylgalactosamine (GalNAc). dIPRP, denaturing ion pair reversed phase; DP, drug product; NR, not required; UPLC, ultra-high performance liquid chromatography Identification of Cemdisiran impurities

DIPRP was coupled to MS (mass spectrometry) to identify Cemdisiran impurities in the co-formulations.

The results confirmed that impurities #1 and #2 in Figure 5 represent Cemdisiran missing 1 or 2 N-acetylgalactosamine (GalNAc). Three GalNAc at the terminus of the ligand are attached to the 3' end of the sense strand of the Cemdisiran molecule. This ligand (with GalNAc) enables the molecule to bind to liver receptors and enter liver cells. β-Hexosaminidase was confirmed to be a host cell protein (HCP) in the drug substance of the Paszelimab formulation, which caused the degradation of Cemdisiran in the co-formulation

Experiment 1. Co-formulations (100:100 and 75:150) were made as above using Paszelimab batch 1. A quantitative method was developed by selected reaction monitoring (SRM)-LC-MS/MS, whereby the concentration of β-hexosaminidase in batch 1 was 2.5× higher compared to batch 2 material.

Co-formulations made using Batch 1 materials were stable at 5°C, 25°C/60% RH, and 40°C/75% RH. The purity of cemdisiran (by dIPRP) in co-formulations made from Pazelimab Batch 1 and Batch 2 at 40°C/75% is shown in Figure 6. The rate of cemdisiran degradation (i.e., formation of impurities and loss of 1 or more GalNAc) was 2.3 times and 2.8 times faster in co-formulations made using Batch 1 materials and Batch 2 materials. The higher rate of cemdisiran degradation was similar to the fold increase in β-hexosaminidase concentration. Table 2-7. Evaluation results of β -hexosaminidase content in the API formulated with Pazelimab used to make co-formulations Process β -hexosaminidase concentration ( ppm molar ratio of β-hex to pasminomab ) β - hexosaminidase concentration (ng/mL) average value SD average value SD 1 3.5 0.3 306 25 2 1.5 0.2 132 15

Experiment 2. β-hexosaminidase incorporation studies under accelerated conditions confirmed that this enzyme is responsible for the degradation of Cemdisiran in liquid co-formulations. Cemdisiran formulations (100 mg/mL) with and without 10 μg/mL β-hexosaminidase were prepared (i.e., Cemdisiran reduced with WFI). Glass bottles were filled with the formulations and stored at 40°C/75% RH. Figure 7 shows the chromatograms of the dIPRP analysis of the two formulations after 0.5 month at 40°C/75% RH. A much smaller sense peak and 3 large impurity peaks (impurities #1, #2, and #3) were present in the stability sample containing β-hexosaminidase. Impurities #1 and #2 are the same as those shown in Figure 4: 1-2 GalNAc residues are lost, and impurity #3 is assumed to be the third and final GalNAc residue lost.

Experiment 1 (pH Study ) . Another stability study (similar to the setup described in the Cemdisiran + Paselimab study above) was initiated using two co-formulations, both containing 50 mg/mL Cemdisiran and 100 mg/mL Paselimab, both made from the same source material (e.g., Paselimab). However, an additional 20 mM histidine was added to one of the co-formulations, resulting in a higher final pH of 6.6. In the co-formulations studied in this experiment, the excipients and final concentrations are shown below: • 50 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 75 mM Arginine HCl, 15 mM Histidine, pH 5.9, 1.5% Sucrose, 0.1125% PS80 • 50 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 75 mM Arginine HCl, 35 mM Histidine, pH 6.6, 1.5% Sucrose, 0.1125% PS80

Figure 8 shows the difference (in %) between the total impurities 1-3 (i.e., loss of 1-3 GalNAc) of the two co-formulations through dIPRP after storage at all three temperatures. The data demonstrate that Cemdisiran degradation was significantly reduced, indicating that the β-hexosaminidase activity is pH-dependent. At higher pH, the β-hexosaminidase activity is reduced.

Experiment 2. Initiate another stability study (similar to Cemdisiran + Pazelimumab) with the following co-formulations: • 50 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 75 mM Arg HCl, 15 mM His, 1.5% sucrose, 0.1125% PS80, pH 6.0, with 5% GlcNAc; • 50 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 75 mM Arg HCl, 15 mM His, 1.5% sucrose, 0.1125% PS80, pH 6.0, with 5% GalNAc; • 100 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 50 mM Arg HCl, 10 mM His, 1.0% sucrose, 0.075% PS80, pH 6.0, with 5% GlcNAc; and 100 mg/mL Cemdisiran, 100 mg/mL Paszelimumab, 50 mM Arg HCl, 10 mM His, 1.0% sucrose, 0.075% PS80, pH 6.0, with 5% GalNAc.

All co-formulations containing GalNAc or GlcNAc showed no significant change in total impurities 1-3 (i.e., loss of 1-3 GalNAc from Cemdisiran) (in %) even after 6 months at 25°C or 3 months at 40°C. See Tables 2-8 to 2-11. Table 2-8. Stability of 50 mg/mL Cemdisiran and 100 mg/mL Paszelimumab plus GlcNAc drug products after storage at 25 °C /60%RH and 40 °C /75%RH ( Batch 3) Preparation 50 mg/mL Cemdisiran , 100 mg/mL Paszelimumab, 15 mM Histidine, 75 mM Arginine HCl, 0.113% (w/v) Polysorbate 80 , 1.5% (w/v) Sucrose, pH 6.0 + 5% GlcNAc analyze Storage length ( months ) t=0 25 ℃ /60%RH 40 ℃ /75%RH 1 3 6 0.5 1 3 Color and ^appearance pass through pass through pass through pass through pass through pass through pass through pH 5.9 5.9 6.0 5.9 6.0 5.9 5.9 ^Particle analysis by MFIb (#/mL) ≧ 10µm 8 NR NR 62 NR NR 31 ≧ 25µm 0 NR NR 8 NR NR 0 Purity of Cemdisiran according to dIPRP (%) 90.9 90.1 90.9 90.4 89.9 89.7 89.5 Total impurities 1, 2 and 3 according to dIPRP (%) ^c 1.1 1.1 1.3 1.2 1.2 1.2 1.7 Total Pazelimumab Recovered (%) 100 99 98 98 102 98 93 Purity of Pazelimumab by SE-FLR-UPLC (%) HMW 1.0 1.2 1.4 1.6 1.8 2.6 6.9 Main Peak 98.5 98.4 97.9 97.5 97.7 96.8 91.6 LMW 0.5 0.4 0.7 0.9 0.5 0.6 1.4 Analysis of charge variants of pazelimab based on iCIEFd ⁽ %) Area 1 31.7 33.1 35.6 33.8 37.3 46.7 67.7 Area 2 57.5 53.7 48.5 51.0 48.7 37.1 19.1 Area 3 10.8 13.2 15.8 15.1 14.0 16.0 13.2 a The sample was evaluated by color and visual appearance if it was clear to slightly opalescent, contained essentially no visible particles, and was colorless to yellow. b Silicone oil droplets and bubbles were removed by removing particles with an aspect ratio ≤ 0.85. c Impurities 1, 2, and 3 were generated by the loss of 1, 2, and 3 N-acetylgalactosamine (GalNAc). d Region 1 corresponds to acidic materials eluting before the main peak, region 2 corresponds to the main peak, and region 3 corresponds to alkaline materials eluting after the main peak. dIPRP, denaturing ion pair reversed phase; FLR, fluorescence; GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine; HMW, high molecular weight; iCIEF, imaged capillary isoelectric focusing; LMW, low molecular weight; MFI, microfluidic imaging; ndIPRP, nondenaturing ion pair reversed phase; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography Table 2-9. Stability of 50 mg/mL Cemdisiran and 100 mg/mL Paszelimumab plus GalNAc Drug Product after Storage at 25 °C /60%RH and 40 °C /75%RH ( Batch 3) Preparation 50 mg/mL Cemdisiran , 100 mg/mL Paszelimumab, 15 mM Histidine, 75 mM Arginine HCl, 0.113% (w/v) Polysorbate 80 , 1.5% (w/v) Sucrose, pH 6.0 + 5% GalNAc analyze Storage length ( months ) t=0 25 ℃ /60%RH 40 ℃ /75%RH 1 3 6 0.5 1 3 Color and ^appearance pass through pass through pass through pass through pass through pass through pass through pH 5.9 5.9 5.9 5.9 6.0 5.9 5.9 ^Particle analysis by MFIb (#/mL) ≧ 10µm 100 102 98 99 102 102 99 ≧ 25µm 12 NR NR 31 NR NR 16 Purity of Cemdisiran according to dIPRP (%) 90.8 90.2 90.8 90.3 89.5 89.6 89.1 Total impurities 1, 2 and 3 according to dIPRP (%) ^c 1.1 1.1 1.2 1.0 1.1 1.1 1.3 Purity of Pazelimumab by SE-FLR-UPLC (%) HMW 1.0 1.1 1.4 1.7 1.9 2.8 8.1 Main Peak 98.6 98.4 97.9 97.4 97.5 96.5 90.4 LMW 0.4 0.4 0.7 0.9 0.6 0.6 1.5 Analysis of charge variants of pazelimab based on iCIEFd ⁽ %) Area 1 31.5 32.3 37.2 36.2 38.4 47.7 72.1 Area 2 57.6 53.6 47.8 47.6 46.5 36.3 16.7 Area 3 11.0 14.1 15.0 16.2 14.2 16.0 11.2 a The sample was evaluated by color and visual appearance if it was clear to slightly opalescent, contained essentially no visible particles, and was colorless to yellow. b Silicone oil droplets and bubbles were removed by removing particles with an aspect ratio ≤ 0.85. c Impurities 1, 2, and 3 were generated by the loss of 1, 2, and 3 N-acetylgalactosamine (GalNAc). d Region 1 corresponds to acidic materials eluting before the main peak, region 2 corresponds to the main peak, and region 3 corresponds to alkaline materials eluting after the main peak. dIPRP, denaturing ion pair reversed phase; FLR, fluorescence; GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine; HMW, high molecular weight; iCIEF, imaged capillary isoelectric focusing; LMW, low molecular weight; MFI, microfluidic imaging; ndIPRP, nondenaturing ion pair reversed phase; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography Table 2-10. Stability of 100 mg/mL Cemdisiran and 100 mg/mL Paszelimumab plus GlcNAc Drug Products after Storage at 25 ℃ /60%RH and 40 ℃ /75%RH ( Batch 3) Preparation 100 mg/mL Cemdisiran , 100 mg/mL Paszelimumab, 10 mM Histidine, 50 mM Arginine HCl, 0.075% (w/v) Polysorbate 80 , 1.0% (w/v) Sucrose, pH 6.0 + 5% GlcNAc analyze Storage length ( months ) t=0 25 ℃ /60%RH 40 ℃ /75%RH 1 3 6 0.5 1 3 Color and ^appearance pass through pass through pass through pass through pass through pass through pass through pH 5.9 5.9 6.0 5.9 6.0 5.9 5.9 ^Particle analysis by MFIb (#/mL) ≧ 10µm 0 NR NR 73 NR NR 46 ≧ 25µm 0 NR NR 54 NR NR 8 Purity of Cemdisiran according to dIPRP (%) 90.5 89.9 90. 8 90.4 90.1 89.6 89.9 Total impurities 1, 2 and 3 according to dIPRP (%) ^c 1.1 1.1 1.3 1.2 1.1 1.2 1.6 Purity of Pazelimumab by SE-FLR-UPLC (%) HMW 1.1 1.5 1.9 2.2 2.4 3.5 8.6 Main Peak 98.4 97.9 97.2 96.9 96.8 95.7 90.1 LMW 0.5 0.6 0.9 0.9 0.7 0.8 1.3 Analysis of charge variants of pazelimab based on iCIEFd ⁽ %) Area 1 31.0 32.3 36.9 38.5 35.4 48.1 70.9 Area 2 58.3 54.1 49.1 48.0 51.2 37.7 18.7 Area 3 10.7 13.6 14.1 13.5 13.4 14.2 10.5 a The sample was evaluated by color and visual appearance if it was clear to slightly opalescent, contained essentially no visible particles, and was colorless to yellow. b Silicone oil droplets and bubbles were removed by removing particles with an aspect ratio ≤ 0.85. c Impurities 1, 2, and 3 were generated by the loss of 1, 2, and 3 N-acetylgalactosamine (GalNAc). d Region 1 corresponds to acidic materials eluting before the main peak, region 2 corresponds to the main peak, and region 3 corresponds to alkaline materials eluting after the main peak. dIPRP, denaturing ion pair reversed phase; FLR, fluorescence; GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine; HMW, high molecular weight; iCIEF, imaged capillary isoelectric focusing; LMW, low molecular weight; MFI, microfluidic imaging; ndIPRP, nondenaturing ion pair reversed phase; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography Table 2-11. Stability of 100 mg/mL Cemdisiran and 100 mg/mL Paszelimumab plus GalNAc drug products after storage at 25 ℃ /60%RH and 40 ℃ /75%RH ( Batch 3) Preparation 100 mg/mL Cemdisiran , 100 mg/mL Paszelimumab, 10 mM Histidine, 50 mM Arginine HCl, 0.075% (w/v) Polysorbate 80 , 1.0% (w/v) Sucrose, pH 6.0 + 5% GalNAc analyze Storage length ( months ) t=0 25 ℃ /60%RH 40 ℃ /75%RH 1 3 6 0.5 1 3 Color and ^appearance pass through pass through pass through pass through pass through pass through pass through pH 5.9 5.9 6.0 5.9 6.0 5.9 5.9 ^Particle analysis by MFIb (#/mL) ≧ 10µm 31 NR NR 8 NR NR N ^A ≧ 25µm 4 NR NR 0 NR NR N ^A Purity of Cemdisiran according to dIPRP (%) 91.1 90.0 91.0 90.7 90.0 89.7 89.9 Total impurities 1, 2 and 3 according to dIPRP (%) ^c 1.0 1.1 1.2 1.0 1.1 1.1 1.3 Purity of Pazelimumab by SE-FLR-UPLC (%) HMW 1.1 1.5 1.9 2.3 2.5 3.7 9.7 Main Peak 98.5 97.9 97.3 96.8 96.7 95.5 88.9 LMW 0.5 0.6 0.9 0.9 0.8 0.8 1.4 Analysis of charge variants of pazelimab based on iCIEFd ⁽ %) Area 1 30.2 32.5 37.3 37.3 34.5 48.7 72.4 Area 2 59.0 53.8 49.3 49.2 52.4 37.1 18.4 Area 3 10.8 13.7 13.3 13.5 13.1 14.3 9.2 a Assessed by color and visual appearance if the sample is clear to slightly opalescent, contains essentially no visible particles, and is colorless to yellow. b Silicone oil droplets and bubbles were removed by removing particles with aspect ratio ≤ 0.85. c Impurities 1, 2, and 3 are caused by the loss of 1, 2, and 3 N-acetylgalactosamine (GalNAc). d Region 1 corresponds to acidic material eluting before the main peak, region 2 corresponds to the main peak, and region 3 corresponds to alkaline material eluting after the main peak. e Sample result is unavailable due to instrumental problems. dIPRP, denaturing ion-pair reversed phase; FLR, fluorescence; GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine; HMW, high molecular weight; iCIEF, imaging capillary isoelectric focusing; LMW, low molecular weight; MFI, microfluidic imaging; ndIPRP, nondenaturing ion-pair reversed phase; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography

The concentration of β-hex in the formulated drug substance (FDS) of pazelimab directly affects the degradation rate of cemdisiran in liquid co-formulations

Two additional co-formulations were made using paslimumab (with low and high measured concentrations of β-hex, batches 3 and 4, respectively) and stored for stability studies.

The two co-formulations were: •100 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 50 mM Arg HCl, 10 mM His, 1.0% sucrose, 0.075% PS80, pH 6.0; and •50 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 75 mM Arg HCl, 15 mM His, 1.5% sucrose, 0.1125% PS80, pH 6.0

Figure 9 shows that co-formulations made with paseritumab containing high amounts of β-hexosaminidase exhibited faster degradation rates of cemdisiran (i.e., higher % of total GalNac impurities via dIPRP) than those with low amounts of β-hexosaminidase. Over time, the square root (sq root) was found to best fit the data and equation.

The data also demonstrated that the rate of cemdisiran degradation is proportional to the amount of β-hexosaminidase. Compared to co-formulations made with paselimab lot 4, co-formulations made with paselimab lot 3 (containing 30% more β-hex compared to lot 4) resulted in 30-35% faster cemdisiran degradation rates for both co-formulations. Example 3 : Formulation Characterization and PS80 ( Polysorbate 80) Range Studies to Identify Co-formulations

To optimize the pH and concentration of the excipients selected for the co-formulation of Cemdisiran and Pasirimab, a Design of Experiment (DOE) study was developed to characterize and explore the excipient design space (see Table 3-1). Twenty-three co-formulation studies were designed, taking into account all the main effects defined by the risk assessment as well as the identified secondary interactions and quadratics. The statistical JMP software was used to establish, evaluate, and confirm that the design had sufficient power and was able to cover >95% of the design space and had good estimation power (i.e., predicted variance <1.0). Each co-formulation also contained 0.15% PS80. Table 3-1. Formulation parameters used in the characterization study of cemdisiran and pazelimab co-formulations factor Low High pH 5.5 7.0 Sucrose concentration (% w/v) 0.8 3.6 L-Arginine hydrochloride concentration (mM) 40 140 Pazelimumab concentration (mg/mL) 90 110 Cemdisiran concentration (mg/mL) 20 100 Histamine concentration (mM) 35 45

Table 3-2 presents a summary of the long-term, accelerated, and pressure stability conditions as well as the freeze-thaw conditions. Table 3-2. Characteristics of the formulation of Cemdisiran + Pazelimumab for stability study Long-term stability Container / Seal Storage temperature Storage length ( months ) Glass bottle with elastic stopper 5℃ 0, 4, 6, 8, 12 and 24 months Acceleration and pressure stability Cultivation temperature Cultivation length 25℃/60%RH 0, 2, and 3 months 40℃/75%RH 0, 0.5, and 1 month

Excipients, excipient concentrations, and pH were selected based on the following desirability criteria: - Minimum HMW formation at 2-8°C; - Minimum formation of acidic charge variants at 2-8°C; - Acceptable tonicity for SC administration; and - Minimum degradation of Cemdisiran at 2-8°C.

The excipients, excipient concentrations, and pH of the co-formulations evaluated in the DOE experiments are shown in Figures 10 and 11. Figure 10 presents the formulation composition of the optimized co-formulation set at 50:100 (Cemdisiran:Paslimab). Figure 11 presents the formulation composition of the optimized co-formulation set at 100:100. Based on the model and expectation criteria, an expectation of 0.66 or 0.78 was considered a high value.

Higher pH (relative to pH 6) resulted in a significant decrease in the degradation of cemdisiran at 2-8°C. At higher pH, a higher rate of acidic charge formation was observed for pazelimab, but this effect was relatively small after storage at 2-8°C for 4 months.

For the 50:100 co-formulation, it was observed that higher arginine HCl concentrations (e.g., 90 mM vs. 50 mM) reduced Cemdisiran degradation and allowed for a near isotonic solution. PS80 Range Study

After selecting the sucrose concentration, arginine HCl concentration, histidine concentration and pH for each co-formulation, a stir stability study was performed to evaluate the concentration of PS80. Surfactants are necessary to prevent protein instability at the air-liquid interface. The following co-formulations were made with 0.025, 0.050, 0.075, 0.1, or 0.2% (w/v) PS80: •100 mg/mL Cemdisiran, 100 mg/mL Paselimab, 50 mM Arginine HCl, 30 mM Histidine, 1% Sucrose, X% PS80, pH 6.5; and •50 mg/mL Cemdisiran, 100 mg/mL Paselimab, 90 mM Arginine HCl, 30 mM Histidine, 1% Sucrose, X% PS80, pH 6.5

Glass bottles were filled with co-formulations and placed on an orbital shaker at 250 RPM in the sideways direction for 48 hours. All co-formulations showed no changes in any of the monitored quality attributes, including %HMW, as shown in Figure 12. Optimizing Co-formulation Stability

Investigational studies were initiated to evaluate long-term, accelerated, and pressure stability of optimized co-formulations of Cemdisiran and Pazelimumab in a single formulation. Glass syringes were filled with the following co-formulations and stored for stability studies: •100 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 50 mM Arginine HCl, 30 mM Histidine, 1% Sucrose, 0.075% PS80, pH 6.5; and •50 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 90 mM Arginine HCl, 30 mM Histidine, 1% Sucrose, 0.075% PS80, pH 6.5

Long-term, accelerated, and pressure stability studies . A summary of the long-term, accelerated, and pressure stability conditions as well as the stirring and freeze-thaw conditions are presented in Table 3-3. Table 3-3. Stability investigation studies for the optimization evaluation of Cemdisiran + Pasqualimab Long-term stability Container / Seal Storage temperature Storage length ( months ) Glass syringe with elastic stopper 5℃ 0, 1, 3, 6, 9, 12, 18, 24, and 36 Acceleration and pressure stability Cultivation temperature Cultivation length 25℃/60%RH 0, 1, 2, 3, and 6 months 40℃/75%RH 0, 0.25, 0.5, 1, 2, and 3 months

After storage at 5°C for 6 months, there were no significant changes in the stability of Pazelimumab (e.g., formation of HMW and charge variants) or the stability of Cemdisiran (e.g., purity) (see Tables 3-4 and 3-5).

At 40°C/75% RH, the purity of cemdisiran (based on dIPRP) decreased in both co-formulations. However, the degradation rate of cemdisiran in these co-formulations was much lower than that in other studies (Figure 13). Table 3-4. Stability of 100 mg/mL cemdisiran and 100 mg/mL paszelimab optimized drug products after storage at 5 °C DP formulations 100 mg/mL Cemdisiran , 100 mg/mL Paszelimumab, 30 mM Histidine, 50 mM Arginine HCl, 0.075% (w/v) Polysorbate 80 , 1.0% (w/v) Sucrose, pH 6.5 Pazelimab FDS batch number 3 analyze Storage length ( months ) t=0 2-8 ℃ 1 3 6 9 12 pH 6.6 6.5 6.6 6.6 6.6 6.6 ^Particle Analysis by MFIa (#/container) ≧ 10µm 81 NR NR 89 NR 153 ≧ 25µm 49 NR NR 0 NR 8 Purity of Cemdisiran according to dIPRP (%) 90.1 90.7 90.7 90.9 90.1 89.6 Total impurities 1, 2 and 3 according to dIPRP (%) ^b 1.1 1.1 1.1 1.3 1.7 1.9 Purity of Pazelimumab by SE-FLR-UPLC (%) HMW 1.1 1.1 1.2 1.4 1.4 1.6 Main Peak 98.1 98.1 98.0 97.8 97.8 97.7 LMW 0.8 0.8 0.8 0.7 0.8 0.8 Analysis of charge variants of pazelimab based on iCIEFc ^(%) Area 1 33.5 34.1 30.5 31.4 31.1 30.1 Area 2 57.4 56.6 59.8 59.3 59.2 59.6 Area 3 9.2 9.3 9.7 9.2 9.7 10.2 Relative efficacy of pazelimab (%) 100 NR NR 134 NR 112 ^a Silicone oil droplets and bubbles were removed by removing particles with aspect ratio ≤ 0.85. ^b Impurities 1, 2, and 3 were generated due to the loss of 1, 2, and 3 N-acetylgalactosamine (GalNAc). ^c Region 1 corresponds to the acidic substances eluted before the main peak, region 2 corresponds to the main peak, and region 3 corresponds to the alkaline substances eluted after the main peak. dIPRP, denaturing ion pair reversed phase; DP, drug product; FDS, formulated drug substance; FLR, fluorescence; HMW, high molecular weight; iCIEF, imaged capillary isoelectric focusing; LMW, low molecular weight; microfluidic imaging; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography Table 3-5. Stability of 50 mg/mL Cemdisiran and 100 mg/mL Paszelimumab Optimized Drug Product after Storage at 5 °C DP formulations 50 mg/mL Cemdisiran , 100 mg/mL Paszelimumab, 30 mM Histidine, 90 mM Arginine Hydrochloride, 0.075% (w/v) Polysorbate 80 , 1.0% (w/v) Sucrose, pH 6.5 Pazelimab FDS batch number 3 analyze Storage length ( months ) t=0 2-8 ℃ 1 3 6 9 12 pH 6.6 6.5 6.5 6.5 6.5 6.5 ^Particle Analysis by MFIa (#/container) ≥ 10µm 169 NR NR 9 NR 121 ≥ 25µm 33 NR NR 0 NR 25 Purity of Cemdisiran according to dIPRP (%) 90.5 90.4 90.4 90.6 89.7 88.9 Total impurities 1, 2 and 3 according to dIPRP (%) ^b 1.1 1.2 1.3 1.6 2.1 2.3 Purity of Pazelimumab by SE-FLR-UPLC (%) HMW 0.9 1.0 1.0 1.1 1.1 1.2 Main Peak 98.4 98.2 98.3 98.2 98.1 98.2 LMW 0.7 0.8 0.7 0.7 0.8 0.6 Analysis of charge variants of pazelimab based on iCIEFc ⁽ %) Area 1 33.5 33.8 32.1 31.9 22.9 24.4 Area 2 56.2 56.8 58.7 58.8 65.9 65.2 Area 3 10.2 9.5 9.2 9.3 11.1 10.4 Relative efficacy of pazelimab (%) 83 NR NR 96 NR 116 ^a Silicone oil droplets and bubbles were removed by removing particles with aspect ratio ≤ 0.85. ^b Impurities 1, 2, and 3 were generated due to the loss of 1, 2, and 3 N-acetylgalactosamine (GalNAc). ^c Region 1 corresponds to the acidic substances eluted before the main peak, region 2 corresponds to the main peak, and region 3 corresponds to the alkaline substances eluted after the main peak. dIPRP, denaturing ion pair reversed phase; DP, drug product; FDS, formulated drug substance; FLR, fluorescence; HMW, high molecular weight; iCIEF, imaged capillary isoelectric focusing; LMW, low molecular weight; microfluidic imaging; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography Example 4 : Clinical trial to evaluate the safety and efficacy of paszelimab and cemdisiran combination therapy in patients with paroxysmal nocturnal hemoglobinuria (PNH) who switched from paszelimab monotherapy (R3918-PNH-2092)

PNH is an extremely rare, life-threatening, acquired genetic disease characterized by chronic intravascular hemolysis due to uncontrolled complement activation and is associated with an increased risk of thrombosis. PNH patients often experience severe fatigue, which negatively impacts their physical function and health-related quality of life (QoL). Despite available treatments, patients may continue to experience breakthrough hemolysis due to inadequate complement inhibition. Cemdisiran and paslimab are therapeutic agents that work together to inhibit terminal complement activity. Cemdisiran is a small interfering RNA (siRNA) that binds to N-acetylgalactosamine and inhibits liver production of complement component C5, while pasirimab is a fully human monoclonal antibody inhibitor of human C5. The combination of Pazelimumab and Cemdisiran is being evaluated in an ongoing Phase 2, randomized, open-label, two-arm study (NCT04811716), which is designed to evaluate the safety and efficacy of Pazelimumab and Cemdisiran combination therapy in PNH patients who are switching from Pazelimab monotherapy (30 mg/kg IV loading dose of Pazelimab followed by 800 mg Pazelimab SC weekly) during an open-label extension trial (see NCT04162470). Safety and efficacy results are presented here, as well as patient-reported outcomes up to Week 16.

One objective of this study was to evaluate the safety and efficacy of two dosing regimens of paselimab plus cemdisiran combination therapy in PNH patients switching from paselimab monotherapy. Another objective of this study was to describe patient-reported fatigue and the effects on function and global health status (GHS)/QoL after treatment with paselimab plus cemdisiran combination therapy in PNH patients switching from paselimab monotherapy. Table 4-1. Baseline Characteristics Features Group 1 ( n =12) Group 2 (n= 10 ) Age, years, mean (SD) 53.2 (16.4) 43.9 (17.2) Gender, male, n(%) 6 (50.0) 6 (60.0) Race, non-Hispanic or Latino, n (%) 12 (100.0) 10 (100.0) Race, n(%) White 1 (8.3) 1 (10.0) Asian 11 (91.7) 9 (90.0) Age of diagnosis of PNH, years, median (Q1:Q3) 45.0 (32:50) 29.5 (24:57) Baseline LDH, U/L, mean (SD) 237.9 (41.1) 237.2 (49.1) Baseline LDH, x ULN, mean (SD) 0.8 (0.2) 0.8 (0.2) Hemoglobin, g/L, mean (SD) 115.4 (17.2) 108.9 (21.5) ^a eGFR, mL/min/1.73m2, mean (SD) 104.1 (21.9) 116.3 (19.6) Total bilirubin, μmol/L, mean (SD) 22.8 (12.3) 33.0 (16.8) Heme-binding protein, g/L, mean (SD) 0.1 (0.1) 0.1 (0.1) CH50, kIU/L, mean (SD) 0.1 (0.3) 0.0 (0.0) ^a n=9 Group 1: Pazelimab 400 mg SC Q4W + Cemdisiran 200 mg SC Q4W. Group 2: Pazelimab 400 mg SC Q2W + Cemdisiran 200 mg SC Q4W. CH50, total complement hemolysis assay; eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase; PNH, paroxysmal nocturnal hemoglobinuria; Q, quartile; SC, subcutaneous; SD, standard deviation; ULN, upper limit of normal. Inclusion criteria

Patients must meet the following criteria to be eligible for inclusion in the study: 1. PNH patients who have been treated with paszelimab monotherapy in the R3918-PNH-1868 study (NCT04162470; "An open-label extension study in patients with paroxysmal nocturnal hemoglobinuria to evaluate the long-term safety, tolerability, and efficacy of REGN3918) [Inclusion criteria for R3918-PNH-1868: PNH patients who have completed and have not discontinued study treatment in one of the parent studies in which the patient participated (the parent study is R3918-PNH-1852 [NCT03946748; "A study to evaluate the safety and efficacy of REGN3918 in patients with paroxysmal nocturnal hemoglobinuria (PNH)", including patients who have not received or have not recently received a complement inhibitor], or R3918-PNH-1853 ["An open-label study to evaluate the efficacy and safety of REGN3918 in patients with paroxysmal nocturnal hemoglobinuria switching from other anti-C5 therapies", including PNH patients currently treated with eculizumab and planning to switch to REGN3918]). 2. Provide signed informed consent from the study patient 3. Be willing and able to comply with clinical/remote visits and study-related procedures Exclusion criteria

Patients who meet any of the following criteria will be excluded from the study. Patients may be rescreened up to 2 times after discussion between the Investigator and Sponsor. 1. Have a documented* positive polymerase chain reaction (PCR) or equivalent test based on regional recommendations for COVID-19 or suspected SARS-CoV-2 infection, and: a. Have not recovered from COVID-19 (i.e., all COVID-19-related symptoms and major clinical findings that could impact patient safety have not resolved), and b. Have not had 2 negative results on a nucleic acid amplification (PCR) test or equivalent test performed based on regional recommendations for COVID-19 to confirm that the patient is SARS-CoV-2 negative, or if the COVID-19 PCR (or equivalent) testing is not feasible, at least 3 months must have passed since the initial diagnosis *Note: COVID-19 screening will not be performed as part of the eligibility assessment for this study 2. Patients with a documented history of cirrhosis or patients with liver disease and evidence of current liver impairment; or patients with ALT or AST (not related to PNH) > 3× ULN at the screening visit (1 repeat laboratory is allowed during the screening period) 3. According to the judgment of the investigator, there are significant protocol deviations in the parent study, and these deviations (if persistent) will affect the study objectives and/or patient safety (e.g., patients repeatedly fail to comply with the dosing regimen) 4. Any new condition or worsening of existing condition that the investigator believes would make the patient unsuitable for inclusion or compromise the patient's safety 5. Known allergy to Cemdisiran or any component of Cemdisiran formulations 6. Pregnant or lactating women 7. Women of childbearing potential (WOCBP)* who are unwilling to take highly effective contraceptive measures before the initial dose/first treatment, during the study, and for at least 52 weeks after the last dose. Highly effective contraceptive measures include: a. Stable use of combined (estrogen and progestin) hormonal contraceptives (oral, vaginal, transdermal) or progestin-only hormonal contraceptives (oral, injectable, implantable) to suppress ovulation starting 2 or more menstrual cycles before screening; b. Intrauterine contraceptive device (IUD); intrauterine hormone-releasing system (IUS); c. Bilateral tubal ligation; d. Vasectomy partner (provided that the vasectomized male partner is the only sexual partner of the WOCBP study participant and the vasectomized partner has been medically evaluated for the success of the surgery); and/or e. Abstinence , *WOCBP is defined as a woman of childbearing potential from postmenopause to postmenopause, unless infertility is permanent. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.

The postmenopausal state is defined as the absence of menstruation for 12 months without other medical reasons. High levels of follicle-stimulating hormone (FSH) in the postmenopausal range can be used to confirm the postmenopausal state in women who are not using hormonal contraception or hormone replacement therapy. However, a single FSH measurement is not sufficient to confirm the occurrence of postmenopausal status in the absence of 12 months of amenorrhea. The above definition is based on the Clinical Trial Facilitation Group (CTFG) guidelines (CTFG, 2020). For women with a documented hysterectomy or tubal ligation, pregnancy testing and contraception are not required. Abstinence is considered a highly effective approach only if it is defined as abstention from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of abstinence needs to be assessed based on the duration of the clinical trial and patient preferences and usual lifestyle. Periodic abstinence (calendar method, temperature method, postovulation method), intercourse interruption method (extracorporeal ejaculation method), spermicide alone and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Note: Use of female or male condoms is not sufficient as a contraceptive measure, but may be considered for safety or prevention of sexually transmitted diseases. Female and male condoms should not be used at the same time

Methods: Patients (n=22) were randomized (1:1) to one of two treatment groups; both groups received Cemdisiran 200 mg subcutaneously (SC) every 4 weeks (Q4W) plus Paszelimab 400 mg SC either Q4W (Group 1) or every 2 weeks (Q2W; Group 2). The study consisted of four phases: - Screening phase (7-8 days), - Open-label treatment phase (OLTP; 28 weeks), - Open-label extension phase (OLEP; 52 weeks) as appropriate, and - Safety follow-up phase (52 weeks). Patients who meet breakthrough hemolysis criteria of persistently elevated lactate dehydrogenase (LDH; >1.5 × upper limit of normal [ULN] on two consecutive measurements spanning at least 2 weeks) at any time during the study will be switched to the intensive paszepine regimen. See Figure 17.

The screening period is approximately 7 to 8 days. Patients will have a minimum OLTP (main study period) duration of approximately 28 weeks. For patients who require intensified treatment, the duration will be longer, with a 28-week treatment regimen from the date of intensified treatment. Patients who do not continue in the elective OLEP will be followed for an additional 52 weeks after the last dose of combination treatment. Patients who choose to participate in the OLEP will continue on open-label treatment for 52 weeks and have a 52-week safety follow-up period after the last dose of study treatment. Patients who complete the elective OLEP may be able to continue study treatment as part of the post-trial visit program. Therefore, patients who participate in the post-trial visit program will not be followed during the safety follow-up period.

Screening (7 to 8 days): The dose of paszelimumab was administered at the study site on the day of the Screening Visit, which occurred on the day of the planned administration of paszelimumab monotherapy. Subsequently, the Day 1 Visit for the first combination therapy dose occurred 7 to 8 days after the last dose of paszelimumab monotherapy.

As part of risk mitigation for this study, patients will need to have a record of meningococcal vaccination and receive updated meningococcal vaccination when indicated. Daily oral antibiotic prophylaxis is recommended throughout the study. Patients will be advised of their risk of gonococcal infection, if applicable, based on their risk level.

In addition to the screening process to determine eligibility, patients were asked to complete a PNH symptom-specific questionnaire daily for 7 consecutive days prior to Visit Day 1. Patients could choose to participate in the optional OLEP (open label extension period), optional future biomedical research, and/or optional pharmacogenomic component by signing separate optional informed consent forms.

Treatment Period (Day 1 to Week 28): Day 1 was planned to be 7 to 8 days after the last dose of pasorizumab monotherapy. After confirmation of eligibility on Day 1, patients were randomized in a 1:1 ratio to 1 of 2 groups: Group 1: pasorizumab 400 mg SC every 4 weeks (Q4W), and cemdisiran 200 mg SC Q4W; Group 2: pasorizumab 400 mg SC every 2 weeks (Q2W), and cemdisiran 200 mg SC Q4W. The last dose of study treatment was administered at Week 24 for Group 1 and at Week 26 for Group 2. Patients returned at Week 28 for safety, efficacy, and other assessments. See Tables 4-2 to 4-5.

Elective Open-Label Extension Period (OLEP): All patients who complete OLTP (including those receiving intensive therapy) will be offered the opportunity to continue the elective 52-week OLEP such that planned switch of combination therapy from OLTP to OLEP is uninterrupted (i.e., Day 1 visit of OLE will correspond to the end-of-treatment (EOT) visit of OLTP).

Patients who did not intensify treatment during the primary study period were switched to OLEP with pazelimumab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W, regardless of their treatment assignment during the primary treatment period. Patients who intensified treatment during the primary study period were switched to OLEP and continued to receive intensified treatment with pazelimumab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W.

The OLEP ends 52 weeks after the first dose of study treatment in the OLEP, even if the patient required intensification of therapy during the OLEP. A post-trial visit may be possible for patients who complete the elective OLEP.

Combining pazelimab and cemdisiran will rapidly and continuously suppress C5 concentrations to pharmacologically inactive levels. A target-mediated drug disposition (TMDD) population PK model for pazelimab and a population PK/PD model for cemdisiran were developed based on individual data from healthy subjects. The models for pazelimab and cemdisiran were combined by incorporating the C5 production inhibition of cemdisiran into the C5 synthesis rate in the pazelimab TMDD model. Simulations were performed using the unified model to inform dosing selection for the combination of pazelimab and cemdisiran. Based on simulations, pazelimab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W will be sufficient to maintain C5 inhibition at biologically inactive levels. Furthermore, at steady state, the simulated total and free pazerimab concentration-time profiles were superimposable, which is consistent with the very low free C5 concentrations predicted by the unified population PK/PD model.

See Tables 4-2 to 4-5 below for the time schedule of different doses administered. Table 4-2. Time Schedule of Events ( Open Label Treatment Period ) Screening period Open Tag Extension ³ Research Procedure ( Interview ) ^{1 , 2} Filter V1 V2 ⁴ V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 EOT ⁵ V13 Week At most -1 0 1 2 4 6 8 10 12 16 20 twenty four 28 sky Up to -8 1 8 15 29 43 57 71 85 113 141 169 197 Range ( days ) -- -- ±3 ±3 ±3 ±3 ±3 ±3 ±3 -7/+3 -7/+3 -7/+3 -7/+3 Screening / Baseline: Include/Exclude x x Informed Consent x Informed consent for OLEP, FBR and genomic research (optional) x Medical History ⁶ x Previous ^medication7 x Demographic Information x height x Documentation for meningococcal vaccination (or revaccination) ⁸ x Gonococcal risk ^assessment9 x Meningococcal Patient Safety ^Card10 x x x x x x x x x x x x x Random grouping x Study Treatment: Group 1 only: Pazelimumab 400 mg SC Q4W ¹¹ x ¹² x x x x x x Group 2 only: Pazelimumab 400 mg SC Q2W ¹¹ x ¹² x x x x x x x x x ¹¹ Cemdisiran 200 mg SC Q4W ¹¹ x ¹² x x x x x x Injection training/patient instruction (if necessary) ¹³ ＜---------------------------------------------x---------------------------------------＞ Patient ^diary14 x ¹⁵ x x x x x x x x x x x x Antibiotic prophylaxis (recommended) ¹⁶ ＜---------------------------------------------x---------------------------------------＞ Revaccination against meningococcal infection (if necessary) ＜---------------------------------------------x---------------------------------------＞ Clinical outcome assessment: FACIT-Fatigue x x x x x x x x x EORTC-QLQ-C30 x x x x x x x x x TSQM x x x x x x x x x PNH symptom specific questionnaire (daily) ¹⁷ ＜---------------------------------------------x---------------------------------------＞ Screening period Open label treatment period 3 Research Procedure ( Interview ) ^{1 , 2} Filter V1 V2 ⁴ V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 EOT ⁵ V13 Week At most -1 0 1 2 4 6 8 10 12 16 20 twenty four 28 sky Up to -8 1 8 15 29 43 57 71 85 113 141 169 197 Range ( days ) -- -- ±3 ±3 ±3 ±3 ±3 ±3 ±3 -7/+3 -7/+3 -7/+3 -7/+3 PGIS x x x x x PGIC x x x x Safety and human body measurements: Weight x x x x x x x x Vital signs x x x x x x x x x Physical examination x x x x Electrocardiogram x x Adverse Events x x x x x x x x x x x x x Breakthrough hemolysis ^assessment18 x x x x x x x x x x x x x Concomitant medication/treatment x x x x x x x x x x x x x Transfer record update x x x x x x x x x x x x x Laboratory Test ¹⁹ : Measuring meningococcal titers (only if required by the parent study) x Coagulation group x x x x x x x x x x x x x Chemistry (long group), including LDH ²⁰ x x x x x x x x x x x x x Hematology ²¹ x x x x x x x x x x x IgG x x x Pregnancy test (WOCBP only): serum (S) or urine (U) s u u u u u u u u Urinalysis x x x x x x x x x x x Pharmacokinetic and Immunogenicity Sampling: Pazerimab concentration sample ²² x x x x x x x x x x x Cemdisiran and its metabolites concentration samples ²³ x x x x Pazelimab immunogenicity sample ²⁴ x x x Cemdisiran Immunogenicity Sample ²⁴ x x x Total C5 (plasma) ²² x x x x x x x x x x x Biomarkers: Free heme x x x x x x x x x Heme binding protein x x x x x Supplement hemolysis analysis (serum CH50) ²⁵ x x x x x x x x x x x Screening period Open label treatment period ³ Research Procedure ( Interview ) ^{1 , 2} Filter V1 V2 ⁴ V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 EOT ⁵ V13 Week At most -1 0 1 2 4 6 8 10 12 16 20 twenty four 28 sky Up to -8 1 8 15 29 43 57 71 85 113 141 169 197 Range ( days ) -- -- ±3 ±3 ±3 ±3 ±3 ±3 ±3 -7/+3 -7/+3 -7/+3 -7/+3 Supplement hemolysis analysis (serum AH50) ²⁵ x x x x x x x x x x x sC5b-9 (plasma) x x x x x x x x x x x PNH red blood cells x x x x PNH Granules x x x x Selective studies: Serum and plasma for FBR (optional) x x x x Whole blood samples for DNA isolation for genomic studies (optional) ²⁶ x Whole blood RNA samples for genomic studies (optional) x x x Footnotes 1. Visits between Week 6 and up to Week 24 may be at the clinical site or another preferred location, such as the patient's home. The location will depend on the availability of home health care visiting professionals and the preferences of the investigators and patients. In the event of travel restrictions due to the global pandemic, alternative mechanisms, such as but not limited to remote medical visits, may be implemented to maintain continuity of study conduct. 2. When multiple procedures are performed on the same day, the order of procedures is as follows: Clinical Outcome Assessment (COA) → Electrocardiogram (ECG) → Vital Signs, Physical Examination, Safety Monitoring, Laboratory Collections → Administration of Study Treatment → Any pre-specified post-dose sample collection. 3. Patients who restart intensive treatment will have their scheduled visits adjusted. Patients may require unscheduled visits as needed, which should then be followed according to the OLTP intensive therapy patient timeline of events. 4. The Day 1 visit should occur 7 to 8 days after the Screening Visit. If a patient is unable to schedule a Screening Visit and Day 1 Visit within a 7 to 8 day window, the patient may be rescreened. 5. If the patient agrees to continue the elective OLEP, the end-of-treatment (EOT) visit of the OLTP will correspond with the Day 1e visit of the OLEP (see Event Timeline (Elective Open-Label Extension Period)). Any common assessments will be performed at one of the two visits. 6. Transfusions over the past 52 weeks, history of breakthrough hemolysis, and laboratory parameters used to measure hemolysis (such as LDH, bilirubin, heme-binding protein, reticulocyte count, and heme) should be obtained if possible. Past history of thrombosis and Neisseria infection will be collected. Ongoing PNH symptoms and signs will also be collected. Whenever possible, information collected from the parent study can be used. 7. Include pasirimab administration. 8. Patients have a documented history of meningococcal vaccination (serotypes A, C, Y, W, and serotype B, if available) in the parent study R3918-PNH-1868 ("An open-label extension study in patients with paroxysmal nocturnal hemoglobinuria to evaluate the long-term safety, tolerability, and efficacy of REGN3918"), but may be re-vaccinated if the previous vaccination was more than 5 years prior to screening. Alternatively, patients may be re-vaccinated using complement inhibitors or local practices according to current national vaccination guidelines. Patients who require re-vaccination may be re-screened. 9. Risk factor assessment for gonococcal infection is recommended, and counseling is recommended for high-risk patients. 10. Patients will be issued a Patient Safety Card at Screening and will be reviewed for risk information. Replacement cards may be provided to patients as needed. 11. During OLTP, doses of Cemdisiran and Pazelimumab SC should be administered on the day of the corresponding study visit whenever possible. Unless otherwise specified, study treatment administration should always be the last procedure after all blood samples have been collected and study assessments have been completed. • If Pazelimumab or Cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 3 days before or up to 3 days after the scheduled dosing date for Q2W dosing, provided that combination administration is performed after the corresponding study visit has been completed. For patients receiving Pazelimumab 400 mg SC Q2W + Cemdisiran 200 mg SC For patients taking Q4W, the dosing range (±3 days) is the same as or narrower than the visit range (±3 days before Week 16 or -7/+3 days of Week 16 and after Week 16). • If paslimab or cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 7 days before or 7 days after the scheduled dosing date for the Q4W dosing, provided that the combination is administered after the corresponding study visit has been completed. For patients receiving paslimab 400 mg SC Q4W + cemdisiran 200 mg SC For patients on Q4W, the visit range (±3 days before Week 16 or -7/+3 days starting at Week 16) is narrower than the dosing range (±7 days). Care must be taken to coordinate dosing at visits during which postdose samples are collected to measure concentrations of cemdisiran and its metabolites. The last SC dose of the combination (pazelimumab and cemdisiran) during the OLTP period was at Week 24 for Group 1, while the last SC dose for Group 2 was at Week 24 and the last dose of pazelimumab was at Week 26. 12. Patients should be monitored for at least 30 minutes after the first cemdisiran injection is completed. A 30-minute monitoring period is not required after the pazelimumab injection. 13. For patients who wish to self-inject or have a designated person inject, injection training will be provided. The site should observe the patient self-injecting or having the designated person inject and confirm adequacy. Patient instruction materials will be provided. SC injections can be performed by site personnel or another health care professional at the patient's home or preferred location, or by the patient or a designated person who has successfully completed injection training. 14. If study treatment is given by the patient or a designated person, the patient will complete a log to record compliance with study treatment administration. If a patient log is provided to the patient, it should be reviewed at each clinic visit and data collected on a case report form (CRF). The log should be collected by the site at the last visit. 15. Patient diaries for Study R3918-PNH-1868 (parent) should be reviewed at the Screening Visit. 16. Daily oral antibiotic prophylaxis for meningococcal disease is recommended, starting on the first day of study treatment administration and continuing until 52 weeks after study treatment discontinuation. 17. Patients will complete a daily PNH symptom-specific questionnaire for 7 consecutive days prior to the Day 1 visit. Patients should complete the PNH symptom-specific questionnaire at the same time each day whenever possible. 18. Evaluation for Breakthrough Hemolysis: If a patient is suspected of having an event of breakthrough hemolysis, additional samples will be collected in addition to the required laboratory collections unless noted in the event schedule for that visit. If the suspected event does not occur at the scheduled visit, a planned unscheduled visit should be conducted to evaluate the patient and collect samples for evaluation of suspected breakthrough hemolysis. Unscheduled blood collection for suspected breakthrough hemolytic events should include at least CBC, reticulocyte count, chemistry, coagulation parameters, D-dimer, total C5, CH50, ADA (for pasorizumab), and drug concentration of pasorizumab (if applicable). 19. Unless otherwise specified, clinical laboratory samples will be collected prior to any study drug administration (pre-dose). For laboratory sample collection, handling, and processing, the same methodology will be applied across study visits to maintain sample quality and minimize hemolysis. The coagulation blood sample (tube) must always be collected first, followed by the blood chemistry sample (tube). 20. Serum LDH, C-reactive protein (CRP), and bilirubin (total and direct) will be assessed as part of the blood chemistry analysis. Blood chemistry samples should be collected prior to study treatment administration (pre-dose). During laboratory collection, handling, and processing, the same methodology will be applied across study visits whenever possible to maintain sample quality and avoid hemolysis during sample processing. Laboratory samples should be repeated if the investigator or sponsor suspects that the laboratory results do not accurately reflect the patient's condition. 21. Hematology samples should be collected prior to study treatment administration (pre-dose). 22. Blood samples for paslimab concentration analysis and total C5 analysis will be obtained on designated days prior to any study treatment administration (pre-dose). 23. Blood samples for analysis of cemdisiran concentrations and its metabolite concentrations will be collected on designated days prior to administration of any study treatment (pre-dose) and 2 to 6 hours after cemdisiran administration. Post-dose samples should be carefully coordinated with the administration of cemdisiran and may be collected in the clinic or by a visiting healthcare professional. 24. Blood samples for immunogenicity will be collected on designated days prior to administration of any study treatment (pre-dose). At the visit for immunogenicity samples, samples should be collected along with drug concentration samples. In the event of a suspected treatment-related SAE (e.g., allergic reaction or anaphylaxis), additional samples for drug concentration and immunogenicity may be collected at or near the onset and resolution of the event. 25. Blood samples for CH50 (efficacy assessment) and AH50 will be obtained before any study treatment is administered (pre-dose). 26. Whole blood samples for DNA extraction (as appropriate) should be collected on Day 1 (pre-dose), but may also be collected at later study visits. Patients who consented to DNA testing and provided samples for analysis in previous paslimab studies do not need to provide a separate consent/sample for this study. Table 4-3. Timeline of events for patients receiving intensive treatment in OLTP Intensive treatment phase ³ in OLTP RV1 RV2 RV3 RV4 RV5 RV6 RV7 RV8 RV9 RV10 RV11 EOT RV12 Week 0r 1r 2r 4r 6r 8r 10r 12r 16r ⁵ 20r ⁵ 24r ⁵ 28r ⁶ sky 1r 8r 15r 29r 43r 57r 71r 85r 113r 141r 169r 197r Range ( days ) -- ±3 ±3 ±3 ±3 ±3 ±3 ±3 -7/+3 -7/+3 -7/+3 -7/+3 Intensive treatment: Pazelimumab 30 mg/kg IV (loading dose) ⁴ x ⁷ Pazelimumab 400 mg SC Q2W ⁴ x ⁷ x x x x x x x x x ⁴ Cemdisiran 200 mg SC Q4W ⁴ x ⁷ x x x x x x Injection training/patient instruction (if necessary) ⁸ ＜----------------------------------------x----------------------------------------------------＞ Patient diary ⁹ x x x x x x x x x x x x Antibiotic prophylaxis (recommended) ¹⁰ ＜----------------------------------------x----------------------------------------------------＞ Revaccination against meningococcal infection (if necessary) ＜----------------------------------------x----------------------------------------------------＞ Clinical outcome assessment: FACIT-Fatigue x x x x x x x x x EORTC-QLQ-C30 x x x x x x x x x TSQM x x x x x x x x x PNH symptom specific questionnaire (daily) ¹¹ ＜----------------------------------------x----------------------------------------------------＞ PGIS x x x x x PGIC x x x x Safety and human body measurements: Meningococcal Patient Safety Card ¹² x x x x x x x x x x x x Weight x x x x x x x x Vital signs x x x x x x x x x Physical examination x x x x Electrocardiogram x Adverse Events x x x x x x x x x x x x Breakthrough hemolysis ^assessment13 x x x x x x x x x x x x Concomitant medication/treatment x x x x x x x x x x x x Transfer record update x x x x x x x x x x x x Laboratory test ¹⁴ Coagulation group x x x x x x x x x x x x Chemistry (long group), including LDH ¹⁵ x x x x x x x x x x x x Intensive treatment phase ³ in OLTP RV1 RV2 RV3 RV4 RV5 RV6 RV7 RV8 RV9 RV10 RV11 EOT RV12 Week 0r 1r 2r 4r 6r 8r 10r 12r 16r ⁵ 20r ⁵ 24r ⁵ 28r ⁶ sky 1r 8r 15r 29r 43r 57r 71r 85r 113r 141r 169r 197r Range ( days ) -- ±3 ±3 ±3 ±3 ±3 ±3 ±3 -7/+3 -7/+3 -7/+3 -7/+3 ^Hematology16 x x x x x x x x x x IgG x x x Pregnancy test (WOCBP only) ¹⁷ u u u u u u u u Urinalysis x x x x x x x x x x Pharmacokinetic and Immunogenicity Sampling: Pazelimab drug concentration sample ¹⁸ x x x x x x x x x x Cemdisiran and its metabolites concentration samples ¹⁹ x x x x Pazelimab immunogenicity sample ²⁰ x x x Cemdisiran Immunogenicity Sample ²⁰ x x x Total C5 (plasma) ¹⁸ x x x x x x x x x x Biomarkers: Free heme x x x x x x x x Heme binding protein x x x x Supplement hemolysis analysis (serum CH50) ²¹ x x x x x x x x x x Supplement hemolysis analysis (serum AH50) ²¹ x x x x x x x x x x sC5b-9 (plasma) x x x x x x x x x x PNH red blood cells x x x x PNH Granules x x x x 1. Visits between Week 6r and Week 24r may be at the clinical site or another preferred location, such as the patient's home. The location will depend on the availability of home health care visiting professionals and the preferences of the investigators and patients. If travel restrictions are imposed due to the global pandemic, alternative mechanisms, such as but not limited to remote medical visits, may be implemented to maintain continuity of study conduct. 2. When multiple procedures are performed on the same day, the order of procedures is as follows: COA→ECG→vital signs, physical examination, safety monitoring, laboratory collection→study drug administration→any pre-specified post-dose sample collection. 3. The intensive treatment schedule will be anchored to the day of intensification (i.e., a reset occurs, the day of intensification becomes the Day 1r visit, and subsequent visits follow the intensive treatment event schedule). Patients receiving intensive treatment will be considered to have completed the study once they have completed the 28-week treatment period of intensive treatment (i.e., after completing the Week 28r EOT assessment). 4. During the intensive treatment period of OLTP, Cemdisiran and Paszelimab SC doses should be given on the day of the corresponding study visit whenever possible. Unless otherwise specified, study treatment administration should always be the last procedure after all blood samples have been collected and study assessments have been completed. If Pazelimumab or Cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 3 days before or up to 3 days after the scheduled dosing date, provided that administration occurs after the corresponding study visit has been completed. For example, given that the visit range for the Week 4r visit is ±3 days, the Day 29r (Week 4r) visit may occur on Days 26r through 32r. Therefore, doses of Pazelimumab and Cemdisiran may be administered on Days 26r through 32r, but only at or after the Week 4r visit assessment. Similarly, given the visit range of -7/+3 days for the Week 16r visit, the Day 113r (Week 16r) visit can be performed on Days 106r to 116r. Doses of paslimumab and cemdisiran can be given on Days 110r to 116r, but only at or after the Week 16r visit assessment. Care must be taken to coordinate dosing at visits where postdose samples are collected to measure concentrations of cemdisiran and its metabolites. For patients receiving intensive therapy in the OLTP, the last SC dose of cemdisiran is at Week 24r, and the last SC dose of paslimumab is at Week 26r. 5. For these visits, the dosing range (±3 days) is narrower than the study visit range (-7/+3 days). 6. If the patient agrees to continue the elective OLEP, the EOT visit of the OLTP will correspond to the Day 1e visit of the OLEP. Any common assessments will be performed once between the two visits. 7. On Day 1r, give Paszelimab IV first, with observation for 30 minutes prior to SC dose administration. Subsequent Paszelimab SC doses will be administered Q2W, and Cemdisiran SC doses will be administered Q4W. SC injections may be administered by site personnel or another healthcare professional at the patient’s home or preferred location, or by the patient or a designated person who has successfully completed injection training. 8. For patients who want to self-inject or have a designated person inject, injection training will be provided. Sites should observe patients self-injecting or having designated personnel inject and confirm adequacy. Patient instruction materials will be provided. 9. If study treatment is given by the patient or a designated person, the patient will fill out a log to record compliance with study treatment administration. If a patient log is provided to the patient, it should be reviewed at each clinic visit and data collected on the CRF. The log should be collected by the site at the last visit. 10. Daily oral antibiotics are recommended to prevent meningococcal disease until 52 weeks after study treatment is discontinued. 11. Patients should complete the PNH symptom-specific questionnaire at the same time each day whenever possible. 12. Patient Safety Card: Sites should review the instructions on the safety card with the patient at each visit. A replacement card may be provided to the patient as needed. 13. Evaluation of Breakthrough Hemolysis: If a patient is suspected of experiencing a breakthrough hemolytic event, an additional sample for pasorizumab drug concentration will be collected in addition to the required laboratory collections, unless noted in the event schedule for that visit. If the suspected event does not occur at the scheduled visit, a scheduled off-site visit should be conducted, the patient will be evaluated and coagulation, chemistry, and pasorizumab drug concentrations will be collected. 14. Clinical laboratory samples will be collected prior to any study drug administration (pre-dose) unless otherwise indicated. During laboratory collection, handling, and processing, the same methodology will be applied across study visits to the extent possible to maintain sample quality and avoid hemolysis. The coagulation blood sample (tube) must always be collected first, followed by the blood chemistry sample (tube). 15. Serum LDH, CRP, and bilirubin (total and direct) will be assessed as part of the blood chemistry analysis. Blood chemistry samples should be collected prior to administration of study treatment (pre-dose). During laboratory collection, handling, and processing, the same methodology will be applied across study visits whenever possible to maintain sample quality and avoid hemolysis during sample processing. Laboratory samples should be repeated if the investigator or sponsor suspects that the laboratory results do not accurately reflect the patient's condition. 16. Hematology samples should be collected prior to administration of study treatment (pre-dose). 17. Pregnancy Testing for WOCBP: Urine testing will be performed at all designated visits. Any positive urine pregnancy test should be confirmed by a serum pregnancy test. 18. On Day 1r, blood samples for pazelimab concentrations and total C5 will be obtained prior to IV administration of pazelimab and within 15 minutes after the end of the IV infusion. At subsequent time points, blood samples for pazelimab drug concentration analysis and total C5 analysis will be obtained prior to any study treatment administration (pre-dose). 19. Blood samples for cemdisiran drug concentration analysis and its metabolite concentrations will be collected on designated days prior to any study treatment administration (pre-dose) and 2 to 6 hours after cemdisiran administration. Post-dose samples should be carefully coordinated with the administration of cemdisiran and may be collected in the clinic or by a visiting healthcare professional. 20. Blood samples for immunogenicity will be collected on designated days prior to any study treatment administration (pre-dose). At the visit for immunogenicity samples, samples should be collected along with drug concentration samples. In the event of a suspected treatment-related SAE (e.g., allergic reaction or anaphylaxis), additional samples for drug concentration and immunogenicity may be collected at or near the onset and resolution of the event. 21. Blood samples for CH50 (efficacy assessment) and AH50 will be obtained prior to the administration of any study treatment (pre-dose). Table 4-4. Event Schedule ( Elective Open Label Extension Period ) Optional Open Label Extension OLEP-1 ³ OLEP-2 ⁵ OLEP-3 ⁵ OLEP-4 ⁵ OLEP-5 ⁵ OLEP-6 ⁵ OLEP-7 Week 0e 8e 16e 24e 32e 40e 52e sky 1e 57e 113e 169e 225e 281e 365e Range ( days ) -- -7/+3 -7/+3 -7/+3 -7/+3 -7/+3 -7/+3 Treatment ⁴ : Pazelimumab 400 mg SC Q2W or Q4W ⁵ x x x x x x x Cemdisiran 200 mg SC Q4W ⁵ x x x x x x x Injection training/patient instruction (if necessary) ⁶ ＜---------------------------------------------x ---------------------------------------------------＞ Patient ^diary7 x x x x x x x Antibiotic prophylaxis (recommended) ⁸ ＜---------------------------------------------x ---------------------------------------------------＞ Revaccination against meningococcal infection (if necessary) ＜---------------------------------------------x ---------------------------------------------------＞ Clinical outcome assessment: FACIT-Fatigue x x x EORTC-QLQ-C30 x x x PGIS x x x PGIC x x x Safety and human body measurements: Meningococcal Patient Safety Card ⁹ x x x x x x x Weight x x x x x x x Vital signs x x x x x x x Physical examination x x x x Electrocardiogram x x Adverse Events x x x x x x x Breakthrough hemolysis ^assessment10 x x x x x x x Concomitant medication/treatment x x x x x x x Transfer record update x x x x x x x Laboratory Test ¹¹ : Coagulation group x x x x x x x Chemistry (long group), including LDH ¹² x x x x x x x ^Hematology13 x x x x x x x Pregnancy test (WOCBP only) ¹⁴ u u u u u u u Urinalysis x x x x x x x Optional Open Label Extension OLEP-1 ³ OLEP-2 ⁵ OLEP-3 ⁵ OLEP-4 ⁵ OLEP-5 ⁵ OLEP-6 ⁵ OLEP-7 Week 0e 8e 16e 24e 32e 40e 52e sky 1e 57e 113e 169e 225e 281e 365e Range ( days ) -- -7/+3 -7/+3 -7/+3 -7/+3 -7/+3 -7/+3 Pharmacokinetics and Immunogenicity: Pazerimab concentration sample ¹⁵ x x x Cemdisiran and its metabolite concentration samples ¹⁶ (before and 2 to 6 hours after administration) x x x Palivizumab immunogenicity sample ¹⁷ x x x Cemdisiran Immunogenicity Sample ¹⁷ x x x Total C5 (plasma) ¹⁵ x x x Biomarkers: Free heme x x Heme binding protein x x Supplement hemolysis analysis (serum CH50) ¹⁸ x x x x Supplement hemolysis analysis (serum AH50) ¹⁸ x x x x sC5b-9 (plasma) x x x x PNH red blood cells x x x PNH Granules x x x Selective studies: Serum and plasma for FBR (optional) x x Whole blood RNA samples for genomic studies (optional) x x 1. The visit may be at the clinical site or another preferred location, such as the patient’s home. The location will depend on the availability of home health care visiting professionals and the preferences of the investigators and patients. If travel restrictions occur due to the global pandemic, alternative mechanisms, such as but not limited to telemedicine visits, may be implemented to maintain continuity of study conduct. 2. When multiple procedures are performed on the same day, the order of procedures is as follows: COA→ECG→vital signs, physical examination, safety monitoring, laboratory collections→study drug administration→any pre-specified post-dose sample collection. 3. Day 1e of OLEP should be scheduled on the same day as Week 28 of OLTP (or Week 28r for patients receiving intensive treatment), and any common assessments will be performed once at the OLTP and OLEP visits. 4. For patients who did not receive intensification therapy during the OLTP: At any time during the OLEP, patients who meet the pre-specified criteria will receive intensification therapy with a loading dose of Pazelimumab 30 mg/kg IV, followed 30 minutes later by Pazelimumab 400 mg SC Q2W and Cemdisiran 200 mg SC Q4W. Patients should be observed at interim intervals for 30 minutes between IV and SC doses. Patients will continue their visit schedule at the next OLEP visit. 5. During the OLEP, Cemdisiran and Pazelimumab SC doses should be given on the day of the corresponding study visit whenever possible. Unless otherwise specified, study treatment administration should always be the last procedure after all blood samples have been collected and study assessments have been completed: • If Pazelimumab or Cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 3 days before or up to 3 days after the scheduled dosing date, provided that the combination is administered after the corresponding study visit has been completed. For patients receiving Pazelimumab 400 mg SC Q2W + Cemdisiran 200 mg SC Q4W, the dosing range (±3 days) is narrower than the visit range (-7/+3 days). •If Pazelimumab or Cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 7 days before or 7 days after the scheduled dosing date, provided that the combination is administered after the corresponding study visit has been completed. For patients receiving Pazelimab 400 mg SC Q4W + Cemdisiran 200 mg SC Q4W, the visit range (-7/+3 days) is narrower than the dosing range (±7 days). Care must be taken to coordinate dosing at visits at which postdose samples are collected to measure concentrations of Cemdisiran and its metabolites. For patients who do not intensify therapy during the OLEP, the last dose of Cemdisiran and Pazelimab is administered at Week 52e. For patients who intensify therapy during the OLEP, the last dose of study treatment will be determined based on the timing of intensification. 6. For patients who want to self-inject or have a designated person inject, injection training will be provided. The site should observe the patient self-injecting or having the designated person inject and confirm adequacy. Patient instruction materials will be provided. 7. If study treatment is given by the patient or a designated person, the patient will fill out a diary to record compliance with study treatment administration. If a patient diary is provided to the patient, it should be reviewed at each clinic visit and data collected in the CRF. The diary should be collected by the site at the last visit. 8. Daily oral antibiotics are recommended to prevent meningococcal disease until 52 weeks after discontinuation of study treatment. 9. Patient Safety Card: Sites should review the instructions on the safety card with the patient at each visit. Replacement cards may be provided to patients as needed. 10. Evaluation for Breakthrough Hemolysis: If a patient is suspected of having a breakthrough hemolytic event, an additional sample for paszelimumab drug concentration will be collected in addition to the required laboratory collections unless noted in the event timeline for that visit. If the suspected event does not occur at the scheduled visit, a planned off-site visit should be conducted, the patient evaluated and drug concentrations for coagulation, chemistry, and paszelimumab collected. 11. Clinical laboratory samples will be collected prior to any study drug administration (pre-dose) unless otherwise noted. Whenever possible, the same methodology will be used across study visits during laboratory collection, handling, and processing to maintain sample quality and avoid hemolysis. The coagulation blood sample (tube) must always be collected first, followed by the blood chemistry sample (tube). 12. Serum LDH, CRP, and bilirubin (total and direct) will be assessed as part of the blood chemistry analysis. Blood chemistry samples should be collected prior to study treatment administration (pre-dose). Whenever possible, the same methodology will be used across study visits during laboratory collection, handling, and processing to maintain sample quality and avoid hemolysis during sample processing. Laboratory samples should be repeated if the Investigator or Sponsor suspects that the laboratory results do not accurately reflect the patient's condition. 13. Hematology samples should be collected prior to study treatment administration (pre-dose). 14. Pregnancy Testing for WOCBP: Urine testing will be performed at all designated visits. Any positive urine pregnancy test should be confirmed by a serum pregnancy test. 15. Blood samples for analysis of pasirimab concentrations and total C5 analysis will be obtained on designated days prior to any study treatment administration (pre-dose). 16. Blood samples for analysis of cemdisiran concentrations and its metabolite concentrations will be collected on designated days prior to any study treatment administration (pre-dose) and 2 to 6 hours after cemdisiran administration. Post-dose samples should be carefully coordinated with the administration of cemdisiran and may be collected in the clinic or by a visiting healthcare professional. 17. Blood samples for immunogenicity will be collected on designated days prior to the administration of any study treatment (pre-dose). At the visit for immunogenicity samples, samples should be collected along with drug concentration samples. In the event of a suspected treatment-related SAE (such as allergic reaction or anaphylaxis), additional samples for drug concentration and immunogenicity may be collected at or near the onset and resolution of the event. 18. Blood samples for CH50 (efficacy assessment) and AH50 will be obtained prior to the administration of any study treatment (pre-dose). Table 4-5. Event Timeline ( Post-Treatment Safety Follow-up Period ) Post-treatment safety follow-up period Patients who discontinue study treatment at OLTP will be asked to remain on study until Week 28 EOT (or Week 28r for patients who restart intensive treatment) and follow the original event schedule, if applicable. After the Week 28 EOT visit, their entry point into the safety follow-up schedule will depend on the number of weeks that have passed since their last dose (i.e., patients who received their last dose of study treatment at EOT 20 weeks after the study treatment will enter the safety follow-up period at Visit FU-4 [26 weeks after the last dose]). Patients who complete Week 28 (last dose given at Week 24 or Week 26 or Week 26r) and choose not to continue treatment in the OLEP, patients who complete the OLEP, and patients who permanently discontinue treatment during the OLEP will begin here: Study Procedure FU-1 FU-2 FU-3 FU-4 Telephone interview FU-5 Telephone interview FU-6 Weeks (after last dose of study drug) 8 12 16 26 38 52 Days (after last dose of study drug) 57 85 113 183 267 365 Range (days) ±10 ±10 ±10 ±10 ±10 ±10 Safety Assessment Meningococcal Patient Safety ^Card1 ＜---------------------------------------------x ---------------------------------------------------＞ Antibiotic prophylaxis (recommended) ² ＜---------------------------------------------x ---------------------------------------------------＞ Vital signs x x x x Physical examination x x Concomitant medication and surgery x x x x x x Adverse Event Reporting x x x x x x Pregnancy Report x x x x x x Laboratory testing Hematology x x x x Blood chemistry x x x x 1. Patient Safety Card: Sites should review the instructions on the safety card with patients at each visit. Replacement cards may be provided to patients as needed. 2. Daily oral antibiotic prophylaxis against meningococcal disease is recommended until 52 weeks after study treatment discontinuation. Intensified Therapy

Patients will be given intensive therapy if they meet both of the following criteria: •   Breakthrough hemolysis not due to complement activation conditions (i.e., intercurrent infection)* * Increased LDH ≥ 2 × ULN due to complement activation conditions •   Inadequate LDH response (i.e., LDH > 1.5 × ULN) (i.e., based on 2 consecutive measurements spanning at least 2 weeks)

Patients’ treatment will be intensified based on their assigned treatment arm, as described below. Patient weight should be assessed on the day of IV pazelimab loading to allow for calculation of appropriate dosing. • Patients randomized to pazelimab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W will receive pazelimab 30 mg/kg IV single dose starting on the day of intensification + intensified pazelimab regimen of 400 mg Q2W starting on the day of intensification and cemdisiran 200 mg Q4W. Patients will continue treatment with the boosted SC dosing regimen for an additional 28 weeks to complete the study, with the last dose of boosted therapy at Week 24r (for Cemdisiran) and Week 26r (for Pazelimab); • Patients randomized to Pazelimab 400 mg SC Q2W and Cemdisiran 200 mg SC Q4W will receive a single dose of Pazelimab 30 mg/kg IV on the day of boost + restart of the assigned Pazelimab 400 mg SC Q2W and Cemdisiran 200 mg SC Q4W starting on the day of boost. Patients will continue on the same SC dosing regimen for an additional 28 weeks to complete the study, with the last dose of enhanced therapy at Week 24r (for Cemdisiran) and Week 26r (for Pazelimumab).

Patients undergoing treatment intensification may require a planned visit prior to intensification. During the OLTP, patients undergoing intensification should follow Table 4-3 (Timeline of Events for Patients Undergoing Intensification in OLTP), with intensification occurring on Day 1 (RV1). Patients who restart intensification will be considered to have completed OLTP once they have received 28 weeks of intensification and completed the 28r-week assessment.

During the OLEP, patients who do not intensify therapy but meet criteria for intensification will receive a single dose of pazerimab 30 mg/kg IV based on current weight on the day of intensification + an intensification regimen of pazerimab 400 mg Q2W starting on the day of intensification and cemdisiran 200 mg Q4W for the remainder of the OLEP. Patients will continue their visit schedule at the next OLEP visit.

Patients who experience breakthrough hemolysis not due to complement activation conditions and meet criteria for intensified therapy are eligible to receive intensified pazelimab only once (either during the primary treatment period or during OLEP), after which no further intensification will be permitted. Note: If LDH increases ≥ 2 × ULN due to acute complement activation conditions during OLTP or OLEP, pazelimab 30 mg/kg IV bolus may be administered. Patient weight should be assessed on the day of IV pazelimab loading to allow calculation of appropriate dose. This is not considered a treatment intensification. There will be no other changes to the study treatment regimen (i.e., customary dosing and frequency of pazelimab and cemdisiran will remain unchanged). Patients will continue to the next visit on their current visit schedule. Note: IV dose should be given first. SC dose should be given at least 30 minutes after IV administration is completed. Primary Objectives

The primary objective of the study was to evaluate the safety and tolerability of 2 dosing regimens of Paszelimab and Cemdisiran combination therapy during the open-label treatment period (OLTP). Secondary Objectives

The secondary objectives of the study are to: • Evaluate the effect of combination therapy on the following parameters of intravascular hemolysis: LDH control, breakthrough hemolysis, and inhibition of total complement hemolytic activity (CH50); • Evaluate the effect of combination therapy on hemoglobin content; • Evaluate the effect of combination therapy on RBC translocation requirements; • Evaluate the effect of combination therapy on COA measuring fatigue and health-related quality of life; • Evaluate the concentrations of total paselimab in serum and total C5 and cemdisiran in plasma; • Evaluate the immunogenicity of paselimab and cemdisiran; • Evaluate the long-term safety and efficacy of paselimab and cemdisiran in the optional open-label extension period (OLEP); • To assess the safety of intensified treatment with Pasqualimab and Cemdisiran. Exploratory objectives

The exploratory objectives of the study are to: • To investigate the effect of the combination therapy on clinical thrombotic events; • To investigate the effect of the combination therapy on renal function and biomarkers of renal injury; • To investigate the effect of the combination therapy on complement activation and intravascular hemolysis associated with PNH and other related diseases; • To investigate the effect of the combination therapy on PNH colony size; • To assess the effect of the combination therapy on treatment satisfaction; • To investigate the effect of the combination therapy on novel COAs that measure specific symptoms of PNH; • To study the mechanism of action of the combination therapy (including its relationship to safety and efficacy), complement pathway biology, PNH and related complement-mediated diseases; • To investigate the effect of combination therapy on PNH symptoms; • To investigate potential differences in genotype and gene expression that may affect the efficacy and safety of combination therapy to further understand C5, PNH, or other conditions associated with complement-mediated damage (for patients who agree to participate in genomic studies); • To investigate the safety and efficacy of paszelimumab and cemdisiran after dose intensification; • To investigate the long-term effect of combination therapy on clinical and PD assessments of selective OLEP. Main evaluation indicators

The primary outcome measure was the incidence and severity of TEAEs during OLTP Week 28. Secondary outcomes

Secondary assessment indicators of OLTP are: • Percent change in LDH from pre-treatment (defined as the average of LDH values on Day -7 and Day 1 [before combination administration]) to end of treatment (defined as the average of LDH values from Week 24 to Week 28); • Maintenance of adequate control of hemolysis, defined as LDH ≦1.5 × ULN from baseline (Day 1) to Week 28 and from Week 4 to Week 28 (inclusive); • Adequate control of hemolysis (defined as LDH ≦1.5 × ULN) at each visit from baseline (Day 1) to Week 28 (inclusive); • Normalization of LDH at each visit, defined as LDH ≦1.0 × ULN from baseline (Day 1) to Week 28 (inclusive); • Area under the curve (AUC) of LDH over time from baseline to Week 28 and from Week 4 to Week 28 (inclusive); • Development of breakthrough hemolysis (as defined herein) from baseline to Week 28; • Hemoglobin stability (defined as patients who did not receive RBC transfusions and whose hemoglobin levels did not fall by ≥2 g/dL) from baseline to Week 28; • Change in hemoglobin level from baseline to Week 28; • Avoidance of transfusions (defined as no RBC transfusions required according to the protocol algorithm) from baseline to Week 28; • RBC transfusion rate and number of units from baseline to Week 28; • Change in CH50 from baseline to Week 28; • Change in fatigue measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale from baseline to week 28; • Change in the Global Health Status/Quality of Life Scale (GHS/QoL) and Physical Function (PF) scores according to the European Organization for Research and Treatment of Cancer: Quality of Life Questionnaire-Core 30 Items (EORTC QLQ-C30) from baseline to week 28; • Total paslimab concentrations in serum and cemdisiran concentrations in plasma assessed throughout the study; • Change in total C5 concentrations from baseline assessed throughout the study; • To assess the immunogenicity of paslimab and cemdisiran as measured by the incidence, titer, and clinical impact of treatment-emergent anti-drug antibody (ADA) responses over time; • The incidence and severity of TEAEs in patients who received treatment intensification during Week 28. Exploratory Assessments

Exploratory evaluation indicators of OLTP are: • Intensification of treatment during the study period; • The incidence of major adverse vascular events (MAVE) from baseline to week 28. MAVE included thrombophlebitis/deep venous thrombosis, pulmonary embolism, myocardial infarction, unstable angina, renal venous or arterial thrombosis, acute peripheral vascular occlusion, hepatic venous thrombosis, portal vein thrombosis, enterovenous/visceral venous thrombosis or infarction, enterovenous/visceral arterial thrombosis or infarction, transient ischemic attack, cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, gangrene (non-traumatic; non-diabetic), and amputation (non-traumatic; non-diabetic); • Change in renal function measured by estimated glomerular filtration rate (eGFR) from baseline to week 28; • Percent change in free hemoglobin from baseline to week 28; • Change in bilirubin from baseline to week 28; • Change in reticulocyte count from baseline to week 28; • Change and percentage change in alternative pathway hemolytic activity assay (AH50) from baseline to week 28; • Ratio of PNH erythrocytes to granulocytes from baseline to week 28; • Change in functional scale scores (role functioning, emotional functioning, cognitive functioning, and social functioning) and symptom scale scores (fatigue, nausea and vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea) of the EORTC QLQ-C30 from baseline to week 28; • Change in the functional scale scores (role functioning, emotional functioning, cognitive functioning, and social functioning) and symptom scale scores (fatigue, nausea and vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea) of the EORTC QLQ-C30 from baseline to week 28; Stability of global health, function, and symptoms as measured by the QLQ-C30; • Comparison of treatment satisfaction (assessed by the Treatment Satisfaction Questionnaire [TSQM]) at baseline and at week 28; • Change from baseline to week 28 in the Patient Global Impression of Severity (PGIS), which includes questions about PNH symptoms, impact, and fatigue; • Patient Global Impression of Change (PGIC) at week 28, which includes questions about PNH symptoms, impact, and fatigue; • Change from baseline to week 28 in PNH symptoms as measured by the PNH Symptom Specific Questionnaire; • Exploratory measures related to the analysis of patients receiving dose intensification and patients participating in OLEP will be provided in the Statistical Analysis Plan (SAP). Breakthrough Hemolysis

Patients who experience breakthrough hemolysis may receive intensified therapy as described herein. Breakthrough hemolysis is defined as an increase in LDH accompanied by signs or symptoms associated with hemolysis: • An increase in LDH occurs when: - If pre-treatment LDH ≦1.5 × ULN, then LDH ≧2 × ULN; or - If pre-treatment LDH >1.5 × ULN, then LDH ≧2 × ULN after initially achieving LDH ≦1.5 × ULN

Signs or symptoms should correspond to those known to be associated with intravascular hemolysis due to PNH and are limited to the following: new or worsening fatigue, headache, dyspnea, hemoglobinuria, abdominal pain, scleral jaundice, erectile dysfunction, chest pain, confusion, dysphagia, new thrombotic events, anemia (including a hemoglobin value that is significantly lower (i.e., a decrease of ≥2 g/dL) compared to the patient's known baseline hemoglobin value). Variability of efficacy

The efficacy of this study was assessed by the following laboratory assessments (Laboratory Variability for Efficacy Assessments): •LDH (serum): LDH, as a measure of intravascular hemolysis, can objectively and accurately measure whether intravascular hemolysis is continuously controlled when patients are switched to the combination of paslimab and cemdisiran; •Hemoglobin: Hemolytic anemia is a marker of PNH; •CH50: CH50 analysis will be used to confirm that PNH patients have achieved complete suppression of tonic activity throughout the dosing interval.

These laboratory variants have been implicated in the characterization and disease mechanisms of PNH (Brodsky, Paroxysmal nocturnal hemoglobinuria. Blood 2014; 124(18):2804-11).

Hemolytic anemia is a clinical manifestation of PNH, and patients often require blood transfusions for symptomatic treatment. The frequency of blood transfusions has been used to assess treatment efficacy in other studies of PNH (Hillmen et al. , The complement inhibitor Eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006; 355(12):1233-43) (Röth et al. , Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. Blood Adv 2018; 2(17):2176-85).

Clinical outcome assessments (COAs) included the following: •FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue)); •EORTC-QLQ-C30 (European Organization for Research and Treatment of Cancer: Quality of Life Questionnaire for Patients with Cancer 30 Items (EORTC-QLQ-C30)); •TSQM (Satisfaction with Medication Questionnaire); •PNH Symptom Specific Questionnaire; •PGIS (Patient Global Impression of Severity); •PGIC (Global Impression of Change).

Patients completed the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale and the European Organization for Research and Treatment of Cancer: Physical Assessment of Functioning and Quality of Life Questionnaire (GHS/QoL). FACIT-Fatigue scores range from 0 to 52, with higher scores indicating lower fatigue. EORTCQLQ-C30 scores range from 0 to 100; high scores on the functional scale represent high/healthy levels of functioning, while high scores on the GHS/QoL represent high quality of life. These assessments were completed at baseline and intermittently throughout the OLTP. Higher scores indicate lower fatigue or higher levels of functioning or GHS/QoL. In this study, all baseline values and assessments were performed before patients received their first dose of their assigned combination therapy. Pretreatment baseline values were provided for a previous Phase 2 trial in which all patients received open-label pazelimab monotherapy (see NCT03946748). Results (22 patients, median duration 57 days )

At the time of this analysis, all 22 randomized patients were ongoing on study (median duration, 57 days), including one patient who completed OLTP and continued on OLEP, and no patient required treatment intensification. At study baseline, patients were well controlled on paslimab monotherapy. Baseline patient demographics and characteristics of this study are summarized in Table 4-1.

Efficacy Results: Twenty-one patients (95.5%) maintained adequate control of hemolysis (LDH; ≦ 1.5 × ULN) until data cutoff (Figures 18 and 19). In addition, LDH values remained below 1.0 × ULN for most of the observation period. Most (90.9%) patients (n=20) met the criteria for hemoglobin stability (no red blood cell transfusion and no decrease in hemoglobin level ≥ 2 g/dL). Two patients received a blood transfusion and therefore did not meet the criteria for hemoglobin stability. Both patients recovered and continued to receive combination therapy during the study. One patient in Group 1 received only a blood transfusion. Another patient in Group 2 experienced a moderate non-severe breakthrough hemolysis (related to chlamydia infection) and a decrease in hemoglobin level ≥ 2 g/dL and also received a blood transfusion. At the time of this analysis, 90.9% (20 of 22) of the patients met the criteria for hemoglobin stability (i.e., no erythrocyte transfusion and no hemoglobin drop of ≥2 g/dL) (Figure 20). CH50 (a measure of total complement hemolytic activity) remained fully suppressed at all measured post-baseline time points, including during the above-mentioned breakthrough hemolytic events.

Treatment-Emergent Adverse Events (TEAEs): No serious TEAEs or TEAEs leading to study drug discontinuation occurred in any patient in either treatment group. Importantly, there were no meningococcal infections or TEAEs leading to death in this study. A total of 12 TEAEs occurred in six patients (27.3%; 3 in each treatment group). One adverse event of particular interest, a mild injection site reaction characterized by stinging lasting 30 minutes, occurred in one patient in Group 1 (8.3%). All TEAEs were mild to moderate in intensity, with the exception of a single serious TEAE of anemia in one patient in the paslimab Q2W + cemdisiran group (Group 2). This patient had previously experienced a moderate, non-serious TEAE of breakthrough hemolysis, which the investigators considered to be unrelated to study treatment.

Patient-Reported Outcomes: Prior to receiving pazelimab monotherapy in a previous Phase 2 trial (NCT03946748), the mean (standard deviation [SD]) FACIT-fatigue score before treatment was 32.3 (15.2), the physical function score was 70.9 (22.5), and the GHS/QoL score was 60.6 (22.4). In this study, baseline values represent the pazelimab monotherapy that patients received before switching to combination therapy. At study baseline, when patients were switched from prior pazelimab monotherapy, the mean (SD) FACIT-fatigue scores were 45.4 (5.5) and 45.0 (3.4) in Group 1 and Group 2, respectively (Figure 21A). During weeks 2-16 of combined treatment, the mean FACIT-Fatigue scores were 40.1-45.6 in Group 1 and 39.2-41.4 in Group 2. At baseline, the mean physical function score was 93.3 in both treatment groups (SD: 8.8 in Group 1 and 9.4 in Group 2, see Figure 21B). During weeks 2-16 of combined treatment, the mean physical function scores were 89.6-95.6 in Group 1 and 81.0-83.3 in Group 2, respectively. The mean scores (SD) at baseline reflected improved GHS/QoL and were similar in both treatment groups: 77.8 (14.4) in Group 1 and 77.4 (20.8) in Group 2 (Figure 21C). During weeks 2-16 of combination therapy, the mean GHS/QoL scores in Group 1 ranged from 68.1 to 77.8, while the mean GHS/QoL scores in Group 2 ranged from 54.2 to 78.6. The patient-reported outcomes are summarized in Table 4-6. Table 4-6. Patient-reported outcomes Visit FACIT- ^Fatigue over time EORTC-QLQ-C30 GHS/QoL ^c over time EORTC-QLQ-C30 ^Physical Function over Timec Pazelimab Q4W + Cemdisiran (n=12) Pazelimab Q2W + Cemdisiran (n=10) Pazelimab Q4W + Cemdisiran (n=12) Pazelimab Q2W + Cemdisiran (n=10) Pazelimab Q4W + Cemdisiran (n=12) Pazelimab Q2W + Cemdisiran (n=10) Before treatment, n twenty two twenty two twenty two Mean [SD] ^a 32.3 (15.2) 60.6 (22.4) 70.9 (22.5) Baseline, n 9 7 9 7 9 7 Mean (SD) 45.4 (5.5) 45.0 (3.4) 77.8 (14.4) 77.4 (20.8) 93.3 (8.8) 93.3 (9.4) Week 2, n 8 8 8 8 8 8 Mean (SD) 45.6 (4.0) 41.4 (8.8) 74.0 (19.6) 71.9 (16.0) 95.0 (7.8) 82.5 (20.1) Week 4, n 9 7 9 7 9 7 Mean (SD) 40.1 (12.0) 40.7 (9.6) 69.4 (29.5) 78.6 (23.0) 89.6 (9.5) 82.9 (22.7) Week 8, n 6 7 6 7 6 7 Mean (SD) 43.0 (7.9) 40.0 (12.7) 68.1 (24.4) 67.9 (32.1) 94.4 (6.6) 81.0 (24.2) Week 12, n 4 5 4 5 4 5 Mean (SD) 44.0 (8.0) 39.2 (7.9) 70.8 (8.3) 60.0 (18.1) 91.7 (10.0) 81.3 (20.8) Week 16, n 3 4 3 4 3 4 Mean (SD) 42.0 (7.8) 39.3 (16.9) 77.8 (25.5) 54.2 (37.6) 95.6 (3.8) 83.3 (29.1) ^{aPretreatment} baseline values were provided by a previous phase 2 trial in which all patients received open-label paslimab monotherapy (NCT03946748). ^b FACIT-Fatigue: Scores range from 0 to 52, with higher scores indicating lower fatigue. ^c EORTC QLQ-C30: Scores range from 0 to 100; high scores on the Functional Scale represent high/healthy levels of functioning, and high scores on the GHS/QoL represent high QoL. Conclusions

The combination of paslimab and cemdisiran was generally well tolerated in PNH patients who switched from paslimab monotherapy (NCT04162470), regardless of the treatment group. More than 90% of patients maintained adequate control of hemolysis and achieved hemoglobin stabilization. In addition, most patients maintained their LDH normalization during the observation period. Therefore, this combination therapy showed significant efficacy in the treatment of PNH patients who switched from paslimab monotherapy.

In addition, PNH patients who switched from pazelimab monotherapy experienced significant improvement in pre-treatment fatigue (FACIT-Fatigue improvement >5 points) and had improvements in physical function and GHS/QoL. Combination therapy maintained improvements in these scores through Week 16, particularly with the pazelimab Q4W and cemdisiran dosing schedules. Although sample size was limited, this evidence suggests that the pazelimab and cemdisiran combination (particularly the Q4W regimen) maintained improvements in patient fatigue, physical function, and GHS/QoL. Results ( Week 28 )

Before receiving pasorizumab monotherapy, the mean (standard deviation [SD]) pretreatment FACIT-fatigue score was 32.3 (15.2) (Table 4-13), the GHS/QoL score was 60.6 (22.4) (Table 4-23), and the physical function score was 70.9 (22.5) (Table 4-33; and Table 4-7). For the current trial, the baseline values represent the effect of pasorizumab monotherapy that patients received before switching to combination therapy. The mean (SD) FACIT-fatigue score at baseline was 45.4 (5.6) in Group 1 (Pazelimumab q4w and Cemdisiran q4w), while it was 45.6 (3.6) in Group 2 (Pazelimumab q2w and Cemdisiran q4w) (Table 4-14; and Table 4-7). During Weeks 2-28, the mean FACIT-fatigue score was 40.3-45.2 in Group 1, while it was 36.5-42.9 in Group 2 (Tables 4-14 to 4-22). The mean (SD) physical function score at baseline was 93.3 (8.8) in Group 1, while it was 94.2 (9.0) in Group 2 (Table 4-34). During weeks 2-28, the mean physical function scores were 90.0-95.0 in group 1 and 82.0-90.9 in group 2 (Tables 4-35, 4-42, and 4-7). The mean (SD) GHS/QoL scores in the two treatment groups were well controlled and similar at baseline (77.8 [14.4] in group 1 and 80.2 [20.9] in group 2) (Table 4-24). During weeks 2-28, the mean GHS/QoL scores were 69.2-77.3 in group 1 and 66.7-75.8 in group 2 (Tables 4-24 to 4-32; and Table 4-7).

At the time of this analysis, all patients had completed OLTP; 23 entered the elective OLEP (Table 4-8). During OLTP, 20 patients (83.3%) maintained controlled lactate dehydrogenase (LDH; ≤1.5 × upper limit of normal [ULN]) at all time points (most patients maintained LDH <1.0 × ULN) (Figure 28). Most patients (75%, n=18) met the criteria for hemoglobin stability (no transfusion and no hemoglobin drop of ≥2 g/dL) (Table 4-10). Two patients had breakthrough hemolysis (both related to complement activation disease) and required transfusion. CH50 (a measure of total complement hemolytic activity) remained completely suppressed in all patients at all post-baseline time points (Table 4-12A, Table 4-12B and Figure 29).

At data cutoff, 16 patients (66.7%; seven in Group 1 and nine in Group 2) had a total of 46 treatment-emergent adverse events (TEAEs); none led to treatment discontinuation; and 43 were mild to moderate (Table 4-11). Two patients had three severe TEAEs, one with anemia and another with two events—gastroenteritis associated with breakthrough hemolytic events. Three patients in Group 2 each had one severe TEAE (COVID-19, upper respiratory tract infection, gastroenteritis as described above). No severe/complex TEAEs were considered related to study treatment, and all resolved. There were no meningococcal infections, thrombotic events, or deaths (Tables 4-12 and 4-13). Summary / Conclusions

Compared with pre-treatment, PNH patients who switched from pazelimab monotherapy had improved baseline scores on GHS/QoL, physical function, and fatigue. Combination therapy maintained improvements in these scores until Week 28, especially with the pazelimab Q4W and cemdisiran dosing schedules. Although these findings need to be further validated in larger datasets, this evidence suggests that pazelimab and cemdisiran combination therapy (particularly the Q4W schedule) leads to and maintains improvements in fatigue, physical function, and quality of life.

Regardless of the treatment group, PNH patients generally tolerated the combination of paslimab and cemdisiran well. Overall, 83.3% maintained adequate control of hemolysis (Table 4-9), most maintained LDH normalization, and 75% achieved hemoglobin stabilization during OLTP. These findings support the continued development of this combination therapy in the treatment of PNH patients. surface 4-7. Patient-Reported Outcomes Visit FACIT- ^Fatigue over time EORTC-QLQ-C30 ^physical function over timeb EORTC-QLQ-C30 GHS/QoL ^b over time Pazelimab Q4W + Cemdisiran (n=12) Pazelimab Q2W + Cemdisiran (n=12) Pazelimab Q4W + Cemdisiran (n=12) Pazelimab Q2W + Cemdisiran (n=12) Pazelimab Q4W + Cemdisiran (n=12) Pazelimab Q2W + Cemdisiran (n=12) Before treatment, n twenty two twenty two twenty two Mean [SD] ^c 32.3 (15.2) 70.9 (22.5) 60.6 (22.4) Baseline, n ^d 9 8 9 8 9 8 Mean (SD) 45.4 (5.6) 45.6 (3.6) 93.3 (8.8) 94.2 (9.0) 77.8 (14.4) 80.2 (20.9) Week 2, n 10 10 10 10 10 10 Mean (SD) 45.2 (4.2) 42.8 (8.4) 94.0 (8.6) 85.3 (18.8) 75.8 (17.8) 75.0 (16.7) Week 4, n 12 11 12 11 12 11 Mean (SD) 40.3 (11.1) 39.9 (9.6) 90.0 (9.2) 84.2 (19.4) 70.8 (25.5) 75.8 (22.5) Week 8, n 10 12 10 12 10 12 Mean (SD) 42.9 (6.6) 39.3 (11.3) 92.7 (7.3) 84.4 (19.4) 69.2 (20.8) 70.1 (26.2) Week 12, n 12 12 12 12 12 12 Mean (SD) 43.5 (7.0) 40.3 (8.9) 91.1 (9.1) 87.8 (15.5) 71.5 (15.3) 72.9 (19.5) Week 16, n 12 12 12 12 12 12 Mean (SD) 44.0 (5.1) 40.8 (11.3) 90.0 (9.6) 85.0 (19.9) 72.2 (22.0) 68.8 (28.9) Week 20, n 11 10 11 10 11 10 Mean (SD) 43.4 (6.8) 36.5 (12.8) 93.9 (8.1) 82.0 (18.9) 77.3 (20.4) 66.7 (24.5) Week 24, n 12 11 12 11 12 11 Mean (SD) 44.1 (7.3) 42.9 (9.1) 90.6 (9.2) 86.1 (19.0) 75.7 (19.0) 73.5 (29.3) Week 28, n 12 11 12 11 12 11 Mean (SD) 43.6 (6.7) 41.7 (10.2) 95.0 (5.8) 90.9 (16.7) 75.0 (16.7) 73.5 (23.8) a FACIT-Fatigue: Scores range from 0 to 52, with higher scores indicating lower fatigue. b EORTC QLQ-C30: Scores range from 0 to 100; high scores on the Functional Scale indicate high/healthy levels of functioning, and high scores on the GHS/QoL indicate high QoL. c Pretreatment baseline values are from a previous phase 2 trial in which all patients received open-label paslimab monotherapy (NCT03946748). d Seven patients in this study completed the PRO instrument after baseline treatment and were therefore excluded from the analysis at this time point. EORTC-QLQ-C30, European Organization for Research and Treatment of Cancer; Quality of Life Questionnaire core 30 items; FACIT-Fatigue, Functional Assessment of Chronic Disease Therapy-Fatigue; GHS, global health status; Q2W, every two weeks; Q4W, every four weeks; QoL, quality of life; SD, standard deviation. surface 4-8. Disposal Table ( Security Analysis Set )- No. 28 Week Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Randomly assigned subjects 12 (100%) 12 (100%) 24 (100%) Security Analysis Set 12 (100%) 12 (100%) 24 (100%) Complete analysis set 12 (100%) 12 (100%) 24 (100%) Status of subjects receiving open-label treatment completed 12 (100%) 12 (100%) 12 (100%) 12 (100%) 24 (100%) 24 (100%) Subjects receiving open label expansion treatment Treatment status Ongoing Discontinued Discontinued reason: Subjective decision 11 (91.7%) 10 (90.9%) 1 (9.1%) 1 (100%) 12 (100%) 12 (100%) 0 0 23 (95.8%) 22 (95.7%) 1 (4.3%) 1 (100%) Subject's study status: Suspended 10 (83.3%) 2 (16.7%) 12 (100%) 0 22 (91.7%) 2 (8.3%) Reason for termination: Subjective decision 2 (100%) 0 2 (100%) Ongoing is defined as not completing all phases and not discontinuing the study. Completed subjects are those who have completed all phases (OLTP, OLEP, and/or safety follow-up) of the study they entered. surface 4-9. From baseline to 28 Maintain adequate control of hemolysis for weeks Pazelimumab Q2W + Cemdisiran (N=12) Q4W + Cemdisiran (N=12) Total (N=24) The proportion of patients maintaining adequate control from baseline to week 28 was normalized to 95% confidence interval (%) Clopper Pearson (95%) confidence interval (%) 9 (75.0%) 50.5-99.5 42.8-94.5 11 (91.7%) 76.0-100.0 61.5-99.8 20 (83.3%) 68.4-98.2 62.6-95.3 surface 4-10. From baseline to 28 Weeks of hemoglobin stability Pazelimumab Q2W + Cemdisiran (N=12) Q4W + Cemdisiran (N=12) Total (N=24) The proportion of patients maintaining stable hemoglobin from baseline to week 28 is close to the normal 95% confidence interval (%) Clopper Pearson (95%) confidence interval (%) 8 (66.7%) 40.0-93.3 34.9-90.1 10 (83.3%) 62.2-100.0 51.6-97.9 18 (75.0%) 57.7-92.3 53.3-90.2 surface 4-11. Adverse events during treatment (TEAE) Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Total number of TEAEs 32 14 46 Total number of serious TEAEs 3 0 3 Total number of relevant TEAEs 8 7 15 Total number of severe TEAEs 3 0 3 Subjects with any TEAE 9 (75.0%) 7 (58.3%) 16 (66.7%) Subjects with any severe TEAE 3 (25.0%) 0 3 (12.5%) Subjects with any relevant TEAEs 3 (25.0%) 4 (33.3%) 7 (29.2%) Subjects with any severe TEAE 2 (16.7%) 0 2 (8.3%) Subjects with any TEAE leading to discontinuation of any study drug 0 0 0 Subjects with any TEAE leading to death 0 0 0 surface 4-12A. Severe TEAE Treatment group: Pazelimab Q2W + Cemdisiran Subject ID AE Number System Organ Class / Preferred Term / Researcher Term AE start date and time (start date)/stop date and time (stop date) TEAE? / SAE? / Severity Related to Poz IV / Poz SC / Cemd Actions taken with Poz IV / Poz SC / Cemd result Are you particularly interested in AE? 348301001 002 Blood and Lymphatic System Disorders / Breakthrough Hemolysis / Breakthrough Hemolysis (25) / (57) Y / N / Moderate N/N/N Not applicable/No change in dosage/No change in dosage Recovered/Resolved with sequelae N 003 Infections and Infestations / Chlamydia Infections / Chlamydia trachomatis Infections (35) / (50) Y / N / Moderate N/N/N Not applicable/No change in dosage/No change in dosage Recovered/Resolved N 004 Blood and Lymphatic System Disorders / Hemolysis / Suspected Unconfirmed Hemolysis (113) / (114) Y / N / Moderate N/N/N Not applicable/No change in dosage/No change in dosage Recovered/Resolved N 005 Blood and lymphatic system diseases / Anemia / Anemia (57) / (112) Y / N / Moderate N/N/N Not applicable/No change in dosage/No change in dosage Recovered/Resolved N 006 Blood and lymphatic system diseases / Anemia / Anemia progression (113) / (127) Y / N / Severe N/N/N Not applicable/No change in dosage/No change in dosage Recovered/Resolved N surface 4-12B. Severe TEAE- Continued Treatment group: Pazelimab Q2W + Cemdisiran Subject ID AE Number System Organ Class / Preferred Term / Researcher Term AE start date and time (start date)/stop date and time (stop date) TEAE? / SAE? / Severity Related to Poz IV / Poz SC / Cemd Actions taken with Poz IV / Poz SC / Cemd result Are you particularly interested in AE? 410304002 003 Systemic diseases and injection site conditions / injection site reactions / injection site reactions (255)/ (323) Y / N / Mild N / N / Y Not applicable/No change in dosage/No change in dosage Recovered/Resolved Y 458301001 001 Musculoskeletal and connective tissue diseases / muscle spasms / muscle cramps (1)/ (1) Y / N / Mild N / N / Y Not applicable/No change in dosage/No change in dosage Recovered/Resolved N 002 Tests/ Increased transaminases/ Elevated AST and ALT (57)/ In progress Y / N / Mild N/N/N Not applicable/No change in dosage/No change in dosage Recovered/Solving N 003 Blood and Lymphatic System Disorders/Breakthrough Hemolysis/Breakthrough Hemolysis (198)/ (201) Y / N / Severe N/N/N Not applicable/No change in dosage/No change in dosage Recovered/Resolved N 005 Infections and Infestations / Gastroenteritis / Infection; Acute Gastroenteritis (194)/ (201) Y / N / Severe N/N/N Not applicable/No change in dosage/No change in dosage Recovered/Resolved N surface 4-13. 1852 Baseline before treatment FACIT- Fatigue ( Complete analysis set ) Visit Pazelimumab (N=24) Baseline value n twenty two Mean (SD) 32.3 (15.15) Median 36.5 Q1 : Q3 18.0 : 45.0 Minimum value: Maximum value 5 : 52 surface 4-14. 2092 Over time FACIT- Fatigue - Baseline to 28 Week ( Complete analysis set ) ( No. 1 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) FACIT Fatigue Baseline Observed Values n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 45.6 (3.62) 46.0 43 : 49 40 : 50 9 45.4 (5.55) 48.0 43 : 49 35 : 50 17 45.5 (4.60) 48.0 43 : 49 35 : 50 Day 15 Observed values n Mean (SD) Median Q1 : Q3 Min : Max 10 42.8 (8.40) 45.5 41 : 49 24 : 51 10 45.2 (4.24) 46.5 40 : 48 39 : 50 20 44.0 (6.59) 46.0 41 : 49 24 : 51 Change from baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -4.0 (7.96) -1.0 -9 : 2 -20 : 3 9 -0.3 (2.45) -1.0 -1 : 1 -4 : 4 17 -2.1 (5.86) -1.0 -3 : 2 -20 : 4 surface 4-15. 2092 Over time FACIT- Fatigue - Baseline to 28 Week ( Complete analysis set ) ( No. 2 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) FACIT Fatigue Day 15 Percent change from baseline n Mean (SD) Median Q1 : Q3 Min : Max 8 -8.9 (18.11) -2.1 -19 : 4 -45 : 8 9 -0.3 (6.09) -2.0 -2 : 2 -9 : 11 17 -4.4 (13.47) -2.0 -6 : 4 -45 : 11 Day 29 Observed values n Mean (SD) Median Q1 : Q3 Min : Max 11 39.9 (9.63) 42.0 30 : 50 25 : 52 12 40.3 (11.08) 44.0 39 : 48 10 : 50 23 40.1 (10.18) 44.0 33 : 49 10 : 52 Change from baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -5.9 (6.88) -5.5 -11 : 0 -17 : 2 9 -6.0 (8.80) -3.0 -11 : 1 -25 : 1 17 -5.9 (7.71) -4.0 -11 : 1 -25 : 2 surface 4-16. 2092 Over time FACIT- Fatigue - Baseline to 28 Week ( Complete analysis set ) ( No. 3 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) FACIT Fatigue Day 29 Percent change from baseline n Mean (SD) Median Q1 : Q3 Min : Max 8 -13.6 (15.99) -11.4 -25 : 0 -40 : 4 9 -14.9 (24.13) -6.4 -22 : 2 -71 : 3 17 -14.3 (20.08) -8.0 -22 : 2 -71 : 4 Day 57 Observed values n Mean (SD) Median Q1 : Q3 Min : Max 12 39.3 (11.25) 42.5 30 : 50 18 : 52 10 42.9 (6.61) 45.0 39 : 47 29 : 51 22 40.9 (9.41) 44.0 37 : 49 18 : 52 Change from baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -8.0 (9.93) -5.5 -17 : 1 -24 : 2 8 -2.9 (3.98) -2.5 -6 : 1 -10 : 1 16 -5.4 (7.77) -3.0 -9 : 1 -24 : 2 surface 4-17. 2092 Over time FACIT- Fatigue - Baseline to 28 Week ( Complete analysis set ) ( No. 4 part ) Parameters (unit) Visit Pazelimumab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) FACIT Fatigue Day 57 Percent change from baseline n Mean (SD) Median Q1 : Q3 Min : Max 8 -18.1 (22.70) -11.9 -36 : 2 -57 : 4 8 -6.6 (9.00) -5.1 -14 : 2 -20 : 3 16 -12.3 (17.71) -6.8 -19 : 2 -57 : 4 Day 85 Observed values n Mean (SD) Median Q1 : Q3 Min. : Max. 12 40.3 (8.92) 41.5 36 : 46 22 : 52 12 43.5 (7.01) 48.0 36 : 48 32 : 52 24 41.9 (8.02) 42.5 36 : 48 22 : 52 Change from baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -4.8 (6.50) -5.0 -8 : 0 -16 : 4 9 -2.0 (2.92) -2.0 -3 : 0 -6 : 3 17 -3.3 (4.97) -2.0 -6 : 0 -16 : 4 surface 4-18. 2092 Over time FACIT- Fatigue - Baseline to 28 Week ( Complete analysis set ) ( No. 5 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) FACIT Fatigue Day 85 Percent change from baseline n Mean (SD) Median Q1 : Q3 Min : Max 8 -10.7 (14.36) -10.7 -18 : 0 -36 : 8 9 -4.8 (6.56) -4.0 -9 : 0 -14 : 6 17 -7.6 (11.00) -5.0 -14 : 0 -36 : 8 Day 113 Observed values n Mean (SD) Median Q1 : Q3 Min : Max 12 40.8 (11.33) 43.5 37 : 48 14 : 52 12 44.0 (5.12) 44.0 41 : 48 33 : 51 24 42.4 (8.76) 44.0 41 : 48 14 : 52 Change from baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -5.6 (10.76) -3.5 -8 : 2 -30 : 4 9 -1.7 (3.24) -2.0 -4 : 1 -6 : 3 17 -3.5 (7.75) -3.0 -5 : 1 -30 : 4 surface 4-19. 2092 Over time FACIT- Fatigue - Baseline to 28 Week ( Complete analysis set ) ( No. 6 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) FACIT Fatigue Day 113 Percent change from baseline n Mean (SD) Median Q1 : Q3 Min : Max 8 -12.8 (24.38) -7.5 -17 : 3 -68 : 8 9 -3.5 (7.10) -5.7 -9 : 2 -12 : 8 17 -7.9 (17.55) -6.8 -10 : 2 -68 : 8 Day 141 Observed values n Mean (SD) Median Q1 : Q3 Min : Max 10 36.5 (12.76) 38.0 25 : 47 19 : 52 11 43.4 (6.77) 46.0 42 : 48 26 : 50 21 40.1 (10.42) 44.0 34 : 47 19 : 52 Change from baseline n Mean (SD) Median Q1 : Q3 Min : Max 8 -8.1 (10.52) -5.0 -17 : 0 -25 : 4 9 -3.0 (4.03) -4.0 -6 : 0 -9 : 4 17 -5.4 (7.97) -4.0 -8 : 0 -25 : 4 surface 4-20. 2092 Over time FACIT- Fatigue - Baseline to 28 Week ( Complete analysis set ) ( No. 7 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) FACIT Fatigue Day 141 Percent change from baseline n 8 9 17 Mean (SD) -18.7 (23.61) -6.9 (10.40) -12.4 (18.30) Median -11.8 -8.0 -8.0 Q1 : Q3 -39 : 0 -12 : 0 -19 : 0 Minimum value: Maximum value -57 : 8 -26 : 11 -57 : 11 Day 169 Observed Values n 11 12 twenty three Mean (SD) 42.9 (9.09) 44.1 (7.30) 43.5 (8.04) Median 45.0 47.0 46.0 Q1 : Q3 40 : 52 40 : 49 40 : 50 Minimum value: Maximum value 21 : 52 26 : 51 21 : 52 Change from baseline n 8 9 17 Mean (SD) -4.6 (8.63) -1.8 (3.56) -3.1 (6.41) Median -2.5 -1.0 -2.0 Q1 : Q3 -8 : 2 -3 : 1 -5 : 1 Minimum value: Maximum value -23 : 4 -9 : 2 -23 : 4 surface 4-21. 2092 Over time FACIT- Fatigue - Baseline to 28 Week ( Complete analysis set ) ( No. 8 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) FACIT Fatigue Day 169 Percent change from baseline n 8 9 17 Mean (SD) -10.4 (19.39) -4.7 (9.38) -7.4 (14.74) Median -5.4 -2.6 -4.1 Q1 : Q3 -18 : 3 -6 : 2 -12 : 3 Minimum value: Maximum value -52 : 8 -26 : 4 -52 : 8 Day 197 Observed Values n 11 12 twenty three Mean (SD) 41.7 (10.15) 43.6 (6.68) 42.7 (8.37) Median 43.0 46.0 45.0 Q1 : Q3 40 : 46 40 : 48 40 : 48 Minimum value: Maximum value 15 : 52 28 : 51 15 : 52 Change from baseline n 8 9 17 Mean (SD) -5.5 (9.90) -2.0 (4.36) -3.6 (7.46) Median -2.0 -2.0 -2.0 Q1 : Q3 -6 : -1 -5 : 2 -5 : 0 Minimum value: Maximum value -29 : 2 -9 : 4 -29 : 4 surface 4-22. 2092 Over time FACIT- Fatigue - Baseline to 28 Week ( Complete analysis set ) ( No. 9 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) FACIT Fatigue Day 197 Percent change from baseline n 8 9 17 Mean (SD) -12.4 (22.45) -4.7 (10.08) -8.3 (16.95) Median -4.2 -4.0 -4.0 Q1 : Q3 -13 : -1 -11 : 4 -13 : 0 Minimum value: Maximum value -66 : 4 -20 : 9 -66 : 9 surface 4-23. 1852 Baseline before treatment EORTC-QLQ-C30 GHS/QoL ( Complete analysis set ) Visit Pazelimumab (N=24) Baseline value n twenty two Mean (SD) 60.606 (22.4466) Median 62.500 Q1 : Q3 50.000 : 75.000 Minimum value: Maximum value 16.67 : 100.00 surface 4-24. 2092 Over time EORTC-QLQ-C30 GHS/QoL- Baseline to 28 Week ( Complete analysis set ) ( No. 1 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Global health status/QoL Baseline Observed value n 8 9 17 Mean (SD) 80.2 (20.86) 77.8 (14.43) 78.9 (17.21) Median 83.3 83.3 83.3 Q1 : Q3 67 : 100 67 : 83 67 : 83 Minimum value: Maximum value 42 : 100 50 : 100 42 : 100 Day 15 Observed values n 10 10 20 Mean (SD) 75.0 (16.67) 75.8 (17.76) 75.4 (16.77) Median 79.2 79.2 79.2 Q1 : Q3 67 : 83 67 : 83 67 : 83 Minimum value: Maximum value 50 : 100 50 : 100 50 : 100 Change from baseline n 8 9 17 Mean (SD) -5.2 (8.84) -0.9 (15.84) -2.9 (12.82) Median -4.2 0.0 0.0 Q1 : Q3 -13 : 0 0 : 8 -8 : 0 Minimum value: Maximum value -17 : 8 -33 : 17 -33 : 17 surface 4-25. 2092 Over time EORTC-QLQ-C30 GHS/QoL- Baseline to 28 Week ( Complete analysis set ) ( No. 2 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Global Health Status/QoL Day 15 Percent Change from Baseline n 8 9 17 Mean (SD) -5.0 (13.48) -0.3 (19.94) -2.5 (16.86) Median -4.2 0.0 0.0 Q1 : Q3 -13 : 0 0 : 13 -10 : 0 Minimum value: Maximum value -25 : 20 -40 : 25 -40 : 25 Day 29 Observed values n 11 12 twenty three Mean (SD) 75.8 (22.50) 70.8 (25.50) 73.2 (23.70) Median 83.3 70.8 75.0 Q1 : Q3 67 : 100 58 : 92 67 : 100 Minimum value: Maximum value 33 : 100 17 : 100 17 : 100 Change from baseline n 8 9 17 Mean (SD) -5.2 (12.55) -11.1 (21.65) -8.3 (17.68) Median -4.2 0.0 0.0 Q1 : Q3 -13 : 0 -17 : 0 -17 : 0 Minimum value: Maximum value -25 : 17 -50 : 17 -50 : 17 surface 4-26. 2092 Over time EORTC-QLQ-C30 GHS/QoL- Baseline to 28 Week ( Complete analysis set ) ( No. 3 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Global Health Status/QoL Day 29 Percent Change from Baseline n 8 9 17 Mean (SD) -7.4 (18.41) -15.0 (29.58) -11.4 (24.52) Median -5.0 0.0 0.0 Q1 : Q3 -18 : 0 -20 : 0 -20 : 0 Minimum value: Maximum value -38 : 25 -75 : 20 -75 : 25 Day 57 Observed Values n 12 10 twenty two Mean (SD) 70.1 (26.22) 69.2 (20.81) 69.7 (23.37) Median 70.8 66.7 66.7 Q1 : Q3 58 : 92 50 : 92 58 : 92 Minimum value: Maximum value 17 : 100 42 : 100 17 : 100 Change from baseline n 8 8 16 Mean (SD) -12.5 (12.60) -10.4 (16.52) -11.5 (14.23) Median -12.5 -4.2 -8.3 Q1 : Q3 -21 : 0 -21 : 0 -21 : 0 Minimum value: Maximum value -33 : 0 -42 : 8 -42 : 8 surface 4-27. 2092 Over time EORTC-QLQ-C30 GHS/QoL- Baseline to 28 Week ( Complete analysis set ) ( No. 4 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Global Health Status/QoL Day 57 Percent Change from Baseline n 8 8 16 Mean (SD) -19.9 (23.20) -13.4 (20.91) -16.7 (21.60) Median -14.6 -5.0 -11.3 Q1 : Q3 -35 : 0 -29 : 0 -29 : 0 Minimum value: Maximum value -60 : 0 -50 : 10 -60 : 10 Day 85 Observed Values n 12 12 twenty four Mean (SD) 72.9 (19.50) 71.5 (15.27) 72.2 (17.14) Median 70.8 66.7 66.7 Q1 : Q3 67 : 88 67 : 83 67 : 83 Minimum value: Maximum value 33 : 100 50 : 100 33 : 100 Change from baseline n 8 9 17 Mean (SD) -6.3 (13.18) -6.5 (13.03) -6.4 (12.68) Median 0.0 0.0 0.0 Q1 : Q3 -13 : 0 -17 : 0 -17 : 0 Minimum value: Maximum value -33 : 8 -33 : 8 -33 : 8 surface 4-28. 2092 Over time EORTC-QLQ-C30 GHS/QoL- Baseline to 28 Week ( Complete analysis set ) ( No. 5 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Global Health Status/QoL Day 85 Percent Change from Baseline n 8 9 17 Mean (SD) -7.3 (20.51) -7.8 (15.63) -7.5 (17.50) Median 0.0 0.0 0.0 Q1 : Q3 -14 : 0 -20 : 0 -20 : 0 Minimum value: Maximum value -50 : 20 -40 : 10 -50 : 20 Day 113 Observed Values n 12 12 twenty four Mean (SD) 68.8 (28.89) 72.2 (22.00) 70.5 (25.18) Median 70.8 79.2 75.0 Q1 : Q3 58 : 92 58 : 83 58 : 83 Minimum value: Maximum value 0 : 100 25 : 100 0 : 100 Change from baseline n 8 9 17 Mean (SD) -11.5 (23.96) -10.0 (19.44) -10.8 (20.99) Median 0.0 0.0 0.0 Q1 : Q3 -13 : 0 -17 : 0 -17 : 0 Minimum value: Maximum value -67 : 0 -58 : 0 -67 : 0 surface 4-29. 2092 Over time EORTC-QLQ-C30 GHS/QoL- Baseline to 28 Week ( Complete analysis set ) ( No. 6 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Global Health Status/QoL Day 113 Percent Change from Baseline n 8 9 17 Mean (SD) -16.3 (35.43) -12.8 (23.60) -14.4 (28.83) Median 0.0 0.0 0.0 Q1 : Q3 -15 : 0 -20 : 0 -20 : 0 Minimum value: Maximum value -100 : 0 -70 : 0 -100 : 0 Day 141 Observed Values n 10 11 twenty one Mean (SD) 66.7 (24.53) 77.3 (20.44) 72.2 (22.57) Median 62.5 83.3 75.0 Q1 : Q3 50 : 83 50 : 100 50 : 92 Minimum value: Maximum value 33 : 100 50 : 100 33 : 100 Change from baseline n 8 9 17 Mean (SD) -9.4 (14.39) -3.7 (17.73) -6.4 (16.01) Median -4.2 0.0 0.0 Q1 : Q3 -21 : 0 -17 : 0 -17 : 0 Minimum value: Maximum value -33 : 8 -33 : 25 -33 : 25 surface 4-30. 2092 Over time EORTC-QLQ-C30 GHS/QoL- Baseline to 28 Week ( Complete analysis set ) ( No. 7 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Global Health Status/QoL Day 141 Percent Change from Baseline n 8 9 17 Mean (SD) -11.8 (22.60) -4.2 (23.39) -7.7 (22.63) Median -5.0 0.0 0.0 Q1 : Q3 -27 : 0 -20 : 0 -20 : 0 Minimum value: Maximum value -50 : 00 -40 : 38 -50 : 38 Day 169 Observed Values n 11 12 twenty three Mean (SD) 73.5 (29.30) 75.7 (18.96) 74.6 (23.90) Median 75.0 75.0 75.0 Q1 : Q3 67 : 100 67 : 92 67 : 100 Minimum value: Maximum value 0 : 100 42 : 100 0 : 100 Change from baseline n 8 9 17 Mean (SD) -9.4 (24.98) -4.6 (16.72) -6.9 (20.46) Median 0.0 0.0 0.0 Q1 : Q3 -13 : 0 -8 : 0 -8 : 0 Minimum value: Maximum value -67 : 17 -42 : 17 -67 : 17 surface 4-31. 2092 Over time EORTC-QLQ-C30 GHS/QoL- Baseline to 28 Week ( Complete analysis set ) ( No. 8 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Global Health Status/QoL Day 169 Percent Change from Baseline n 8 9 17 Mean (SD) -11.3 (39.80) -5.3 (20.33) -8.1 (30.15) Median 0.0 0.0 0.0 Q1 : Q3 -15 : 0 -10 : 0 -10 : 0 Minimum value: Maximum value -100 : 40 -50 : 20 -100 : 40 Day 197 Observed Values n 11 12 twenty three Mean (SD) 73.5 (23.81) 75.0 (16.67) 74.3 (19.93) Median 66.7 75.0 66.7 Q1 : Q3 67 : 100 67 : 83 67 : 83 Minimum value: Maximum value 17 : 100 50 : 100 17 : 100 Change from baseline n 8 9 17 Mean (SD) -9.4 (23.33) -1.9 (13.03) -5.4 (18.39) Median 0.0 0.0 0.0 Q1 : Q3 -25 : 0 -17 : 0 -17 : 0 Minimum value: Maximum value -50 : 25 -17 : 17 -50 : 25 surface 4-32. 2092 Over time EORTC-QLQ-C30 GHS/QoL- Baseline to 28 Week ( Complete analysis set ) ( No. 9 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Global Health Status/QoL Day 197 Percent Change from Baseline n 8 9 17 Mean (SD) -8.5 (38.08) -2.2 (17.34) -5.2 (28.20) Median 0.0 0.0 0.0 Q1 : Q3 -27 : 0 -20 : 0 -20 : 0 Minimum value: Maximum value -75 : 60 -25 : 25 -75 : 60 surface 4-33. 1852 Baseline before treatment EORTIC-QLQ-C30 Physiological functions ( Complete analysis set ) Visit Pazelimumab (N=24) Baseline value n twenty two Mean (SD) 70.909 (22.4947) Median 76.667 Q1 : Q3 53.333 : 86.667 Minimum value: Maximum value 26.67 : 100.00 surface 4-34. 2092 Over time EORTC-QLQ-C30 Physiological functions - Baseline to 28 Week ( Complete analysis set ) ( No. 1 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Physiological function Baseline Observed value n 8 9 17 Mean (SD) 94.2 (9.04) 93.3 (8.82) 93.7 (8.65) Median 96.7 100.0 100.0 Q1 : Q3 93 : 100 87 : 100 93 : 100 Minimum value: Maximum value 73 : 100 80 : 100 73 : 100 Day 15 Observed values n 10 10 20 Mean (SD) 85.3 (18.80) 94.0 (8.58) 89.7 (14.90) Median 93.3 100.0 93.3 Q1 : Q3 73 : 100 87 : 100 83 : 100 Minimum value: Maximum value 40 : 100 80 : 100 40 : 100 Change from baseline n 8 9 17 Mean (SD) -10.8 (21.06) 0.0 (3.33) -5.1 (15.19) Median 0.0 0.0 0.0 Q1 : Q3 -13 : 0 0 : 0 0 : 0 Minimum value: Maximum value -60 : 0 -7 : 7 -60 : 7 surface 4-35. 2092 Over time EORTC-QLQ-C30 Physiological functions - Baseline to 28 Week ( Complete analysis set ) ( No. 2 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Physiological function Day 15 Percent change relative to baseline n 8 9 17 Mean (SD) -11.0 (21.16) 0.1 (3.45) -5.2 (15.30) Median 0.0 0.0 0.0 Q1 : Q3 -14 : 0 0 : 0 0 : 0 Minimum value: Maximum value -60 : 0 -7 : 7 -60 : 7 Day 29 Observed values n 11 12 twenty three Mean (SD) 84.2 (19.38) 90.0 (9.21) 87.2 (14.90) Median 93.3 93.3 93.3 Q1 : Q3 67 : 100 80 : 97 80 : 100 Minimum value: Maximum value 47 : 100 73 : 100 47 : 100 Change from baseline n 8 9 17 Mean (SD) -13.3 (20.78) -3.0 (9.49) -7.8 (16.20) Median -3.3 0.0 0.0 Q1 : Q3 -27 : 0 0 : 0 -7 : 0 Minimum value: Maximum value -47 : 0 -27 : 7 -47 : 7 surface 4-36. 2092 Over time EORTC-QLQ-C30 Physiological functions - Baseline to 28 Week ( Complete analysis set ) ( No. 3 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Physiological function Day 29 Percent change relative to baseline n 8 9 17 Mean (SD) -14.1 (21.46) -2.8 (9.63) -8.1 (16.77) Median -3.3 0.0 0.0 Q1 : Q3 -28 : 0 0 : 0 -7 : 0 Minimum value: Maximum value -50 : 0 -27 : 8 -50 : 8 Day 57 Observed Values n 12 10 twenty two Mean (SD) 84.4 (19.35) 92.7 (7.34) 88.2 (15.39) Median 93.3 93.3 93.3 Q1 : Q3 80 : 97 87 : 100 87 : 100 Minimum value: Maximum value 40 : 100 80 : 100 40 : 100 Change from baseline n 8 8 16 Mean (SD) -13.3 (23.367) -0.8 (6.61) -7.1 (17.80) Median 0.0 0.0 0.0 Q1 : Q3 -23 : 0 -3 : 3 -7 : 0 Minimum value: Maximum value -60 : 0 -13 : 7 -60 : 7 surface 4-37. 2092 Over time EORTC-QLQ-C30 Physiological functions - Baseline to 28 Week ( Complete analysis set ) ( No. 4 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Physiological Function Day 57 Percent Change from Baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -13.7 (23.85) 0.0 -25 : 0 -60 : 0 8 -0.6 (6.97) 0.0 -3 : 4 -13 : 8 16 -7.1 (18.28) 0.0 -7 : 0 -60 : 8 Day 85 Observed values n Mean (SD) Median Q1 : Q3 Min. : Max. 12 87.8 (15.53) 93.3 80 : 100 53 : 100 12 91.1 (9.14) 93.3 80 : 100 80 : 100 24 89.4 (12.58) 93.3 80 : 100 53 : 100 Change from baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -10.8 (17.07) -3.3 -17 : 0 -47 : 0 9 -3.0 (5.88) 0.0 -7 : 0 -13 : 7 17 -6.7 (12.69) 0.0 -7 : 0 -47 : 7 surface 4-38. 2092 Over time EORTC-QLQ-C30 Physiological functions - Baseline to 28 Week ( Complete analysis set ) ( No. 5 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Physiological Function Day 85 Percent Change from Baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -11.1 (17.31) -3.3 -18 : 0 -47 : 0 9 -3.0 (6.07) 0.0 -7 : 0 -13 : 7 17 -6.8 (12.92) 0.0 -7 : 0 -47 : 7 Day 113 Observed values n Mean (SD) Median Q1 : Q3 Min : Max 12 85.0 (19.92) 93.3 77 : 100 40 : 100 12 90.0 (9.64) 93.3 83 : 97 73 : 100 24 87.5 (15.52) 93.3 80 : 100 40 : 100 Change from baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -13.3 (23.37) 0.0 -23 : 0 -60 : 0 9 -3.0 (3.51) 0.0 -7 : 0 -7 : 0 17 -7.8 (16.54) 0.0 -7 : 0 -60 : 0 surface 4-39. 2092 Over time EORTC-QLQ-C30 Physiological functions - Baseline to 28 Week ( Complete analysis set ) ( No. 6 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Physiological Function Day 113 Percent Change from Baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -13.7 (23.85) 0.0 -25 : 0 -60 : 0 9 -3.1 (3.77) 0.0 -7 : 0 -8 : 0 17 -8.1 (16.89) 0.0 -7 : 0 -60 : 0 Day 141 Observed values n Mean (SD) Median Q1 : Q3 Min : Max 10 82.0 (18.87) 90.0 67 : 100 47 : 100 11 93.9 (8.14) 100.0 87 : 100 80 : 100 21 88.3 (15.19) 93.3 80 : 100 47 : 100 Change from baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -12.5 (18.67) -6.7 -17 : 0 -53 : 0 9 0.0 (3.33) 0.0 0 : 0 -7 : 7 17 -5.9 (14.12) 0.0 -7 : 0 -53 : 7 surface 4-40. 2092 Over time EORTC-QLQ-C30 Physiological functions - Baseline to 28 Week ( Complete analysis set ) ( No. 7 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Physiological Function Day 141 Percent Change from Baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -13.1 (18.77) -6.9 -19 : 0 -53 : 0 9 -0.1 (3.45) 0.0 0 : 0 -7 : 7 17 -6.1 (14.35) 0.0 -7 : 0 -53 : 7 Day 169 Observed values n Mean (SD) Median Q1 : Q3 Min : Max 11 86.1 (18.96) 93.3 73 : 100 40 : 100 12 90.6 (9.19) 93.3 83 : 100 73 : 100 23 88.4 (14.53) 93.3 80 : 100 40 : 100 Change from baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -12.5 (20.30) -6.7 -13 : 0 -60 : 0 9 -2.2 (4.71) 0.0 0 : 0 -13 : 0 17 -7.1 (14.81) 0.0 -7 : 0 -60 : 0 surface 4-41. 2092 Over time EORTC-QLQ-C30 Physiological functions - Baseline to 28 Week ( Complete analysis set ) ( No. 8 part ) Parameters (unit) Visit Pazelimumab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Physiological Function Day 169 Percent Change from Baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -13.0 (20.27) -6.9 -15 : 0 -60 : 0 9 -2.2 (4.71) 0.0 0 : 0 -13 : 0 17 -7.3 (14.90) 0.0 -7 : 0 -60 : 0 Day 197 Observed values n Mean (SD) Median Q1 : Q3 Min : Max 11 90.9 (16.67) 100.0 93 : 100 47 : 100 12 95.0 (5.77) 96.7 90 : 100 87 : 100 23 93.0 (12.14) 100.0 93 : 100 47 : 100 Change from baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -6.7 (19.19) 0.0 -3 : 0 -53 : 7 9 -0.7 (9.09) 0.0 0 : 0 -13 : 20 17 -2.7 (14.73) 0.0 0 : 0 -53 : 20 surface 4-42. 2092 Over time EORTC-QLQ-C30 Physiological functions - Baseline to 28 Week ( Complete analysis set ) ( No. 9 part ) Parameters (unit) Visit Pazelimab Q2W + Cemdisiran (N=12) Pazelimab Q4W + Cemdisiran (N=12) Total (N=24) Physiological Function Day 197 Percent Change from Baseline n Mean (SD) Median Q1 : Q3 Minimum : Maximum 8 -6.6 (19.24) 0.0 -3 : 0 -53 : 7 9 1.5 (10.59) 0.0 0 : 0 -13 : 25 17 -2.3 (15.34) 0.0 0 : 2 -53 : 25 result (twenty four Randomly assigned patients completed OLTP ,and twenty three Selective OLEP)

At data cutoff, all 24 randomized patients had completed OLTP, and 23 entered the elective OLEP. No patient required treatment intensification.

At study baseline, patients receiving pazelimab monotherapy were adequately controlled (Table 4-43). Table 4-43. Baseline Characteristics Features Group 1 (n=12) Group 2 (n=12) Age, years, mean (SD) 53.2 (16.4) 41.4 (16.9) Gender, male, n(%) 6 (50.0) 7 (58.3) Race, non-Hispanic or Latino, n (%) 12 (100.0) 12 (100.0) Race, n(%) Asian 11 (91.7) 10 (83.3) White 1 (8.3) 1 (8.3) other 0 1 (8.3) Age of diagnosis of PNH, years, median (Q1:Q3) 45.0 (32:50) 30.0 (23:49) Baseline LDH, U/L, mean (SD) 237.9 (41.1) 237.0 (44.4) Baseline LDH, x ULN, mean (SD) 0.79 (0.18) 0.79 (0.17) Hemoglobin, g/L, mean (SD) 115.4 (17.2) 108.3 (21.4) ^a eGFR, mL/min/1.73m ² , mean (SD) 104.1 (21.9) 117.8 (18.2) Total bilirubin, μmol/L, mean (SD) 22.8 (12.3) 31.5 (15.6) Heme-binding protein, g/L, mean (SD) 0.1 (0.1) 0.1 (0.1) CH50, kIU/L, mean (SD) 0.1 (0.3) 0.0 (0.0) ^a n=11. Group 1: pazelimab 400 mg SC Q4W + cemdisiran 200 mg SC Q4W. Group 2: pazelimab 400 mg SC Q2W + cemdisiran 200 mg SC Q4W. CH50, total complement hemolysis assay; eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase; PNH, paroxysmal nocturnal hemoglobinuria; Q, quartile; Q2W, every 2 weeks; Q4W, every 4 weeks; SC, subcutaneous; SD, standard deviation; ULN, upper limit of normal.

Throughout the OLTP period, most patients achieved LDH ≤ 1.5 × ULN at each visit (Figure 33), with the majority of patients having LDH values < 1.0 × ULN during most of the observation period.

Two patients (both from group 2) experienced one episode of moderate non-severe breakthrough hemolysis (one associated with chlamydia infection and one associated with gastroenteritis).

A total of four patients received a transfusion from baseline to Week 28 (Day 197; all patients were from Group 2). This included two patients who experienced breakthrough hemolysis (both patients continued to receive combination therapy after receiving a transfusion).

At the time of this primary analysis, 75.0% (18 of 24) met the criteria for stable hemoglobin (ie, no red blood cell transfusion and no hemoglobin drop of ≥2 g/dL; Figure 34).

CH50, a measure of total complement hemolytic activity, remained completely inhibited at all measured post-baseline time points, including during the above-mentioned breakthrough hemolytic events.

A total of 46 treatment-emergent adverse events (TEAEs) were reported by 16 patients (66.7%), none of which led to treatment discontinuation; 43 were mild to moderate in intensity.

Three severe TEAEs occurred in two patients: one patient had anemia and the other patient had two events (gastroenteritis associated with breakthrough hemolysis).

Three patients in Group 2 each had one serious TEAE (COVID-19, upper respiratory tract infection, and gastroenteritis as described above).

No severe or serious TEAEs were considered related to study treatment and all resolved. There were no meningococcal infections, thrombotic events, or deaths.

At the time of this primary analysis, the combination of paszelimab and cemdisiran was well tolerated by PNH patients who switched from paszelimab monotherapy, regardless of treatment arm.

Most patients maintained adequate control of hemolysis, and most maintained normalized LDH (<1.0 × ULN).

Most patients (75%) achieved hemoglobin stabilization during OLTP.

These findings support the continued development of the combination of Pazelimumab and Cemdisiran in the treatment of patients with PNH. Case 5 : Clinical trial evaluating the safety and efficacy of Pazelimumab and Cemdisiran in patients with paroxysmal nocturnal hemoglobinuria (PNH) switching from Eculizumab (R3918-PNH-20105)

PNH is an extremely rare acquired disease caused by mutations in the phosphatidylinositol class A ( PIGA ) gene, which results in impaired expression of complement regulatory proteins on the surface of hematopoietic cells. Clinical manifestations of PNH include hemolytic anemia, hemoglobinuria, and thrombosis. Complement component C5 inhibitors (such as eculizumab) are part of the current standard of care for patients with PNH; however, this is an intravenous therapy that relies on nurses to administer the drug. In addition, some patients have an incomplete response to treatment and may still experience breakthrough hemolytic events. Pasquale and Cemdisiran are subcutaneous maintenance regimens that can be self-administered. The two agents work together to inhibit terminal complements through complementary mechanisms of action. The efficacy and safety of the combination of pazelimab and cemdisiran is being evaluated in an ongoing phase 2, open-label, single-arm study in patients with PNH switching from eculizumab (NCT04888507).

The study has 4 phases: a screening period of up to 42 days, a 32-week open-label treatment period (OLTP (primary study period), which is longer for patients who switch to treatment intensification), an optional 52-week OLEP (open-label extension period (optional period)), and a 52-week post-treatment safety follow-up period. Phase 4 begins when a patient completes or permanently discontinues study treatment (e.g., when study drug is discontinued early, when a patient who refuses the optional OLEP completes study treatment in the OLTP, or when study treatment is completed in the optional OLTP). See Figure 25 for a study flow chart.

This article presents the safety and efficacy results. The baseline characteristics of the subjects are shown in Table 5-1. Table 5-1. Baseline demographic information and clinical characteristics Pazelimumab 400 mg Q4W + cemdisiran 200 mg SC Q4W (n=6) Age when filtering, years, median (minimum:maximum) 52.0 (36:65) Male, n(%) 3 (50.0) Race, White, n(%) 6 (100.0) BMI, kg/m ² , median (minimum:maximum) 27.2 (24.7:49.7) Eculizumab dose, n (%) Standard (900 mg Q2W) 4 (66.7) Nonstandard (1200 or 1500 mg Q2W) 2 (33.3) LDH, ^a U/L, median (minimum:maximum) 221.5 (178.5:288.5) Hemoglobin, g/L, median (minimum:maximum) 110.0 (97:142) Total PNH RBC, ^b % Mean (SD) 64.1 (36.9) PNH PMN, ^b % Mean (SD) 73.4 (26.9) PNH mononuclear sphere, ^b % Mean (SD) 80.7 (23.7) Total bilirubin, μmol/L, median (minimum:maximum) 12.2 (8.7:19.5) Reticulocytes, 10^9/L, median (minimum:maximum) 173.8 (77.4:388.3) eGFR, mL/min/1.73m ² , median (minimum:maximum) 109.5 (80:121) Creatinine, μmol/L, median (minimum:maximum) 57.5 (35.88) a. LDH value before treatment. b. The central laboratory was missing three samples, so the PNH strain data from the local laboratory before the study were used. BMI, body mass index; eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase; PMN, polymorphonuclear neutrophil; PNH, paroxysmal nocturnal hemoglobinuria; Q2W, every 2 weeks; Q4W, every 4 weeks; RBC, red blood cell; SC, subcutaneous; SD, standard deviation. Inclusion criteria

Patients must meet the following criteria to be eligible for inclusion in the study: 1. Male or female aged ≥18 years at the time of consent; 2. Confirmed paroxysmal nocturnal hemoglobinuria as confirmed by previous experience with high-sensitivity flow cytometry; 3. Treated with stable (i.e., no change in dose or frequency) ileumab therapy at the labeled dosing regimen or at a higher dose and/or more frequently than the labeled regimen for at least 12 weeks prior to the screening visit; 4. Provide signed informed consent from the study patient; 5. Willing and able to comply with clinical/remote visits and study-related procedures; 6. Able to understand and complete study-related questionnaires. Exclusion criteria

Patients who meet any of the following criteria will be excluded from the study: 1. Experience of bone marrow transplantation or organ transplantation; 2. Body weight <40 kg at screening; 3. Current medication plan for adjustment (start, stop or change dose/dosing interval) of the following background concomitant medications (if applicable) during the screening and treatment period: erythropoietin, immunosuppressive drugs, corticosteroids, antithrombotic agents, anticoagulants, iron supplements and folic acid; 4. Any complement inhibitor therapy (except eculizumab) used within 12 weeks before the screening visit or planned to be used during the study; 5. Any 2 of the following 3 abnormalities at the screening visit (repeated measurement is allowed once during the screening period): a. Peripheral blood absolute neutrophil count (ANC) <500/μL [<0.5 × 10 ⁹ /L]; or b. Peripheral blood platelet count <20,000/μL; or c. Abnormal peripheral blood reticulocyte count, defined as <20,000/μL or <1%; 6. Known hypocellular bone marrow based on experience of bone marrow cellularity reduction and/or bone marrow cellularity composition ≤25% adjusted for age; 7. No documented meningococcal vaccination within 5 years prior to the screening visit, unless there is a record of vaccination during the screening period and before the start of study treatment; 8. Inability to take antibiotics to prevent meningococci if required by local standards of care; 9. Any active ongoing infection or recent infection requiring systemic treatment with antibiotics, antivirals, or antifungals within 2 weeks of screening or during the screening period; 10. Documented history of systemic fungal disease or unresolved tuberculosis (TB) during the screening period, or evidence of active or latent tuberculosis infection (LTBI). Assessment of active TB and LTBI should be consistent with local practice or guidelines, including those related to risk assessment and the use of tuberculin skin testing or T-cell interferon gamma release analysis; 11. Positive hepatitis B surface antigen or hepatitis C virus RNA at screening. Note: Cases with unclear explanations should be discussed with the medical supervisor; 12. History of human immunodeficiency virus (HIV) infection 13. Based on regional recommendations for COVID-19 or suspected SARS-CoV-2 infection, documented* polymerase chain reaction (PCR) or equivalent test positive, and: a. Has not recovered from COVID-19 (i.e., all COVID-19-related symptoms and major clinical findings that may affect the patient's safety have not been resolved), and b. Has not had 2 negative results on a nucleic acid amplification (PCR) test or equivalent test based on regional recommendations for COVID-19 to confirm that the patient is SARS-CoV-2 negative, or if COVID-19 PCR (or equivalent) testing is not feasible, at least 3 months have passed since the initial diagnosis. *Note: COVID-19 screening will not be performed as part of the eligibility assessment for this study; 14. Known hereditary complement deficiency; 15. Documented history of active, uncontrolled, persistent systemic autoimmune disease; 16. Patients with a documented history of cirrhosis or liver disease with evidence of current liver impairment, or patients with ALT or AST (not related to PNH) greater than 3 × ULN at the screening visit (one repeat assessment is allowed during the screening period); 17. Patients with eGFR <30 mL/min/1.73 ^m2 (based on the Chronic Kidney Disease-Epidemiology Collaboration 2009 [CKD-EPI]) at the screening visit (one repeat assessment is allowed during the screening period); 18. Recent unstable medical conditions within the past 3 months before the screening visit, excluding PNH and PNH-related complications (e.g. myocardial infarction, New York Heart Association Class III or IV congestive heart failure, severe uncontrolled arrhythmia, cerebrovascular accident, active gastrointestinal bleeding); 19. Major surgery is expected during the study period; 20. History of cancer in the past 5 years, excluding adequately treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma in situ; 21. Known allergy to any component of pasirimab, cemdisiran, or their respective formulations; 22. Known or documented functional or anatomical asplenia; 23. Any clinically significant abnormality identified at screening that, in the judgment of the investigator or any sub-investigator, will prevent the safe completion of the study or limit the assessment of the evaluation indicators, such as patients with major systemic diseases or expected short life expectancy; 24. Considered for any reason, including but not limited to the following reasons: • deemed unable to meet specific protocol requirements, such as planned visits, • deemed unable to perform or tolerate long-term injections, • any other actual or expected situation (e.g., geographical, social) that the investigator believes will limit or restrict the patient's participation in the study for the duration of the study, • a member of a vulnerable group, such as an institutionalized person; 25. Clinical site research team members and/or their immediate family members, unless approved in advance; 26. Pregnant or lactating women 27. Women of childbearing potential (WOCBP)* who are unwilling to use highly effective contraceptive measures before the initial dose/first treatment, during the study, and for at least 52 weeks after the last dose. Highly effective contraceptive measures include: a. Stable use of combined (estrogen and progestin) hormonal contraceptives (oral, vaginal, transdermal) or progestin-only hormonal contraceptives (oral, injectable, implantable) to suppress ovulation starting 2 or more menstrual cycles before screening; b. Intrauterine contraceptive device (IUD); intrauterine hormone-releasing system (IUS); c. Bilateral tubal ligation; d. Vasectomy partner (provided that the vasectomized male partner is the only sexual partner of the WOCBP study participant and the vasectomized partner has received a medical evaluation of the success of the surgery); and/or e. Abstinence , . *WOCBP is defined as a woman of childbearing potential from postmenarche until postmenopause, unless infertility is permanent. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. The postmenopausal state is defined as the absence of menstruation for 12 months without other medical reasons. High levels of follicle-stimulating hormone (FSH) in the postmenopausal range can be used to confirm the postmenopausal state in women who are not using hormonal contraception or hormone replacement therapy. However, a single FSH measurement is not sufficient to confirm the occurrence of the postmenopausal state in the absence of 12 months of amenorrhea. The above definition is based on the Clinical Trials Facilitation and Coordination Group (CTFG. 2020. Recommendations related to contraception and pregnancy testing in clinical trials. Vol. v1.1. Clinical Trials Facilitation and Coordination Group). For women with a history of hysterectomy or tubal ligation, pregnancy testing and contraception are not necessary. Abstinence is considered a highly effective approach only if it is defined as abstention from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of abstinence needs to be assessed based on the duration of the clinical trial and patient preferences and usual lifestyle. Periodic abstinence (calendar method, temperature sign method, post-ovulation method), intercourse interruption method (extracorporeal ejaculation method), use of spermicide only and lactational amenorrhoea method (LAM) are not acceptable contraceptive methods. Female condoms and male condoms should not be used at the same time; 28. Participation in another interventional clinical study or use of any experimental treatment within 30 days before the screening visit or within 5 half-lives of the research product (whichever is longer); 29. Patients with a history of significant multiple intolerance and/or severe allergies (including latex gloves) or patients with allergic reactions or significant multiple intolerance to prescription or over-the-counter drugs; 30. Patients who have not yet been vaccinated with Streptococcus pneumoniae and Haemophilus influenzae type B vaccines if recommended by current national/local vaccination guidelines. (Note that previously unvaccinated patients should receive these vaccines during the screening period if recommended by current national/local vaccination guidelines.) Methods

This Phase 2 trial included a screening period (up to 42 days), a 32-week open-label treatment period (OLTP), an optional 52-week open-label extension period, and a 52-week post-treatment safety follow-up period. Patients were switched from eculizumab treatment to the combination of pazelimab and cemdisiran. Pazelimab was administered as an IV loading dose prior to the first dose of subcutaneous pazelimab. Pazelimab was administered subcutaneously and cemdisiran was administered subcutaneously every 4 weeks.

Adequately controlled hemolysis was defined as lactate dehydrogenase (LDH) ≤1.5 × ULN. Breakthrough hemolysis was defined as an increase in LDH (LDH ≥2 × ULN if pre-treatment LDH was ≤1.5 × ULN; or LDH ≥2 × ULN after initially achieving LDH ≤1.5 × ULN if pre-treatment LDH was >1.5 × ULN) accompanied by signs or symptoms related to hemolysis.

Patients continue to receive background eculizumab at their usual dose/frequency for the first approximately 2 weeks, and cemdisiran is introduced alone. Introduce Cemdisiran Treatment and Background Concomitant Eculizumab Treatment Day 1 (day the patient is scheduled to take eculizumab): Cemdisiran 200 mg SC and eculizumab ≥ 900 mg IV (at the patient's usual dose). Note: If cemdisiran is not administered on Day 1, eculizumab may be administered up to 2 days after cemdisiran. Day 15: For patients receiving eculizumab Q14 days (labeled dosing regimen): Day 15 (± 2 days), i.e., Days 13 to 17; For patients taking eculizumab more frequently than Q14 days: Patients should take the dose within 2 days of their usual scheduled dosing.

During the transition to eculizumab treatment, the following dosing regimen of pazelimab/cemdisiran combination therapy was administered: Pazelimab/cemdisiran combination therapy: Day 29 (Week 4): pazelimab 60 mg/kg IV loading dose followed (after a delay of at least 30 minutes) pazelimab 400 mg SC and cemdisiran 200 mg SC; Day 57 (Week 8) to Day 197 (Week 28): pazelimab 400 mg SC and cemdisiran 200 mg SC Q4W maintenance regimen (±7 days).

Although the overall goal of the proposed dosing regimen is to prevent hemolysis, the transition period at the start of combination therapy is designed to mitigate the potential for formation of large drug-target-drug (DTD) immune complexes from eculizumab-C5-pazelimab during the treatment transition period. The infusion of a dose of cemdisiran plus a loading dose of pazelimab should minimize the formation of large DTD immune complexes. A previous clinical study described adverse reactions (e.g., serum sickness-like reactions, rash) after switching from eculizumab to another anti-C5 mAb (coralizumab), which were attributed to the formation of immune complexes between C5 and 2 noncompetitive C5 mAbs (Röth et al., Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. Blood Adv 2018; 2(17):2176-85). See Nishidate et al ., Validation of a method to analyze size distribution of crovalimab-complement C5-eculizumab complexes in human serum. Bioanalysis. 2022 Jul;14(13):935-947-Epub 2022 Jul 29；Nishimura et al. , Mitigating Drug-Target-Drug Complexes in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Switch C5 Inhibitors. Clin Pharmacol Ther. 2023 Apr;113(4):904-915-Epub 2023 Feb 12. Similarly, paszelimab has been shown to bind C5 noncompetitively with eculizumab (R3918-PH-19074), so it is possible that higher-order immune complexes are formed in the presence of eculizumab and C5. In vitro studies were performed to simulate what might happen if pazelimab was administered to patients previously treated with eculizumab. Neither pazelimab nor an antibody with the amino acid sequence of eculizumab (eculizumab*) alone formed higher order multimers than a 1:2 mAb:C5 complex. Pazelimab was added to preformed eculizumab*:C5 complexes in the presence of excess pazelimab (5:1:1 pazelimab:eculizumab*:C5) and equimolar amounts of total mAb to C5 (1:1:2 pazelimab:eculizumab*:C5). Under conditions of excess pazelimab, the majority of complexes observed (~86%) were trimers or pentamers (mAb:C5 molar ratios of 2:1 or 3:2, respectively), with the remainder comprising large DTD immune complexes. At equimolar ratios of total mAb and C5, the majority of samples (~86%) consisted of heterogeneous large DTD immune complexes larger than pentamers. In summary, although the combination of eculizumab* and pazelimab is able to form heterogeneous complexes with C5, the presence of excess pazelimab reduces the formation of higher order immune complexes relative to conditions where total mAb and C5 are present at equimolar concentrations. In the current study, Cemdisiran 200 mg SC was provided over a 4-week lead-in period. This is expected to reduce C5 production and thus reduce the total C5 (eculizumab*-C5 complex plus free C5) content (approximately 86% reduction in total C5 on day 29 compared to day 1) before initiating pazelimab/cemdisiran combination therapy. Therefore, the potential for large DTD immune complex formation should be significantly reduced. To further minimize the risk of large DTD immune complex formation when initiating pazelimab/cemdisiran combination therapy, a loading dose of pazelimab 60 mg/kg IV was provided. Based on the documented mean trough concentration of eculizumab of 97 mg/L (Soliris, 2021) and the predicted concentrations of pazelimab over time, the molar concentration of pazelimab should be in excess of eculizumab following the IV loading dose, with an estimated ratio of approximately 17:1. Introducing the cemdisiran dose plus the pazelimab loading dose is believed to be the best solution to this problem and provide rapid and sustained maximal C5 inhibition after initiation of combination therapy and throughout the dosing interval. In addition to being part of an approach to mitigate the potential for large DTD immune complex formation, an IV loading dose of pazelimab 60 mg/kg should ensure rapid and complete suppression of C5 to avoid any breakthrough hemolysis that may occur during treatment transitions. Based on simulation results, a dosing regimen of paszelimumab/cemdisiran 400 mg/200 mg Q4W with an IV loading dose followed by a SC maintenance dose should rapidly and sustainably inhibit C5 to the point of bioinactivity, starting on day 29.

See Tables 5-2 to 5-5 below for the dosing schedule for different doses. Table 5-2. Timeline of events during the open-label treatment period Study Procedure ¹ Screening period Open label treatment period Visit # V1a V1b ² V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 EOT V14 Week Up to -6 0 1 212 4 6 8 10 12 16 20 twenty four 28 32 sky Up to -42 1 8 15 29 43 57 71 85 113 141 169 197 225 Range (days) ±2 ±2 ±3 ±3 ±3 ±3 ±3 ±7 ±7 ±7 ±7 ±7 Screening / Baseline: Inclusion/Exclusion Criteria X X X Informed Consent X OLEP Informed Consent X FBR informed consent (optional) X Informed Consent for Genomic Testing (Optional) X Medical History ³ X Previous medication ⁴ X X Demographic Information X height X Meningococcal vaccination/ ^{revaccination5} X Pneumococcal and Haemophilus influenzae type B vaccinations (if necessary) X Tuberculosis History and ^Assessment6 X Gonorrhea Risk Assessment7 X Meningococcal Patient Safety ^Card8 X X X X X X X X X X X X X Enrollment X treatment: Cemdisiran 200 mg SC Q4W ^9,11 X X X X X X X X Administer pazelimumab IV 60 mg/kg for ¹⁰ X Administer pazelimumab 400 mg SC Q4W ¹¹ X X X X X X X Eculizumab ¹² X X Injection training/patient instruction, as ^needed13 X X X X X X X X X Patient ^diary14 X X X X X X X X Concomitant medication and surgery ＜------------------------------------------------------------X----------------------------------------＞ Study Procedure ¹ Screening period Open label treatment period Visit # V1a V1b ² V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 EOT V14 Week Up to -6 0 1 212 4 6 8 10 12 16 20 twenty four 28 32 sky Up to -42 1 8 15 29 43 57 71 85 113 141 169 197 225 Range (days) ±2 ±2 ±3 ±3 ±3 ±3 ±3 ±7 ±7 ±7 ±7 ±7 Transfer record update ＜-----------------------------------------------------------------X-----------------------------------------------------＞ Antibiotic prophylaxis (recommended) ¹⁵ ＜---------------------------------------------------------------------X-----------------------------＞ Revaccination against meningococcal infection (if necessary) ＜----------------------------------------------------------------X-----------------------------------------------------＞ Clinical outcome assessment: FACIT-Fatigue X X X X X X X X X X EORTC-QLQ-30 X X X X X X X X X X TSQM X X X X X X X X X X PNH symptom-specific questionnaire (daily) ¹⁶ X X X X X X X X X X X X X X PGIS X X X X X X PGIC X X X X X Safety and human body measurements: Weight X X X X X X X X Vital signs X X X X X X X X X X Physical examination X X X X X Electrocardiogram X X X Adverse Events ＜--------------------------------------------------------------------X--------------------------------------------------＞ Breakthrough hemolysis ^assessment17 ＜-------------------------------------------------------------------X---------------------------------------------------＞ Laboratory Test ¹⁸ : Measure meningococcal titer (only if required by local practice/regulations) X Hematology X X ² X X X X X X X X X X X Coagulation group X X ² X X X X X X X X X X X X X Chemistry, including LDH ¹⁹ X X ² X X X X X X X X X X X X X Hepatitis B and C testing X Pregnancy test (for applicable patients) ²⁰ X X X X X X X X X X Study Procedure ¹ Screening period Open label treatment period Visit # V1a V1b ² V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 EOT V14 Week Up to -6 0 1 212 4 6 8 10 12 16 20 twenty four 28 32 sky Up to -42 1 8 15 29 43 57 71 85 113 141 169 197 225 Range (days) ±2 ±2 ±3 ±3 ±3 ±3 ±3 ±7 ±7 ±7 ±7 ±7 Urinalysis X X X X X X X X X X X Pharmacokinetics, Total C5 , and Immunogenicity Sampling: Blood samples of pazelimab concentration ²¹ X X X X X X X X Cemdisiran and metabolite concentrations in blood samples ²² X X X Eculizumab concentration in blood samples ²¹ X X X X X X X X X Total C5 concentration in blood samples ²¹ X X X X X X X X X X X Blood samples for pazelimab immunogenicity ²³ X X X Cemdisiran immunogenicity in blood samples ²³ X X X Biomarkers: Free heme X X X X X X X X X Heme binding protein X X X X Supplement hemolysis analysis (serum CH50) ²¹ X X X X X X X X X X X Supplement hemolysis analysis (serum AH50) ²¹ X X X X X X X X X X X sC5b-9 (plasma) X X X X X X X X X X X PNH red blood cells X X X PNH Granules X X X Selective drug genomics and future biomedical research: Future studies Serum and plasma (optional) ²⁴ X X X X X X Whole blood samples for DNA isolation (optional) ²⁵ X Whole blood RNA samples (depending on the situation) X X Footnotes 1. Study procedures: When multiple procedures are performed on the same day, the order of procedures is as follows: COA assessment, ECG and/or vital signs, blood collection, administration of study treatment, and any pre-specified post-dose sample collection. 2. Screening Visit 1b can be combined with Visit 1a if LDH is available the day before or on the day of eculizumab administration. Visit 1b and additional interim visits may also require repeat blood collection, vaccinations, etc. 3. Medical History: If possible, a history of transfusions, breakthrough hemolysis, and laboratory parameters used to measure hemolysis (such as LDH, bilirubin, heme-binding protein, reticulocyte count, and hemoglobin) in the past year should be obtained. If feasible, a history of thrombosis and Neisseria infection at any time in the past will be collected. Ongoing PNH symptoms and signs will also be collected. 4. Past medications: including detailed eculizumab dosing history (past 26 weeks) and meningococcal vaccination history (past 5 years); all other prior medications for 12 weeks prior to screening. 5. Patients will need to be vaccinated with meningococcal vaccine unless documentation is provided of previous immunization within the past 5 years prior to screening, or less than 5 years if vaccinated with complement inhibitors as per national vaccination guidelines or as required by local practice. For patients who require meningococcal vaccine during the screening period, it is best to administer it at least 2 weeks prior to Day 1 or at other time points as per local practice or national guidelines. 6. Tuberculosis history and evaluation. Screening by tuberculin skin test or T-cell interferon gamma release assay may be performed at the investigator's discretion based on local practice or guidelines. 7. Risk factor assessment for gonorrheal infection is recommended, and counseling is recommended for high-risk patients. 8. Patient Safety Card: Provide patients with a patient safety card for meningococcal infection on the first day or any other visit, if necessary. Sites should review the instructions on the safety card with patients at each visit. 9. Cemdisiran Administration: The first day of cemdisiran administration will follow the patient's usual eculizumab dosing schedule. 10. Pazerizumab IV administration: The administration on Day 29 should precede the SC administration. After IV administration is completed, patients should be observed for at least 30 minutes and if there are no clinical concerns, SC administration of the combination should be continued. Patients should be monitored for at least an additional 30 minutes after the first SC dose. 11. SC doses of Pazelimumab and Cemdisiran should be administered Q4W (every 28 days) beginning on Day 29 (Week 4). Beginning on Day 57 (Week 8), SC administration of Cemdisiran and Pazelimumab may be continued at the patient’s home by site personnel or another healthcare professional or by the patient or a designated person at the patient’s preferred location after adequate training. The last SC dose of the combination during the OLTP period is at Week 28. During the Q4W dosing interval beginning on Day 57, Cemdisiran and Pazelimumab SC doses should be administered on the day of the corresponding study visit whenever possible. Unless otherwise specified, study treatment administration should always be the last procedure after all blood samples and study assessments have been completed. If Pazelimumab or Cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 7 days before or up to 7 days after the scheduled dosing date, provided that dosing occurs after the corresponding study visit has been completed. For example, the Day 57 (Week 8) visit could occur on Days 54 to 60, given the visit coverage. Pazelimumab and cemdisiran at corresponding doses may be administered on Days 54 through 64, but only after the Week 8 visit assessments have been completed. Similarly, given the coverage of the visits, the Day 113 (Week 16) visit may be conducted on Days 106 through 120. Pazelimumab and cemdisiran at corresponding doses may be administered on Days 106 through 120, but only after the Week 16 visit assessments have been completed. Pazelimumab and cemdisiran should be administered on the same day whenever possible. Care must be taken to coordinate dosing at visits where postdose samples are collected to measure concentrations of cemdisiran and its metabolites. 12. Eculizumab Dosing: Continue the patient’s eculizumab dosing at the usual dosing frequency and interval. The eculizumab dose on Day 1 (when the first dose of Cemdisiran is administered) may be administered up to 2 days later. NOTE: Week 2 visits should be scheduled based on the patient’s typical dosing frequency. For patients receiving eculizumab at the following frequencies: • Every 12 days - Visit should be scheduled on Day 13 (± 2 days). • Every 13 days - Visit should be scheduled on Day 14 (± 2 days). • Every 14 days - Visit should be scheduled on Day 15 (± 2 days). Eculizumab doses should be administered based on the usual dosing frequency and must be administered at or after the visit and appropriate assessments have been performed. 13. For patients who wish to self-inject or have a designated person inject, injection training will be provided. Site staff should observe the patient's self-injection or injection by a designated person and confirm adequacy. Patient instruction materials will be provided. 14. If necessary, based on patient self-administration/designated person administration, the patient will complete a diary to record information about study treatment administration starting at the Day 57 visit or subsequent visits. If a patient diary is provided to the patient, it should be reviewed at each clinic visit and data collected on the Case Report Form (CRF). The log should be collected by the site at the last visit. 15. Daily oral antibiotic prophylaxis against meningococcal disease is recommended, starting on the first day of study treatment administration and continuing until 52 weeks after discontinuation of pasirimab/cemdisiran. If meningococcal vaccination occurred less than 2 weeks prior to Day 1, antibiotic prophylaxis must be initiated at least 2 weeks prior to vaccination. 16. Patients will complete the PNH symptom-specific questionnaire daily for at least 14 days prior to the Day 1 visit. Patients should complete the PNH symptom-specific questionnaire at the same time each day whenever possible. 17. Evaluation for Breakthrough Hemolysis: If a patient is suspected of having a breakthrough hemolytic event, additional samples will be collected for coagulation parameters, chemistry, hematology, reticulocyte count, D-dimer, total C5, CH50, ADA (for paselimab), and drug concentrations for paselimab and eculizumab, in addition to the required laboratory collections, unless noted in the event timeline for that visit. If the suspected event does not occur at the scheduled visit, a planned off-site visit should be conducted and the patient evaluated and coagulation parameters, chemistry, hematology, reticulocyte count, total C5, CH50, and drug concentrations of paslimab and eculizumab collected. 18. During laboratory collection, handling, and processing, the same methodology will be applied to study visits whenever possible to maintain sample quality and avoid hemolysis. The coagulation blood sample (tube) must always be collected first, followed by the blood chemistry sample (tube). Laboratory samples should be repeated if the investigator or sponsor suspects that the laboratory results do not accurately reflect the patient's condition. 19. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. The clotting blood sample (test tube) must always be collected first, followed by the blood chemistry sample (test tube). During the Screening Period, on the day of eculizumab administration (or if not possible, the day before), obtain chemistries including LDH before eculizumab administration. On Day 1 and all subsequent visits, obtain chemistries including LDH before any study treatment administration. 20. Pregnancy Testing for WOCBP: Serum testing will be performed at the Screening Visit and urine testing will be performed at all other designated visits. Any positive urine test should be confirmed by a serum pregnancy test. 21. Collection of Blood Samples for Pazerizumab, Eculizumab Concentrations, Total C5, CH50 (Efficacy Assessment), and AH50: Obtain samples before any study drug administration (pre-dose). On Day 29, blood samples will be obtained prior to IV administration of pasirimab and within 15 minutes after the end of the IV infusion. 22. Blood samples for concentrations of cemdisiran and its metabolites will be collected prior to administration of any study treatment (predose) and 2 to 6 hours after administration of cemdisiran. Postdose samples should be carefully coordinated with the administration of cemdisiran and may be collected in the clinic or by a visiting healthcare professional. 23. Blood samples for immunogenicity will be collected prior to administration of any study treatment (predose). At the visit for immunogenicity samples, samples should be collected along with drug concentration samples. In the event of a suspected SAE (e.g., allergic reaction or anaphylaxis), additional samples for drug concentration and immunogenicity may be collected at or near the time of the event. 24. Serum and plasma for future studies (optional): Samples should be collected with patient consent and as permitted by local regulatory policies. They may be stored for up to 15 years or as permitted by local regulatory policies (whichever is shorter) for future biomedical research. 25. Whole blood samples for DNA extraction (optional) should be collected on Day 1 (before dosing) but may also be collected at later study visits. Table 5-3. Timeline of events during the treatment period ( for patients receiving intensive treatment in OLTP ) Study Procedure ¹ Intensive treatment period in OLTP Visit # RV1 RV2 RV3 RV4 RV5 RV6 RV7 RV8 RV9 RV10 RV11 RV12 EOT RV13 Week 0r 1r 2r 4r 6r 8r 10r 12r 16r 20r 24r 28r 32r sky 1r 8r 15r 29r 43r 57r 71r 85r 113r 141r 169r 197r 225r Range (days) ±2 ±2 ±3 ±3 ±3 ±3 ±3 -7/+3 -7/+3 -7/+3 -7/+3 -7/+3 Treatment: ² Administer pazelimab IV 30 mg/kg X Administer paszelimab 400 mg SC Q2W ³ X X X X X X X X X X X3 Cemdisiran 200 mg SC Q4W ³ X X X X X X X X Injection training/patient instruction, as ^needed4 X X X X X X X X X X X X Patient diary ⁵ X X X X X X X X X X X X Concomitant medication and surgery ＜--------------------------------------------------------------------X---------------------------------------------------＞ Transfer record update ＜--------------------------------------------------------------------X---------------------------------------------------＞ Antibiotic prophylaxis (recommended) ⁶ ＜---------------------------------------------------------------------X-----------------------------------------------＞ Revaccination against meningococcal infection (if necessary) ＜--------------------------------------------------------------------X---------------------------------------------------＞ Clinical outcome assessment: FACIT-Fatigue X X X X X X X X X X EORTC-QLQ-30 X X X X X X X X X X TSQM X X X X X X X X X X PNH symptom specific questionnaire (daily) ⁷ X X X X X X X X X X X X X PGIS X X X X X X PGIC X X X X X Safety and human body measurements: Meningococcal Patient Safety ^Card8 ＜--------------------------------------------------------------------X---------------------------------------------------＞ Weight X X X X X X X X Vital signs X X X X X X X X X Physical examination X X X X Electrocardiogram X X Adverse Events ＜--------------------------------------------------------------------X---------------------------------------------------＞ Study Procedure ¹ Intensive treatment period in OLTP Visit # RV1 RV2 RV3 RV4 RV5 RV6 RV7 RV8 RV9 RV10 RV11 RV12 EOT RV13 Week 0r 1r 2r 4r 6r 8r 10r 12r 16r 20r 24r 28r 32r sky 1r 8r 15r 29r 43r 57r 71r 85r 113r 141r 169r 197r 225r Range (days) ±2 ±2 ±3 ±3 ±3 ±3 ±3 -7/+3 -7/+3 -7/+3 -7/+3 -7/+3 Breakthrough Hemolysis ^Evaluation9 ＜----------------------------------------------------------------X---------------------------------------------------＞ Laboratory tests: Measure meningococcal titer (only if required by local practice/regulations) X Hematology X X X X X X X X X X X Coagulation group X X X X X X X X X X X X X Chemistry, including LDH ¹¹ X X X X X X X X X X X X X Pregnancy test (for applicable patients) ¹² X X X X X X X X X Urinalysis X X X X X X X X X X Pharmacokinetics, Total C5 and Immunogenicity Sampling: Blood samples of pazelimumab concentration ¹³ X X X X X X X X X X Cemdisiran and metabolite concentrations in blood samples ¹⁴ X X X Total C5 concentration in blood samples ¹³ X X X X X X X X X X X Blood samples for pazelimab immunogenicity ¹⁵ X X X Cemdisiran immunogenicity in blood samples ¹⁵ X X X Biomarkers: Free heme X X X X X X X X X Heme binding protein X X X X Complement hemolysis analysis (serum CH50) ¹³ X X X X X X X X X X X Supplement hemolysis analysis (serum AH50) ¹³ X X X X X X X X X X X sC5b-9 (plasma) X X X X X X X X X X X PNH red blood cells X X X PNH Granules X X X Footnotes 1. Study Procedures: When multiple procedures are performed on the same day, the order of procedures is as follows: COA assessment, ECG and/or vital signs, blood collection, administration of study treatment, and any pre-specified post-dose sample collection. 2. Patients should be monitored for at least 30 minutes after completion of Pazelimumab 30 mg/kg IV. Subsequent SC doses will be administered Q2W (Pazelimumab) and Q4W (Cemdisiran) and may be administered at the patient's home by site personnel or other healthcare professionals, or by the patient or designated personnel. For patients receiving intensive treatment in the OLTP, the final SC dose of Cemdisiran is on Day 197r, Week 28r, and the final SC dose of Pazelimumab is on Day 211r (Week 30r). 3. Pazelimumab and Cemdisiran SC Dosing: Pazelimumab SC doses should be given Q2W (every 14 days), while cemdisiran doses should be given Q4W (every 28 days), on the day of the corresponding study visit (whenever possible and applicable). Unless otherwise specified, study treatment administration should always be the last procedure after all blood samples and study assessments have been completed. If administration of Pazelimumab or Cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 3 days before or up to 3 days after the scheduled dosing date, as long as dosing occurs after the corresponding study visit has been completed. For example, considering the visit window, the Day 29r (Week 4r) visit can be conducted on Day 26r to Day 32r. Therefore, doses of Pazelimumab and Cemdisiran can therefore be given on Days 26r to 32r, but only if or after the Week 4r visit assessment has been performed. Similarly, given the visit coverage, the Day 113r (Week 16r) visit can be performed on Days 106r to 116r. Doses of Pazelimumab and Cemdisiran can be given on Days 110r to 116r, but only if or after the Week 16r visit assessment has been performed. Cemdisiran doses should be administered on the same day as the Pazelimumab Q4W dose whenever possible. The last dose of Cemdisiran is at Week 28r, and the last dose of Pazelimumab is at Week 30r. 4. For patients who wish to self-inject or have a designated person inject, injection training will be provided. Sites should observe patients self-injecting or having a designated person inject and confirm adequacy. Patient instruction materials will be provided. 5. If needed, based on patient self-administration/designated person administration, patients will complete a log to record information about study treatment administration. If a patient log is provided to the patient, it should be reviewed at each clinic visit and data collected on the CRF. The log should be collected by the site at the last visit. 6. Daily oral antibiotics are recommended to prevent meningococcal disease until 52 weeks after discontinuation of Pasqualizumab/Cemdisiran. 7. Patients should try to complete the PNH symptom-specific questionnaire at the same time each day whenever possible. 8. Patient Safety Card: Sites should review the instructions on the safety card with the patient at each visit. 9. Evaluation of Breakthrough Hemolysis: If a patient is suspected of having a breakthrough hemolytic event, additional samples will be collected for coagulation parameters, chemistry, hematology, reticulocyte count, D-dimer, total C5, CH50, ADA (for pasorizumab), and drug concentration of pasorizumab in addition to the required laboratory collections unless noted in the event schedule for that visit. If the suspected event does not occur at the scheduled visit, a scheduled off-site visit will be conducted and the patient will be evaluated and coagulation parameters, chemistry, hematology, reticulocyte count, total C5, CH50, and drug concentration of pasorizumab collected. 10. During laboratory collection, handling, and processing, the same methodology will be applied across study visits whenever possible to maintain sample quality and avoid hemolysis. The coagulation blood sample (test tube) must always be collected first, followed by the blood chemistry sample (test tube). 11. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. 12. Pregnancy Testing for WOCBP: Urine testing will be performed at all designated visits. 13. Collection of Blood Samples for Pazerizumab Concentrations, Total C5, CH50 (Efficacy Assessment), and AH50: Samples will be obtained prior to any study drug administration (pre-dose). On Day 1, Pazerizumab concentrations and total C5 will be obtained prior to IV administration of Pazerizumab and within 15 minutes after the end of the IV infusion. 14. Blood samples for concentrations of Cemdisiran and its metabolites will be collected prior to any study treatment administration (pre-dose) and 2 to 6 hours after Cemdisiran administration. Postdose samples should be carefully coordinated with the administration of Cemdisiran and may be collected in the clinic or by a visiting healthcare professional. 15. Blood samples for immunogenicity will be collected prior to administration (pre-dose) of any study treatment. At the visit for immunogenicity samples, samples should be collected along with drug concentration samples. In the event of a suspected SAE (e.g., allergic reaction or anaphylaxis), additional samples for drug concentration and immunogenicity may be collected at or near the time of the event. Table 5-4. Timeline of Events ( Elective Open-Label Extension Period ) Research Procedure ( Interview ) ^1,2 Optional Open Label Extension OLEP-1 ³ OLEP-2 OLEP-3 OLEP-4 OLEP-5 OLEP-6 OLEP-7 Week 0e 8e 16e 24e 32e 40e 52e sky 1e 57e 113e 169e 225e 281e 365e Range ( days ) ⁴ -- -7/+3 -7/+3 -7/+3 -7/+3 -7/+3 -7/+3 Treatment ⁵ : Revaccination against meningococcal infection (if necessary) ＜ X ＞ Pazelimumab 400 mg SC Q2W or Q4W ⁶ X X X X X X X Cemdisiran 200 mg SC Q4W ⁶ X X X X X X X Injection training/patient instruction (if necessary) ⁷ ＜ X ＞ Patient diary ⁸ X X X X X X X Antibiotic prophylaxis (recommended) ⁹ ＜ X ＞ Clinical outcome assessment: FACIT-Fatigue X X X EORTC-QLQ-C30 X X X PGIS X X X PGIC X X X Safety and human body measurements: Meningococcal Patient Safety ^Card10 X X X X X X X Weight X X X X X X X Vital signs X X X X X X X Physical examination X X X X Electrocardiogram X X Adverse Events X X X X X X X Breakthrough Hemolysis ^Assessment11 X X X X X X X Concomitant medication/treatment X X X X X X X Transfer record update X X X X X X X Research Procedure ( Interview ) ^1,2 Optional Open Label Extension OLEP-1 ³ OLEP-2 OLEP-3 OLEP-4 OLEP-5 OLEP-6 OLEP-7 Week 0e 8e 16e 24e 32e 40e 52e sky 1e 57e 113e 169e 225e 281e 365e Range ( days ) ⁴ -- -7/+3 -7/+3 -7/+3 -7/+3 -7/+3 -7/+3 Laboratory Test ¹² : Measure meningococcal titer (only if required by local practice/regulations) X Coagulation group X X X X X X X Chemistry (long group), including LDH ¹³ X X X X X X X ^Hematology14 X X X X X X X Pregnancy test (WOCBP only) ¹⁵ X X X X X X X Urinalysis X X X X X X X Pharmacokinetics, Total C5 and Immunogenicity: Blood samples of pazelimumab concentration ¹⁶ X X X Cemdisiran and metabolite concentrations in blood samples ¹⁷ X X X Total C5 concentration in blood samples ¹⁶ X X X Blood samples for pazelimab ^{immunogenicity18} X X X Cemdisiran immunogenicity in blood samples ¹⁸ X X X Biomarkers: Free heme X X Heme binding protein X X Complement hemolysis analysis (serum CH50) 19 X X X X Supplement hemolysis analysis (serum AH50) 19 X X X X sC5b-9 (plasma) X X X X PNH red blood cells X X X PNH Granules X X X Selective studies: Future studies Serum and plasma (optional) X X Whole blood RNA sample (optional) X X Footnotes 1. Visits may be at the clinical site or at another preferred location, such as the patient's home. The location will depend on the availability of home health care visiting professionals and the preferences of the investigators and patients. If travel restrictions are imposed due to the global pandemic, alternative mechanisms, such as but not limited to telemedicine visits, may be implemented to maintain continuity of study conduct. 2. Study Procedures (Visits): When multiple procedures are performed on the same day, the order of procedures is as follows: COA assessment, ECG and/or vital signs, blood collection, administration of study treatment, and any pre-specified post-dose sample collection. 3. Day 1e of OLEP should be scheduled on the same day as OLTP Week 32 (or Week 32r for patients receiving intensive therapy), and any common assessments will be performed once at both the OLTP and OLEP visits. 4. During OLEP, Cemdisiran and Paszelimab SC doses should be given on the same day as the corresponding study visit whenever possible. Unless otherwise specified, study treatment administration should always be the last procedure after all blood samples have been collected and study assessments have been completed. If paslimab or cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 3 days before or up to 3 days after the scheduled dosing date for patients on the intensification regimen (paslimab dosing Q2W) or up to 7 days before or up to 7 days after the scheduled dosing date for patients on the maintenance regimen (paslimab dosing Q4W), provided that dosing occurs after the corresponding study visit has been completed. Care must be taken to coordinate dosing at visits where postdose samples are collected to measure concentrations of cemdisiran and its metabolites. 5. For patients who did not receive intensified therapy during the OLTP: At any time during the OLEP, patients who meet pre-specified criteria will receive intensified therapy consisting of a 30 mg/kg IV loading dose of Pazelimumab, followed 30 minutes later by Pazelimumab 400 mg SC Q2W and Cemdisiran 200 mg SC Q4W. Patients will continue their visit schedule at the next OLEP visit. 6. Unless otherwise specified, study treatment administration should always be the last procedure after all blood samples and study assessments have been completed. For patients who did not receive intensified therapy during the OLEP, the last dose of Cemdisiran and Pazelimumab was administered at Week 52e. For patients who intensify therapy during the OLEP, the final dose of study treatment will be determined based on the timing of intensification. 7. For patients who want to self-inject or have their injections administered by a designated person, injection training will be provided. The site should observe the patient self-injecting or having their injections administered by a designated person and confirm adequacy. Patient instruction materials will be provided. 8. If study treatment is administered by the patient or a designated person, the patient will fill out a diary to record compliance with study treatment administration. If a patient diary is provided to the patient, it should be reviewed at each clinic visit and data collected into the CRF. The diary should be collected by the site at the last visit. 9. Daily oral antibiotics are recommended to prevent meningococcal disease until 52 weeks after discontinuation of study treatment. 10. Patient Safety Card: Sites should review the instructions on the safety card with the patient at each visit. 11. Evaluation for Breakthrough Hemolysis: If a patient is suspected of having a breakthrough hemolytic event, additional samples will be collected for coagulation parameters, chemistry, hematology, reticulocyte count, D-dimer, total C5, CH50, ADA (for paselimab), and drug concentrations for paselimab in addition to the required laboratory collections unless noted in the event timeline for that visit. If the suspected event does not occur at the time of the scheduled visit, a scheduled off-site visit will be conducted and the patient will be evaluated and coagulation parameters, chemistry, hematology, reticulocyte count, total C5, CH50, and drug concentrations for paselimab will be collected. 12. Unless otherwise specified, clinical laboratory samples will be collected prior to the administration of any study drug (pre-dose). The coagulation blood sample (test tube) must always be collected first, followed by the blood chemistry sample (test tube). During laboratory sample collection, handling, and processing, the same methodology will be applied across study visits whenever possible to maintain sample quality and avoid hemolysis. 13. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. Blood chemistry samples should be collected prior to the administration of study treatment (pre-dose). If the investigator or sponsor suspects that the laboratory results do not accurately reflect the patient's condition, laboratory samples should be repeated. 14. Hematology samples should be collected prior to the administration of study treatment (pre-dose). 15. Pregnancy Testing for WOCBP: Urine testing will be performed at all designated visits. Any positive urine pregnancy test should be confirmed by a serum pregnancy test. 16. Blood samples for analysis of pasirizumab concentrations and total C5 analysis will be obtained on designated days prior to any study treatment administration (pre-dose). If patients receive intensified therapy during the open-label expansion period, PK samples should be obtained before and 15 minutes after IV pasirizumab administration. 17. Blood samples for analysis of cemdisiran drug concentrations and its metabolite concentrations will be collected on designated days prior to any study treatment administration (pre-dose) and 2 to 6 hours after cemdisiran administration. Post-dose samples should be carefully coordinated with the administration of Cemdisiran and may be collected in the clinic or by a visiting healthcare professional. 18. Blood samples for immunogenicity will be collected on designated days prior to the administration of any study treatment (pre-dose). At the visit for the immunogenicity sample, the sample should be collected along with the drug concentration sample. In the event of a suspected treatment-related SAE (such as allergic reaction or anaphylaxis), additional samples for drug concentration and immunogenicity may be collected at or near the onset and resolution of the event. 19. Blood samples for CH50 (an indicator of efficacy assessment) and AH50 will be obtained prior to the administration of any study treatment (pre-dose). Table 5-5. Timeline of Events during the Post-Treatment Safety Follow-up Period ( All Patients ) Study Procedure 52- week post-treatment safety follow-up period Interview # ¹ FU-1 FU-2 FU-3 FU-4 Telephone interview FU-5 Telephone interview FU-6 Weeks (after last dose of study drug) 8 12 16 26 38 52 sky 253 281 309 379 463 561 Range (days) ±10 ±10 ±10 ±10 ±10 ±10 Safety Assessment: Meningococcal Patient Safety Card 2 ＜------------------------------------------------X---------------------------------------＞ Antibiotic prophylaxis (recommended)3 ＜---------------------------------------------X-----------------------------------------＞ Vital signs X X X X Physical examination X X Concomitant medication and surgery X X X X X X Adverse Events ＜------------------------------------------X------------------------------------------＞ Pregnancy Report ＜------------------------------------------X------------------------------------------＞ Laboratory tests: Hematology X X X X Chemistry X X X X Footnote 1. Patients who discontinue study treatment at OLTP or enhanced OLTP will be asked to continue on study until Week 32 EOT (or Week 32r EOT) and follow the original event schedule, if applicable. After the Week 32 or Week 32r EOT visit, the entry point for the safety follow-up schedule will depend on the number of weeks that have passed since the patient's last dose (e.g., a patient who receives their last dose of study treatment at EOT 20 weeks after the last dose will enter the safety follow-up period at Visit FU-4 [26 weeks after the last dose]). Patients who choose not to continue treatment in the OLEP after completing Week 32r in the OLTP, patients who complete the elective OLEP but do not continue study treatment as part of the Post-Trial Visit Program, and patients who permanently discontinue treatment during the OLEP will have a safety follow-up period in FU-1. 2. Patient Safety Card: Sites should review the instructions on the safety card with the patient at each visit. Replacement cards may be provided to patients as needed. 3. Daily oral antibiotic prophylaxis against meningococcal disease is recommended until 52 weeks after discontinuation of study treatment. Primary Objectives

The primary objective of the study is to evaluate the safety and tolerability of the combination of paslimab and cemdisiran in PNH patients switching from eculizumab. Secondary Objectives

The secondary objectives of the study are to: • Evaluate the effect of combination therapy on the following intravascular hemolysis parameters: LDH control, breakthrough hemolysis, and CH50 inhibition • Evaluate the effect of combination therapy on LDH stability during the transition period from eculizumab monotherapy to the combination of pasorizumab and cemdisiran • Evaluate the effect of combination therapy on red blood cell (RBC) transfusion requirements • Evaluate the effect of combination therapy on hemoglobin content • Evaluate the effect of combination therapy on clinical outcome assessments (COA) measuring fatigue and health-related quality of life (HRQoL) • Evaluate the concentrations of total pasorizumab and eculizumab in serum; and total cemdisiran and C5 protein in plasma • Evaluate the immunogenicity of paszelimumab and cemdisiran • Evaluate safety after dose escalation • Evaluate long-term safety and efficacy of the combination during the optional open-label extension period (OLEP) Exploratory objectives

The exploratory objectives of the study are to: • Explore the need for intensified therapy; • Explore the effect on clinical thrombotic events; • Explore the effect on renal function and biomarkers of renal injury; • Explore the effect on complement activation and intravascular hemolysis associated with PNH and other related diseases; • Explore the effect on PNH colony size; • Assess the effect on COA measuring treatment satisfaction (TSQM); • Explore the effect of a novel COA measuring PNH specific symptoms; • Explore the effect on PNH symptoms; • Explore potential differences in genotype and gene expression that may affect the efficacy and safety of combination therapy to further understand C5, PNH, or other conditions associated with complement-mediated damage (for patients who agree to participate in genomic studies); • Explore the mechanism of action of paszelimumab and cemdisiran (related to efficacy and/or safety), complement pathway biology, PNH and related complement-mediated diseases; • Explore the efficacy of paszelimumab and cemdisiran after dose intensification; • Explore the long-term impact of combination therapy on clinical and PD assessments in selective OLEP. Main evaluation indicators

The primary study outcome measure was the incidence and severity of TEAEs during Day 225 of OLTP. Secondary outcome measures

Secondary outcomes of the OLTP were: •Percent change in LDH from pre-treatment (defined as the mean of LDH values at the screening visit [obtained no more than one day before eculizumab administration] and baseline (Day 1 visit, before cemdisiran and eculizumab administration) to the end of treatment [defined as the mean of LDH values at Day 197 and Day 225 in the OLTP]); •Percent change in LDH from pre-treatment to Day 29; •Proportion of patients who were transfusion-free (defined as no red blood cell transfusion required according to the protocol algorithm, i.e., transfusion avoided) from baseline to Day 225 and from Day 29 to Day 225, inclusive; •RBC translocation rate and number of units from baseline to day 225, and from day 29 to day 225 (inclusive). Proportion of patients with breakthrough hemolysis from baseline to day 225, and from day 29 to day 225 (inclusive) •Proportion of patients maintaining adequate control of hemolysis, defined as LDH ≦ 1.5 × ULN from baseline (day 1) to day 225, and from day 57 to day 225 (inclusive); •Proportion of patients with adequate control of hemolysis at each visit from baseline (day 1) to day 225 (inclusive); •Proportion of patients with normalized LDH (defined as LDH ≦ 1.0 × ULN) at each visit from baseline (day 1) to day 225 (inclusive); • Area under the curve (AUC) of LDH over time from baseline to day 225 and from day 57 to day 225 (inclusive); • Proportion of patients with stable hemoglobin (defined as patients who did not undergo RBC transfusion and whose hemoglobin level did not decrease by ≥ 2 g/dL) from baseline to day 225 and from day 29 to day 225 (inclusive); • Change in hemoglobin level from baseline to day 225 (inclusive); • Change in fatigue measured by the FACIT-Fatigue scale from baseline to day 225 (inclusive); • Change in fatigue measured by the European Organization for Research and Treatment of Cancer: Core 30 Items Quality of Life Questionnaire (EORTC) from baseline to day 225 =QLQ-C30), changes in Global Health Status/Quality of Life Scale (GHS), and Physical Function (PF) scores; • Change in total CH50 from baseline to day 225 (inclusive); • Concentrations of total paselumab and eculizumab in serum, and total cemdisiran in plasma, assessed throughout the study; • Changes from baseline in total C5 concentrations assessed throughout the study; • Immunogenicity to paselumab and cemdisiran, as measured by the incidence, titer, and clinical effects of treatment-emergent anti-drug antibody (ADA) reactions over time; • Incidence and severity of TEAEs in patients who received dose intensification through day 225r;

Secondary outcomes for the optional OLEP were: • Incidence and severity of TEAEs during the 52-week OLEP period in patients treated with the combination of pasqualone and cemdisiran; • Change and percentage of change in LDH from Day 1e (OLEP baseline) to Week 24e and Week 52e; • Proportion of patients with no transfusions (defined as no RBC transfusion required according to the protocol algorithm) (i.e., transfusion avoidance) from Day 1e to Week 24e and Week 52e; • Rate and number of RBC transfusions from Day 1e to Week 24e and Week 52e; • Proportion of patients with breakthrough hemolysis from Day 1e to Week 24e and Week 52e; •Proportion of patients who maintained adequate control of their hemolysis, defined as LDH ≦1.5 × ULN from Day 1e to Week 24e and Week 52e (inclusive); •Proportion of patients whose hemolysis was adequately controlled at each visit from Day 1e to Week 24e and Week 52e (inclusive); •Proportion of patients whose LDH was normalized, defined as LDH ≦1.0 × ULN at each visit from Day 1e to Week 24e and Week 52e (inclusive); •AUC of LDH over time from Day 1 to Week 24e and Week 52e (inclusive) •Proportion of patients with stable hemoglobin (defined as patients who did not undergo RBC transfusion and whose hemoglobin level did not decrease by ≥2 g/dL) from Day 1e to Week 24e and Week 52e; • Changes in hemoglobin levels from day 1e to week 24e and week 52e of OLEP; • Changes in fatigue measured by the FACIT-Fatigue scale from day 1e to week 52e of OLEP; • Changes in the GHS/QoL scale PF score according to the EORTC QLQ-C30 from day 1e to week 52e of OLEP; • Changes in CH50 from day 1e to week 16e, week 24e, and week 52e of OLEP; • Total pasirimab concentrations in serum, and total C5 and Cemdisiran concentrations in plasma were assessed over time during OLEP; • To evaluate the immunogenicity of paszelimumab and cemdisiran as measured by the incidence, titer, and clinical impact of ADA responses that occur during treatment during OLEP over time. Exploratory Assessments

The exploratory evaluation indicators of OLTP are: • The proportion of patients who require intensive treatment during the entire study period; •Incidence of MAVEs from baseline to day 225, defined as adverse events of special interest, including thrombophlebitis/deep venous thrombosis, pulmonary embolism, myocardial infarction, unstable angina, renal venous or arterial thrombosis, acute peripheral vascular occlusion, hepatic venous thrombosis, portal vein thrombosis, enterocecal/visceral venous thrombosis or infarction, enterocecal/visceral arterial thrombosis or infarction, transient ischemic attack, cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, gangrene (non-traumatic; non-diabetic), and amputation (non-traumatic; non-diabetic); • Change in renal function measured by estimated glomerular filtration rate (eGFR) from baseline to day 225; • Percent change in free hemoglobin from baseline to day 225; • Change in bilirubin from baseline to day 225; • Change in reticulocyte count from baseline to day 225; • Change and percentage change in AH50 from baseline to day 225; • Ratio of erythrocytes to granulocytes in PNH from baseline to day 225; • EORTC from baseline to day 225 • Changes in the functional scale scores (role functioning, emotional functioning, cognitive functioning, and social functioning) and symptom scale scores (fatigue, nausea and vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea) of the QLQ-C30; • Proportion of patients with stable global health, function, and symptoms measured by the EORTC QLQ-C30 from baseline to day 225; • Comparison of treatment satisfaction (as assessed by the TSQM) at baseline (with eculizumab) versus treatment at day 225 (with paslimab/cemdisiran); • Changes in PNH symptoms from baseline to day 225 as measured by the restart of the PNH symptom-specific questionnaire; • Change in Patient Global Impression of Severity (PGIS) from baseline to day 225, including questions about PNH symptoms, impact, and fatigue; • Change in Patient Global Impression (PGIC) at day 225, including questions about PNH symptoms, impact, and fatigue; • Genotyping and gene expression analysis (by RNA sequencing) to identify any potential differences affecting efficacy and safety. Variability in efficacy

The laboratory variability used to assess efficacy-efficacy in this study was assessed by the following laboratory assessments: •LDH (serum) •Hemoglobin •CH50

These laboratory variables are relevant to the characterization and disease mechanism of PNH (Brodsky, Paroxysmal nocturnal hemoglobinuria, Blood 2014; 124(18):2804-11). Lactate dehydrogenase, as a measure of intravascular hemolysis, can objectively and accurately measure whether the intravascular hemolysis control that patients receive on eculizumab is maintained when they are switched to the combination of paslimab and cemdisiran. CH50 analysis will be used to confirm that PNH patients have achieved complete suppression of tonic activity throughout the dosing interval. Transfer Records

Hemolytic anemia is a clinical manifestation of PNH, and patients usually require blood transfusions for symptomatic treatment. The frequency of blood transfusions has been used to assess treatment efficacy in other studies of PNH (Hillmen, 2006) (Röth, 2018). Clinical outcome measures

Patients will complete the following clinical outcome measures: •FACIT-Fatigue; •EORTC QLQ-C30; •TSQM; •PNH Symptom Specific Questionnaire; •PGIS; •PGIC. Safety Variants

Safety variables in this study included: •TEAEs; •Weight; •Vital signs; •Electrocardiogram (ECG); •Physical examination; •Routine safety laboratory tests (hematology, chemistry, urinalysis, and pregnancy test [for women of childbearing age or WOCBP]); •Concomitant medications and treatments Screening period

During the Screening Period, patients will be evaluated to determine their eligibility for the study.

Screening visits are conducted up to 42 days before Day 1 (the day eculizumab is scheduled to be administered). Additional interim screening visits may be conducted as needed, for example to obtain LDH values for pre-treatment assessment on the day of eculizumab administration (or if this is not possible, the day before eculizumab administration) and before eculizumab administration.

Historical data will be collected, including but not limited to eculizumab administration, concomitant medications, hemolytic parameters, and transfusions. Data regarding signs and symptoms of PNH will also be collected during the screening period.

Patients will require vaccination/revaccination with meningococcal vaccine unless documentation is provided of previous immunization within the past 5 years prior to screening, or less than 5 years if vaccinated with complement inhibitors according to current national vaccination guidelines or as required by local practice. For patients who require meningococcal vaccination during the screening period, it is best to do so at least 2 weeks prior to Day 1, unless local practice or national guidelines specify a different vaccination schedule. If vaccination is less than 2 weeks prior to the start of study treatment, patients must receive antibiotic prophylaxis for at least 2 weeks from the date of vaccination.

During the screening period, patients who have not yet received pneumococcal and Haemophilus influenzae type b vaccinations per current national/local vaccination guidelines will need to be vaccinated to be eligible for study participation.

In addition to meningococcal infections, fatal or serious gonococcal infections have been reported in patients receiving eculizumab. Therefore, risk assessment and counseling regarding the potential risk of gonococcal infection will be performed according to local practice.

Patients will be evaluated for active or latent tuberculosis infection based on local practice or applicable guidelines. Based on the risk assessment, the need for screening using a tuberculin skin test or T-cell interferon-gamma release assay will be determined. If applicable, these results will be interpreted by the investigator. Further management and treatment will be the responsibility of the investigator.

In addition to the screening procedure, patients were asked to complete a PNH symptom-specific questionnaire daily for at least 14 consecutive days before the Day 1 visit.

Patients may choose to participate in the optional OLEP, optional future biomedical research, and/or optional pharmacogenomics portions of the study by signing separate optional informed consent forms (ICFs). Open-label treatment period

Patients who meet all eligibility criteria will be enrolled in the study and receive the first dose of study medication during Day 1, which should occur on the day the patient is scheduled to be treated with eculizumab. As described herein, patients will be administered eculizumab and cemdisiran on Day 1 (Note: eculizumab may be administered up to 2 days after cemdisiran on Day 1 to account for logistical complexities associated with its administration). Eculizumab will be administered alone on Day 15 (+2 days or earlier, depending on the patient's usual dosing frequency). The first dose of combination SC treatment of paszelimumab and cemdisiran (without background eculizumab) will be administered on Day 29 and continue Q4W thereafter. Prior to the first SC dose of the combination on Day 29, an IV loading dose of pazelimab will be administered during the switch from eculizumab to pazelimab to rapidly achieve high concentrations of pazelimab to achieve complete C5 inhibition as soon as possible. SC doses will be administered at least 30 minutes after the completion of IV dosing, and patients should be observed during the interval. Patients will also be monitored for at least 30 minutes after completion of the first SC injection of the pazelimab and cemdisiran combination.

After the first SC dose of the combination of Pazelimumab and Cemdisiran on Day 29, subsequent administration of study treatment may continue by site personnel, healthcare professionals (if available), or by the patient or designee at the patient's preferred site. These options for study treatment administration will depend on investigator and patient preferences, local regulations, and the availability of healthcare professionals. If self-administration (or administration by a designee) is performed, the investigator or a qualified investigator-designee will provide adequate injection training on the maintenance regimen of Pazelimumab and Cemdisiran at the time of planned administration. Following training, observation of self-administration (or administration by a designee) will be conducted by clinical site personnel and may be performed in person at the patient's home or via telemedicine. Once this observation is deemed satisfactory, the patient/designee may then be dosed with the maintenance regimen of Pasqualimumab and Cemdisiran, respectively, for the remainder of the study. Patient diaries will be provided prior to commencing self-administration to record data on study treatment administration. The diary should be completed at the time of each study drug administration. Safety Considerations

Breakthrough hemolysis was assessed by the investigator throughout the study and is defined as described herein. During the study, patients who meet the criteria for breakthrough hemolysis or an inadequate LDH response may be eligible for intensified therapy as described herein. Breakthrough Hemolysis

Breakthrough hemolysis is defined as an increase in LDH accompanied by signs or symptoms associated with hemolysis: • An increase in LDH occurs when: - if pre-treatment LDH was ≦1.5 × ULN, then LDH ≧2 × ULN; or - if pre-treatment LDH was >1.5 × ULN, then LDH ≧2 × ULN after initially achieving LDH ≦1.5 × ULN. Note: Pre-treatment LDH is defined as the average of the LDH values at the screening visit and the Day 1 visit •Signs or symptoms should correspond to those known to be associated with intravascular hemolysis due to PNH, limited to the following: new onset or worsening fatigue, headache, dyspnea, hemoglobinuria, abdominal pain, scleral jaundice, erectile dysfunction, chest pain, confusion, dysphagia, new thrombotic events, anemia (including a significantly lower hemoglobin value (i.e., a decrease of ≥2 g/dL) compared to the patient's known baseline hemoglobin value).

The decision to transfuse red blood cells during a study should be made according to the criteria described in this document.

During the screening period and while the patient is receiving study treatment, red blood cell transfusions may be performed based on the following predefined criteria, which will trigger transfusions as clinically indicated, but the actual number of units transfused is at the discretion of the investigator: • RBC transfusions if the hemoglobin level is ≤9 g/dL and new or worsening signs or symptoms of anemia are severe enough to warrant transfusion; or • RBC transfusions if the hemoglobin level is ≤7 g/dL with or without signs or symptoms of anemia.

Patients should be closely monitored throughout the study for early signs and symptoms of meningococcal infection and evaluated promptly if infection is suspected. Patients will be provided with a Patient Safety Card that describes the signs and symptoms of suspected meningococcal infection, instructions to follow in the event of a potential meningococcal infection, and information for non-study staff healthcare providers to be aware of. Daily oral antibiotic prophylaxis is recommended.

During intravenous infusions of paszelimab, patients should be observed for at least 30 minutes after the infusion due to concern for potential IV infusion reactions. In addition, clinical sites must have emergency equipment and medications available for immediate use to treat infusion reactions. All infusion reactions must be reported as adverse events (AEs) and graded. Patients should also be observed for at least 30 minutes after the first SC injection of the paszelimab and cemdisiran combination.

During the treatment transition from eculizumab to pazelimab, investigators should be aware of possible AEs due to the risk of formation of large multimers of the eculizumab-C5-pazelimab complex (i.e., large drug-target-drug (DTD) immune complexes). Study Procedures

Study procedures during the treatment period include laboratory efficacy assessments (LDH, hemoglobin, and CH50), transfer record updates, clinical outcome assessments, body weight, and routine safety assessments (vital signs, physical examination, ECG, safety laboratory tests). Treatment-emergent adverse events and concomitant medications will be monitored throughout the study. Patients will provide blood samples for biomarkers, drug concentrations for potential PK and PD assessments, immunogenicity, and exploratory assessments. Study procedures are listed in Table 5-2 by visit and described herein. Study procedures (including sample collection for laboratory analysis) may be performed at the study clinic or other location more convenient for the patient (including home visits) if this option is available and approved. The last dose of study treatment for patients who did not receive dose intensification was administered on Day 197 (Week 28). Patients will return at the Week 32 End of Treatment (EOT) visit for safety, efficacy, and other assessments. For patients who restart intensified therapy during the study, the last dose of study treatment will be administered at Week 30. Patients will return at the Week 32 EOT visit for safety, efficacy, and other assessments (Table 5-3). Elective Open Label Extension Period

All patients who complete study treatment in the OLTP (including those who receive the intensified regimen) will have the opportunity to continue to the optional 52-week OLEP, in which treatment with pasizumab and cemdisiran is scheduled uninterrupted from the OLTP to the OLEP (i.e., the Day 1e visit of the OLEP will correspond to the EOT visit of the OLTP, and any common assessments will be performed once during the two visits). Study assessments and conduct of the optional OLEP are as previously described for the OLTP and are detailed in Table 5-4 (Timeline of Events for the Elective OLEP).

Patients who do not receive intensified therapy during an elective OLEP but meet the criteria for treatment intensification described herein will follow the dosing schedule described herein, with the new schedule beginning on the day of intensification and will continue their visit schedule at the next OLEP visit.

This means that starting on the day of intensification (the day that predefined criteria are met), patients will receive a single IV dose of Pazelimumab 30 mg/kg, followed by SC doses of Pazelimumab and Cemdisiran on the same day. Thereafter, patients will receive Pazelimumab 400 mg Q2W and Cemdisiran 200 mg Q4W starting on the day of intensification (±3 days). The OLEP visit schedule will remain unchanged.

For patients who complete an elective OLEP, a post-trial visit for treatment may be possible. Treatment Intensification

Patients meeting treatment intensification criteria will receive a single dose of paselumab 30 mg/kg IV on day 1 (can begin on day 57) in addition to a reduced-frequency maintenance regimen of paselumab 400 mg SC Q2W and cemdisiran 200 mg SC Q4W (±3 days) for 32 weeks starting on day 1.

Intensified regimens provide additional C5 inhibition that some patients may need but that is not available with standard dosing. Patients will receive intensification of their paslimab treatment as described here starting on Day 57 if both of the following criteria are met: • Breakthrough hemolysis not due to complement activation conditions (i.e., intercurrent infection); and • Persistent LDH inadequacy (i.e., LDH >1.5 × ULN) (i.e., based on 2 consecutive measurements spanning at least 2 weeks).

During the OLTP period, patients receiving treatment intensification may need to have a planned outpatient visit prior to starting. The start date of the intensification regimen should be re-anchored as the baseline for the OLTP intensification treatment period (Day 1r), and thereafter follow a similar schedule of follow-up visits and assessments as for newly enrolled patients (see Table 5-3). Patients receiving intensification treatment will be considered to have completed OLTP once they complete the 32-week treatment period of the intensification regimen.

During the elective OLEP, patients who do not receive intensified therapy but meet criteria for treatment intensification will follow the dosing schedule described herein, with the new schedule starting on the day of intensification and continuing for the remainder of the OLEP. Patients will continue their visit schedule at the next OLEP visit (Table 5-4).

Patients are eligible to receive intensified pazelimab only once (either during the primary treatment phase or during elective OLEP), and no further intensification will be allowed after that. NOTE: After Day 29, patients with an increase in LDH ≥ 2 × ULN due to acute activating disease during OLTP, intensified OLTP, or elective OLEP may receive IV pazelimab at the discretion of the investigator at 30 mg/kg. The patient's weight should be assessed on the day of IV pazelimab loading so that the appropriate dose can be calculated. This is not considered a treatment intensification as the regimen is not changed and does not require its schedule to be reset to Day 1.

Assess patient weight on the day of IV paszelimab loading to calculate appropriate dose. The IV dose should be administered first. The SC dose should be given at least 30 minutes after completion of IV administration. NOTE: Patients who experience breakthrough hemolysis due to non-complementary activation conditions and meet criteria for treatment intensification are eligible to receive intensified paszelimab only once (either during the primary treatment phase or during elective OLEP), and no further intensification will be permitted after that time.

If there is an increase in LDH ≥ 2 × ULN due to an acute activating condition (i.e., intermittent infection) following OLTP, Day 29 of Intensified OLTP, or at any time during Elective OLEP, an IV loading dose of paselimab 30 mg/kg IV may be given at the discretion of the investigator and in consultation with the Sponsor. Patient weight should be assessed on the day of IV paselimab loading so that the appropriate dose can be calculated. This is not considered a treatment intensification. There will be no other changes to the study treatment regimen (i.e., regular dosing and frequency of paselimab and cemdisiran will remain unchanged). Patients will continue to the next visit on their current visit schedule. Results ( 5 patients who completed Day 169 )

As of this data analysis, 6 patients were enrolled, 5 of whom were currently receiving treatment. Although one patient discontinued treatment after 29 days, the remaining 5 patients continued treatment for at least 169 days, with one patient completing OLTP (Day 225).

As of data cutoff, no patient had lactate dehydrogenase (LDH) levels above 1.5 × ULN (Figures 22 and 23) or experienced breakthrough hemolytic events, including two patients previously treated with higher doses of eculizumab (1200 mg and 1500 mg every 2 weeks, respectively). In addition, all assessed time points remained normal (≦1.0 × ULN) except for two LDH values. All patients achieved hemoglobin stabilization (Figure 24). No patient underwent erythrocyte transfusion, and hemoglobin did not decrease by ≧ 2 g/dl. CH50 (a measure of terminal complement activity) remained fully suppressed at 0 kIU/L throughout the study until data cutoff.

There were no severe or serious TEAEs. Importantly, there were no meningococcal infections or adverse events attributable to the potentially large drug-target-drug immune complexes, or TEAEs leading to death in this study. One patient discontinued study treatment on Days 2 and 16 due to two mild, non-severe TEAEs of headache. Conclusions

These results demonstrate that in PNH patients switching from eculizumab therapy, including those treated with doses higher than standard of care, the combination of paszelimab and cemdisiran was generally well tolerated, providing sustained control of intravascular hemolysis without any breakthrough hemolytic events. Thus, this combination therapy demonstrated significant efficacy in the treatment of PNH patients switching from eculizumab therapy. Results ( 5 patients who completed Day 225 )

Six patients were enrolled. Five patients completed OLTP (Day 225); one patient discontinued treatment after 29 days due to a treatment-emergent adverse event (TEAE) (Table 5-12).

At baseline, lactate dehydrogenase (LDH) was adequately controlled with eculizumab. No patient had a transfusion in the year prior to enrollment, but one patient had a history of breakthrough hemolysis. During the 32-week OLTP, no patient had an LDH greater than 1.5 times the upper limit of normal (ULN) (Figure 30) or a breakthrough hemolytic event (Table 5-6), including two patients who had previously been treated with higher doses of eculizumab (1200 mg and 1500 mg every 2 weeks, respectively). In addition, all evaluation time points remained normal (≦1.0 × ULN) except for two LDH values (Figure 30). During the OLTP, all patients achieved hemoglobin stability (no red blood cell transfusion and hemoglobin level did not fall ≧2 g/dL) (Table 5-7), and no patient required a transfusion. CH50, a measure of terminal complement activity, remained completely suppressed at 0 kIU/L throughout the study (Tables 5-8).

One patient discontinued study treatment on Days 2 and 16 due to two mild, non-serious TEAEs of headache. One subject had a severe TEAE of endometrial hyperplasia due to prolonged, intermittent postmenopausal bleeding requiring hospitalization for a preemptive hysterectomy/oophorectomy; the event was considered unrelated to study treatment by the investigators and sponsors (Table 5-9). There were no meningococcal infections, TEAEs due to potential large drug-target-drug immunocomplexes, thrombotic events, or TEAEs leading to death (Tables 5-10 and 5-11). Summary / Conclusions

The results showed that the combination of pazelimab and cemdisiran was generally well tolerated and provided sustained control of intravascular hemolysis without any breakthrough hemolytic events in PNH patients who were switched from eculizumab therapy, including those who received higher than standard doses. The results support the continued development of the pazelimab and cemdisiran combination therapy. Table 5-6. Breakthrough Hemolysis ( Full Analysis Set ) Pazelimumab 400 mg SC Q4W + Cemdisiran 200 mg SC Q4W (N=6) Patients with breakthrough hemolysis from baseline to day 225 (number and percentage) 0 Normality approximates 95% confidence interval (%) 0.0 - 0.0 Clopper Pearson 95% confidence interval (%) 0.0 - 45.9 Patients with breakthrough hemolysis from baseline day 29 to day 225 (number and percentage) 0 Normality approximates 95% confidence interval (%) 0.0 - 0.0 Clopper Pearson 95% confidence interval (%) 0.0 - 45.9 Table 5-7. Hemoglobin stability ( complete analysis set ) Pazelimumab 400 mg SC Q4W + Cemdisiran 200 mg SC Q4W (N=6) Number and percentage of patients with stable hemoglobin from baseline to day 225 6 (100%) Normality approximates 95% confidence interval (%) 100.0 - 100.0 Clopper Pearson 95% confidence interval (%) 54.1 - 100.0 Number and percentage of patients with stable hemoglobin from day 29 to day 225 6 (100%) Normality approximates 95% confidence interval (%) 100.0 - 100.0 Clopper Pearson 95% confidence interval (%) 54.1 - 100.0 Table 5-8. Summary of CH50 (kIU/L) - Change from Baseline over Time ( Full Analysis Set ) Pazelimumab 400 mg SC Q4W + Cemdisiran 200 mg SC Q4W (N=6) Value at visit Change from baseline Visit n Mean (SD) Median Q1:Q3 Min:Max n Mean (SD) Median Q1:Q3 Min:Max Baseline 6 0.0(0.0) 0.0 0:0 0:0 Visit 3 (Day 8) 6 0.0(0.0) 0.0 0:0 0:0 6 0.0(0.0) 0.0 0:0 0:0 Visit 4 (Day 15) 6 0.0(0.0) 0.0 0:0 0:0 6 0.0(0.0) 0.0 0:0 0:0 Interview 5 (Day 29) 6 0.0(0.0) 0.0 0:0 0:0 6 0.0(0.0) 0.0 0:0 0:0 Interview 7 (Day 57) 6 0.0(0.0) 0.0 0:0 0:0 6 0.0(0.0) 0.0 0:0 0:0 Interview 9 (Day 85) 5 0.0(0.0) 0.0 0:0 0:0 5 0.0(0.0) 0.0 0:0 0:0 Visit 10 (Day 113) 4 0.0(0.0) 0.0 0:0 0:0 4 0.0(0.0) 0.0 0:0 0:0 Visit 11 (Day 141) 5 0.0(0.0) 0.0 0:0 0:0 5 0.0(0.0) 0.0 0:0 0:0 Visit 12 (Day 169) 5 0.0(0.0) 0.0 0:0 0:0 5 0.0(0.0) 0.0 0:0 0:0 Interview 13 (Day 197) 4 0.0(0.0) 0.0 0:0 0:0 4 0.0(0.0) 0.0 0:0 0:0 Visit 14/EOT (Day 225)/OLEP-1 (Day 1e) 5 0.0(0.0) 0.0 0:0 0:0 5 0.0(0.0) 0.0 0:0 0:0 Table 5-9. Summary of treatment-emergent serious adverse events by system organ class and preferred term ( full analysis set ) System Organ Class MedDRA Preferred Term Pazelimumab 400 mg SC Q4W + Cemdisiran 200 mg SC Q4W (N=6) Number of serious adverse events during treatment 1 Number of subjects with at least one treatment-emergent serious adverse event 1(16.7%) Reproductive system and breast diseases Endometrial hyperplasia 1(16.7%) 1(16.7%) Table 5-10. Summary of treatment-emergent adverse events of particular interest ( safety analysis set ) Categories and subcategories of AE of particular interest Pazelimumab 400 mg SC Q4W + Cemdisiran 200 mg SC Q4W (N=6) Of particular interest is the number of TEAEs twenty three Number of subjects with at least one TEAE of special interest 5(83.3%) Suspected Neisseria infection 0 Moderate or severe infusion reaction 0 Any thrombotic or embolic event 0 Moderate or severe allergic reaction, possibly related to study treatment 0 Adverse events, possibly due to suspected large DTD immune complex 0 Elevated liver transaminases 0 Other AESI (mild infusion reaction, mild allergy or injection site reaction) Infusion reaction Allergy or hypersensitivity reaction Injection site reaction 5(83.3%) 0 0 5(83.3%) Table 5-11. Summary of treatment-emergent adverse events leading to death by system organ class and preferred term ( safety analysis set ) System Organ Class MedDRA Preferred Term Pazelimumab 400 mg SC Q4W + Cemdisiran 200 mg SC Q4W (N=6) Number of TEAEs leading to death 0 Number of subjects with at least one TEAE leading to death 0 Table 5-12. Patient Disposition ( Safety Analysis Set ) Treatment group: Pazelimab 400 mg SC Q4W + Cemdisiran 200 mg SC Q4W Subject ID Age/Gender Last dose (study day) OLTP treatment completion status/reasons for treatment suspension OLEP treatment completion status/reasons for discontinuation of treatment Study completion status/reason for termination of study 826001001 63/M (253) Finish In progress In progress 826001002 65/F (253) Finish In progress In progress 826001003 40/F (225) Finish In progress In progress 826001004 36/M (225) Finish In progress In progress 826001004 51/M (29) Discontinuation/Adverse Events Discontinuation/Subject Withdrawal 826001006 53/F (225) Finish In progress In progress Results ( 5 patients who completed open-label treatment : median duration of treatment 229 days [ range: 56-280 days ] )

Six patients were enrolled (Table 5-13), and five completed OLTP (median [range] treatment duration: 229 [56-280] days). One patient discontinued study treatment after 29 days due to two mild, non-serious treatment-emergent adverse events (TEAEs) headache on Days 2 and 16, both of which occurred before the administration of combination therapy on Day 29. Table 5-13. Baseline Demographics and Clinical Characteristics Pazelimumab 400 mg Q4W + cemdisiran 200 mg SC Q4W (n=6) Age, years, median ( minimum : maximum ) 52.0 (36:65) Male, n (%) 3 (50.0) Race, White, n (%) 6 (100.0) BMI , kg/m ² , median ( minimum : maximum ) 27.2 (24.7:49.7) Eculizumab dose, n (%) Standard (900 mg Q2W) 4 (66.7) Nonstandard (1200 or 1500 mg Q2W) 2 (33.3) LDH , ^a U/L , median ( minimum : maximum ) 231.5 (175:291) Hemoglobin, g/L , median ( minimum : maximum ) 110.0 (97:142) Total PNH RBC , ^b % Mean (SD) 56.5 (32.3) PNH PMN , ^b % Mean (SD) 64.7 (28.0) PNH mononuclear sphere, ^b % Mean (SD) 81.7 (15.9) Total bilirubin, µmol/L , median ( minimum : maximum ) 12.2 (8.7:19.5) Reticulocytes, 10 ⁹ /L , median ( minimum : maximum ) 173.8 (77.4:388.3) eGFR , mL/min/1.73 m ² , median ( minimum : maximum ) 109.5 (80:121) Creatinine, µmol/L , median ( min : max ) 57.5 (35:88) ^a . Pretreatment values. ^b . The central laboratory was missing three samples, so prestudy PNH strain data from the local laboratory were used. BMI, body mass index; eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase; PMN, polymorphonuclear neutrophil; PNH, paroxysmal nocturnal hemoglobinuria; Q2W, every 2 weeks; Q4W, every 4 weeks; RBC, red blood cell; SC, subcutaneous; SD, standard deviation.

All patients had LDH values ≤1.5 × ULN at all assessed time points; four of the six patients maintained normal LDH values (≤1.0 × ULN) at all assessed time points (Figure 31).

No patients experienced breakthrough hemolytic events, including two patients who were previously treated with higher doses of eculizumab (1200 mg or 1500 mg every 2 weeks, respectively).

The changes in hemoglobin levels over time for each patient are shown in Figure 32; no patient who received an erythrocyte transfusion had a hemoglobin drop of ≥2 g/dL.

CH50 (a measure of terminal complement activity) remained completely suppressed at 0 kIU/L throughout the study.

One subject experienced a severe TEAE of endometrial hyperplasia due to prolonged, intermittent postmenopausal bleeding requiring hospitalization for preemptive hysterectomy/oophorectomy; this event was considered unrelated to study treatment.

The most common TEAEs were mild injection site reactions (n=5, 83.3%; none led to treatment discontinuation) and headache (n=3, 50.0%). Importantly, there were no meningococcal infections, adverse events attributable to potentially large drug-target-drug immunocomplexes, or TEAEs leading to death.

In patients with PNH who switched from eculizumab therapy, the combination of paszelimab and cemdisiran therapy was generally well tolerated and provided sustained control of intravascular hemolysis.

No patient experienced breakthrough hemolytic events.

The study results support the continued development of the combination of pazelimumab and cemdisiran. Results (52- week open-label expansion data )

Patients who completed the 32-week open-label treatment period (OLTP) were eligible for the optional 52-week OLEP. Patients were adult PNH patients who switched from stable eculizumab therapy to the combination (pazelimab 400 mg and cemdisiran 200 mg) SC every 4 weeks in the OLTP. The study enrolled two patients who were previously treated with a higher dose of eculizumab (1200 mg or 1500 mg every 2 weeks).

All five patients who completed the OLTP were enrolled and completed the OLEP. After completing the OLEP, all patients were transferred to the expanded access program to continue the combination of paslimab and cemdisiran. Lactate dehydrogenase (LDH) was adequately controlled with eculizumab at OLTP baseline and remained controlled during the 32-week OLTP. During the 52-week OLEP, no patient had an LDH greater than 1.5 × upper limit of normal (ULN; Figure) at any planned study visit, nor did any patient meet protocol criteria for breakthrough hemolysis (either by central or local laboratory value; defined as an increase in LDH [LDH ≧ 2 × ULN if pretreatment LDH ≦ 1.5 × ULN, or LDH ≧ 2 × ULN after initially achieving LDH ≦ 1.5 × ULN if pretreatment LDH > 1.5 × ULN] accompanied by signs or symptoms related to hemolysis). Two patients who had previously received higher doses of eculizumab also maintained control of their LDH levels throughout the OLTP and OLEP. Four of the five patients remain transfusion-free, but one patient required a transfusion during hospitalization for an acute complement activation episode. This patient had two severe and serious adverse events of treatment-emergent respiratory tract infections resulting in acute hemolysis that did not meet the trial criteria for breakthrough hemolysis but were still reported as adverse events based on clinical judgment. The investigators and sponsors assessed these events as unrelated to treatment. CH50 (a measure of terminal complement activity at a fixed time point) remained suppressed in all patients throughout the study. No other severe or serious adverse events were reported. There were no meningococcal infections, thrombotic events, or TEAEs leading to death.

The results showed that the combination of pazelimab and cemdisiran was generally well tolerated and provided long-term sustained control of intravascular hemolysis without any breakthrough hemolytic events in PNH patients who switched from eculizumab therapy. The results support the continued development of the combination of pazelimab and cemdisiran. Example 6 : A randomized, open-label, eculizumab- and ravulizumab-controlled, noninferiority study to evaluate the efficacy and safety of pazelimab and cemdisiran combination therapy in patients with paroxysmal nocturnal hemoglobinuria currently being treated with eculizumab or ravulizumab (R3918-PNH-2022)

This randomized, open-label, eculizumab-versus-ravlizumab-controlled, noninferiority study was terminated early due to recruitment issues.

Patients treated with eculizumab were eligible if they had received eculizumab at the labeled dosing of 900 mg IV Q 14 days for at least 12 weeks prior to the screening visit.

Patients treated with ravelizumab were eligible if they received IV Q8W ravelizumab at the following labeled dosing based on body weight (BW): 3000 mg for BW ≧40 kg to <60 kg, 3300 mg for BW ≧60 kg to <100 kg, and 3600 mg for BW ≧100 kg for at least 24 weeks prior to the screening visit.

The study (Figure 26) has the following phases: a 6-week screening period and a 36-week open-label treatment period (OLTP). Patients who complete the OLTP in the anti-C5 standard of care arm and plan to enroll in the subsequent open-label, long-term extension study of the paslimab and cemdisiran combination must participate in the post-OLTP switch period. Patients who discontinue study treatment and those who refuse to join the OLE study will undergo a safety off-treatment follow-up period of up to 52 weeks. Screening Period

The first Screening Visit should be scheduled up to 6 weeks before Day 1 (Table 6-1). Screening Visit 1 should be scheduled based on the patient’s pre-study eculizumab or ravelizumab dosing regimen. For patients receiving eculizumab at Screening: • Screening Visit 1 should be scheduled on or the day before the eculizumab dose and may be up to 6 weeks before Day 1. • At Visit 2e, patients will be given an eCOA device to take home. • Day 1 should be scheduled on or up to 2 days before the patient’s scheduled eculizumab dose.

For patients receiving Ravelizumab at Screening: • Screening Visit 1 should be scheduled approximately 6 weeks after the Ravelizumab dose • Visit 2r should be scheduled on or up to 2 days before the patient’s next scheduled Ravelizumab dose. This will be the last non-study Ravelizumab dose. Additional laboratory samples for baseline assessments will be collected at this visit, and the patient will be provided with an eCOA device to take home. • Day 1 Visit should be scheduled 26 to 28 days after the last Ravelizumab dose at Visit 2r.

Additional interim screening visits may be performed if necessary (e.g., repeat blood draws).

Historical data such as, but not limited to, eculizumab or ravulizumab administration, concomitant medications, hemolysis parameters, and RBC transfusions will be collected.

Because of the risk of meningococcal infection, patients will need to be vaccinated with meningococcal vaccines according to local eculizumab or ravulizumab prescribing information (if applicable) and with complement inhibitors according to current national vaccination guidelines or local practice for at least 5 years prior to screening. For patients who need to be vaccinated with meningococcal vaccines during the screening period, vaccination should ideally be performed at least 2 weeks before Day 1 or at another time point according to local practice or national guidelines/local eculizumab or ravulizumab prescribing information (if applicable). If vaccination is less than 2 weeks before starting study treatment, antibiotic prophylaxis must be given at least 2 weeks after vaccination.

In addition to meningococcal infections, fatal or serious gonococcal infections have been reported in patients receiving complement inhibitor therapy. Therefore, patients will undergo risk assessment and counseling regarding the potential risk of gonococcal infection according to local practice or national guidelines.

Patients who have not yet received Streptococcus pneumoniae and Haemophilus influenzae type b vaccines may receive these vaccines during the screening period or on the day of randomization, depending on the investigator's judgment and taking into account existing national guidelines.

Patients will be assessed for active or latent tuberculosis (TB) infection based on local practice or applicable guidelines. Based on the risk assessment, the need for screening using a tuberculin skin test or T-cell interferon-gamma release assay will be determined. If applicable, these results will be interpreted by the investigators. Further management and treatment of TB will be the responsibility of the investigators. Randomization

Day 1 (randomization) must occur on the day of the patient's scheduled eculizumab dose or 4 weeks after the last dose of revlizumab (i.e., 26 to 28 days), if applicable. If the randomization day cannot be scheduled on the day of the patient's next eculizumab dose or 4 weeks after the last dose of revlizumab, a 1 to 2 day range is allowed so that the randomization day can be 1 to 2 days before the next scheduled eculizumab dose or 26 to 28 days after the last dose of revlizumab (if applicable).

Patients who meet all eligibility criteria will be randomized in a 1:1 ratio to either anti-C5 standard of care (i.e., continuation of existing treatment with eculizumab or ravulizumab) or treatment with pasizumab and cemdisiran.

The random grouping will be stratified according to the criteria described in this article:

Eligible patients will be randomized in a 1:1 ratio according to the labeled weight-based dosing algorithm to receive treatment with the combination of SC Pasqualizumab 400 mg and Cemdisiran 200 mg Q4W, or continue their anti-C5 standard of care treatment with either Eculizumab 900 mg IV Q2W or IV Ravelizumab, based on the central randomization scheme provided to the designated study pharmacist (or qualified designee) via the interactive web response system (IRWS). Randomization will be stratified based on the following factors: • Screening visit LDH value (≦1.5 × ULN or >1.5 × ULN) Note: Enrollment of patients with LDH levels >1.5 × ULN at the screening visit will be capped at 20% of the total enrollment population. • RBC/whole blood transfusion in the past year before randomization (yes/no) • Anti-C5 standard of care treatment at screening (eculizumab and ravulizumab) Open label treatment period (OLTP)

The treatment duration is 36 weeks. Treatment dosing is based on the patient's PNH treatment prior to screening and their treatment assignment: • Pasqualimumab and Cemdisiran Group: . Patients receiving eculizumab at screening will receive the following during the study: Day 1 Cemdisiran 200 mg SC followed by a 2-hour observation period, and eculizumab 900 mg IV (+2 days for eculizumab, from day 1 to day 3) Day 15 (Week 2) Eculizumab 900 mg IV (±2 days, from day 13 to day 17) Day 29 (Week 4) A single IV loading dose of 60 mg/kg of pazelimab. After a 30-minute observation period, this IV infusion was followed by 400 mg SC of pazelimab and 200 mg SC of cemdisiran, followed by a 2-hour observation period after the last dose of study drug. Day 57 (Week 8) Pazelimumab 400 mg SC and Cemdisiran 200 mg SC (±7 days) maintenance regimen followed by a 2-hour observation period after the last study drug dose on Day 57, and after Day 57, Pazelimumab 400 mg SC and Cemdisiran 200 mg SC Q4W (±7 days) Note that a 2-hour observation period will begin after the SC dose of pazelimumab on Day 85 (Week 12). For subsequent doses after the third dose of each study treatment, the observation period may be shortened to 30 minutes if the patient feels the combination is well tolerated (based on the investigator's judgment). Patients who receive ravulizumab at screening will receive the following during the study: Day 1 Cemdisiran 200 mg SC (26 to 28 days after last dose of ravulizumab) followed by a 2-hour observation period Day 29 (Week 4) A single IV loading dose of 60 mg/kg of pazelimab. After a 30-minute observation period, this IV infusion was followed by 400 mg SC of pazelimab and 200 mg SC of cemdisiran, followed by a 2-hour observation period after the last dose of study drug. Day 57 (Week 8) Pazelimumab 400 mg SC and Cemdisiran 200 mg SC (±7 days) maintenance regimen followed by a 2-hour observation period after the last study drug dose on Day 57, and after Day 57, Pazelimumab 400 mg SC and Cemdisiran 200 mg SC Q4W (±7 days) Note that a 2-hour observation period will begin after the SC dose of pazelimumab on Day 85 (Week 12). For subsequent doses after the third dose of each study drug, the observation period may be shortened to 30 minutes if the patient feels the combination is well tolerated (based on the investigator's judgment). • Anti-C5 Standard of Care Group: Patients receiving eculizumab at screening will continue to receive eculizumab during the study: Day 1 Eculizumab 900 mg IV Q2W (+2 days) Day 15 (Week 2) Eculizumab 900 mg IV Q2W (±2 days) Patients who received Ravelizumab at screening will continue to receive Ravelizumab during the study: Day 29 (Week 4) Ravelizumab IV Q8W (±7 days) as indicated, weight-based dosing

During IV infusions of pazelimumab, due to concern for potential IV infusion reactions, patients should be observed for at least 30 minutes after the infusion and prior to administration of the first SC injection of pazelimumab and cemdisiran.

A 2-hour observation period should begin after the first 3 doses of paszelimumab and cemdisiran, whether used alone or in combination. For subsequent doses after the third dose of each study treatment, the observation period may be shortened to 30 minutes if the patient feels the combination is well tolerated (based on the investigator's judgment).

Although the overall goal of the recommended dosing regimen is to prevent hemolysis, the initiation of treatment is also designed to mitigate the potential for large drug-target-drug (DTD) immune complex formation during treatment transitions between eculizumab-C5-pazelimab or ravulizumab-C5-pazelimab. As explained herein, an induction dose of cemdisiran plus a 60 mg/kg IV loading dose of pazelimab was included to minimize large DTD immune complex formation. Post-Open-Label Treatment Period (Post-OLTP)

Patients who complete the OLTP (i.e., the Day 253 End of Study [EOS] visit) will be offered the opportunity to participate in another study, the Follow-On OLE study. Screening for the next study can be performed while the patient is at the OLTP, as described in paragraph 9.1.1.1 footnote #1.

For patients who complete the 36-week OLTP in the pasizumab and cemdisiran groups, treatment is planned to be switched from the current study to the OLE without interruption, where the Day 1 visit of the OLE will correspond to the EOT/EOS visit of the current study.

Patients who complete the 36-week OLTP in the anti-C5 standard of care group and are scheduled to participate in the OLE study will undergo a switch period to the combination of cemdisiran and pasirimab in the same manner as those who were switched to the combination at the start of the study as follows:

Patients treated with Eculizumab: • Switch Day 1 (OLTP Week 36): Cemdisiran 200 mg SC followed by a 2-hour observation period, and Eculizumab 900 mg IV (±2-day treatment range) • Switch Day 15 (Switch Period Week 2): Eculizumab 900 mg IV (±2 days) • Switch Day 29 (Switch Period Week 4): Pazelimumab 60 mg/kg IV loading dose. After a 30-minute observation period, this IV infusion is followed by Pazelimab 400 mg SC and Cemdisiran 200 mg SC, followed by a 2-hour observation period after the last dose of study drug. Patients will switch to the OLE study after completing the Week 4t visit.

Patients treated with Ravelizumab: • Switch Day 1 (OLTP Week 36): IV Ravelizumab at labeled weight-based dosing • Switch Day 29 (Switch Period Week 4): Cemdisiran 200 mg SC followed by a 2-hour observation period • Switch Day 57 (Switch Period Week 8): Pazelimab 60 mg/kg IV loading dose. After a 30-minute observation period, this IV infusion is followed by Pazelimab 400 mg SC and Cemdisiran 200 mg SC, followed by a 2-hour observation period after the last dose of study drug. Patients will switch to the OLE study after completing the Week 8t visit.

This approach is applicable to patients randomized to the anti-C5 standard of care group and planned to participate in the OLE study, ensuring that consistent dosing is used when switching from eculizumab or ravulizumab to the combination of pasizumab and cemdisiran and that there is no impact on the study efficacy analysis during the randomized treatment period. According to Table 6-4, patients who discontinue treatment and those who refuse to participate in the OLE follow-up study will undergo a safety off-treatment follow-up period (FUP) of up to 52 weeks. Patients who discontinue study treatment should be treated according to local standards of care and continue to receive 52 weeks of off-treatment safety FUP monitoring. Investigators switching patients from combination therapy to another anti-C5 mAb should be aware of possible adverse events resulting from the formation of large DTD immune complexes.

The primary study was considered completed when all patients completed the 36-week treatment period or discontinued the study early. Additional data collected during the switch period and safety off-treatment FUP will be described separately.

Study assessments and procedures are presented by study period and visit in Table 6-1 (OLTP), Table 6-2 (conversion period for eculizumab group), Table 6-3 (conversion period for ravelizumab group), and Table 6-4 (FUP). See Figure 26. Table 6-1. Timeline of events during the open-label treatment period Research Procedure ( Interview ) ¹ Filter Open Label Treatment Period (OLTP) Used for ravu For ecu EOS Visit # V1 ² V2n V2e V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 V15 Week Up to ‑6 -4 -4 to ‑2 0 2 4 6 8 10 12 16 20 twenty four 28 32 36 sky Up to ‑42 -28 -28 to ‑14 1 ³ 15 29 43 57 71 85 113 141 169 197 225 253 Range (days) +2 ±2 ±3 ±3 ±3 ±3 ±3 ±7 ±7 ±7 ±7 ±3 ±3 Screening / Baseline ² : Provide eCOA equipment X X Include/Exclude X X X X Informed Consent X FBR Informed Consent (depending on the situation) X Genomics Informed Consent (depending on the situation) X Medical History ⁴ X Previous medication ⁵ X Demographics X height X Hepatitis B and C testing X Meningococcal vaccination/ ^{revaccination6} ＜------------- X ----------＞ Pneumococcal and Haemophilus influenzae type B vaccinations (if necessary) ⁷ ＜------------- X ----------＞ Tuberculosis history and ^assessment8 X Gonorrhea Risk ^Assessment9 X Random grouping X treatment: IVRS/IWRS X X X X X X X X X X X X X X Timing of ecu/ravu (non-IMP) during screening Administer eculizumab 900 mg IV Q2W (only in patients already receiving eculizumab) X ＜---- Q2W ---＞ Administer Ravelizumab IV Q8W as indicated by weight-based dosing (only for patients already receiving Ravelizumab) X ³⁶ Pazelimab and Cemdisiran Group Administer eculizumab 900 mg IV (this is a non-IMP – only for patients who have previously received eculizumab) X ¹¹ X ¹¹ Administer 60 mg/kg IV loading dose of pazelimumab X ¹² Cemdisiran 200 mg SC Q4W ^13,14 X X X X X X X X X X ³⁷ Administer pazelimab 400 mg SC Q4W ^12,14 X X X X X X X X X ³⁷ Anti-C5 SOC: Eculizumab IMP Group Administer eculizumab 900 mg IV Q2W for ¹⁵ X X X X X X X X X X X X X ³⁷ Administer Cemdisiran 200 mg SC (only when OLE is added) X ³⁷ Anti-C5 SOC: Ravelizumab IMP Group Administer Ravelizumab IV Q8W ¹⁶ according to label weight-based dosing X X X X X ³⁷ Medications and treatments X X X X X X X X X X X X X X X X Transfer record update X X X X X X X X X X X X X X X X Antibiotic prophylaxis (recommended) ¹⁹ ＜-----------------------------------X----------------------＞ Clinical Outcome Assessment (COA) : FACIT-Fatigue X X X X X X X X X X X EORTC-QLQ-C30 X X X X X X X X X X X EQ-5D-5L X X TSQM X X X X X X X X X X PNH symptom-specific questionnaire (daily, from Day -14 to end of study) ²⁰ ＜-------------------------------------------X-----------------------------------------＞ PGIS (PNH symptoms/effects/fatigue) X X X X X X X PGIC (PNH symptoms/effects/fatigue) X X X Safety and human body measurements: Meningococcal Patient Safety ^Card10 X X X X X X X X X X X X X Ravelizumab group only: provide patients with Ravelizumab safety leaflet X Eculizumab-only group: provide patients with the Eculizumab safety leaflet X Weight X X X X X X X X X X Vital Signs ²¹ X X X X X X X X X X X X X X Physical ^{Examination22} X X X X X X Electrocardiogram X X X Adverse Events X X X X X X X X X X X X X X X X Breakthrough hemolysis ^assessment23 X X X X X X X X X X X X X X X X Laboratory Test ²⁴ : Measure meningococcal titer (only if required by local practice/regulations) X Patients who received ravulizumab before screening: additional sample (blood draw before ravu administration) Blood chemistry X Hematology X Coagulation group X Free heme X Heme binding protein X ^Hematology25 X X X X X X X X X X X X Coagulation group X X X X X X X X X X X X X X Blood chemistry (long panel), including LDH ²⁶ X X X X X X X X X X X X X X D-Dimer X X X IgG X X X Pregnancy test (for applicable patients) ²⁷ X X X X X X X X X X X Urinalysis X X X X X X X X X X X Direct antiglobulin test (DAT or Coombs test) X X X X X X X X X Pharmacokinetics, ADA and ^Total C5 Sampling28 : Pazelimumab and Cemdisiran Group Blood samples for pazelimumab concentration X X ²⁹ X X X X X X X X Cemdisiran and metabolite concentrations in blood samples ³⁰ X X X X Blood samples of Pazerimab ADA ³¹ X X X X Cemdisiran ADA blood sample ³¹ X X X X Total C5 concentration in blood samples X X X X X X X X X X X Anti-C5 Standard of Care Group Blood samples for eculizumab concentrations (patients receiving eculizumab only) X X X X X X Blood samples for Ravelizumab concentrations (patients receiving Ravelizumab only) X X X X X X Cemdisiran and metabolite concentrations in blood samples ³⁰ X ³² Blood samples of Pazerimab ADA ³¹ X ³³ Cemdisiran ADA blood sample ³¹ X ³³ Total C5 concentration in blood samples X X X X X X X X X X X Biomarkers: Free heme ²⁸ X ³⁴ X X X X X X Heme-binding protein ²⁸ X ³⁴ X X X X X X Hemolysis analysis (CH50 & AH50) ²⁸ X ³⁴ X X X X X X X X X sC5b-9 (plasma) ²⁸ X ³⁴ X X X X X X X PNH red blood cell ²⁸ X X X PNH granules and single core balls ²⁸ X X X Exploratory study serum samples ²⁸ X ³⁴ X X X X X X X Exploratory study plasma samples ²⁸ X ³⁴ X X X X X X X Selective Pharmacogenomics (DNA and RNA) : Whole blood for DNA isolation (optional) ³⁵ X Whole blood for RNA isolation (optional) X X X Footnotes 1. When multiple procedures are performed on the same day, the order of procedures is as follows: clinical outcome assessments, electrocardiogram (ECG) and/or vital signs, blood collection, and study treatment administration. Patients who are screened in this study (R3918-PNH-2022) and complete the R3918-PNH-2021 study will have all assessments performed as indicated in the SOE. This means that the Screening Visit 1 in the R3918-PNH-2022 study may be performed at Week 24 of the R3918-PNH-2021 study, while the V2r in the R3918-PNH-2022 study is performed at Week 26 of the R3918-PNH-2021 study before the ravulizumab dose. Assessments common to both studies should not be repeated. 2. Screening Visit 1 should be scheduled based on the patient's pre-study dosing regimen. For patients receiving eculizumab, Screening Visit 1 should be scheduled on the day of or the day before eculizumab administration. For patients receiving ravelizumab, Screening Visit 1 should be scheduled approximately 6 weeks after the last ravelizumab administration. Additional Screening Visits may be scheduled as needed. 3. For patients receiving ravelizumab, Day 1 Visit should be performed 4 weeks (i.e., 26 to 28 days) after the last dose of ravelizumab. 4. If possible, a medical history for the past 52 weeks should be obtained, including transfusions, history of breakthrough hemolysis, and laboratory parameters used to measure hemolysis (e.g., LDH, bilirubin, heme-binding protein, reticulocyte count, and hemoglobin). History of past thrombosis and Neisseria infection will be collected. Patients identified with a C5 mutation during the study should have this information included as part of the patient’s medical history. Patients who have an inadequate response to treatment with eculizumab or ravlizumab during the study may be asked to undergo mutation analysis as part of the study if the patient consents to testing. 5. Include detailed eculizumab or ravlizumab dosing history and meningococcal vaccination history and other vaccinations if applicable. 6. Patients will be vaccinated with meningococcal vaccines unless documentation is provided of immunization within the past 5 years prior to screening, or less than 5 years if vaccinated with complement inhibitors according to current national vaccination guidelines/local eculizumab or ravlizumab prescription information as needed. For patients who require meningococcal vaccination during the screening period, it should ideally be administered at least 2 weeks prior to Day 1 or at other time points based on local eculizumab or ravulizumab prescribing information/national guidelines. 7. Pneumococcal and Haemophilus influenzae type B vaccines should be administered according to current national/local vaccination guidelines. 8. History and evaluation of tuberculosis: Screening may be performed by tuberculin skin test or T-cell interferon gamma release assay at the investigator’s discretion based on local practice or guidelines. 9. Risk factor assessment for gonorrhea will be performed based on local practice/national guidelines, and regular testing and counseling will be recommended for high-risk patients. 10. Patient Safety Card: Provide patients with a Meningococcal Infection Patient Safety Card on Day 1 or any other visit, if needed. Sites should review the instructions on the safety card with patients at each visit. 11. Eculizumab may be administered up to 2 days after the Day 1 visit or within 2 days of the Day 15 visit. If eculizumab administration does not coincide with the day of the clinic visit (if applicable), the clinic visit should always precede the eculizumab infusion for patients receiving Q2W eculizumab dosing. 12. Pazerizumab Administration: Administer study treatment to patients who previously received eculizumab or ravelizumab and were randomized to the pazerizumab/cemdisiran group. 13. Cemdisiran Administration: Administer study treatment to patients randomized to the Pazelimumab/Cemdisiran group. 14. Pazelimumab and Cemdisiran doses should be given Q4W (every 28 days) and on the day of the corresponding study visit whenever possible. Study treatment administration should always be the last procedure after all blood samples and study assessments have been completed. If Pazelimumab or Cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 7 days before or up to 7 days after the scheduled dosing date, as long as dosing occurs after the corresponding study visit has been completed. For example, the Week 8 (Day 57) visit could be performed on Days 54 to 60, depending on the visit coverage. Therefore, doses of Pazelimumab and Cemdisiran may be given on Days 54 through 64, but only if the Week 8 visit assessment has been performed or after. Similarly, the Week 16 (Day 113) visit may be performed on Days 106 through 120, depending on visit coverage. Doses of Pazelimumab and Cemdisiran may be given on Days 106 through 120, but only if the Week 16 visit assessment has been performed or after. Pazelimumab and Cemdisiran should be administered on the same day whenever possible. A 2-hour observation period should begin after the first 3 doses of Pazelimumab and Cemdisiran, whether used individually or in combination. For subsequent dosing after the third dose of each study treatment, the observation period may be shortened to 30 minutes, provided that the patient feels the combination is well tolerated (based on the judgment of the investigator). 15. Eculizumab Administration: Administer study treatment with eculizumab to patients who previously received eculizumab and were randomized to the anti-C5 standard of care group. Time points at Weeks 14, 18, 22, 26, 30, and 34 are not included in the event schedule, but eculizumab should be administered at these time points. If eculizumab administration does not coincide with the date of the clinic visit (if applicable), the clinic visit should always precede the eculizumab infusion. Patients who choose to participate in the OLE should follow the event schedule for the conversion period after the completion of the OLTP (Table 6-2). 16. Only patients who plan to continue in the follow-on OLE study will receive a dose of study treatment at the EOS Week 36 visit of the OLTP. In addition, patients who receive eculizumab or ravulizumab during the OLTP should continue to follow the event schedule for the conversion period (Table 6-2) after the OLTP is completed. Note: Patients who complete the OLTP but refuse to participate in the OLE study will not receive study treatment at the EOS Week 36 visit, but should continue to follow the event schedule for the follow-up period (Table 6-4). 17. Intentionally left blank 18. Intentionally left blank 19. Daily oral antibiotic prophylaxis for meningococcal disease is recommended, starting on the first day of study treatment administration and continuing for 52 weeks after discontinuation of paszepine/cemdisiran. Follow local prescribing information/national guidelines/local practice for post-treatment prophylaxis with eculizumab or ravulizumab. If the meningococcal vaccine was given less than 2 weeks prior to Day 1, antibiotic prophylaxis must be continued for at least 2 weeks from the date of vaccination. 20. Patients will complete a PNH symptom-specific questionnaire daily for 14 days prior to the Day 1 visit and continuing through the OLTP. 21. Vital signs include temperature, sitting blood pressure, and pulse. If applicable, vital signs will be obtained before medication administration after the patient has been seated for at least approximately 5 minutes. 22. Physical examination will include assessment of the head and neck, lungs, heart, abdomen, extremities, and skin. Any possible abnormalities indicated by the patient's history should be carefully examined and evaluated. 23. Evaluation of Breakthrough Hemolysis: If a patient is suspected of having a breakthrough hemolytic event, in addition to the required laboratory collections, CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, drug concentrations of pazerimumab/cemdisiran/eculizumab/ravlizumab (depending on the patient's randomization/enrollment), additional samples of ADA (for pazerimumab), and exploratory study serum and plasma will be collected unless noted in the event schedule for that visit. If the suspected event does not occur at the time of the scheduled visit, a scheduled off-site visit should be conducted to evaluate the patient and collect CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, drug concentrations for pazerimumab/cemdisiran/eculizumab/ravlizumab, and ADA (for pazerimumab) samples if applicable, as well as exploratory study serum and plasma. 24. During laboratory collection, handling, and processing, the same methodology will be applied at the study visit whenever possible to maintain sample quality and avoid hemolysis during sample processing. If the investigator or sponsor suspects that the laboratory results do not accurately reflect the patient's condition and LDH ≧ 2 × ULN plus potassium ≧ 6 mmol/L, consideration should be given to repeating the laboratory sample as clinically indicated. Unless otherwise noted, blood should always be collected before study treatment administration. The coagulation blood sample must always be collected first, followed immediately by the blood chemistry sample. 25. Hemoglobin will be assessed as part of the hematology analysis. Hematology samples should be collected before study treatment administration. 26. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. During the screening period, obtain chemistries including LDH on the day of eculizumab or ravlizumab administration (or if not possible, the day before). Chemistry including LDH will be obtained on Day 1 and all subsequent visits prior to any study treatment administration (if applicable). 27. Pregnancy Testing: Serum testing will be performed at the Screening Visit and urine testing will be performed at all other visits. 28. Blood Sample Collection for Paselimab, Cemdisiran, Eculizumab, Ravelizumab Concentrations, Total C5, CH50, AH50, Free Heme, Heme Binding Protein, sC5b-9, PNH Erythrocytes, Granulocytes, Monocytes, and Exploratory Study Serum and Plasma Samples: Samples will be obtained prior to any study drug administration (pre-dose). PK and ADA sampling is applicable to those receiving treatment (i.e., drug concentrations of Paselimab will be obtained only in patients receiving Paselimab). An eculizumab PK sample should be obtained at screening in all patients receiving eculizumab, and a ravlizumab PK sample should be obtained at screening in all patients receiving ravlizumab. 29. For patients receiving IV infusion of paszelimab: Where permitted, blood samples will be obtained prior to IV administration of paszelimab and within 15 minutes after the end of the IV infusion. 30. Where permitted, blood samples for concentrations of cemdisiran and its metabolites will be collected before (pre-dose) and 1 to 4 hours after administration of any study treatment. Post-dose samples may be collected in the clinic or by a visiting healthcare professional, if available. 31. Where permitted, blood samples for ADA will be collected prior to (pre-dose) administration of any study drug. In the event of a suspected SAE (e.g., allergic reaction or anaphylaxis), additional samples for PK, ADA, and other analyses may be collected at or near the time of the event. 32. Samples for measurement of cemdisiran and its metabolites concentrations will be collected at this visit only for patients who are receiving eculizumab and wish to continue during the switch period and enter the OLE. 33. Pazerizumab and cemdisiran ADA samples will be collected pre-dose at this visit for patients who are receiving eculizumab or ravulizumab and wish to continue during the switch period and enter the OLE. 34. All biomarkers collected exclusively at V3/Day 1 must be collected pre-dose. 35. Whole blood samples for DNA extraction (as appropriate) should be collected on Day 1 (predose), but may be collected at a later study visit. 36. For patients receiving revlizumab, the Visit 2r procedure should be completed on the day of or up to 2 days before the revlizumab dose. Day 1 must be scheduled within 4 weeks after revlizumab dose or within 26 to 28 days from the date of revlizumab dose. 37. Study treatment at Week 36 (paszepine/cemdisiran, eculizumab, or revlizumab) is only for patients who intend to continue in the OLE. Patients who refuse to participate in the OLE will not receive a dose at Week 36. Table 6-2. Timeline of Events for the Switching Period: Patients Receiving Eculizumab in the OLTP and Planning to Participate in the OLE Research Procedure ( Interview ) ¹ Conversion period for patients receiving eculizumab in OLTP ( only patients who completed OLTP and were scheduled to enter OLE ) Visit # ( 2 weeks after last dose of eculizumab at OLTP week 36 ) ^TV1e 2 TV2e Weeks (after last dose of study treatment at OLTP Week 36) 2t 4t sky 15t 29t Range (days) ±2 ±2 Baseline: Meningococcal Patient Safety Card ³ X X treatment: IVRS/IWRS X X Anti-C5 standard of care group: Eculizumab ⁴ Administer pazelimumab 60 mg/kg IV for ⁵ X Administer Cemdisiran 200 mg SC ⁵ X Administer paszelimab 400 mg SC ⁵ X Administer eculizumab 900 mg IV Q2W for ⁵ X Concomitant medications and treatments X X Transfer record update X X Antibiotic prophylaxis (recommended) ⁷ X X Safety and human body measurements: Weight X X Vital signs X X Adverse Events X X Breakthrough Hemolysis ^Evaluation8 X X Laboratory Test ⁹ : Hematology ¹⁰ X X Coagulation group X X Blood chemistry (long panel), including LDH ¹¹ X X Pregnancy test (for applicable patients) ¹² X Pharmacokinetics and Total C5 Sampling: Patients who previously received eculizumab Pazerimab concentration in blood samples ¹³ X Blood samples for eculizumab concentration X Total C5 samples ¹⁴ X CH50 X X Footnotes 1. When multiple procedures are performed on the same day, the order of procedures is as follows: vital signs, blood draw (coagulation draw first, followed by chemistry draw, followed by all other labs), and study drug administration. It is particularly important that scheduled blood draws be performed prior to administration of study treatment, especially for efficacy parameters such as LDH (i.e., measures that reflect the time point at which the dosing interval ends). 2. Switch Period Day 1 is the day the Week 36 eculizumab dose is administered in the OLTP. During the Switch Period, eculizumab may be administered within 2 days of all visits at which eculizumab dosing is administered. If eculizumab dosing does not coincide with an outpatient visit day (if applicable), the outpatient visit should always precede the eculizumab infusion. 3. Patient Safety Card: Provide the patient with a Meningococcal Infection Patient Safety Card at any visit if needed. Sites should review the instructions on the safety card with the patient at each visit. 4. Patients randomized to the anti-C5 standard of care group receiving eculizumab, who complete the 36-week OLTP and are scheduled to participate in the OLE study, will be switched from eculizumab to combination therapy as follows: At the end-of-treatment visit at Week 36 of the OLTP, patients will receive Cemdisiran 200 mg and Eculizumab 900 mg IV. The final dose of Eculizumab 900 mg IV is at the Week 2t visit during the switch period, followed by Paselimab 60 mg/kg IV and Paselimab 400 mg SC and Cemdisiran 200 mg SC at the Week 4t visit. Patients will be switched to the OLE study after completion of the Week 4t visit. 5. All study treatments (i.e., Pazelimumab, Cemdisiran, and Eculizumab) should be administered as the last procedure after all blood samples have been collected and study assessments have been completed. A 2-hour observation period should begin after administration of Cemdisiran on Switch Day 1 (OLTP Week 36). On Day 29 (Switch Period Week 4), after completion of Pazelimumab 60 mg/kg IV dosing, patients should be monitored for at least 30 minutes prior to administration of Pazelimumab/Cemdisiran SC. A 2-hour observation period should begin after the last administration of study drug (either Pazelimumab or Cemdisiran SC). 6. Intentionally left blank 7. Daily oral antibiotic prophylaxis against meningococcal disease is recommended, starting on the first day of study treatment administration and continuing for up to 52 weeks after discontinuation of pasirizumab/cemdisiran. Follow local prescribing information/national guidelines/local practice for post-treatment prophylaxis with eculizumab or ravulizumab. 8. If a patient is suspected of having a breakthrough hemolytic event, in addition to the required laboratory collections, CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, and drug concentrations of paselumab, cemdisiran, eculizumab, or ravulizumab, ADA (for paselumab), and additional samples of exploratory study serum and plasma will be collected unless noted in the event schedule for that visit. If the suspected event does not occur at the scheduled visit, a planned off-site visit should be conducted to evaluate the patient and collect CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, drug concentrations of eculizumab or ravulizumab/paselumab/cemdisiran, and ADA (for paselumab) if applicable, and additional samples of exploratory study serum and plasma. 9. During laboratory collection, handling, and processing, the same methodology will be applied at the study visit whenever possible to maintain sample quality and avoid hemolysis during sample processing. If the investigator or sponsor suspects that the laboratory results do not accurately reflect the patient's condition and LDH ≧ 2 × ULN plus potassium ≧ 6 mmol/L, consideration should be given to repeating the laboratory sample as clinically indicated. Unless otherwise indicated, blood should always be collected prior to study treatment administration. 10. Hemoglobin will be assessed as part of the hematology analysis. Hematology samples should be collected prior to study treatment administration. 11. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. Obtain chemistries including LDH prior to any study treatment administration. 12. Pregnancy Testing: A urine test will be performed. 13. For patients receiving IV infusion of paselumab: blood samples will be collected prior to IV administration of paselumab and within 15 minutes after the end of IV infusion. 14. Blood samples for CH50 and total C5 will be collected prior to dosing. Table 6-3. Timeline of events during the conversion period: patients receiving ravulizumab in the OLTP and scheduled to participate in the OLE Research Procedure ( Interview ) ¹ Conversion period for patients receiving ravulizumab in OLTP ( only patients who completed OLTP and were scheduled to enter OLE ) Visit # ( 4 weeks after last dose of Ravelizumab at OLTP week 36 ) ^TV1r 2 TV2r Weeks (after last dose of study treatment at OLTP Week 36) 4t 8t sky 29t 57t Range (days) ±2 ±2 Baseline: Meningococcal Patient Safety Card ³ X X treatment: IVRS/IWRS X X Anti-C5 Standard of care group: Ravelizumab ⁶ Administer Cemdisiran 200 mg SC ⁵ X X Administer pazelimumab 60 mg/kg IV for ⁵ X Administer paszelimab 400 mg SC ⁵ X Concomitant medications and treatments X X Transfer record update X X Antibiotic prophylaxis (recommended) ⁷ X X Safety and human body measurements: Weight X X Vital signs X X Adverse Events X X Breakthrough Hemolysis ^Evaluation8 X X Laboratory Test ⁹ : Hematology ¹⁰ X X Coagulation group X X Blood chemistry (long panel), including LDH ¹¹ X X Pregnancy test (for applicable patients) ¹² X X Pharmacokinetics and Total C5 Sampling: Patients who previously received ravulizumab Pazerimab concentration in blood samples ¹³ X Blood samples for ravulizumab concentration X Total C5 samples ¹⁴ X CH50 X X ¹⁴ Footnotes 1. When multiple procedures are performed on the same day, the order of procedures is as follows: vital signs, blood draw (coagulation draw first, followed by chemistry draw, followed by all other labs), and study drug administration. It is particularly important that scheduled blood draws be performed prior to administration of study treatment, especially for efficacy parameters such as LDH (i.e., measures that reflect the time point at which the dosing interval ends). 2. Transition Period Day 1 is the day the Week 36 dose of ravulizumab is administered in the OLTP. 3. Patient Safety Card: Provide the patient with a Meningococcal Infection Patient Safety Card at any visit, if requested. Sites should review the instructions on the safety card with the patient at each visit. 4. Intentionally left blank 5. All study treatments (i.e., Pazelimumab and Cemdisiran) should be administered as the last procedure after all blood samples have been collected and study assessments have been completed. A 2-hour observation period should begin after administration of Cemdisiran on Switch Day 29 (Switch Week 4). On Day 57 (Switch Week 8), after completion of Pazelimumab 60 mg/kg IV, patients should be monitored for at least 30 minutes prior to administration of Pazelimumab/Cemdisiran SC. A 2-hour observation period should begin after the last administration of study drug (either Pazelimumab or Cemdisiran SC). 6. Patients randomized to the anti-C5 standard of care arm receiving Ravelizumab, who complete the 36-week OLTP and are scheduled to participate in the OLE study, will be switched from Ravelizumab to the combination therapy as follows: At the OLTP Week 36 End of Treatment Visit, patients will receive the last dose of Ravelizumab. They will enter the switch period at Week 4t (4 weeks after the last dose of Ravelizumab) with Visit 1. At the Week 4t Visit, they will receive Cemdisiran 200 mg SC. At the Week 8t Visit, they will receive Pazilimab 60 mg/kg IV in combination with Pazilimab 400 mg SC and Cemdisiran 200 mg SC. They will switch to the OLE study after completing the Week 8t visit. 7. Daily oral antibiotic prophylaxis against meningococcal disease is recommended, starting on the first day of study treatment administration and continuing for up to 52 weeks after discontinuation of pasirizumab/cemdisiran. Follow local prescribing information/national guidelines/local practice regarding post-treatment prophylaxis with eculizumab or ravulizumab. 8. If a patient is suspected of having a breakthrough hemolytic event, in addition to the required laboratory collections, CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, and drug concentrations of paselumab, cemdisiran, eculizumab, or ravulizumab, ADA (for paselumab), and additional samples of exploratory study serum and plasma will be collected unless noted in the event schedule for that visit. If the suspected event does not occur at the scheduled visit, a planned off-site visit should be conducted to evaluate the patient and collect CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, drug concentrations of eculizumab or ravulizumab/paselumab/cemdisiran, and ADA (for paselumab) if applicable, as well as additional samples of exploratory study serum and plasma. 9. During laboratory collection, handling, and processing, the same methodology will be applied at the study visit whenever possible to maintain sample quality and avoid hemolysis during sample processing. If the investigator or sponsor suspects that the laboratory results do not accurately reflect the patient's condition and LDH ≧ 2 × ULN plus potassium ≧ 6 mmol/L, consideration should be given to repeating the laboratory sample as clinically indicated. Unless otherwise specified, blood should always be collected prior to study treatment administration. 10. Hemoglobin will be assessed as part of the hematology analysis. Hematology samples should be collected prior to study treatment administration. 11. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. Obtain chemistries including LDH prior to any study treatment. 12. Pregnancy Testing: A urine test will be performed. 13. For patients receiving IV infusion of paslimab: obtain blood samples prior to IV administration of paslimab and within 15 minutes after the end of the IV infusion. 14. Blood samples for CH50 and total C5 will be collected before dosing. Table 6-4. Timeline of events during the safety off-treatment follow-up period Visit FU-1 FU-2 FU-3 FU-4 FU-5 Telephone interview FU-6 Telephone interview FU-7 Weeks (after last dose of study drug) 4 8 12 16 26 38 52 Range (days) ±10 ±10 ±10 ±10 ±10 ±10 ±10 Weight X X X X X Vital signs X X X X X Physical examination X X Concomitant medication/treatment X X X X X X X Adverse Event Reporting X X X X X X X Pregnancy Report X X X X X X X Antibiotic prophylaxis (recommended) ¹ X X X X X X X Meningococcal Patient Safety Card ² X X X X X X X Laboratory testing Hematology X X X X X Blood chemistry X X X X X Monthly urine pregnancy test (WOCBP) ³ ＜------------------------------------X--------------------------------＞ Pharmacokinetics and ADA sampling: Pazelimab PK samples X ADA samples of Pazelimumab X ADA Sample of Cemdisiran X Total C5 (plasma) X Footnotes 1. Antibiotic Prophylaxis (Recommended): Daily oral antibiotic prophylaxis for meningococcal infection is recommended, starting at FU-1 and continuing for up to 52 weeks after discontinuation of pasirizumab/cemdisiran. Follow local prescribing information/national guidelines/local practice for post-treatment prophylaxis with eculizumab or ravulizumab. 2. Patient Safety Card for Meningococcal Infection: Patient Safety Card: Provide the patient with a Patient Safety Card for Meningococcal Infection at FU-1 or any other visit, if indicated. Sites should review the instructions on the safety card with the patient at each visit. 3. Pregnancy Testing: Urine pregnancy testing will be performed monthly for WOCBP only. If the pregnancy test is performed by home test kit, patients should be reminded to call the investigators monthly to inform them of their pregnancy test results and to call the investigators as soon as possible if the pregnancy test result is positive.

Patients must meet the following criteria to be eligible for inclusion in the study: 1. Male or female aged ≥18 years or legal age of majority (whichever is older) at the time of consent 2. Confirmed PNH as confirmed by previous testing with high-sensitivity flow cytometry 3. (i) Continuous treatment with eculizumab* 900 mg IV Q 14 days for at least 12 weeks prior to the screening visit. or (ii) continued treatment with ravulizumab* IV Q8W (based on BW) for at least 24 weeks prior to the screening visit as follows: 3000 mg for BW ≧40 kg to <60 kg, 3300 mg for BW ≧60 kg to <100 kg, 3600 mg for BW ≧100 kg. Note: Patients randomized to the Revulizumab group who choose to participate in the R3918-PNH-2021 trial (a randomized, open-label, Revulizumab-controlled study designed to evaluate the efficacy and safety of paszelimab and cemdisiran combination therapy in patients with paroxysmal nocturnal hemoglobinuria who are not or have not recently received compensatory inhibitor therapy) must complete the open-label treatment period to be considered eligible for this study. * Biosimilar drugs are not allowed unless approved by the organizer. 4. Provide signed informed consent from the study patient. 5. Willing and able to comply with clinical/remote visits and study-related procedures. 6. Able to understand study-related questionnaires. Exclusion Criteria Note: If a patient fails screening, the patient may be rescreened (up to 2 times) if the study is ongoing and the Principal Investigator determines that the patient may be eligible after rescreening.

Patients meeting any of the following criteria will be excluded from the study: 1. Screening LDH >1.5 x ULN, patients not receiving their C5 inhibitor at the labeled dosing interval prior to the screening LDH assessment. 2. Previous organ transplant, bone marrow transplant, or other hematologic transplant. 3. Weight <40 kg at the screening visit. 4. Current medication plan for adjustment (start, discontinue, or change dose/dosing interval) of the following background concomitant medications (if applicable) during the screening and treatment periods: erythropoietin, immunosuppressive drugs, corticosteroids, antithrombotics, anticoagulants, iron supplements, and folic acid. 5. Planned use of any cytokine inhibitor therapy (other than study treatment) other than eculizumab or ravulizumab within 26 weeks prior to the screening visit or during the study. 6. Any of the following abnormalities at the screening visit (each parameter is allowed to be repeated twice during the screening period): a. Peripheral blood absolute neutrophil count (ANC) <500/μL (<0.5 × 10 ⁹ /L); or b. Peripheral blood platelet count <30,000/μL or c. Abnormal peripheral blood reticulocyte count, defined as <60,000/μL (<0.06 × 10 ⁶ /μL, <60 × 10 ⁹ /L) Note: Patients will not be excluded if the parameter no longer meets the exclusion criteria after repeat testing. Note: Patients who received acute treatment for these conditions (e.g., platelet transfusion, granulocyte colony stimulating factor) during the screening period and within 1 month before screening will not be eligible. 7. Not eligible for meningococcal vaccination requirement for eculizumab or ravulizumab based on current local prescribing information (if available) and no documented meningococcal vaccination within 5 years prior to the minimum screening visit. Note: Patients who have not been previously vaccinated will be eligible if they are willing to receive vaccination prior to starting study treatment and have vaccination documented prior to randomization. 8. Have contraindications to receiving meningococcal vaccination. 9. Unable to take antibiotics to prevent meningococci (if required by local eculizumab or ravulizumab prescribing information (if applicable) or national guidelines/local practice, or if vaccination was given less than 2 weeks from the start of study treatment). 10. Any active ongoing infection or recent infection requiring systemic treatment with antibiotics, antivirals, or antifungals within 2 weeks prior to screening or during the screening period. 11. Documented history of systemic fungal disease or unresolved TB, or evidence of active or latent TB infection (LTBI) during the screening period (ie, if LTBI treatment has not been completed). Evaluation of active TB and LTBI should be consistent with local practice or guidelines, including those related to risk assessment and the use of tuberculin skin testing or T-cell interferon gamma release assays. 12. Positive hepatitis B surface antigen or hepatitis C virus RNA during the screening period. Note: Cases with unclear interpretation should be discussed with the medical supervisor. 13. Patients known to have HIV with a history of opportunistic infection within the past 1 year, any history of HIV-related malignancy, a documented CD4 count <500 cells/μL or a detectable viral load within the past 6 months (Note: CD4 count and viral load must be available within the past 6 months and can be performed by a local laboratory during the screening period if needed). Note: Patients can be tested for local HIV if required by local requirements or local regulations. 14. Documented history of a positive RT-PCR, antigen or serology test, or other health authority authorized test for SARS-CoV-2, and: a. Have not recovered from COVID-19 (i.e., all COVID-19-related symptoms and major clinical findings that could affect patient safety should resolve to baseline), and b. Have not had 2 negative results on a health authority authorized nucleic acid amplification (RT-PCR) test or other health authority authorized test for COVID19 at least 48 hours apart prior to Day 1. Note: COVID-19 screening will not be performed as part of the eligibility assessment for this study 15. Known hereditary complement deficiency 16. Documented history of active, uncontrolled, persistent systemic autoimmune disease 17. Patients with a documented history of cirrhosis or liver disease with evidence of current compromised liver function, or patients with ALT or AST (not associated with PNH or its complications) greater than 3 × ULN at the screening visit (one repeat assessment of abnormal parameters is allowed during the screening period if AST or ALT returns to > 3 × ULN). 18. Patients with eGFR < 30 mL/min/1.73m ² (based on the Chronic Kidney Disease-Epidemiology Collaboration equation 2009) at the screening visit (one repeat assessment is allowed during the screening period). 19. Any recent unstable medical condition within the past 3 months before the screening visit, excluding PNH and PNH-related complications (e.g., myocardial infarction, New York Heart Association ≥ Grade III or IV congestive heart failure, severe uncontrolled arrhythmia, cerebrovascular accident, active gastrointestinal bleeding) 20. Major surgery is expected during the study 21. History of cancer in the past 5 years, excluding adequately treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma in situ 22. Participation in another interventional clinical study (except R3918-PNH-2021) or use of any experimental treatment within 30 days before the screening visit or within 5 half-lives of the investigational product (whichever is longer), except for eculizumab or ravlizumab. 23. Known allergy to eculizumab or ravlizumab (if applicable), pasirizumab, cemdisiran, or any component of their respective formulations. 24. Patients with functional or anatomical asplenia 25. Any clinically significant abnormality confirmed at screening that, in the judgment of the investigator or any sub-investigator, will prevent the safe completion of the study or limit the assessment of the evaluation indicators, such as major systemic diseases or patients with a short expected life span 26. Patients who are considered unsuitable for this study by the investigator or sub-investigator for any reason, for example, a. They are considered unable to meet specific protocol requirements, such as planned visits. b. They are considered unable to perform or tolerate long-term injections. c. Any other actual or expected circumstances (such as geographic, social, etc.) that the investigator believes will limit or restrict the patient's participation during the duration of the study. d. A member of a vulnerable group, such as an institutionalized person (this may also include patients who have been institutionalized pursuant to an order issued by a judicial or administrative authority, if applicable) e. A patient who is ineligible to participate in a clinical trial due to local regulations (e.g., subject to legal protection measures [such as L1121-8 or L1121-8-1 in France], etc.). 27. Clinical site research team members and/or their immediate family members, unless approved in advance by the Sponsor. 28. Pregnant or breastfeeding women. 29. Women of childbearing potential (WOCBP)* who are unwilling to use highly effective contraceptive measures before the start of the initial dose/first treatment, during the study, and for at least 52 weeks after the last dose. Highly effective contraceptive measures include: a. Stable use of combined (estrogen and progestin) hormonal contraceptives (oral, vaginal, transdermal) or progestin-only hormonal contraceptives (oral, injectable, implantable) to suppress ovulation starting 2 or more menstrual cycles before screening; b. Intrauterine contraceptive device (IUD); intrauterine hormone-releasing system (IUS); c. Bilateral tubal ligation or tubal occlusion; d. Vasectomy partner (provided that the vasectomized male partner is the only sexual partner of the WOCBP study participant and the vasectomized partner has been medically evaluated for the success of the surgery); and/or e. Abstinence , . *WOCBP is defined as a woman of childbearing potential from postmenarche to postmenopause, unless infertility is permanent. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. The postmenopausal state is defined as the absence of menstruation for 12 months without other medical reasons. High levels of follicle-stimulating hormone (FSH) in the postmenopausal range can be used to confirm the postmenopausal state in women who are not using hormonal contraception or hormone replacement therapy. However, a single FSH measurement is not sufficient to confirm the occurrence of the postmenopausal state in the absence of 12 months of amenorrhea. The above definition is based on the Clinical Trials Facilitation Group (CTFG) guidelines. Pregnancy testing and contraception are required for WOCBP. Pregnancy testing and contraception are not required for women who are postmenopausal or permanently infertile. Abstinence is considered a highly effective approach only if it is defined as abstention from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of abstinence needs to be assessed based on the duration of the clinical trial and the preferences and usual lifestyle of the subjects. Periodic abstinence (calendar method, symptomatic temperature method, postovulation method), intercourse interruption method (extracorporeal ejaculation method), spermicide-only method, and lactational amenorrhea method (LAM) are not acceptable methods of contraception. Female and male condoms should not be used at the same time 30. No response to treatment with eculizumab or ravelizumab (Note: No response refers to patients whose LDH does not decrease after treatment with eculizumab or ravelizumab; patients with poor response to treatment with eculizumab or ravelizumab are not excluded, provided that all other eligibility criteria are met) 31. Hemoglobin ≤ 7 g/dL (Note: Patients may receive blood transfusions during the screening period and are eligible if the repeat hemoglobin returns to > 7 g/dL before randomization. Repeat measurements are allowed more than 2 times). Primary Objective

The primary objective of the study was to evaluate the effect of the combination of paszelimab and cemdisiran on hemolysis as assessed by LDH after 36 weeks of treatment in PNH patients who switched from eculizumab or ravelizumab treatment to the combination compared with patients who continued their eculizumab or ravelizumab treatment. Secondary Objectives

The secondary objectives of the study are to: • Evaluate the effect of combination therapy of Pazlimab and Cemdisiran compared with standard of care anti-C5 therapy (eculizumab or ravelizumab) on: . Transfusion requirements and transfusion parameters . Measures of hemolysis: LDH control, breakthrough hemolysis, and CH50 inhibition . Hemoglobin levels . Fatigue assessed by Clinical Outcome Assessment (COA) . HRQoL assessed by COA . Safety and tolerability • Evaluate the concentrations of total Pazlimab and total eculizumab or total ravelizumab in serum and the concentrations of cemdisiran and total C5 protein in plasma • Evaluate the immunogenicity of Pazlimab and Cemdisiran Exploratory Objectives

The exploratory objectives of the study are to: • To investigate the effects on clinical thrombotic events; • To investigate the effects on renal function and renal damage biomarkers; • To investigate the effects on complement activation and hemolysis associated with PNH and other related diseases; • To investigate the effects on PNH colony size; • To investigate the effects on COA (treatment satisfaction questionnaire (TSQM), QoL (European Quality of Life Five Dimensions Five Levels Scale [EQ-5D-5L] and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Items [EORTC-QLQ-C30]), and PNH-specific symptoms • Build a molecular understanding of PNH and related diseases and investigate mechanisms of action (including relationships to safety and efficacy) and complement pathway biology. • Explore whether potential differences in patient efficacy and safety are associated with genotype and gene expression, and use selective whole blood DNA and RNA collected from consenting patients to further investigate C5, PNH, or other conditions associated with complement-mediated impairment. Main Outcome Measures

The primary outcome measure was the percentage change in LDH from baseline to EOT at Week 36 (Day 253). Key secondary outcomes

Key secondary outcomes were: •Avoidance of transfusions from Day 1 to Week 36 (defined as no red blood cell transfusion required according to the protocol algorithm based on hemoglobin values after Day 1) •Breakthrough hemolysis from Day 1 to Week 36 (inclusive) in patients with baseline LDH ≦ 1.5× ULN •Hemoglobin stability from Day 1 to Week 36 (inclusive) (defined as patients who did not receive an red blood cell transfusion and whose hemoglobin level did not decrease by ≧2 g/dL from baseline) •Maintenance of adequate control of hemolysis, defined as LDH ≦1.5× ULN from Week 8 to Week 36 (inclusive) •Adequate control of hemolysis (defined as LDH ≦1.5× ULN) from Week 8 to Week 36 (inclusive) •LDH normalization, defined as LDH ≦1.0 × ULN from week 8 to week 36 (inclusive) •Change in fatigue measured by FACIT-Fatigue scale from baseline to week 36 •Change in PF score of EORTC-QLQ-C30 from baseline to week 36 •Change in Global Health Status (GHS)/QoL scale score of EORTC-QLQ-C30 from baseline to week 36 Other secondary assessment indicators

Other secondary outcomes were: •Avoidance of transfusions from Week 4 to Week 36 (inclusive) (defined as no RBC transfusion required according to the protocol algorithm based on hemoglobin values after Day 1) •Breakthrough hemolysis from Week 4 to Week 36 (inclusive) in patients with baseline LDH ≤1.5× ULN •Hemoglobin stability from Week 4 to Week 36 (inclusive) (defined as patients who did not receive RBC transfusions and whose hemoglobin levels did not decrease by ≥2 g/dL from baseline) •Maintenance of adequate control of hemolysis, defined as LDH ≤1.5× ULN from Day 1 to Week 36 (inclusive) •Adequate control of hemolysis from Day 1 to Week 36 (defined as LDH ≤1.5× ULN) • Normalization of LDH (defined as LDH ≦1.0 × ULN) from Day 1 to Week 36 (inclusive) • RBC translocation rate and number of units per protocol algorithm from Day 1 to Week 36 and from Week 4 to Week 36 • Change in hemoglobin content from baseline to Week 36 • Incidence and severity of treatment-emergent SAEs, TEAEs of special interest, and TEAEs leading to discontinuation of treatment within 36 weeks • Change and percentage change in total CH50 from baseline to Week 36 • Total C5 concentrations assessed in plasma throughout the study • Total pasirimab concentrations assessed in serum throughout the study • Cemdisiran concentrations assessed in plasma throughout the study •Total eculizumab or total ravelizumab concentrations in serum will be assessed throughout the study •The incidence of treatment-emergent anti-drug antibodies (ADA) to paszelimab will be assessed throughout the study •The incidence of treatment-emergent ADA to cemdisiran will be assessed through 36 weeks Exploratory Measures

Exploratory assessments were: •Incidence of major adverse vascular events (MAVEs) from day 1 to week 36 and from week 4 to week 36 •Incidence of breakthrough hemolysis in patients with baseline LDH ≤1.5× ULN from day 1 to week 36 •Change in renal function measured by estimated glomerular filtration rate (eGFR) from day 1 before treatment to week 36 •Percent change in free hemoglobin from baseline to week 36 •Change in heme-binding protein from baseline to week 36 •Change in total bilirubin from baseline to week 36 •Change in reticulocyte count from baseline to week 36 • Change and percentage of change in alternative pathway hemolytic activity assay (AH50) from baseline to week 36 • Change from baseline to week 36 in PNH erythrocytes, granulocytes, and monocytes • Change from baseline to week 36 in treatment satisfaction as assessed by TSQM • Change from baseline to week 36 in EQ-5D-5L scores • Change from baseline to week 36 in PNH symptoms as measured by the PNH Symptom Specific Questionnaire scores • Change from baseline to week 36 in EORTC-QLQ-C30 functional scale scores (role functioning, emotional functioning, cognitive functioning, and social functioning) and symptom scale scores (fatigue, nausea and vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea) • Stability of global health, function, and symptoms measured by the EORTC-QLQ-C30 from baseline to week 36 Efficacy variability - laboratory variability used to assess treatment efficacy

The efficacy of this study was assessed by the following laboratory assessments: •LDH (serum): LDH is a measure of intravascular hemolysis and can objectively and accurately measure whether intravascular hemolysis is continuously controlled when patients are switched to the combination of paslimab and cemdisiran. •Hemoglobin: Hemolytic anemia is a marker of PNH

These laboratory variants have been associated with the characterization and disease mechanisms of PNH (Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood 2014; 124(18):2804-2811.). Transfer Records

Hemolytic anemia is the clinical manifestation of PNH, and patients usually require blood transfusions for symptomatic treatment. Transfusion frequency has been used to assess efficacy in other studies of PNH (Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J, Luzzatto L, et al. Effect of the complement inhibitor Eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007; 110(12):4123-4128) (Röth A, Egyed M, Ichikawa S, Kim JS, Nagy Z, Gaàl Weisinger J, et al. The SMART Anti-hC5 Antibody (SKY59/RO7112689) Shows Good Safety and Efficacy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). Blood 2018; 132(Suppl 1):535).

A brief description of the COA is provided in paragraph 9.2.3 and includes the following: •FACIT-Fatigue •EORTC-QLQ C30 •TSQM •EQ-5D-5L •PNH Symptom Specific Questionnaire Safety Variability and Anthropometric Variability

Safety and anthropometric variables in this study included: • Meningococcal vaccination/revaccination, • Pneumococcal and Haemophilus influenzae type B vaccination (if indicated) • Concomitant medications and procedures • Height • Weight • Vital signs • Physical examination • Electrocardiogram (ECG) • AEs • Evaluation of breakthrough hemolysis • Routine safety laboratory studies (hematology, chemistry, coagulation parameters, direct antiglobulin test, urinalysis, and pregnancy test [for women of childbearing age or WOCBP]) Example 7 : A randomized, open-label, ravulizumab-controlled, noninferiority study to evaluate the efficacy and safety of paszelimab and cemdisiran combination therapy in patients with paroxysmal nocturnal hemoglobinuria who have not received or have not recently received compensatory inhibitor therapy (R3918-PNH-2021)

This is a randomized, open-label, ravulizumab-controlled, noninferiority study that plans to recruit patients with PNH who are naïve or have not recently received induction therapy with induction therapy inhibitors.

The study consists of the following periods: a screening period of up to 6 weeks and a 26-week OLTP with either Revulizumab or Paselimab in combination with Cemdisiran (Figure 27). Patients who complete the Revulizumab OLTP and are scheduled to screen for the R3918-PNH-2022 study or to participate in a subsequent open-label, long-term extension study of Paselimab and Cemdisiran combination will follow additional post-OLTP procedures. Patients who discontinue study treatment and those who do not continue in R3918-PNH-2022 or decline to participate in the OLE study will undergo a safety off-treatment follow-up period of up to 52 weeks. Screening Period

Patients will be evaluated during a screening period of up to 6 weeks prior to Day 1 to determine their eligibility for the study. Historical data related to previous and concomitant medications, hemolysis parameters, RBC transfusions, and symptoms of PNH will be collected.

Additional interim screening visits may be performed if necessary (e.g., repeat blood draws).

Due to the risk of meningococcal infection, patients will need to be vaccinated with meningococcal vaccines according to local ravelizumab prescribing information (if applicable) and with complement inhibitors according to current national vaccination guidelines or local practice for at least 5 years prior to screening. For patients who need to be vaccinated with meningococcal vaccines during the screening period, vaccination should ideally be done at least 2 weeks before Day 1, or at any other time point according to local practice or national guidelines/local ravelizumab prescribing information (if applicable). If vaccination is less than 2 weeks before the start of study treatment, patients must receive antibiotic prophylaxis for at least 2 weeks from the date of vaccination.

Patients who had not yet received Streptococcus pneumoniae and Haemophilus influenzae type b vaccines could receive these vaccines during screening or on the day of randomization, depending on the investigator's judgment and taking into account applicable national guidelines.

In addition to meningococcal infections, fatal or serious gonococcal infections have been reported in patients receiving serotonin inhibitor therapy. Therefore, patients will undergo risk assessment and counseling regarding the potential risk of gonococcal infection according to local practice or national guidelines.

Patients will be evaluated for active or latent tuberculosis (TB) infection based on local practice or applicable guidelines. Based on the risk assessment, the need for screening using a tuberculin skin test or T-cell interferon-gamma release assay will be determined. If applicable, these results will be interpreted by the investigator. Further management and treatment will be the responsibility of the investigator.

Patients who complete the screening assessment and are deemed eligible will be randomized in a 1:1 ratio to the combination arm or the ravulizumab arm. Randomization will be stratified based on factors described herein - Patients will be randomized in a 1:1 ratio to receive the combination of SC paszelimab 400 mg and cemdisiran 200 mg Q4W or IV ravulizumab using an Interactive Web Response System (IWRS) with a labeled weight-based dosing algorithm. Stratified, blocked randomization will be performed using the following stratification factors: • RBC/whole blood transfusion within the past year before randomization (yes/no) Note: The upper limit of enrollment for patients who have not had an RBC transfusion within the past year before randomization is 20% of the total enrollment population. • Screening visit LDH level (2.0 to <4.0 × ULN or ≧4.0 × ULN)

Random grouping of segments will be done centrally. Open Label Treatment Period (OLTP)

The treatment period is 26 weeks (Table 7-1). Patients will receive the corresponding treatment according to the treatment allocation described below. • Ravelizumab group: . Patients randomized to the Ravelizumab group will start Ravelizumab treatment on Day 1 (+2 days) according to the Ravelizumab prescription information as follows: Day 1 (Revilizumab may be given on the same day as the procedure or up to 2 days after the visit): Weight-based loading dose (≥40 kg to <60 kg, 2400 mg IV; ≥60 kg to <100 kg, 2700 mg IV; ≥100 kg, 3000 mg IV) Day 15 (because the first maintenance dose is given 2 weeks after the loading dose, the Week 2 [Day 15] visit should be scheduled on or up to 2 days before the day of ravulizumab administration). Weight-based maintenance dose (≥40 kg to <60 kg, 3000 mg IV; ≥60 kg to <100 kg, 3300 mg IV; ≥100 kg, 3600 mg IV) and every 8 weeks (Q8W) thereafter (± 7 days) • Pazelimumab and Cemdisiran Group: Patients randomized to the Pazelimumab and Cemdisiran combination group will receive the following treatments during the study: Day 1* A single loading dose of pazelimumab 30 mg/kg IV, followed by pazelimumab 400 mg SC and cemdisiran 200 mg SC (combination maintenance dose) Day 29 Combination maintenance dose (Pazerimab 400 mg and Cemdisiran 200 mg) SC and then Q4W NOTE: On Day 1, the time from completion of the IV infusion of Pazelimumab to the start of the combination SC injection should be at least 30 minutes. Monitor patients for at least an additional 30 minutes after completion of the first SC injection of Pazelimumab and Cemdisiran. Note that Pazelimumab and Cemdisiran should be administered at different anatomic sites (e.g., left thigh, right thigh) on the day of the SC injection. The injection site should be rotated for subsequent injections.

In addition, clinical sites must have emergency equipment and medications available for immediate use to treat infusion reactions. All infusion reactions must be reported as AEs and graded. Dosing of the Pazerimab and Cemdisiran Maintenance Regimen

After dosing on Day 1, subsequent dosing may be continued by site personnel or healthcare professionals in the patient's home (if feasible and approved by the Sponsor), or the Pazelimumab and Cemdisiran combination may be administered by the patient or a designee at the patient's preferred site. These different options for dosing will depend on investigator and patient preferences, local regulations, and healthcare professional availability and Sponsor approval. If the Pazelimumab and Cemdisiran combination is self-administered/designee-administered, adequate injection training on the Pazelimumab and Cemdisiran maintenance regimen will be provided at the time of scheduled dosing. Following training, observation of self-administration/designee-administration will be conducted by clinical site personnel or a visiting healthcare professional/virtual visit. Once this observation is deemed satisfactory, the patient/designee may then be individually administered the maintenance regimen of Pasqualimab and Cemdisiran for the remainder of the study. Patients who self-administer/have their designee administer study medication should complete a patient diary to collect information regarding study treatment administration. They should also be contacted by the study site to ensure that study medication administration is proceeding as planned. Post-Open-Label Treatment Period (Post-OLTP)

All patients who complete 26 weeks of OLTP study treatment will be invited to participate in the long-term OLE study of the combination treatment.

Patients randomized to ravelizumab who complete the 26-week OLTP and plan to enroll in the next study will receive an additional dose of ravelizumab at OLTP week 26. These patients will first be invited to participate in the R3918-PNH 2022 study (a combination study of paszepine and cemdisiran in PNH patients currently treated with either eculizumab or ravelizumab). If R3918-PNH-2022 is open for enrollment, patients will be screened as described for the R3918-PNH-2022 study.

If a patient does not meet the eligibility requirements for the R3918-PNH-2022 study, or enrollment in R3918-PNH-2022 has ended, the patient may continue to participate in the OLE study. Switching from Revulizumab to Cemdisiran and Pazlimab should be performed as follows (Table 7-2): • Switch Day 1 (OLTP Week 26): Revulizumab at the labeled weight-based dose • Switch Day 29 (Switch Period Week 4): Cemdisiran 200 mg SC • Switch Day 57 (Switch Period Week 8): Pazlimab 60 mg/kg IV loading dose, followed by Pazlimab 400 mg SC and Cemdisiran 200 mg SC

This approach was designed to ensure consistent dosing when switching from revlizumab to pasirimab and cemdisiran combination therapy for patients randomized to revlizumab and planned to enroll directly in the OLE study.

For patients randomized to the paslimab and cemdisiran combination, the Day 1 visit of the OLE study will occur 2 weeks after the end-of-study (EOS) visit at Week 26 of the current study to ensure that study treatment is not interrupted.

Patients who discontinue study treatment and those who do not continue in R3918-PNH-2022 or decline to participate in the OLE study will receive a safety off-treatment follow-up period of up to 52 weeks per Table 7-3. Patients who discontinue study treatment should be treated according to local standards of care while continuing to be monitored during the 52-week off-treatment safety follow-up period. Investigators who switch patients from combination therapy to another anti-C5 mAb should be aware of the potential for AEs resulting from large DTD immune complex formation.

The primary study was considered completed when all patients completed the 26-week treatment period or discontinued the study early. Additional data collected during the transition period and the safety off-treatment follow-up period are described separately. Timeline of Events

In light of the public health emergency related to COVID-19, continuity of clinical research conduct and oversight may require the implementation of temporary or alternative mechanisms. Examples of such mechanisms may include, but are not limited to, any of the following: telephone contact, virtual visits, telemedicine visits, online conferencing, non-invasive remote monitoring devices, use of local clinic or laboratory sites, and home visits by technology-savvy staff. In addition, no waivers will be granted for deviations from protocol enrollment criteria due to COVID-19. All temporary mechanisms employed and deviations from planned study procedures should be documented as being related to COVID-19 and in effect only for the duration of the public health emergency.

Study assessments and procedures are presented by study period and visit in Table 7-1 (OTLP), Table 7-2 (Conversion Period), and Table 7-3 (Safety Follow-up Period). See Figure 27. Table 7-1. Timeline of Events for the Open-Label Treatment Period   Filter Open Label Treatment Period (OLTP) ¹ Research Procedure ( Interview ) ² EOS V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 Week Up to -6 -4 to -2 0 2 4 8 10 12 16 18 20 twenty four 26 sky Up to -42 -28 to ‑14 1 15 29 57 71 85 113 127 141 169 183 Range (days) ±2 ±3 ±3 ±3 ±3 ±7 ±3 ±3 ±7 ±3 Screening / Baseline: Provide eCOA equipment X Include/Exclude X X X Informed Consent X FBR Informed Consent (depending on the situation) X Genomics Informed Consent (depending on the situation) X Medical History ³ X Previous medication ⁴ X Demographic Information X height X Hepatitis B and C testing X Meningococcal vaccination/ ^{revaccination5} ＜------- X ------＞ Pneumococcal and Haemophilus influenzae type B vaccinations (if necessary) ⁶ ＜------- X ------＞ Tuberculosis history and ^assessment7 X Gonorrhea Risk ^Assessment8 X Random grouping X treatment: IVRS/IWRS X X X X X X X X X X X X Ravelizumab group Ravelizumab IV Q8W ¹⁰ X X X X X ³⁰ Pazelimab and Cemdisiran treatment group ¹¹ Pazelimab 30 mg/kg IV loading dose X ¹² Pazelimab 400 mg SC Q4W ¹² X ¹² X X X X X X ³¹ Cemdisiran 200 mg SC Q4W ¹² X X X X X X X ³¹ Injection training/patient ^{instruction12} X X X X X X Patient diary ¹³ X X X X X X X X X Concomitant medication and surgery X X X X X X X X X X X X X Transfer record update X X X X Xrecent X X X X X X X X Antibiotic prophylaxis (recommended) ¹⁴ ＜---------------------------------X---------------------------------＞ Clinical Outcome Assessment (COA) : FACIT-Fatigue X X X X X X X X X EORTC-QLQ-C30 X X X X X X X X X EQ-5D-5L X X TSQM X X X X X X X X PNH symptom-specific questionnaire (daily) ¹⁵ ＜---------------------------X-------------------------------------＞ PGIS (PNH symptoms/effects/fatigue) X X X X X X X X X PGIC (PNH symptoms/effects/fatigue) X X X X Safety and human body measurements: Ravelizumab group only: provide patients with Ravelizumab safety leaflet X Meningococcal Patient Safety Card ⁹ X X X X X X X X X X X Weight X X X X X X X X X X X X Vital Signs ¹⁶ X X X X X X X X X X X X Physical ^{Examination17} X X X X X Electrocardiogram X X X Adverse Events X X X X X X X X X X X X X Breakthrough hemolysis ^assessment18 X X X X X X X X X X X X X Laboratory Test ¹⁹ : Measure meningococcal titer (only if required by local practice/regulations) X Hematology ²⁰ X X X X X X X X X X X Coagulation parameters X X X X X X X X X X X X Blood chemistry (long panel), including LDH ²¹ X X X X X X X X X X X X D-Dimer X X X X IgG X X X Pregnancy test (for applicable patients): serum (S) or urine (U) S U U U U U U U U Urinalysis X X X X X X X X X X Direct antiglobulin test (DAT or Coombs test) X X X Pharmacokinetics, ADA and Total C5 Sampling: Pazelimumab and Cemdisiran Group Pazelizumab PK sample ²² X X X X X X X X Cemdisiran and its metabolites PK sample ²³ X X X Pazelimab ADA sample ²⁵ X X X Cemdisiran ADA Sample ²⁵ X X X Total C5 (plasma) ²⁷ X X X X X X X X X Ravelizumab group Ravelizumab PK ²⁴ X X X X X X X X X Pazelimab ADA sample ²⁵ X ²⁶ Cemdisiran ADA Sample ²⁵ X ²⁶ Total C5 (plasma) ²⁷ X X X X X X X X X Biomarkers: Free heme ²⁷ X X ²⁸ X X X X X X Heme-binding protein ²⁷ X ²⁸ X X X X X X Complement hemolysis analysis (serum CH50 and AH50) ²⁷ X ²⁸ X X X X X X X X X sC5b-9 (plasma) ²⁷ X ²⁸ X X X X X X X X X PNH erythrocyte ²⁷ X X X PNH granules and single core spheres ²⁷ X X X Exploratory study serum samples ²⁷ X ²⁸ X X X X Exploratory study plasma samples ²⁷ X ²⁸ X X X X Selective Pharmacogenomics (RNA & DNA) Whole blood samples for DNA isolation (optional) ²⁹ X Whole blood samples for RNA isolation (optional) X X X Footnotes 1. Study procedure visits on Days 15, 71, 113, 127, 141, and 169 may be at the clinical site or another preferred location (such as the patient's home). The location will depend on the availability of the home healthcare visiting professional (if approved by the Sponsor) and the preference of the investigator and the patient. Visits may also be conducted at another preferred location based on extenuating circumstances (e.g., due to SARS-CoV-2 infection), provided that they can be evaluated by the visiting healthcare professional. 2. When multiple procedures are performed on the same day, the order of procedures will be as follows: COA assessment; ECG/vital signs/physical examination; blood collection (coagulation blood draw first, followed by chemistry blood draw, followed by all other labs); and study treatment administration. It is particularly important that a planned blood draw be performed prior to administration of Ravelizumab or Pasqualizumab and Cemdisiran, especially for efficacy parameters such as LDH (i.e., a measure that reflects the time point at which the dosing interval ends). During blood sample collection, handling, and processing, the same methodology will be applied across study visits whenever possible to maintain sample quality and avoid hemolysis during sample processing. Repeating laboratory samples should be considered if clinically indicated if the investigator or sponsor suspects that the laboratory results do not accurately reflect the patient's condition and if LDH ≧2 × ULN plus potassium ≧6 mmol/L. Specific instructions for avoiding hemolysis are provided in the relevant paragraphs of the protocol. 3. If possible, a medical history should be obtained for the past 52 weeks including transfusions, history of breakthrough hemolysis, and laboratory parameters used to measure hemolysis (such as LDH, bilirubin, heme-binding protein, reticulocyte count, and hemoglobin). History of past thrombosis and Neisseria infection will be collected. Patients with a known C5 mutation (i.e., C5 variant R885H/C) are not eligible, but if a C5 mutation is suspected and confirmed during the study, this information should be included as part of the patient's medical history. Patients who have an inadequate response to ravlizumab treatment during the study may be asked to undergo mutation analysis as part of the study if the patient consents to testing. 4. Include a detailed history of medications used to treat PNH, vaccination history with meningococcal vaccines, and other vaccinations (if applicable). 5. Patients will need to be vaccinated with meningococcal vaccine unless documentation is provided of previous immunization within the past 5 years, or less than 5 years if vaccinated with complement inhibitors as per current national vaccination guidelines/local Ravelizumab prescribing information. For patients who need to be vaccinated with meningococcal vaccine during the screening period/period, it should ideally be administered at least 2 weeks prior to Day 1 or at other time points as per local Ravelizumab prescribing information/national guidelines. 6. Pneumococcal and Haemophilus influenzae type B vaccines should be administered as per current national/local vaccination guidelines. 7. Screening may be performed by tuberculin skin test or T-cell interferon gamma release assay at the investigator’s discretion as per local practice or guidelines. 8. Risk factor assessment for gonorrhea will be performed according to local practice/national guidelines, and high-risk patients will be advised to undergo regular testing and counseling. 9. Patients will be provided with a Patient Safety Card for Meningococcal Infection on Day 1 or any other visit, if needed. Sites should review the instructions on the safety card with patients at each visit. 10. Patients randomized to revlizumab will receive revlizumab on Day 1 (or up to 2 days after the Day 1 visit) according to the labeled dosing of the first dose of revlizumab, which is based on patient weight (≧40 kg to <60 kg, 2400 mg IV; ≧60 kg to <100 kg, 2700 mg IV; ≧100 kg, 3000 mg IV). The first maintenance dose should be administered 2 weeks after the loading dose as follows: (≥40 kg to <60 kg, 3000 mg IV; ≥60 kg to <100 kg, 3300 mg IV; ≥100 kg, 3600 mg IV). Thereafter, maintenance doses should be administered IV Q8W (±7 days). Because the first maintenance dose is administered 2 weeks after the loading dose, the Week 2 visit should be conducted within the visit window, on or before the day of the Ravelizumab dose. If Ravelizumab dosing does not coincide with the clinic visit date (if applicable), the clinic visit should always be administered prior to the Ravelizumab infusion, assuming that both treatment and visit windows are adhered to. Body weight should be measured prior to administration of revlizumab so that dosing can be based on weight. Patients who choose not to participate in the follow-on OLE study or who are not screened for the R3918-PNH-2022 study will receive the final dose of revlizumab at Week 18 (Day 127). 11. Patients randomized to the pazelimab and cemdisiran combination group will receive pazelimab 30 mg/kg IV plus pazelimab 400 mg SC and cemdisiran 200 mg SC on Day 1. Patients should be monitored for at least 30 minutes after completion of pazelimab 30 mg/kg IV and should be monitored for at least an additional 30 minutes after completion of the first pazelimab and cemdisiran SC dose. Subsequent SC doses of the combination will be administered Q4W and may be administered by site personnel or another healthcare professional, if available, in the patient's home or by the patient or a designee at the patient's preferred location. The last dose of the SC combination in the OLTP will be at Week 24. Pazelimumab and Cemdisiran doses should be administered Q4W (every 28 days) whenever possible and on the day of the corresponding study visit, if possible. Study treatment administration should always be the last procedure after all blood samples have been collected and study assessments have been completed. If Pazelimumab or Cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 7 days before or up to 7 days after the scheduled dosing date, as long as administration occurs after the corresponding study visit has been completed. For example, depending on the visit coverage, the Week 8 (Day 57) visit could be conducted on Days 54 to 60. Therefore, doses of Pazelimumab and Cemdisiran could be given on Days 54 to 64, but only if or after the Week 8 visit assessment has been performed. Similarly, depending on the visit coverage, the Week 16 (Day 113) visit could be conducted on Days 106 to 120. Doses of Pazelimumab and Cemdisiran could be given on Days 106 to 120, but only if or after the Week 16 visit assessment has been performed. Pazelimumab and Cemdisiran should be administered on the same day if possible. 12. If the Sponsor agrees to self-injection, injection training will be provided to patients who wish to self-inject or have a designated person inject them. The site should observe the patient's syringe preparation and self-injection or injection by a designated person and confirm adequacy. Patient instruction materials will be provided (or reviewed as needed). 13. Patient Log: If necessary, for self-administration or designated person administration of paslimumab and cemdisiran combination treatment only, a patient log may be provided to collect information about study treatment administration. The patient log may be provided at the Week 4 visit or subsequent visits. If the patient log is provided to the patient, it should be reviewed at each clinic visit and data collected on the Case Report Form (CRF). The log should be collected by the site at the last visit. 14. Daily oral antibiotic prophylaxis against meningococcal disease is recommended, starting on the first day of study treatment administration and continuing until 52 weeks after discontinuation of pasirizumab and cemdisiran. Follow local prescribing information/national guidelines/local practice regarding post-treatment prophylaxis with ravulizumab. If meningococcal vaccination was given less than 2 weeks prior to Day 1, patients must receive antibiotic prophylaxis for at least 2 weeks from the date of vaccination. 15. Patients will complete a PNH symptom-specific questionnaire daily for 14 days prior to the Day 1 visit and continuing through the OLTP. 16. Vital signs include temperature, sitting blood pressure, and pulse. If applicable, pre-dose vital signs will be obtained after the patient has been seated for at least approximately 5 minutes. 17. The physical examination will include an assessment of the head and neck, lungs, heart, abdomen, extremities, and skin. Any possible abnormalities indicated by the patient's medical history should be carefully examined and evaluated. 18. If a breakthrough hemolytic event is suspected in a patient, in addition to the required laboratory collections, CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, drug concentrations of Paselimab/Revlizumab/Cemdisiran, ADA (for Paselimab), and additional samples of exploratory study serum and plasma will be collected unless noted in the event timeline for that visit. If the suspected event does not occur at a scheduled visit, a planned outpatient visit should be conducted, the patient should be evaluated, and CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, drug concentrations for Ravelizumab/Paselimab/Cemdisiran, and ADA (for Paselimab) should be collected. In addition, exploratory study serum and plasma samples should be collected. 19. Clinical laboratory samples will be collected prior to study drug administration. Coagulation blood samples must always be collected first, followed by blood chemistry samples. The same methodology will be applied across study visits whenever possible to maintain sample quality and avoid hemolysis during sample processing. 20. Hemoglobin will be assessed as part of the hematology analysis. Hematology samples should be collected prior to study treatment administration. 21. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. Blood chemistry samples should be collected prior to study treatment administration. 22. Blood samples for pazelimab PK will be obtained on designated days prior to pazelimab administration. On Study Visit Day 1, blood samples will be obtained prior to IV administration of pazelimab and within 15 minutes after the end of the pazelimab IV infusion. 23. Cemdisiran and its metabolite PK samples will be collected prior to cemdisiran administration and 1 to 4 hours after administration on designated days. Post-dose samples may be collected in the clinic or by a visiting healthcare professional, if available. 24. Blood samples for raflizumab PK will be obtained prior to IV administration of raflizumab and within 15 minutes after the end of the raflizumab IV infusion. 25. Blood samples for ADA will be obtained prior to any study drug administration on designated days. In the event of a suspected SAE (e.g., allergic reaction or anaphylaxis), additional blood samples for PK, ADA, and other analyses may be collected at or near the time of the event. 26. Blood samples will be collected prior to dosing to assess ADA for paszelimab and cemdisiran for patients randomized to the combination arm and for patients in the ravelizumab arm who will continue the transition phase. 27. Blood samples for total C5, free heme, heme phenotype, CH50, AH50, sC5b-9, and PNH erythrocytes, granulocytes, monocytes, and exploratory study serum and plasma will be obtained prior to dosing of ravelizumab or combination on designated days. 28. All biomarkers specifically collected on V3/Day 1 must be collected prior to dosing. 29. Whole blood samples for DNA extraction (as appropriate) should be collected on Day 1 (pre-dose), but may also be collected at later study visits. 30. Patients will be dosed with Revulizumab at Week 26 only if they intend to continue on OLE or R3918-PNH-2022. Patients who do not continue on the paszepine/cemdisiran combination on subsequent studies will not receive a dose of Revulizumab at EOS. 31. For patients planning to participate in the OLE, Day 1 of the R3918-PNH-2050 study must be scheduled 4 weeks after the Week 24 dose of the combination therapy (i.e., 2 weeks after the Week 26 EOS visit in the R3918-PNH-2021 study) to ensure that treatment dosing is not interrupted. Table 7-2. Event schedule for the conversion period ( patients who complete ravulizumab in the OLTP and plan to participate in the OLE ) Research Procedure ( Interview ) ¹ Conversion period ( only patients who completed OLTP of ravulizumab and planned to enter OLE ) ² Visit # ( 4 weeks after last dose of Ravelizumab at OLTP week 26 ) TV1 TV2 Weeks (after last dose of Ravelizumab at OLTP week 26) 4t 8t sky 29t 57t Range (days) ±2 ±2 Baseline Meningococcal Patient Safety Card ³ X X treatment: IVRS/IWRS X X Ravelizumab group Pazelimab 60 mg/kg was administered ^{4, 6} X Pazelimumab 400 mg SC ^{5, 6} X Cemdisiran 200 mg SC ^{5, 6} X X Concomitant medication and surgery X X Transfer record update X X Antibiotic prophylaxis (recommended) ⁶ X X Safety and human body measurements: Weight X X Vital signs X X Adverse Events X X Breakthrough Hemolysis ^Evaluation7 X X Laboratory Test ⁸ : Hematology ⁹ X X Coagulation parameters X X Blood chemistry (long panel), including LDH ¹⁰ X X Pregnancy test (for applicable patients): Urine (U) U U Urinalysis X X Pharmacokinetics and Total C5 Sampling: Pazelimumab PK sample ¹¹ X Ravelizumab PK samples X Total C5 (plasma) X ¹² Biomarkers: CH50 X X ¹² Footnote 1. When multiple procedures are performed on the same day, the order of procedures is as follows: vital signs, blood draw (coagulation draw performed first, followed by chemistry draw, followed by all other laboratories), and study drug administration. It is particularly important to obtain scheduled blood draws prior to administration of Ravelizumab or Pasqualizumab and Cemdisiran, especially for efficacy parameters such as LDH (i.e., a measure of the time point reflecting the end of the dosing interval). During blood sample collection, handling, and processing, the same methodology will be applied across study visits to the extent possible to maintain sample quality and avoid hemolysis during sample processing. If the investigator or sponsor suspects that the laboratory results do not accurately reflect the patient's condition and LDH ≧ 2 × ULN plus potassium ≧ 6 mmol/L, consideration should be given to repeating the laboratory sample if clinically necessary. Specific instructions for avoiding hemolysis are provided. 2. Patients randomized to the ravulizumab group and completing the 26-week OLTP: If enrollment in R3918-PNH-2022 is open and the patient has been screened but is not eligible for the R3918-PNH-2022 study, the patient can continue in the OLE study after completing the conversion period. If enrollment in R3918-PNH-2022 is no longer open, or the patient is not interested in participating in R3918-PNH-2022 but is interested in participating in the OLE study, the patient can enter the conversion period directly. 3. Provide patients with a Meningococcal Infection Patient Safety Card at each visit, if needed. Sites should review the instructions on the safety card with patients at each visit. 4. Patients randomized to Ravelizumab who complete the 26-week OLTP and are scheduled to participate in the OLE study will be switched from Ravelizumab to combination therapy as follows: The final Ravelizumab maintenance dose (per the labeled weight-based dosing algorithm) will be administered IV at the EOS visit at Week 26 of the OLTP. Patients will receive Cemdisiran 200 mg SC at Week 4t, followed by Paselimab 60 mg/kg IV with Paselimab 400 mg SC and Cemdisiran 200 mg SC at Week 8t. 5. All study treatments (i.e., pazelimumab, cemdisiran, and ravlizumab) should be administered as the last procedure, after all blood samples have been collected and study assessments have been completed. Patients should be monitored for at least 30 minutes after completion of pazelimab 60 mg/kg IV administration. Patients should be monitored for at least 30 minutes after completion of the first pazelimab SC dose and the first cemdisiran SC dose. 6. Daily oral antibiotic prophylaxis against meningococcal disease is recommended, starting on the first day of study treatment administration and continuing until 52 weeks after discontinuation of pazelimumab and cemdisiran. Refer to Local Prescribing Information/National Guidelines/Local Practice for post-treatment prophylaxis with ravlizumab. 7. If a patient is suspected of having a breakthrough hemolytic event, in addition to the required laboratory collections, CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, drug concentrations of paselumab, ravulizumab, and cemdisiran, ADA (for paselumab), and additional samples of exploratory study serum and plasma will be collected unless otherwise noted in the event schedule for that visit. If the suspected event does not occur at the scheduled visit, a planned outpatient visit should be conducted, the patient should be evaluated and CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, drug concentrations for Ravelizumab/Paselimab/Cemdisiran, and ADA (for Paselimab) should be collected. In addition, exploratory study serum and plasma samples should be collected. 8. Clinical laboratory samples will be collected prior to study drug administration. The same methodology will be applied at study visits whenever possible to maintain sample quality and avoid hemolysis during sample processing. 9. Hemoglobin will be assessed as part of the hematology analysis. Hematology samples should be collected prior to study treatment administration. 10. Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. Blood chemistry samples should be collected prior to study treatment administration. 11. Blood samples for pazelimumab PK will be obtained prior to pazelimumab IV administration and within 15 minutes after the end of pazelimumab IV infusion. 12. All biomarkers and total C5 collected exclusively at TV2 must be collected prior to dosing.

FUP was used for patients who discontinued treatment for any reason, including patients who completed OLTP but refused to participate in the next study.

Patients in the ravulizumab group who complete OLTP (i.e., last dose of study drug at Week 18 and EOS at Week 26) will enter FUP at Visit FU-3 (i.e., 12 weeks after last dose of study drug).

Patients in the paslimab/cemdisiran group who complete the OLTP (i.e., last dose of study drug at Week 24 and EOS at Week 26) will enter the FUP at Visit FU-1 (i.e., 4 weeks after the last dose of study drug).

For patients who discontinue and do not complete OLTP, they will receive an ET visit. Thereafter, their entry point into FUP will depend on the number of weeks that have passed since receiving their last dose of study treatment. Table 7-3. Timeline of events during the safety off-treatment follow-up period Visit FU-1 FU-2 FU-3 FU-4 FU-5 Telephone interview FU-6 Telephone interview FU-7 Weeks (after last dose of study drug) 4 8 12 16 26 38 52 Range (days) ±10 ±10 ±10 ±10 ±10 ±10 ±10 Weight X X X X X Vital signs X X X X X Physical examination X X Concomitant medication/treatment X X X X X X X Adverse Event Reporting X X X X X X X Pregnancy Report X X X X X X X Antibiotic prophylaxis (recommended) ¹ ＜-------------------------------------X---------------------------------------＞ Meningococcal Patient Safety Card ² X X X X X X X Laboratory testing Hematology X X X X X Blood chemistry X X X X X Monthly urine pregnancy test (WOCBP) ³ ＜-------------------------------------X---------------------------------------＞ Pharmacokinetics, ADA , and Total C5 Sampling: Pazelimab PK samples X ADA samples of Pazelimumab X ADA Sample of Cemdisiran X Total C5 (plasma) X Footnotes 1. Antibiotic Prophylaxis (Recommended): Daily oral antibiotic prophylaxis for meningococcal disease is recommended and continued for up to 52 weeks after discontinuation of pasirizumab and cemdisiran. Follow local prescribing information/national guidelines/local practice for post-treatment prophylaxis with ravulizumab. 2. Patient Safety Card for Meningococcal Disease: Provide patients with a Patient Safety Card for Meningococcal Infection at FU-1 or any other visit (if indicated). Sites should review the instructions on the safety card with patients at each visit. 3. Pregnancy Testing: Perform urine pregnancy tests monthly for WOCBP only. If performed by home test kit, patients should be reminded to call investigators monthly to inform them of their pregnancy test results and to call investigators as soon as possible if the pregnancy test result is positive.

The study population will include adult male and female patients with confirmed PNH with active signs and symptoms and evidence of hemolysis who are either naive or have not recently been treated with a complement inhibitor. The treatment allocation method and stratification factors are described:

Patients will be randomized in a 1:1 ratio to treatment with a combination of SC paszelimab 400 mg and cemdisiran 200 mg Q4W or IV ravulizumab using an Interactive Web Response System (IWRS) with a labeled weight-based dosing algorithm. Stratified, block randomization will be performed using the following stratification factors: • RBC/whole blood transfusion within the past 1 year before randomization (yes/no) Note: Enrollment of patients who have not had an RBC transfusion within the past 1 year before randomization is capped at 20% of the total enrollment population. • Screening visit LDH level (2.0 to <4.0 × ULN or ≧4.0 × ULN)

The randomization segment will be conducted collectively. Note: The upper limit of enrollment for patients who have not had RBC transfusion in the past year before Day 1 is 20% of the total enrollment population. Inclusion Criteria

Patients must meet the following criteria to be eligible for inclusion in the study. 1. Male or female aged ≥18 years or legal age of majority (whichever is older) at the time of consent 2. PNH confirmed by high-sensitivity flow cytometry at the screening visit, with PNH granulocytes (i.e., polymorphonuclear neutrophils [PMNs]) or monocytes ≥5% 3. Active disease within 3 months of the screening visit, defined as the presence of 1 or more PNH-related signs or symptoms (e.g., fatigue, hemoglobinuria, abdominal pain, shortness of breath [dyspnea], anemia [hemoglobin < 10 g/dL], history of MAVE [including thrombosis], dysphagia, or erectile dysfunction) or experience of RBC transfusion due to PNH 4. LDH level ≥2 × ULN 5. Willing and able to comply with clinical/remote visits and study-related procedures 6. Provide signed informed consent from study patients 7. Able to understand study-related questionnaires Exclusion criteria Note: If a patient fails screening, and the study is ongoing, and the investigator determines that the patient may be eligible after rescreening, the screener may be rescreened (up to 2 times).

Patients who meet any of the following criteria will be excluded from the study: 1. Previous treatment with eculizumab within 3 months before screening, with ravulizumab within 6 months before screening, or with other complement inhibitors within 5 half-lives of the respective agent before screening. 2. Previous organ transplant, bone marrow transplant, or other hematological transplant. 3. Body weight < 40 kg at the screening visit. 4. Current medication plan for adjustment (start, discontinue, or change dose/dosing interval) of the following background concomitant medications (if applicable) during the screening and treatment periods: erythropoietin, immunosuppressive drugs, corticosteroids, antithrombotics, anticoagulants, iron supplements, and folic acid. 5. Planned use of any complement inhibitor treatment other than study drug during the treatment period. 6. Any of the following abnormalities at the screening visit (each parameter is allowed to be measured twice during the screening period): a. Peripheral blood absolute neutrophil count (ANC) <500/μL (<0.5 × 10 ⁹ /L) or b. Peripheral blood platelet count <30,000/μL or c. Peripheral blood reticulocyte count abnormal, defined as <60,000/μL (<0.06 × 10 ⁶ /μL, <60 × 10 ⁹ /L) Note: If the parameter no longer meets the exclusion criteria after repeated testing, the patient will not be excluded. Note: Patients receiving acute treatment for these conditions (e.g., platelet transfusions, granulocyte colony stimulating factors) during the screening period and within 1 month prior to screening will not be eligible. 7. Not eligible for meningococcal vaccination requirement for ravulizumab based on current local prescribing information (if any) and no documented meningococcal vaccination within 5 years prior to the screening visit at least. Note: Patients will be eligible if they are willing to receive vaccinations prior to starting study treatment and have vaccinations documented prior to randomization. 8. Any contraindications to receiving meningococcal vaccination. 9. Inability to take antibiotics to prevent meningococcal disease (if required by local ravelizumab prescribing information (if applicable) or national guidelines/local practice, or if required for vaccination less than 2 weeks from the start of study treatment). 10. Any active ongoing infection or recent infection requiring continued systemic treatment with antibiotics, antivirals, or antifungals within 2 weeks of screening or during the screening period. 11. Documented history of systemic fungal disease or unresolved tuberculosis, or evidence of active or latent tuberculosis infection (LTBI) during the screening period (i.e., if LTBI treatment was not completed). Assessment of active TB and LTBI should be consistent with local practice or guidelines, including those related to risk assessment and the use of tuberculin skin testing or T-cell interferon gamma release assays. 12. Positive hepatitis B surface antigen or hepatitis C virus RNA during screening. Note: Cases with unclear interpretation should be discussed with the medical supervisor. 13. Patients known to have HIV with a history of opportunistic infection within the past 1 year, any history of HIV-related malignancy, a documented CD4 count <500 cells/μL or a history of detectable viral load within the past 6 months (Note: CD4 count and viral load must be available within the past 6 months and can be performed by a local laboratory during the screening period if necessary) Note: Patients can be tested for local HIV if required by local requirements or local regulations. 14. Documented history of a positive* RT-PCR, antigen or serology test, or other health authority authorized test for SARS-CoV-2, and: a. Have not recovered from COVID-19 (i.e., all COVID-19 related symptoms and major clinical findings that could impact patient safety should resolve to baseline), and b. Have not had 2 negative results on a health authority authorized nucleic acid amplification (RT-PCR) test or other health authority authorized test for COVID-19 at least 48 hours apart prior to Day 1. Note: COVID-19 screening will not be performed as part of the eligibility assessment for this study 15. Known genetic complement deficiency. 16. Documented active, uncontrolled, persistent systemic autoimmune disease. 17. Patients with a documented history of cirrhosis or liver disease with evidence of current compromised liver function, or patients with ALT or AST (not related to PNH or its complications) greater than 3 × ULN at the screening visit (if AST or ALT returns to > 3 × ULN, 1 repeat laboratory assessment of abnormal parameters is allowed during the screening period). 18. Patients with eGFR < 30 mL/min/ ^1.73m2 (based on the Chronic Kidney Disease-Epidemiology Collaboration 2009 [CKD-EPI]) at the screening visit (one repeat assessment is allowed during the screening period). 19. Any recent unstable medical condition within the past 3 months before the screening visit, excluding PNH and PNH-related complications (e.g., myocardial infarction, New York Heart Association ≥ Grade III or IV congestive heart failure, severe uncontrolled arrhythmia, cerebrovascular accident, active gastrointestinal bleeding). 20. Any major surgery is expected during the study period. 21. Any history of cancer within the past 5 years, excluding adequately treated basal cell carcinoma, squamous cell carcinoma, or cervical carcinoma in situ. 22. Participation in another interventional clinical study or use of any experimental treatment within 30 days prior to the screening visit or within 5 half-lives of the investigational product (whichever is longer), except for complement inhibitors. 23. Known allergy to any component of Eculizumab, Ravelizumab, Paserizumab, Cemdisiran or their respective formulations. 24. Previous discontinuation of Eculizumab or Ravelizumab for safety reasons or due to lack of efficacy. 25. Patients with functional or anatomical asplenia. 26. Any clinically significant abnormality confirmed at screening that, in the judgment of the investigator, will prevent the safe completion of the study or limit the assessment of the evaluation indicators, such as patients with major systemic diseases or short expected life expectancy. 27. Patients who, for any reason, are considered unsuitable for the study by the Investigator or any Sub-Investigator, e.g. a. are considered unable to meet specific protocol requirements, such as scheduled visits. b. are considered unable to perform or tolerate chronic injections. c. any other actual or anticipated circumstances (e.g. geographical, social) that the Investigator considers would restrict or limit the patient's participation for the duration of the study. d. are members of a vulnerable group, such as institutionalized persons (this may also include patients who have been institutionalized pursuant to an order issued by a judicial or administrative authority, if applicable). e. are ineligible to participate in clinical trials due to local regulations (e.g., under legal protection measures [e.g., L1121-8 or L1121-8-1 in France], etc.). 28. Clinical site research team members and/or their immediate family members, unless approved in advance by the sponsor. 29. Pregnant or breastfeeding women. 30. Women of childbearing potential (WOCBP)* who are unwilling to take highly effective contraceptive measures before the initial dose/first treatment, during the study, and for at least 52 weeks after the last dose. Highly effective contraceptive measures include: a. Stable use of combined (estrogen and progestin) hormonal contraceptives (oral, vaginal, transdermal) or progestin-only hormonal contraceptives (oral, injectable, implantable) to suppress ovulation starting 2 or more menstrual cycles before screening; b. Intrauterine contraceptive device (IUD); intrauterine hormone-releasing system (IUS); c. Bilateral tubal ligation or tubal occlusion; d. Vasectomy partner (provided that the vasectomized male partner is the only sexual partner of the WOCBP study participant and the vasectomized partner has received a medical evaluation of the success of the surgery); and/or e. Abstinence , *WOCBP is defined as a woman of childbearing potential from postmenarche to postmenopause, unless infertility is permanent. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. Postmenopausal status is defined as the absence of menstruation for 12 months without other medical reasons. High levels of follicle-stimulating hormone (FSH) in the postmenopausal range can be used to confirm the postmenopausal state in women who are not using hormonal contraception or hormone replacement therapy. However, a single FSH measurement is not sufficient to confirm the occurrence of postmenopausal status in the absence of 12 months of amenorrhea. The above definition is based on the Clinical Trials Facilitation Group (CTFG) guidelines. Pregnancy testing and contraception are required for WOCBP. Pregnancy testing and contraception are not required for women who are postmenopausal or permanently infertile. Abstinence is considered a highly effective approach only if it is defined as abstention from heterosexual intercourse during the entire period of risk associated with the study drug. The reliability of abstinence needs to be assessed based on the duration of the clinical trial and the preferences and usual lifestyle of the subjects. Periodic abstinence (calendar method, sign temperature method, postovulation method), intercourse interruption method (extracorporeal ejaculation method), spermicide-only use, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception. Female and male condoms should not be used simultaneously. 31. Hemoglobin ≤ 7 g/dL (Note: Patients may receive a transfusion during the screening period and are eligible if the hemoglobin returns to > 7 g/dL before randomization. Repeat measurements are allowed more than 2 times.) Primary Objective

The primary objective of the study was to evaluate the effects of pasizumab and cemdisiran combination therapy versus ravulizumab therapy on hemolysis and RBC translocation over a 26-week treatment period in patients with active PNH who were not receiving or had not recently received a complement inhibitor. Secondary Objectives

The secondary objectives of the study are to: • Evaluate the effects of combination therapy with Paselimab and Cemdisiran versus treatment with Ravelizumab on: . Measures of hemolysis . Translocation parameters . Hemoglobin levels . Fatigue assessed by Clinical Outcome Assessment (COA) . HRQoL assessed by COA . Safety and tolerability . Complement activation • Evaluate the concentrations of total Paselimab and total Ravelizumab in serum and Cemdisiran and total C5 protein in plasma • Evaluate the immunogenicity of Paselimab and Cemdisiran Exploratory Objectives

The exploratory objectives of the study were to investigate the effects of the combination of pasizumab and cemdisiran versus ravulizumab alone on: • Clinical thrombotic events • Renal function and renal damage biomarkers • Complement activation and hemolysis associated with PNH and other related diseases • PNH colony size • COAs measuring treatment satisfaction (TSQM), QoL (European Quality of Life Five Dimensions Five Levels [EQ-5D-5L] and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Items [EORTC-QLQ-C30]), and PNH-specific symptoms • Build a molecular understanding of PNH and related diseases and investigate mechanisms of action (including relationships to safety and efficacy) and complement pathway biology • Explore whether potential differences in patient efficacy and safety are associated with genotype and gene expression, and use selective whole blood DNA and RNA collected from consenting patients to further investigate C5, PNH, or other conditions associated with complement-mediated impairment Co-primary outcome measures

Co-primary outcomes were: •Percent change in LDH from baseline to Week 26 •Avoidance of transfusions from Day 1 to Week 26 (defined as no RBC transfusions required according to the protocol algorithm based on post-baseline hemoglobin values) Key secondary outcomes

Key secondary outcomes were: • Maintenance of adequate control of hemolysis, defined as LDH ≦1.5 × ULN from Week 8 to Week 36 (inclusive) • Breakthrough hemolysis from Day 1 post-baseline to Week 26 (defined as LDH ≧2 × ULN [after initially achieving LDH ≦1.5 × ULN] with signs or symptoms associated with hemolysis) • Adequate control of hemolysis (defined as LDH ≦1.5 × ULN) from Week 8 to Week 26 (inclusive) • Hemoglobin stability from Day 1 (post-baseline) to Week 26 (defined as patients who did not receive RBC transfusion and whose hemoglobin did not decrease by ≧2 g/dL from baseline) • From Week 8 to Week 26 (inclusive) LDH normalized (defined as LDH ≦1.0 × ULN) • Change in fatigue measured by FACIT-Fatigue scale from baseline to week 26 • Change in PF score of EORTC-QLQ-C30 from baseline to week 26 • Change in Global Health Status (GHS)/QoL scale score of EORTC-QLQ-C30 from baseline to week 26 Other secondary assessment indicators

Other secondary outcomes were: • RBC translocation rate and number of units per protocol algorithm from day 1 to week 26 after baseline • Time to first LDH ≦1.5 × ULN and ≦1.0 × ULN • Percentage of days with LDH ≦1.5 × ULN from week 8 to week 26 (inclusive) • Change in hemoglobin from baseline to week 26 • Incidence and severity of treatment-emergent serious AEs, special treatment-emergent adverse events (TEAEs), and TEAEs leading to treatment discontinuation within 26 weeks • Change and percentage change in total CH50 from baseline to week 26 • Total C5 concentration in plasma assessed throughout the study • Total pasorizumab concentrations in serum assessed throughout the study • Cemdisiran concentrations in plasma assessed throughout the study • Total ravlizumab concentrations in serum assessed throughout the study • Incidence of treatment-emergent anti-drug antibodies (ADA) to pasorizumab assessed throughout the study • Incidence of treatment-emergent ADA to cemdisiran assessed in the study Exploratory measures

Exploratory assessments were: • The incidence of MAVEs from day 1 to week 26 (defined as adverse events of special interest [AESI], including thrombophlebitis/deep venous thrombosis, pulmonary embolism, myocardial infarction, unstable angina, renal venous or arterial thrombosis, acute peripheral vascular occlusion, hepatic venous thrombosis, portal vein thrombosis, enterovenous/visceral venous thrombosis or infarction, enterovenous/visceral arterial thrombosis or infarction, transient ischemic attack, cerebral arterial occlusion/cerebrovascular accident, cerebral venous occlusion, gangrene [non-traumatic; non-diabetic], and amputation [non-traumatic; non-diabetic]); •Breakthrough hemolysis rate from day 1 after baseline to week 26 •Change in renal function measured by estimated glomerular filtration rate (eGFR) from baseline to week 26 •Percent change in free hemoglobin from baseline to week 26 •Change in heme-binding protein from baseline to week 26 •Change in total bilirubin from baseline to week 26 •Change in reticulocyte count from baseline to week 26 •Change and percentage change in alternative pathway hemolytic activity assay (AH50) from baseline to week 26 •Change in PNH erythrocytes, granulocytes, and monocytes from baseline to week 26 • Comparison of treatment satisfaction (assessed by TSQM) at baseline and at week 26 • Changes in EQ-5D-5L scores from baseline to week 26 • Changes in PNH symptoms measured by the PNH symptom-specific questionnaire from baseline to week 26 • Changes in the functional scale scores (role functioning, emotional functioning, cognitive functioning, and social functioning) and symptom scale scores (fatigue, nausea and vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea) of the EORTC QLQ-C30 from baseline to week 26 • Improvements in GHS, function, and symptoms measured by the EORTC QLQ-C30 from baseline to week 26 • Improvements in the PNH symptoms measured by the EORTC-QLQ-C30 from baseline to week 26 Time to first clinically significant improvement in HRQoL and symptoms as measured by the GHS Functional and Symptom Scales Laboratory variability used to assess treatment efficacy

The efficacy of this study was assessed by the following laboratory assessments: •LDH (serum): LDH is a measure of intravascular hemolysis and can objectively and accurately measure the control of intravascular hemolysis. •Hemoglobin: Hemolytic anemia is a marker of PNH

These laboratory variants have been implicated in the characterization and disease mechanisms of PNH (Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood 2014; 124(18):2804-2811). Transfer Records

Hemolytic anemia is the clinical manifestation of PNH, and patients usually require blood transfusions for symptomatic treatment. Transfusion frequency has been used to assess efficacy in other studies of PNH (Hillmen P, Muus P, Dührsen U, Risitano AM, Schubert J, Luzzatto L, et al. Effect of the complement inhibitor Eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007; 110(12):4123-4128) (Röth A, Egyed M, Ichikawa S, Kim JS, Nagy Z, Gaàl Weisinger J, et al. The SMART Anti-hC5 Antibody (SKY59/RO7112689) Shows Good Safety and Efficacy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). Blood 2018; 132(Suppl 1):535.). Clinical Outcome Assessments

COA includes the following: •FACIT-Fatigue •EORTC-QLQ C30 •TSQM •EQ-5D-5L •PNH symptom-specific questionnaire Safety variability and anthropometric variability

Safety and anthropometric variables in this study included: • Meningococcal vaccination/revaccination, • Pneumococcal and Haemophilus influenzae type B vaccination (if indicated) • Concomitant medications and procedures • Height • Weight • Vital signs • Physical examination • Electrocardiogram (ECG) • AEs • Evaluation of breakthrough hemolysis • Routine safety laboratory tests (hematology, chemistry, coagulation parameters, direct antiglobulin test, urinalysis, and pregnancy test [for women of childbearing age or WOCBP]) Interim Results (Week 26)

Patients who received the combination therapy (which may be referred to as "pazelimab Q4W + cemdisiran" or "combo") demonstrated better hemolysis control, LDH normalization, and lack of breakthrough hemolysis compared to patients who received the ravulizumab monotherapy regimen alone ("ravulizumab").

Adequate control of hemolysis is defined as achieving LDH ≤1.5 × ULN (considered a clinically relevant threshold; ULN = upper limit of normal). Symptomatic patients with LDH >1.5 × ULN (LDH = lactate dehydrogenase) are typically started on pharmacological therapy. LDH ≤1.5 × ULN is associated with improved symptoms, QoL, and transfusions while receiving complement inhibitor (CI) therapy. Maintaining adequate control of hemolysis is defined as a sustained decrease in LDH ≤1.5 × ULN at all visits from Week 8 to Week 26 (inclusive) with no breakthrough hemolytic events. Normalization of LDH is defined as achieving LDH ≤1 × ULN. Breakthrough hemolysis is defined as an increase in LDH to ≥ 2 × ULN, plus signs or symptoms of hemolysis, after an initial LDH ≤ 1.5 × ULN has been achieved.

Twenty-two patients completed the treatment period (11 in each group), of whom 46 were randomized for analysis (Tables 7-4 and 7-5). Table 7-4. Participant Disposition During Open Label Treatment Period - Cohort A Analysis Set Pazelimab Q4W + Cemdisiran (N=24) Ravelizumab (N=22) Randomly assigned subjects 24 (100%) 22 (100%) Participants who completed the 26th week visit 11 (45.8%) 11 (50.0%) Table 7-5. Study Participation - Cohort A Analysis Set Pazelimab Q4W + Cemdisiran (N=24) Ravelizumab (N=22) Study participation time ( days) [1] n twenty four twenty two Mean (SD) 131.7 (67.42) 156.2 (73.51) Median 148.5 179.5 Q1 : Q3 76 : 190 103 : 211 Minimum value: Maximum value 1 : 208 16 : 243 Duration of study participation, n (%) [1] ＞= 1 day 24 (100%) 22 (100%) ＞= 4 weeks 22 (91.7%) 21 (95.5%) ＞= 8 weeks 20 (83.3%) 19 (86.4%) ＞= 16 weeks 15 (62.5%) 16 (72.7%) ＞= 20 weeks 14 (58.3%) 14 (63.6%) ＞= 24 weeks 11 (45.8%) 12 (54.5%) ＞= 26 weeks 11 (45.8%) 11 (50.0%) [1] The duration of the study was defined as: [date of last study exposure] - [date of first dose] + 1

The baseline characteristics of the two groups were generally similar (Table 7-6). Table 7-6. Baseline characteristics - Combo ( Pazerizumab Q4W + Cemdisiran) and Ravelimab, mid-term Pazelimab Q4W + Cemdisiran (n=24) Ravelizumab (n=22) Age ( mean, years) (SD) 46.7 (16.2) 41.1 (17.5) male% 50% 54.5% LDH , mean (xULN) (SD) 6.6 (3.1) 5.9 (3.6) Hemoglobin ( mean value, g/L) 84.6 87.9 PNH RBC strains, mean (SD) 34% (22.7) 34% (29.7) PNH mononuclear colonies, average 85% 84% PNH granulocytes, average 72% 73% Total bilirubin ( mean, umol/L) (SD) 31 (26.6) 30 (22.4) Reticulocytes ( mean, 10 ⁹ /L)* 210 (125.2) 172 (67.3) Transfers in the previous year ( % of patients , # of transfers) 75%, 6 73%, 6.5 AA/MDS^( % of patients , # of patients) 17%, 4 23%, 5 *Median reticulocyte count: 175 and 174 x 10 ⁹ /L ^1 respectively MDS patients in each group

Ninety-one percent of combo patients and 73% of ravulizumab patients maintained adequate control of hemolysis (LDH ≦ 1.5 × ULN) (Table 7-7). No patients (n=46) met the protocol criteria for breakthrough hemolysis. One patient receiving combo had a perturbation in LDH levels from Day 179 to Day 181 due to viral fever (LDH increased on Day 182, V13). Table 7-7. Patients who maintained adequate control of hemolysis - Analysis set of cohort A Pazelimab Q4W + Cemdisiran (n=24) Ravelizumab (n=22) Patient-responder who completed OLTP 10/11 (90.9%) 8/11 (72.7%) Patients still in progress in OLTP Non-responders 1/13 (7.69%) 1/11 (9.09%) Status to be determined 12/13 (92.3%) 10/11 (90.9%)

A higher proportion of Combo patients achieved adequate control of hemolysis (LDH ≦ 1.5 × ULN, per visit) compared to Ravelizumab patients. The LDH measurement results per visit for each patient are shown in Tables 7-8. LDH measurement results above the reference range are indicated by "(H)", while LDH measurement results below the reference range are indicated by "(L)".

The mean percent change from baseline in LDH in Combo patients and Ravelizumab patients are summarized graphically in Figure 35. Combo patients achieved a greater percent change from baseline to Week 26 and lower mean LDH compared to Ravelizumab patients. Baseline LDH for subjects who completed Week 26 was: Combo: 6.5 × ULN and Ravelizumab: 5.7 × ULN. The mean % change from baseline at Week 26 was: Comb: -83.8 and Ravelizumab: -78.5. Table 7-8. Clinical Laboratory Tests - LDH ( Full Analysis Set ) Subject ID Age / Gender Visit Reference range result Pazelimab q4w + Cemdisiran 158003102 39/F Screening interview 1 135 - 330 U/L 717(H) Interview 3 135 - 330 U/L 695(H) Interview 4 135 - 330 U/L 251 Interview 5 135 - 330 U/L 395(H) Interview 6 135 - 330 U/L 244 Interview 7 135 - 330 U/L 224 Interview 8 135 - 330 U/L 297 158007102 66/M Screening interview 1 135 - 281 U/L 2580(H) Interview 3 135 - 281 U/L 2520(H) Interview 4 135 - 281 U/L 597(H) Interview 5 135 - 281 U/L 456(H) Interview 6 135 - 281 U/L 500(H) Interview 7 135 - 281 U/L 515(H) Interview 8 135 - 281 U/L 664(H) Interview 9 135 - 281 U/L 434(H) Interview 10 135 - 281 U/L 457(H) 380003101 40/F Screening interview 1 135 - 330 U/L 1650(H) Interview 3 135 - 330 U/L 1695(H) Interview 4 135 - 330 U/L 327 Interview 5 135 - 330 U/L 291 Interview 6 135 - 330 U/L 307 410002101 65/F Screening interview 1 135 - 330 U/L 957(H) Interview 3 135 - 330 U/L 1010(H) Interview 4 135 - 330 U/L 298 Interview 5 135 - 330 U/L 266 Interview 6 135 - 330 U/L 260 Interview 7 135 - 330 U/L 248 Interview 8 135 - 330 U/L 255 Interview 9 135 - 330 U/L 259 Interview 10 135 - 330 U/L 250 Interview 11 135 - 330 U/L 282 Visit 12 135 - 330 U/L 283 Interview 13 135 - 330 U/L 280 410005102 61/M Screening interview 1 135 - 281 U/L 2565(H) Interview 3 135 - 281 U/L 3000(H) Interview 4 135 - 281 U/L 276 Interview 5 135 - 281 U/L 190 Interview 6 135 - 281 U/L 159 Interview 7 135 - 281 U/L 183 Interview 8 135 - 281 U/L 219 Interview 9 135 - 281 U/L 184 Interview 10 135 - 281 U/L 186 Interview 11 135 - 281 U/L 191 Visit 12 135 - 281 U/L 176 Interview 13 135 - 281 U/L 169 410005105 39/M Screening interview 1 135 - 281 U/L 1065(H) Interview 3 135 - 281 U/L 1165(H) Interview 4 135 - 281 U/L 250 Interview 5 135 - 281 U/L 158 Interview 6 135 - 281 U/L 167 410006101 36/F Screening interview 1 135 - 330 U/L 1544(H) Interview 3 135 - 330 U/L 1581(H) Interview 4 135 - 330 U/L 232 Interview 5 135 - 330 U/L 194 Interview 6 135 - 330 U/L 223 Interview 7 135 - 330 U/L 186 Interview 8 135 - 330 U/L 177 Interview 9 135 - 330 U/L 212 Interview 10 135 - 330 U/L 172 Interview 11 135 - 330 U/L 185 Visit 12 135 - 330 U/L 177 Interview 13 135 - 330 U/L 165 410007101 40/M Screening interview 1 135 - 281 U/L 1586(H) Interview 3 135 - 281 U/L 1485(H) Interview 4 135 - 281 U/L 280 Interview 5 135 - 281 U/L 202 Interview 6 135 - 281 U/L 217 Interview 6 135 - 281 U/L 216 Interview 7 135 - 281 U/L 229 Interview 8 135 - 281 U/L 200 Interview 9 135 - 281 U/L 198 Interview 10 135 - 281 U/L 200 Interview 11 135 - 281 U/L 202 Visit 12 135 - 281 U/L 233 Interview 13 135 - 281 U/L 230 410007102 58/M Screening interview 1 135 - 281 U/L 1845(H) Interview 3 135 - 281 U/L 3015(H) Interview 4 135 - 281 U/L 300(H) Interview 5 135 - 281 U/L 175 Interview 6 135 - 281 U/L 204 Interview 7 135 - 281 U/L 211 Interview 8 135 - 281 U/L 203 Interview 9 135 - 281 U/L 198 Interview 10 135 - 281 U/L 204 Interview 11 135 - 281 U/L 182 Visit 12 135 - 281 U/L 200 Interview 13 135 - 281 U/L 201 410008101 73/M Screening interview 1 135 - 281 U/L 949(H) Interview 3 135 - 281 U/L 699(H) Interview 4 135 - 281 U/L 279 Interview 5 135 - 281 U/L 274 Interview 6 135 - 281 U/L 232 Interview 7 135 - 281 U/L 273 Interview 8 135 - 281 U/L 331(H) Interview 8 135 - 281 U/L 392(H) Interview 9 135 - 281 U/L 278 Interview 10 135 - 281 U/L 273 Interview 11 135 - 281 U/L 305(H) Planned overseas visits 111.01 135 - 281 U/L 250 Visit 12 135 - 281 U/L 280 Interview 13 135 - 281 U/L 239 458001101 44/M Screening interview 1 135 - 281 U/L 2145(H) Interview 3 135 - 281 U/L 1950(H) Interview 4 135 - 281 U/L 295(H) Interview 5 135 - 281 U/L 197 Interview 6 135 - 281 U/L 191 Interview 7 135 - 281 U/L 277 Interview 8 135 - 281 U/L 201 Interview 9 135 - 281 U/L 236 Interview 10 135 - 281 U/L 236 Interview 11 135 - 281 U/L 216 Visit 12 135 - 281 U/L 208 Interview 13 135 - 281 U/L 238 458002101 46/M Screening interview 1 135 - 281 U/L 2760(H) Interview 3 135 - 281 U/L 2370(H) Interview 4 135 - 281 U/L 251 Interview 5 135 - 281 U/L 208 Interview 6 135 - 281 U/L 313(H) Interview 6 135 - 281 U/L 257 Interview 7 135 - 281 U/L 323(H) Interview 8 135 - 281 U/L 274 Interview 9 135 - 281 U/L 263 Interview 10 135 - 281 U/L 201 Interview 11 135 - 281 U/L 209 Visit 12 135 - 281 U/L 210 Interview 13 135 - 281 U/L 212 Track 1 135 - 281 U/L 200 458002103 43/F Screening interview 1 135 - 330 U/L 2340(H) Planned overseas visits 101.01 135 - 330 U/L 3105(H) Interview 3 Planned overseas visits 104.02 135 - 330 U/L 520(H) Interview 4 135 - 330 U/L 390(H) Interview 5 135 - 330 U/L 221 Interview 6 135 - 330 U/L 145 Interview 7 135 - 330 U/L 157 Interview 8 135 - 330 U/L 142 458003101 39/M Screening interview 1 135 - 281 U/L 2565(H) Planned overseas visits 102.01 135 - 281 U/L 3330(H) Interview 3 135 - 281 U/L 2550(H) Interview 4 135 - 281 U/L 328(H) Interview 5 135 - 281 U/L 209 Interview 6 135 - 281 U/L 175 Interview 7 135 - 281 U/L 199 Interview 8 135 - 281 U/L 193 Interview 9 135 - 281 U/L 256 Interview 10 135 - 281 U/L 187 Interview 11 135 - 281 U/L 220 Visit 12 135 - 281 U/L 177 Interview 13 135 - 281 U/L 177 458003102 29/M Screening interview 1 135 - 281 U/L 1755(H) Interview 3 135 - 281 U/L 2145(H) Interview 4 135 - 281 U/L 231 Interview 5 135 - 281 U/L 179 Interview 6 135 - 281 U/L 174 Interview 7 135 - 281 U/L 169 Interview 8 135 - 281 U/L 171 Interview 9 135 - 281 U/L 196 Interview 10 135 - 281 U/L 176 Interview 11 135 - 281 U/L 175 Visit 12 135 - 281 U/L 180 Interview 13 135 - 281 U/L 449(H) 616002101 21/F Screening interview 1 135 - 330 U/L 677(H) Planned overseas visits 102.01 135 - 330 U/L 870(H) Interview 3 135 - 330 U/L 864(H) Interview 4 135 - 330 U/L 301 Interview 5 135 - 330 U/L 242 Interview 6 135 - 330 U/L 237 Interview 7 135 - 330 U/L 231 Interview 8 135 - 330 U/L 248 702001102 47/M Screening interview 1 135 - 281 U/L 2535(H) Interview 3 135 - 281 U/L 3270(H) Interview 4 135 - 281 U/L 258 Interview 5 135 - 281 U/L 141 Interview 6 135 - 281 U/L 176 Interview 7 135 - 281 U/L 152 Interview 8 135 - 281 U/L 165 Interview 9 135 - 281 U/L 164 Interview 10 135 - 281 U/L 164 Interview 11 135 - 281 U/L 177 724001101 48/F Screening interview 1 135 - 330 U/L 1206(H) Interview 3 135 - 330 U/L 805(H) Interview 4 135 - 330 U/L 395(H) Interview 5 135 - 330 U/L 312 Interview 6 135 - 330 U/L 297 Interview 7 135 - 330 U/L 246 Interview 8 135 - 330 U/L 255 Interview 9 135 - 330 U/L 246 Interview 10 135 - 330 U/L 203 Interview 11 135 - 330 U/L 262 Visit 12 135 - 330 U/L 239 Interview 13 135 - 330 U/L 230 724002101 87/F Screening interview 1 135 - 330 U/L ＞1260(H) Interview 3 135 - 330 U/L 1218(H) Interview 4 135 - 330 U/L 319 Interview 5 135 - 330 U/L 248 Interview 6 135 - 330 U/L 246 Interview 8 135 - 330 U/L 229 Interview 9 135 - 330 U/L 263 Interview 11 135 - 330 U/L 243 764003102 49/F Screening interview 1 135 - 330 U/L 2385(H) 764004101 56/M Screening interview 1 135 - 281 U/L 2490(H) Interview 3 135 - 281 U/L 2565(H) Interview 4 135 - 281 U/L 268 764005101 50/F Screening interview 1 135 - 330 U/L 2550(H) Interview 3 135 - 330 U/L 3720(H) Interview 4 135 - 330 U/L 228 792001103 21/F Screening interview 1 135 - 330 U/L 1183(H) Interview 3 135 - 330 U/L 1875(H) Interview 4 135 - 330 U/L 340(H) Interview 5 135 - 330 U/L 262 840001102 23/F Screening interview 1 135 - 330 U/L 2640(H) Interview 3 135 - 330 U/L 2145(H) Interview 6 135 - 330 U/L 387(H) Interview 7 135 - 330 U/L 217 Ravelizumab 124001102 58/M Screening interview 1 135 - 281 U/L 2340(H) Screening interview 1 135 - 281 U/L 1015(H) Interview 3 135 - 281 U/L 1380(H) Interview 4 135 - 281 U/L 273 Interview 5 135 - 281 U/L 245 Interview 6 135 - 281 U/L 213 Interview 7 135 - 281 U/L 232 Interview 8 135 - 281 U/L 225 Interview 9 135 - 281 U/L 220 Interview 10 135 - 281 U/L 232 124001103 21/M Screening interview 1 135 - 281 U/L 1380(H) Interview 3 135 - 281 U/L 860(H) Interview 4 135 - 281 U/L 588(H) Interview 5 135 - 281 U/L 553(H) Interview 6 135 - 281 U/L 618(H) Interview 7 135 - 281 U/L 638(H) Interview 8 135 - 281 U/L 504(H) Interview 9 135 - 281 U/L 393(H) 124001105 36/M Screening interview 1 135 - 281 U/L 520(H) Screening interview 1 135 - 281 U/L 571(H) Interview 3 135 - 281 U/L 515(H) 158001101 34/M Screening interview 1 135 - 281 U/L 1890(H) Interview 3 135 - 281 U/L 1710(H) Interview 4 135 - 281 U/L 503(H) Interview 5 135 - 281 U/L 407(H) 158001101 34/M Interview 6 135 - 281 U/L 442(H) Interview 7 135 - 281 U/L 538(H) Interview 8 135 - 281 U/L 440(H) Interview 9 135 - 281 U/L 463(H) Interview 10 135 - 281 U/L 557(H) Interview 11 135 - 281 U/L 394(H) Visit 12 135 - 281 U/L 459(H) Interview 13 135 - 281 U/L 488(H) Tv1r 135 - 281 U/L 482(H) Planned overseas visits 215.01 135 - 281 U/L 329(H) 158003101 66/M Screening interview 1 135 - 281 U/L 1028(H) Interview 3 135 - 281 U/L 1044(H) Interview 4 135 - 281 U/L 246 Interview 5 135 - 281 U/L 179 Interview 6 135 - 281 U/L 162 Planned overseas visits 107.01 135 - 281 U/L 193 Interview 8 135 - 281 U/L 191 Interview 9 135 - 281 U/L 171 Interview 10 135 - 281 U/L 188 158007101 20/M Screening interview 1 135 - 281 U/L 2115(H) Interview 3 135 - 281 U/L 2085(H) Interview 4 135 - 281 U/L 472(H) Interview 5 135 - 281 U/L 292(H) Interview 6 135 - 281 U/L 307(H) Interview 7 135 - 281 U/L 248 Interview 8 135 - 281 U/L 242 Interview 9 135 - 281 U/L 376(H) Interview 10 135 - 281 U/L 226 Interview 11 135 - 281 U/L 239 Visit 12 135 - 281 U/L 297(H) Interview 13 135 - 281 U/L 277 Planned overseas visits 113.01 135 - 281 U/L 225 392004101 75/M Screening interview 1 135 - 281 U/L 1538(H) Interview 3 135 - 281 U/L 1236(H) Interview 4 135 - 281 U/L 337(H) Interview 5 135 - 281 U/L 276 410001102 62/M Screening interview 1 135 - 281 U/L 1380(H) Interview 3 135 - 281 U/L 2055(H) Interview 4 135 - 281 U/L 623(H) Interview 5 135 - 281 U/L 619(H) Interview 6 135 - 281 U/L 664(H) Interview 7 135 - 281 U/L 661(H) Interview 8 135 - 281 U/L 594(H) Interview 9 135 - 281 U/L 684(H) Interview 10 135 - 281 U/L 716(H) Interview 11 135 - 281 U/L 642(H) Visit 12 135 - 281 U/L 681(H) Interview 13 135 - 281 U/L 735(H) 410001104 33/M Screening interview 1 135 - 281 U/L 1254(H) Screening interview 1 135 - 281 U/L 1345(H) Interview 3 135 - 281 U/L 1252(H) Interview 4 135 - 281 U/L 551(H) Interview 5 135 - 281 U/L 465(H) Interview 6 135 - 281 U/L 450(H) Interview 7 135 - 281 U/L 448(H) Interview 8 135 - 281 U/L 509(H) Interview 9 135 - 281 U/L 480(H) Interview 10 135 - 281 U/L 493(H) Interview 11 135 - 281 U/L 461(H) Visit 12 135 - 281 U/L 485(H) Interview 13 135 - 281 U/L 494(H) 410003101 47/M Screening interview 1 135 - 281 U/L 2010(H) Interview 3 135 - 281 U/L 2025(H) Interview 4 135 - 281 U/L 188 Interview 5 135 - 281 U/L 158 Interview 6 135 - 281 U/L 169 Interview 7 135 - 281 U/L 168 Interview 8 135 - 281 U/L 166 Interview 8 135 - 281 U/L 130(L) Interview 9 135 - 281 U/L 149 Interview 10 135 - 281 U/L 165 Interview 11 135 - 281 U/L 154 Visit 12 135 - 281 U/L 151 Interview 13 135 - 281 U/L 183 Tv1r 135 - 281 U/L 178 Tv2r 135 - 281 U/L 149 410004101 67/M Screening interview 1 135 - 281 U/L 684(H) Interview 3 135 - 281 U/L 1125(H) Interview 4 135 - 281 U/L 313(H) Interview 5 135 - 281 U/L 272 Interview 6 135 - 281 U/L 253 Interview 7 135 - 281 U/L 236 Interview 8 135 - 281 U/L 224 Interview 9 135 - 281 U/L 251 Interview 10 135 - 281 U/L 235 Interview 11 135 - 281 U/L 225 Visit 12 135 - 281 U/L 229 Interview 13 135 - 281 U/L 251 410005101 20/F Screening interview 1 135 - 330 U/L 2355(H) Interview 3 135 - 330 U/L 2265(H) Interview 4 135 - 330 U/L 400(H) Interview 5 135 - 330 U/L 333(H) Interview 6 135 - 330 U/L 327 Interview 7 135 - 330 U/L 328 Interview 8 135 - 330 U/L 279 Interview 9 135 - 330 U/L 311 Interview 10 135 - 330 U/L 303 Interview 11 135 - 330 U/L 259 Visit 12 135 - 330 U/L 256 Interview 13 135 - 330 U/L 272 Planned overseas visits 214.01 135 - 330 U/L 277 Planned overseas visits 215.01 135 - 330 U/L 307 410005103 23/F Screening interview 1 135 - 330 U/L 2160(H) Interview 3 135 - 330 U/L 1684(H) Interview 4 135 - 330 U/L 331(H) Interview 5 135 - 330 U/L 280 Interview 6 135 - 330 U/L 267 Interview 7 135 - 330 U/L 257 Interview 8 135 - 330 U/L 217 Interview 9 135 - 330 U/L 214 Interview 10 135 - 330 U/L 216 Interview 11 135 - 330 U/L 217 410008102 25/F Screening interview 1 135 - 330 U/L 1120(H) Interview 3 135 - 330 U/L 962(H) Interview 4 135 - 330 U/L 381(H) Interview 5 135 - 330 U/L 276 Interview 6 135 - 330 U/L 234 Interview 7 135 - 330 U/L 265 Interview 8 135 - 330 U/L 280 Interview 9 135 - 330 U/L 234 Interview 10 135 - 330 U/L 284 Interview 11 135 - 330 U/L 252 Visit 12 135 - 330 U/L 244 Interview 13 135 - 330 U/L 303 Tv1r 135 - 330 U/L 248 Tv2r 135 - 330 U/L 241 410008103 51/F Screening interview 1 135 - 330 U/L 1560(H) Interview 3 135 - 330 U/L 1160(H) Planned overseas visits 103.02 135 - 330 U/L 496(H) Interview 4 135 - 330 U/L 305 Interview 5 135 - 330 U/L 271 Interview 6 135 - 330 U/L 236 Interview 7 135 - 330 U/L 257 Interview 8 135 - 330 U/L 223 Interview 9 135 - 330 U/L 200 Interview 10 135 - 330 U/L 260 Interview 11 135 - 330 U/L 245 Visit 12 135 - 330 U/L 260 Interview 13 135 - 330 U/L 220 458001102 30/F Screening interview 1 135 - 330 U/L 3180(H) Planned overseas visits 102.01 135 - 330 U/L 2760(H) Interview 3 135 - 330 U/L 2580(H) Interview 4 135 - 330 U/L 323 Interview 5 135 - 330 U/L 244 Interview 6 135 - 330 U/L 255 Interview 7 135 - 330 U/L 264 Interview 8 135 - 330 U/L 314 Interview 9 135 - 330 U/L 252 Interview 10 135 - 330 U/L 245 Interview 11 135 - 330 U/L 193 Visit 12 135 - 330 U/L 261 Interview 13 135 - 330 U/L 329 Planned overseas visits 113.02 135 - 330 U/L 258 458002102 45/F Screening interview 1 135 - 330 U/L 1271(H) Interview 3 135 - 330 U/L 1725(H) Interview 4 135 - 330 U/L 277 Interview 5 135 - 330 U/L 208 Interview 6 135 - 330 U/L 263 Interview 6 135 - 330 U/L 285 Interview 7 135 - 330 U/L 334(H) Interview 8 135 - 330 U/L 193 Interview 9 135 - 330 U/L 207 Interview 10 135 - 330 U/L 199 Interview 11 135 - 330 U/L 202 Visit 12 135 - 330 U/L 184 Interview 13 135 - 330 U/L 220 Planned overseas visits 214.01 135 - 330 U/L 190 702001101 61/F Screening interview 1 135 - 330 U/L 1530(H) Interview 3 135 - 330 U/L 1560(H) Interview 4 135 - 330 U/L 380(H) Interview 5 135 - 330 U/L 237 Interview 6 135 - 330 U/L 246 Interview 7 135 - 330 U/L 245 Interview 8 135 - 330 U/L 250 Interview 9 135 - 330 U/L 244 Interview 10 135 - 330 U/L 246 Interview 11 135 - 330 U/L 243 Visit 12 135 - 330 U/L 252 724001102 20/F Screening interview 1 135 - 330 U/L 883(H) Interview 3 135 - 330 U/L 993(H) Interview 4 135 - 330 U/L 292 Interview 5 135 - 330 U/L 228 Interview 6 135 - 330 U/L 289 Interview 7 135 - 330 U/L 220 Interview 8 135 - 330 U/L 188 764002101 36/F Screening interview 1 135 - 330 U/L 2580(H) Interview 3 135 - 330 U/L 2700(H) Interview 4 135 - 330 U/L 515(H) Interview 5 135 - 330 U/L 342(H) Interview 6 135 - 330 U/L 336(H) Interview 7 135 - 330 U/L 396(H) Interview 8 135 - 330 U/L 317 764002103 32/M Screening interview 1 135 - 281 U/L 6045(H) Interview 3 135 - 281 U/L 5415(H) Interview 4 135 - 281 U/L 326(H) Interview 5 135 - 281 U/L 337(H) Interview 6 135 - 281 U/L 347(H) Interview 7 135 - 281 U/L 348(H) 764004102 42/F Screening interview 1 135 - 330 U/L 4230(H) Interview 3 135 - 330 U/L 2880(H) Interview 4 135 - 330 U/L 586(H)

In the ravlizumab group, one patient with an inadequate response (subject ID. 158-001-101) had normalized LDH after switching to the combo (the first of the 4 crossovers). See Figure 40, which shows LDH levels before and after switching to the combo over time.

As shown in Figure 40, the patient who switched from Ravelizumab treatment (Subject ID. 158-001-101) received 200 mg SC Cemdisiran 4 weeks after the last dose of Ravelizumab, and then received an IV loading dose of 60 mg/kg Paselimab and the first SC dose of the combination (200 mg Cemdisiran and 400 mg Paselimab) 4 weeks later. Another SC maintenance dose of the combination was given 4 weeks later.

As shown in Tables 7-9 and 7-10, a higher proportion of patients in Combo patients achieved adequate control of hemolysis (i.e., LDH ≤ 1.5 × ULN per visit) and LDH normalization (i.e., LDH ≤ 1.5 × ULN per visit) compared to patients on Ravelizumab. Table 7-9. Percentage of patients with LDH ≤ 1.5 ULN per visit - Analysis set of cohort A ( number of patients in brackets ) Week Combo Ravelizumab 2 95 (22) 67 (21) 4 95 (20) 85 (20) 8 95 (20) 79 (19) 10 94 (17) 79 (19) 12 94 (17) 78 (18) 16 93 (14) 81 (16) 18 92 (13) 80 (15) 20 100 (13) 85 (13) twenty four 100 (11) 75 (12) 26 91 (11) 73 (11) Table 7-10. Percentage of patients with LDH <= 1.0 ULN by visit - Analysis set for cohort A ( number of patients in brackets ) Week Combo Ravelizumab 2 68 (22) 33 (21) 4 90 (20) 60 (20) 8 90 (20) 63 (19) 10 88 (17) 63 (19) 12 88 (17) 78 (18) 16 93 (14) 69 (16) 18 92 (13) 80 (15) 20 92 (13) 77 (13) twenty four 100 (11) 67 (12) 26 91 (11) 73 (11)

The majority of patients in both treatment groups (Combo and Ravelizumab) achieved controlled LDH (less than 1.5 × ULN) by Week 4 and maintained control at the Week 26 endpoint. See Figure 36. Five patients failed to achieve adequate control of LDH by Week 8 - 4 patients in the Ravelizumab group and 1 patient in the Combo group. See Figure 37. A higher proportion of patients achieved LDH normalization (≦1 × ULN, per visit) in Combo patients compared to Ravelizumab patients (Table 7-11). Table 7-11. Clinical Laboratory Tests - LDH/ULN ( Full Analysis Set ) Subject ID Visit Analytical interview Analytical Value LDH to ULN ratio ≤ 1 LDH to ULN ratio ≤ 1.5 Pazelimab q4w + Cemdisiran 158003102 Screening interview 1 2.17 Interview 3 Baseline 2.11 N N Interview 4 Week 2 0.76 Y Y Interview 5 Week 4 1.2 N Y Interview 6 Week 8 0.74 Y Y Interview 7 Week 10 0.68 Y Y Interview 8 Week 12 0.9 Y Y 158007102 Screening interview 1 9.18 Interview 3 Baseline 8.97 N N Interview 4 Week 2 2.12 N N Interview 5 Week 4 1.62 N N Interview 6 Week 8 1.78 N N Interview 7 Week 10 1.83 N N Interview 8 Week 12 2.36 N N Interview 9 Week 16 1.54 N N Interview 10 Week 18 1.63 N N 380003101 Screening interview 1 5 Interview 3 Baseline 5.14 N N Interview 4 Week 2 0.99 Y Y Interview 5 Week 4 0.88 Y Y Interview 6 Week 8 0.93 Y Y 410002101 Screening interview 1 2.9 Interview 3 Baseline 3.06 N N Interview 4 Week 2 0.9 Y Y Interview 5 Week 4 0.81 Y Y Interview 6 Week 8 0.79 Y Y Interview 7 Week 10 0.75 Y Y Interview 8 Week 12 0.77 Y Y Interview 9 Week 16 0.78 Y Y Interview 10 Week 18 0.76 Y Y Interview 11 Week 20 0.85 Y Y Visit 12 Week 24 0.86 Y Y Interview 13 Week 26 0.85 Y Y 410005102 Screening interview 1 9.13 Interview 3 Baseline 10.68 N N Interview 4 Week 2 0.98 Y Y Interview 5 Week 4 0.68 Y Y Interview 6 Week 8 0.57 Y Y Interview 7 Week 10 0.65 Y Y Interview 8 Week 12 0.78 Y Y Interview 9 Week 16 0.65 Y Y Interview 10 Week 18 0.66 Y Y Interview 11 Week 20 0.68 Y Y Visit 12 Week 24 0.63 Y Y Interview 13 Week 26 0.6 Y Y 410005105 Screening interview 1 3.79 Interview 3 Baseline 4.15 N N Interview 4 Week 2 0.89 Y Y Interview 5 Week 4 0.56 Y Y Interview 6 Week 8 0.59 Y Y 410006101 Screening interview 1 4.68 Interview 3 Baseline 4.79 N N Interview 4 Week 2 0.7 Y Y Interview 5 Week 4 0.59 Y Y Interview 6 Week 8 0.68 Y Y Interview 7 Week 10 0.56 Y Y Interview 8 Week 12 0.54 Y Y Interview 9 Week 16 0.64 Y Y Interview 10 Week 18 0.52 Y Y Interview 11 Week 20 0.56 Y Y Visit 12 Week 24 0.54 Y Y Interview 13 Week 26 0.5 Y Y 410007101 Screening interview 1 5.64 Interview 3 Baseline 5.28 N N Interview 4 Week 2 1 Y Y Interview 5 Week 4 0.72 Y Y Interview 6 Week 8 0.77 Y Y Interview 6 Week 8 0.77 Y Y Interview 7 Week 10 0.81 Y Y Interview 8 Week 12 0.71 Y Y Interview 9 Week 16 0.7 Y Y Interview 10 Week 18 0.71 Y Y Interview 11 Week 20 0.72 Y Y Visit 12 Week 24 0.83 Y Y Interview 13 Week 26 0.82 Y Y 410007102 Screening interview 1 6.57 Interview 3 Baseline 10.73 N N Interview 4 Week 2 1.07 N Y Interview 5 Week 4 0.62 Y Y Interview 6 Week 8 0.73 Y Y Interview 7 Week 10 0.75 Y Y Interview 8 Week 12 0.72 Y Y Interview 9 Week 16 0.7 Y Y Interview 10 Week 18 0.73 Y Y Interview 11 Week 20 0.65 Y Y Visit 12 Week 24 0.71 Y Y Interview 13 Week 26 0.72 Y Y 410008101 Screening interview 1 3.38 Interview 3 Baseline 2.49 N N Interview 4 Week 2 0.99 Y Y Interview 5 Week 4 0.98 Y Y Interview 6 Week 8 0.83 Y Y Interview 7 Week 10 0.97 Y Y Interview 8 Week 12 1.18 N Y Interview 8 Week 12 1.4 N Y Interview 9 Week 16 0.99 Y Y Interview 10 Week 18 0.97 Y Y Interview 11 Week 20 1.09 N Y Planned overseas visits 111.01 0.89 Visit 12 Week 24 1 Y Y Interview 13 Week 26 0.85 Y Y 458001101 Screening interview 1 7.63 Interview 3 Baseline 6.94 N N Interview 4 Week 2 1.05 N Y Interview 5 Week 4 0.7 Y Y Interview 6 Week 8 0.68 Y Y Interview 7 Week 10 0.99 Y Y Interview 8 Week 12 0.72 Y Y Interview 9 Week 16 0.84 Y Y Interview 10 Week 18 0.84 Y Y Interview 11 Week 20 0.77 Y Y Visit 12 Week 24 0.74 Y Y Interview 13 Week 26 0.85 Y Y 458002101 Screening interview 1 9.82 Interview 3 Baseline 8.43 N N Interview 4 Week 2 0.89 Y Y Interview 5 Week 4 0.74 Y Y Interview 6 Week 8 1.11 N Y Interview 6 Week 8 0.91 Y Y Interview 7 Week 10 1.15 N Y Interview 8 Week 12 0.98 Y Y Interview 9 Week 16 0.94 Y Y Interview 10 Week 18 0.72 Y Y Interview 11 Week 20 0.74 Y Y Visit 12 Week 24 0.75 Y Y Interview 13 Week 26 0.75 Y Y 458002103 Screening interview 1 7.09 Planned overseas visits 101.01 Baseline 9.41 N N Planned overseas visits 104.02 1.58 Interview 4 Week 2 1.18 N Y Interview 5 Week 4 0.67 Y Y Interview 6 Week 8 0.44 Y Y Interview 7 Week 10 0.48 Y Y Interview 8 Week 12 0.43 Y Y 458003101 Screening interview 1 9.13 Planned overseas visits 102.01 11.85 Interview 3 Baseline 9.07 N N Interview 4 Week 2 1.17 N Y Interview 5 Week 4 0.74 Y Y Interview 6 Week 8 0.62 Y Y Interview 7 Week 10 0.71 Y Y Interview 8 Week 12 0.69 Y Y Interview 9 Week 16 0.91 Y Y Interview 10 Week 18 0.67 Y Y Interview 11 Week 20 0.78 Y Y Visit 12 Week 24 0.63 Y Y Interview 13 Week 26 0.63 Y Y 458003102 Screening interview 1 6.25 Interview 3 Baseline 7.63 N N Interview 4 Week 2 0.82 Y Y Interview 5 Week 4 0.64 Y Y Interview 6 Week 8 0.62 Y Y Interview 7 Week 10 0.6 Y Y Interview 8 Week 12 0.61 Y Y Interview 9 Week 16 0.7 Y Y Interview 10 Week 18 0.63 Y Y Interview 11 Week 20 0.62 Y Y Visit 12 Week 24 0.64 Y Y Interview 13 Week 26 1.6 N N 616002101 Screening interview 1 2.05 Planned overseas visits 102.01 2.64 Interview 3 Baseline 2.62 N N Interview 4 Week 2 0.91 Y Y Interview 5 Week 4 0.73 Y Y Interview 6 Week 8 0.72 Y Y Interview 7 Week 10 0.7 Y Y Interview 8 Week 12 0.75 Y Y 702001102 Screening interview 1 9.02 Interview 3 Baseline 11.64 N N Interview 4 Week 2 0.92 Y Y Interview 5 Week 4 0.5 Y Y Interview 6 Week 8 0.63 Y Y Interview 7 Week 10 0.54 Y Y Interview 8 Week 12 0.59 Y Y Interview 9 Week 16 0.58 Y Y Interview 10 Week 18 0.58 Y Y Interview 11 Week 20 0.63 Y Y 724001101 Screening interview 1 3.65 Interview 3 Baseline 2.44 N N Interview 4 Week 2 1.2 N Y Interview 5 Week 4 0.95 Y Y Interview 6 Week 8 0.9 Y Y Interview 7 Week 10 0.75 Y Y Interview 8 Week 12 0.77 Y Y Interview 9 Week 16 0.75 Y Y Interview 10 Week 18 0.62 Y Y Interview 11 Week 20 0.79 Y Y Visit 12 Week 24 0.72 Y Y Interview 13 Week 26 0.7 Y Y 724002101 Screening interview 1 3.82 Interview 3 Baseline 3.69 N N Interview 4 Week 2 0.97 Y Y Interview 5 Week 4 0.75 Y Y Interview 6 Week 8 0.75 Y Y Interview 8 Week 12 0.69 Y Y Interview 9 Week 16 0.8 Y Y Interview 11 Week 20 0.74 Y Y 764003102 Screening interview 1 Baseline 7.23 N N 764004101 Screening interview 1 8.86 Interview 3 Baseline 9.13 N N Interview 4 Week 2 0.95 Y Y 764005101 Screening interview 1 7.73 Interview 3 Baseline 11.27 N N Interview 4 Week 2 0.69 Y Y 792001103 Screening interview 1 3.58 Interview 3 Baseline 5.68 N N Interview 4 Week 2 1.03 N Y Interview 5 Week 4 0.79 Y Y 840001102 Screening interview 1 8 Interview 3 Baseline 6.5 N N Interview 6 Week 8 1.17 N Y Interview 7 Week 10 0.66 Y Y Ravelizumab 124001102 Screening interview 1 8.33 Screening interview 1 3.61 Interview 3 Baseline 4.91 N N Interview 4 Week 2 0.97 Y Y Interview 5 Week 4 0.87 Y Y Interview 6 Week 8 0.76 Y Y Interview 7 Week 10 0.83 Y Y Interview 8 Week 12 0.8 Y Y Interview 9 Week 16 0.78 Y Y Interview 10 Week 18 0.83 Y Y 124001103 Screening interview 1 4.91 Interview 3 Baseline 3.06 N N Interview 4 Week 2 2.09 N N Interview 5 Week 4 1.97 N N Interview 6 Week 8 2.2 N N Interview 7 Week 10 2.27 N N Interview 8 Week 12 1.79 N N Interview 9 Week 16 1.4 N Y 124001105 Screening interview 1 1.85 Screening interview 1 2.03 Interview 3 Baseline 1.83 N N 158001101 Screening interview 1 6.73 Interview 3 Baseline 6.09 N N Interview 4 Week 2 1.79 N N Interview 5 Week 4 1.45 N Y Interview 6 Week 8 1.57 N N Interview 7 Week 10 1.91 N N Interview 8 Week 12 1.57 N N Interview 9 Week 16 1.65 N N Interview 10 Week 18 1.98 N N Interview 11 Week 20 1.4 N Y Visit 12 Week 24 1.63 N N Interview 13 Week 26 1.74 N N 158003101 Screening interview 1 3.66 Interview 3 Baseline 3.72 N N Interview 4 Week 2 0.88 Y Y Interview 5 Week 4 0.64 Y Y Interview 6 Week 8 0.58 Y Y Planned overseas visits 107.01 Week 10 0.69 Y Y Interview 8 Week 12 0.68 Y Y Interview 9 Week 16 0.61 Y Y Interview 10 Week 18 0.67 Y Y 158007101 Screening interview 1 7.53 Interview 3 Baseline 7.42 N N Interview 4 Week 2 1.68 N N Interview 5 Week 4 1.04 N Y Interview 6 Week 8 1.09 N Y Interview 7 Week 10 0.88 Y Y Interview 8 Week 12 0.86 Y Y Interview 9 Week 16 1.34 N Y Interview 10 Week 18 0.8 Y Y Interview 11 Week 20 0.85 Y Y Visit 12 Week 24 1.06 N Y Interview 13 Week 26 0.99 Y Y 392004101 Screening interview 1 5.47 Interview 3 Baseline 4.4 N N Interview 4 Week 2 1.2 N Y Interview 5 Week 4 0.98 Y Y 410001102 Screening interview 1 4.91 Interview 3 Baseline 7.31 N N Interview 4 Week 2 2.22 N N Interview 5 Week 4 2.2 N N Interview 6 Week 8 2.36 N N Interview 7 Week 10 2.35 N N Interview 8 Week 12 2.11 N N Interview 9 Week 16 2.43 N N Interview 10 Week 18 2.55 N N Interview 11 Week 20 2.28 N N Visit 12 Week 24 2.42 N N Interview 13 Week 26 2.62 N N 410001104 Screening interview 1 4.46 Screening interview 1 4.79 Interview 3 Baseline 4.46 N N Interview 4 Week 2 1.96 N N Interview 5 Week 4 1.65 N N Interview 6 Week 8 1.6 N N Interview 7 Week 10 1.59 N N Interview 8 Week 12 1.81 N N Interview 9 Week 16 1.71 N N Interview 10 Week 18 1.75 N N Interview 11 Week 20 1.64 N N Visit 12 Week 24 1.73 N N Interview 13 Week 26 1.76 N N 410003101 Screening interview 1 7.15 Interview 3 Baseline 7.21 N N Interview 4 Week 2 0.67 Y Y Interview 5 Week 4 0.56 Y Y Interview 6 Week 8 0.6 Y Y Interview 7 Week 10 0.6 Y Y Interview 8 Week 12 0.59 Y Y Interview 8 Week 12 0.46 Y Y Interview 9 Week 16 0.53 Y Y Interview 10 Week 18 0.59 Y Y Interview 11 Week 20 0.55 Y Y Visit 12 Week 24 0.54 Y Y Interview 13 Week 26 0.65 Y Y 410004101 Screening interview 1 2.43 Interview 3 Baseline 4 N N Interview 4 Week 2 1.11 N Y Interview 5 Week 4 0.97 Y Y Interview 6 Week 8 0.9 Y Y Interview 7 Week 10 0.84 Y Y Interview 8 Week 12 0.8 Y Y Interview 9 Week 16 0.89 Y Y Interview 10 Week 18 0.84 Y Y Interview 11 Week 20 0.8 Y Y Visit 12 Week 24 0.81 Y Y Interview 13 Week 26 0.89 Y Y 410005101 Screening interview 1 7.14 Interview 3 Baseline 6.86 N N Interview 4 Week 2 1.21 N Y Interview 5 Week 4 1.01 N Y Interview 6 Week 8 0.99 Y Y Interview 7 Week 10 0.99 Y Y Interview 8 Week 12 0.85 Y Y Interview 9 Week 16 0.94 Y Y Interview 10 Week 18 0.92 Y Y Interview 11 Week 20 0.78 Y Y Visit 12 Week 24 0.78 Y Y Interview 13 Week 26 0.82 Y Y 410005103 Screening interview 1 6.55 Interview 3 Baseline 5.1 N N Interview 4 Week 2 1 N Y Interview 5 Week 4 0.85 Y Y Interview 6 Week 8 0.81 Y Y Interview 7 Week 10 0.78 Y Y Interview 8 Week 12 0.66 Y Y Interview 9 Week 16 0.65 Y Y Interview 10 Week 18 0.65 Y Y Interview 11 Week 20 0.66 Y Y 410008102 Screening interview 1 3.39 Interview 3 Baseline 2.92 N N Interview 4 Week 2 1.15 N Y Interview 5 Week 4 0.84 Y Y Interview 6 Week 8 0.71 Y Y Interview 7 Week 10 0.8 Y Y Interview 8 Week 12 0.85 Y Y Interview 9 Week 16 0.71 Y Y Interview 10 Week 18 0.86 Y Y Interview 11 Week 20 0.76 Y Y Visit 12 Week 24 0.74 Y Y Interview 13 Week 26 0.92 Y Y 410008103 Screening interview 1 4.73 Interview 3 Baseline 3.52 N N Planned overseas visits 103.02 1.5 Interview 4 Week 2 0.92 Y Y Interview 5 Week 4 0.82 Y Y Interview 6 Week 8 0.72 Y Y Interview 7 Week 10 0.78 Y Y Interview 8 Week 12 0.68 Y Y Interview 9 Week 16 0.61 Y Y Interview 10 Week 18 0.79 Y Y Interview 11 Week 20 0.74 Y Y Visit 12 Week 24 0.79 Y Y Interview 13 Week 26 0.67 Y Y 458001102 Screening interview 1 9.64 Planned overseas visits 102.01 8.36 Interview 3 Baseline 7.82 N N Interview 4 Week 2 0.98 Y Y Interview 5 Week 4 0.74 Y Y Interview 6 Week 8 0.77 Y Y Interview 7 Week 10 0.8 Y Y Interview 8 Week 12 0.95 Y Y Interview 9 Week 16 0.76 Y Y Interview 10 Week 18 0.74 Y Y Interview 11 Week 20 0.58 Y Y Visit 12 Week 24 0.79 Y Y Interview 13 Week 26 1 Y Y 458002102 Screening interview 1 3.85 Interview 3 Baseline 5.23 N N Interview 4 Week 2 0.84 Y Y Interview 5 Week 4 0.63 Y Y Interview 6 Week 8 0.8 Y Y Interview 6 Week 8 0.86 Y Y Interview 7 Week 10 1.01 N Y Interview 8 Week 12 0.58 Y Y Interview 9 Week 16 0.63 Y Y Interview 10 Week 18 0.6 Y Y Interview 11 Week 20 0.61 Y Y Visit 12 Week 24 0.56 Y Y Interview 13 Week 26 0.67 Y Y 702001101 Screening interview 1 4.64 Interview 3 Baseline 4.73 N N Interview 4 Week 2 1.15 N Y Interview 5 Week 4 0.72 Y Y Interview 6 Week 8 0.75 Y Y Interview 7 Week 10 0.74 Y Y Interview 8 Week 12 0.76 Y Y Interview 9 Week 16 0.74 Y Y Interview 10 Week 18 0.75 Y Y Interview 11 Week 20 0.74 Y Y Visit 12 Week 24 0.76 Y Y 724001102 Screening interview 1 2.68 Interview 3 Baseline 3.01 N N Interview 4 Week 2 0.88 Y Y Interview 5 Week 4 0.69 Y Y Interview 6 Week 8 0.88 Y Y Interview 7 Week 10 0.67 Y Y Interview 8 Week 12 0.57 Y Y 764002101 Screening interview 1 7.82 Interview 3 Baseline 8.18 N N Interview 4 Week 2 1.56 N N Interview 5 Week 4 1.04 N Y Interview 6 Week 8 1.02 N Y Interview 7 Week 10 1.2 N Y Interview 8 Week 12 0.96 Y Y 764002103 Screening interview 1 21.51 Interview 3 Baseline 19.27 N N Interview 4 Week 2 1.16 N Y Interview 5 Week 4 1.2 N Y Interview 6 Week 8 1.23 N Y Interview 7 Week 10 1.24 N Y 764004102 Screening interview 1 12.82 Interview 3 Baseline 8.73 N N Interview 4 Week 2 1.78 N N

Hemoglobin (Hb) was similar across treatment groups in those completing Week 26. A summary of changes in hemoglobin measurements from baseline over 26 weeks is shown in Table 7-12. Individual hemoglobin measurements are shown by visit in Table 7-13. See also Figure 42, which summarizes hemoglobin values over time for Combo patients and Ravelizumab patients. Table 7-12. Summary of changes in hemoglobin over 26 weeks. Baseline mean Hb* ( all patients ) Baseline mean Hb^ ( 26- week completers ) Week 26 Hb ^ Change from baseline Combo 84.6 82.1 102.5 +20.5 Ravelizumab 87.9 83.4 96.2 +12.8 Hb = hemoglobin; reference range (g/L): 110 to 155 females, 125 to 170 males n=24 combo, 22 ravelizumab; ^n=11 combo and ravelizumab Table 7-13. Clinical laboratory tests - hemoglobin ( complete analysis set ) Subjects Age / Gender Visit Reference range Result (g/L) ( Overflow mark ) Pazelimab q4w + Cemdisiran 158003102 39/F Screening interview 1 110 - 155 g/L 124 Interview 3 110 - 155 g/L 130 Interview 4 110 - 155 g/L 140 Interview 5 110 - 155 g/L 130 Interview 6 110 - 155 g/L 130 Interview 8 110 - 155 g/L 131 158007102 66/M Screening interview 1 125 - 170 g/L 74(L) Interview 3 125 - 170 g/L 53(L) Interview 4 125 - 170 g/L 71(L) Interview 5 125 - 170 g/L 65(L) Interview 6 125 - 170 g/L 61(L) Interview 8 125 - 170 g/L 47(L) Interview 9 125 - 170 g/L 79(L) Interview 10 125 - 170 g/L 93(L) 380003101 40/F Screening interview 1 110 - 155 g/L 76(L) Interview 3 110 - 155 g/L 88(L) Interview 4 110 - 155 g/L 90(L) Interview 5 110 - 155 g/L 86(L) Interview 6 110 - 155 g/L 79(L) 410002101 65/F Screening interview 1 110 - 155 g/L 104(L) Interview 3 110 - 155 g/L 94(L) Interview 4 110 - 155 g/L 91(L) Interview 5 110 - 155 g/L 96(L) Interview 6 110 - 155 g/L 101(L) Interview 8 2022-12-23T09:30(86) 100(L) Central Laboratory 410002101 65/F Interview 9 110 - 155 g/L 101(L) Interview 10 Interview 11 110 - 155 g/L 100(L) Visit 12 110 - 155 g/L 105(L) Interview 13 110 - 155 g/L 105(L) 410005102 61/M Screening interview 1 125 - 170 g/L 75(L) Interview 3 125 - 170 g/L 69(L) Interview 4 125 - 170 g/L 94(L) Interview 5 125 - 170 g/L 90(L) Interview 6 125 - 170 g/L 84(L) Interview 8 125 - 170 g/L 90(L) Interview 9 125 - 170 g/L 95(L) Interview 10 125 - 170 g/L 94(L) Interview 11 125 - 170 g/L 89(L) Visit 12 125 - 170 g/L 87(L) Interview 13 125 - 170 g/L 83(L) 410005105 39/M Screening interview 1 125 - 170 g/L 109(L) Interview 3 125 - 170 g/L 110(L) Interview 4 125 - 170 g/L 115(L) Interview 5 125 - 170 g/L 119(L) Interview 6 125 - 170 g/L 125 410006101 36/F Screening interview 1 110 - 155 g/L 96(L) Interview 3 110 - 155 g/L 99(L) Interview 4 110 - 155 g/L 114 Interview 5 110 - 155 g/L 122 410006101 36/F Interview 6 110 - 155 g/L 125 Interview 8 110 - 155 g/L 134 Interview 9 110 - 155 g/L 152 Interview 10 110 - 155 g/L 132 Interview 11 110 - 155 g/L 150 Visit 12 110 - 155 g/L 141 Interview 13 110 - 155 g/L 133 410007101 40/M Screening interview 1 125 - 170 g/L 77(L) Interview 3 125 - 170 g/L 93(L) Interview 4 125 - 170 g/L 105(L) Interview 5 125 - 170 g/L 107(L) Interview 6 125 - 170 g/L 98(L) Interview 8 125 - 170 g/L 100(L) Interview 9 125 - 170 g/L 113(L) Interview 10 125 - 170 g/L 117(L) Interview 11 Planned overseas visits 111.01 125 - 170 g/L 103(L) Visit 12 125 - 170 g/L 107(L) Interview 13 125 - 170 g/L 98(L) 410007102 58/M Screening interview 1 125 - 170 g/L 79(L) Interview 3 125 - 170 g/L 90(L) Interview 4 125 - 170 g/L 106(L) Interview 5 Planned overseas visits 105.01 125 - 170 g/L 93(L) Interview 6 125 - 170 g/L 111(L) Interview 8 125 - 170 g/L 98(L) 410007102 58/M Interview 9 125 - 170 g/L 103(L) Interview 10 125 - 170 g/L 109(L) Interview 11 125 - 170 g/L 109(L) Visit 12 125 - 170 g/L 101(L) Interview 13 125 - 170 g/L 97(L) 410008101 73/M Screening interview 1 125 - 170 g/L 79(L) Planned overseas visits 102.01 125 - 170 g/L 93(L) Interview 3 125 - 170 g/L 77(L) Interview 4 125 - 170 g/L 76(L) Interview 5 125 - 170 g/L 71(L) Interview 7 125 - 170 g/L 73(L) Planned overseas visits 108.01 125 - 170 g/L 72(L) Interview 8 125 - 170 g/L 82(L) Interview 9 125 - 170 g/L 87(L) Interview 10 125 - 170 g/L 87(L) Interview 11 125 - 170 g/L 67(L) Planned overseas visits 111.01 125 - 170 g/L 78(L) Visit 12 125 - 170 g/L 72(L) Interview 13 125 - 170 g/L 67(L) 458001101 44/M Screening interview 1 125 - 170 g/L 47(L) Interview 3 125 - 170 g/L 55(L) Interview 4 125 - 170 g/L 56(L) Interview 5 125 - 170 g/L 81(L) Interview 6 125 - 170 g/L 75(L) Interview 8 125 - 170 g/L 88(L) Interview 9 125 - 170 g/L 75(L) 458001101 44/M Interview 10 125 - 170 g/L 71(L) Interview 11 125 - 170 g/L 93(L) Visit 12 125 - 170 g/L 86(L) Interview 13 125 - 170 g/L 83(L) 458002101 46/M Screening interview 1 125 - 170 g/L 69(L) Interview 3 125 - 170 g/L 82(L) Interview 4 125 - 170 g/L 86(L) Interview 5 125 - 170 g/L 95(L) Interview 6 125 - 170 g/L 116(L) Interview 8 Planned overseas visits 108.01 125 - 170 g/L 117(L) Interview 9 125 - 170 g/L 114(L) Interview 10 125 - 170 g/L 122(L) Interview 11 125 - 170 g/L 121(L) Visit 12 125 - 170 g/L 128 Interview 13 125 - 170 g/L 123(L) Track 1 125 - 170 g/L 129 458002103 43/F Screening interview 1 110 - 155 g/L 118 Interview 3 110 - 155 g/L 97(L) Interview 4 110 - 155 g/L 114 Interview 5 110 - 155 g/L 113 Interview 6 110 - 155 g/L 124 Interview 8 110 - 155 g/L 128 458003101 39/M Screening interview 1 125 - 170 g/L 107(L) Interview 3 125 - 170 g/L 94(L) 458003101 39/M Interview 4 125 - 170 g/L 106(L) Interview 5 125 - 170 g/L 107(L) Interview 6 125 - 170 g/L 114(L) Interview 8 125 - 170 g/L 108(L) Interview 9 125 - 170 g/L 106(L) Interview 10 125 - 170 g/L 109(L) Interview 11 125 - 170 g/L 101(L) Visit 12 125 - 170 g/L 117(L) Interview 13 125 - 170 g/L 120(L) 458003102 29/M Screening interview 1 125 - 170 g/L 68(L) Interview 3 125 - 170 g/L 70(L) Interview 4 125 - 170 g/L 76(L) Interview 5 125 - 170 g/L 79(L) Interview 6 125 - 170 g/L 89(L) Interview 8 125 - 170 g/L 98(L) Interview 9 125 - 170 g/L 107(L) Interview 10 125 - 170 g/L 106(L) Interview 11 125 - 170 g/L 108(L) Visit 12 125 - 170 g/L 109(L) Interview 13 125 - 170 g/L 100(L) 616002101 21/F Screening interview 1 110 - 155 g/L 81(L) Planned overseas visits 102.01 110 - 155 g/L 85(L) Interview 3 110 - 155 g/L 82(L) Interview 4 110 - 155 g/L 83(L) Interview 5 110 - 155 g/L 87(L) Interview 6 110 - 155 g/L 86(L) 616002101 21/F Interview 8 110 - 155 g/L 95(L) 702001102 47/M Screening interview 1 125 - 170 g/L 81(L) Interview 3 125 - 170 g/L 68(L) Interview 4 125 - 170 g/L 108(L) Interview 5 125 - 170 g/L 105(L) Interview 6 125 - 170 g/L 94(L) Interview 8 125 - 170 g/L 97(L) Interview 9 125 - 170 g/L 102(L) Interview 10 125 - 170 g/L 97(L) Interview 11 125 - 170 g/L 104(L) 724001101 48/F Screening interview 1 110 - 155 g/L 102(L) Interview 3 110 - 155 g/L 80(L) Interview 4 110 - 155 g/L 87(L) Interview 5 110 - 155 g/L 78(L) Interview 6 110 - 155 g/L 74(L) Interview 8 110 - 155 g/L 79(L) Interview 9 110 - 155 g/L 93(L) Interview 10 110 - 155 g/L 80(L) Interview 11 110 - 155 g/L 79(L) Visit 12 110 - 155 g/L 105(L) Interview 13 110 - 155 g/L 119 724002101 87/F Screening interview 1 110 - 155 g/L 112 Interview 3 110 - 155 g/L 105(L) Interview 4 110 - 155 g/L 105(L) Interview 5 110 - 155 g/L 98(L) 724002101 87/F Interview 6 110 - 155 g/L 105(L) Interview 8 110 - 155 g/L 105(L) Interview 9 110 - 155 g/L 116 Interview 11 110 - 155 g/L 110 764003102 49/F Screening interview 1 110 - 155 g/L 83(L) 764004101 56/M Screening interview 1 125 - 170 g/L 74(L) Interview 3 125 - 170 g/L 65(L) Interview 4 125 - 170 g/L 70(L) 764005101 50/F Screening interview 1 110 - 155 g/L 103(L) Interview 3 110 - 155 g/L 89(L) Interview 4 110 - 155 g/L 86(L) 792001103 21/F Screening interview 1 110 - 155 g/L 82(L) Planned overseas visits 101.01 110 - 155 g/L 88(L) Planned overseas visits 102.01 110 - 155 g/L 91(L) Interview 3 110 - 155 g/L 68(L) Interview 4 110 - 155 g/L 85(L) Interview 5 110 - 155 g/L 89(L) 840001102 23/F Screening interview 1 110 - 155 g/L 105(L) Interview 3 110 - 155 g/L 89(L) Interview 5 Interview 6 110 - 155 g/L 96(L) Ravelizumab 124001102 58/M Screening interview 1 125 - 170 g/L 107(L) Screening interview 1 Planned overseas visits 102.01 125 - 170 g/L 131 Interview 3 125 - 170 g/L 124(L) Interview 4 125 - 170 g/L 124(L) Interview 5 125 - 170 g/L 139 Interview 7 Interview 9 125 - 170 g/L 121(L) Interview 10 124001103 21/M Screening interview 1 125 - 170 g/L 69(L) Interview 3 125 - 170 g/L 71(L) Interview 4 125 - 170 g/L 80(L) Interview 5 125 - 170 g/L 67(L) Interview 7 Planned overseas visits 108.01 125 - 170 g/L 75(L) Interview 9 125 - 170 g/L 78(L) 124001105 36/M Screening interview 1 125 - 170 g/L 138 Screening interview 1 125 - 170 g/L 141 Interview 3 125 - 170 g/L 129 158001101 34/M Screening interview 1 125 - 170 g/L 84(L) Interview 3 125 - 170 g/L 83(L) Interview 4 125 - 170 g/L 79(L) Interview 5 125 - 170 g/L 77(L) Interview 6 125 - 170 g/L 75(L) Interview 8 125 - 170 g/L 76(L) 158001101 34/M Interview 9 125 - 170 g/L 82(L) Interview 10 125 - 170 g/L 84(L) Interview 11 125 - 170 g/L 81(L) Visit 12 125 - 170 g/L 84(L) Interview 13 125 - 170 g/L 85(L) Tv1r 125 - 170 g/L 82(L) Planned overseas visits 215.01 125 - 170 g/L 82(L) 158003101 66/M Screening interview 1 125 - 170 g/L 144 Interview 3 125 - 170 g/L 137 Interview 4 125 - 170 g/L 142 Interview 5 125 - 170 g/L 139 Interview 6 125 - 170 g/L 138 Interview 8 125 - 170 g/L 135 Interview 9 125 - 170 g/L 137 Interview 10 125 - 170 g/L 138 158007101 20/M Screening interview 1 125 - 170 g/L 72(L) Interview 3 125 - 170 g/L 75(L) Interview 4 125 - 170 g/L 89(L) Interview 5 125 - 170 g/L 98(L) Interview 6 125 - 170 g/L 110(L) Interview 8 125 - 170 g/L 119(L) Interview 9 125 - 170 g/L 114(L) Interview 10 125 - 170 g/L 120(L) Interview 11 125 - 170 g/L 115(L) Visit 12 125 - 170 g/L 117(L) Interview 13 125 - 170 g/L 110(L) 158007101 20/M Planned overseas visits 113.01 392004101 75/M Screening interview 1 125 - 170 g/L 100(L) Interview 3 125 - 170 g/L 97(L) Interview 4 125 - 170 g/L 94(L) Interview 5 125 - 170 g/L 98(L) 410001102 62/M Screening interview 1 Planned overseas visits 102.01 Planned overseas visits 102.02 Interview 3 125 - 170 g/L 66(L) Interview 4 125 - 170 g/L 78(L) Interview 5 125 - 170 g/L 78(L) Interview 6 125 - 170 g/L 76(L) Interview 8 125 - 170 g/L 79(L) Interview 9 125 - 170 g/L 66(L) Interview 10 125 - 170 g/L 89(L) Interview 11 125 - 170 g/L 76(L) Visit 12 125 - 170 g/L 76(L) Interview 13 125 - 170 g/L 75(L) 410001104 33/M Screening interview 1 125 - 170 g/L 81(L) 125 - 170 g/L 62(L) 125 - 170 g/L 75(L) Screening interview 1 Planned overseas visits 102.01 125 - 170 g/L 77(L) Interview 3 125 - 170 g/L 62(L) 410001104 33/M Interview 4 125 - 170 g/L 71(L) Interview 5 125 - 170 g/L 55(L) Interview 6 125 - 170 g/L 54(L) Interview 8 125 - 170 g/L 53(L) Interview 9 125 - 170 g/L 55(L) Interview 10 125 - 170 g/L 68(L) Interview 11 125 - 170 g/L 53(L) Visit 12 125 - 170 g/L 56(L) Interview 13 125 - 170 g/L 69(L) 410003101 47/M Screening interview 1 125 - 170 g/L 113(L) Interview 3 125 - 170 g/L 120(L) Interview 4 125 - 170 g/L 127 Interview 5 125 - 170 g/L 137 Interview 7 125 - 170 g/L 123(L) Interview 8 Interview 9 125 - 170 g/L 129 Interview 10 125 - 170 g/L 119(L) Interview 11 125 - 170 g/L 123(L) Visit 12 125 - 170 g/L 132 Interview 13 125 - 170 g/L 125 Tv1r 125 - 170 g/L 121(L) Tv2r 125 - 170 g/L 126 410004101 67/M Screening interview 1 125 - 170 g/L 98(L) Interview 3 125 - 170 g/L 103(L) Interview 4 125 - 170 g/L 104(L) Interview 5 125 - 170 g/L 110(L) 410004101 67/M Interview 6 125 - 170 g/L 109(L) Interview 8 125 - 170 g/L 110(L) Interview 9 125 - 170 g/L 115(L) Interview 10 125 - 170 g/L 118(L) Interview 11 125 - 170 g/L 116(L) Visit 12 125 - 170 g/L 122(L) Interview 13 125 - 170 g/L 121(L) 410005101 20/F Screening interview 1 110 - 155 g/L 88(L) Interview 3 110 - 155 g/L 81(L) Interview 4 110 - 155 g/L 75(L) Interview 5 110 - 155 g/L 92(L) Interview 6 110 - 155 g/L 90(L) Interview 8 110 - 155 g/L 89(L) Interview 9 110 - 155 g/L 98(L) Interview 10 110 - 155 g/L 96(L) Interview 11 110 - 155 g/L 95(L) Visit 12 110 - 155 g/L 100(L) Interview 13 110 - 155 g/L 99(L) Planned overseas visits 214.01 110 - 155 g/L 92(L) Planned overseas visits 215.01 110 - 155 g/L 86(L) 410005103 23/F Screening interview 1 110 - 155 g/L 75(L) Interview 3 110 - 155 g/L 90(L) Interview 4 110 - 155 g/L 89(L) Interview 5 110 - 155 g/L 101(L) Interview 6 110 - 155 g/L 96(L) Interview 8 110 - 155 g/L 104(L) 410005103 23/F Interview 9 110 - 155 g/L 102(L) Interview 10 110 - 155 g/L 113 Interview 11 110 - 155 g/L 98(L) 410008102 25/F Screening interview 1 110 - 155 g/L 97(L) Interview 3 110 - 155 g/L 91(L) Interview 4 110 - 155 g/L 92(L) Interview 5 110 - 155 g/L 100(L) Interview 6 110 - 155 g/L 109(L) Interview 8 110 - 155 g/L 115 Interview 9 110 - 155 g/L 109(L) Interview 10 110 - 155 g/L 101(L) Interview 11 110 - 155 g/L 112 Visit 12 110 - 155 g/L 112 Interview 13 110 - 155 g/L 111 Tv1r 110 - 155 g/L 112 Tv2r 410008103 51/F Screening interview 1 110 - 155 g/L 93(L) Interview 3 Planned overseas visits 103.02 110 - 155 g/L 96(L) Interview 4 110 - 155 g/L 95(L) Interview 5 110 - 155 g/L 104(L) Interview 6 110 - 155 g/L 110 Interview 8 110 - 155 g/L 97(L) Interview 9 110 - 155 g/L 118 Interview 10 110 - 155 g/L 103(L) Interview 11 110 - 155 g/L 100(L) 410008103 51/F Visit 12 110 - 155 g/L 103(L) Interview 13 110 - 155 g/L 108(L) 458001102 30/F Screening interview 1 110 - 155 g/L 84(L) Interview 3 110 - 155 g/L 83(L) Interview 4 110 - 155 g/L 86(L) Interview 5 110 - 155 g/L 85(L) Interview 6 110 - 155 g/L 92(L) Interview 8 110 - 155 g/L 91(L) Interview 9 110 - 155 g/L 81(L) Interview 10 110 - 155 g/L 78(L) Interview 11 110 - 155 g/L 92(L) Visit 12 110 - 155 g/L 83(L) Interview 13 110 - 155 g/L 75(L) Planned overseas visits 113.02 110 - 155 g/L 82(L) 458002102 45/F Screening interview 1 110 - 155 g/L 79(L) Planned overseas visits 102.01 110 - 155 g/L 70(L) Interview 3 110 - 155 g/L 60(L) Interview 4 Planned overseas visits 104.01 110 - 155 g/L 76(L) Interview 5 110 - 155 g/L 76(L) Interview 6 110 - 155 g/L 72(L) Interview 8 110 - 155 g/L 73(L) Interview 9 110 - 155 g/L 78(L) Interview 10 110 - 155 g/L 71(L) Interview 11 110 - 155 g/L 80(L) Visit 12 110 - 155 g/L 80(L) 458002102 45/F Interview 13 110 - 155 g/L 80(L) Planned overseas visits 214.01 110 - 155 g/L 76(L) 702001101 61/F Screening interview 1 110 - 155 g/L 69(L) Planned overseas visits 101.02 110 - 155 g/L 84(L) Interview 3 110 - 155 g/L 49(L) Interview 4 110 - 155 g/L 54(L) Interview 5 110 - 155 g/L 72(L) Interview 6 110 - 155 g/L 58(L) Interview 8 110 - 155 g/L 67(L) Interview 9 110 - 155 g/L 71(L) Interview 10 110 - 155 g/L 62(L) Interview 11 110 - 155 g/L 81(L) Visit 12 110 - 155 g/L 64(L) 724001102 20/F Screening interview 1 110 - 155 g/L 120 Interview 3 110 - 155 g/L 103(L) Interview 4 110 - 155 g/L 102(L) Interview 5 110 - 155 g/L 96(L) Interview 6 110 - 155 g/L 96(L) Interview 8 110 - 155 g/L 97(L) 764002101 36/F Screening interview 1 110 - 155 g/L 74(L) Planned overseas visits 102.01 110 - 155 g/L 94(L) Interview 3 110 - 155 g/L 62(L) Interview 4 110 - 155 g/L 59(L) Interview 5 110 - 155 g/L 82(L) Interview 6 110 - 155 g/L 63(L) 764002101 36/F Interview 8 110 - 155 g/L 81(L) 764002103 32/M Screening interview 1 125 - 170 g/L 108(L) Interview 3 125 - 170 g/L 73(L) Interview 4 125 - 170 g/L 74(L) Interview 5 125 - 170 g/L 73(L) Interview 6 125 - 170 g/L 90(L) 764004102 42/F Screening interview 1 110 - 155 g/L 93(L) Interview 3 110 - 155 g/L 82(L) Interview 4 110 - 155 g/L 75(L)

Avoidance of transfers was similar in those completing Week 26. See Table 7-14. Hemolysis (intravascular, extravascular), bone marrow insufficiency, and other factors such as blood loss may lead to transfers. Due to the small sample size, other factors may be unbalanced. See also Figure 41 for a summary of per-protocol transfers between groups. Table 7-14. Summary of Patients Receiving Transfers All patients on study with transfer ( regardless of eligibility ) On-study patients with transfer ( completers ) Combo 46% 36% Ravelizumab 32% 36%

The complement hemolysis assay (CH50) is an in vitro functional assay that measures the activity of terminal complement in a patient's blood and measures the ability of an individual's blood to lyse sensitized (antibody-coated) sheep red blood cells (RBCs). Results are reported as the reciprocal of the serum dilution required to lyse 50% of the antibody-coated sheep RBCs. If elevated, terminal complement activity is present. This assay is sensitive to a decrease or absence of any component of the classical pathway (C1, C2, C3, C4) or terminal complement activity (C5 to C9). The CH50 assay results for individual patients are shown in Tables 7-15 by visit. Results are flagged as falling into the overflow range (H=high and L=low). CH50 data for patients on Ravelizumab showed a sawtooth pattern consistent with drug trough levels, while CH50 for Combo patients remained close to 100% inhibition at all time points. See Figure 38. CH50 data from inadequate responders to Ravelizumab showed incomplete terminal complement inhibition. See Figure 39. A patient who was switched to combo treatment is shown (Subject ID 158-001-101). Table 7-15. Clinical Laboratory Tests - CH50 ( Full Analysis Set ) Subject ID Age / Gender Visit Reference range, in standard units Result, in standard units ( overflow indicator ) Pazelimab q4w + Cemdisiran 158003102 39/F Interview 3 176 - 382 U/mL 340 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) 158007102 66/M Interview 3 176 - 382 U/mL 359 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 6(L) Interview 6 176 - 382 U/mL 1(L) Interview 8 176 - 382 U/mL 14(L) Interview 9 176 - 382 U/mL 1(L) Interview 10 176 - 382 U/mL 0(L) 380003101 40/F Interview 3 176 - 382 U/mL 304 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 410002101 65/F Interview 3 176 - 382 U/mL 342 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 10 176 - 382 U/mL 0(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 0(L) Interview 13 176 - 382 U/mL 0(L) 410005102 61/M Interview 3 176 - 382 U/mL 199 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 10 176 - 382 U/mL 0(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 0(L) Interview 13 176 - 382 U/mL 0(L) 410005105 39/M Interview 3 176 - 382 U/mL 250 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 410006101 36/F Interview 3 176 - 382 U/mL 306 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 10 176 - 382 U/mL 0(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 0(L) Interview 13 176 - 382 U/mL 0(L) 410007101 40/M Interview 3 176 - 382 U/mL 248 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 10 176 - 382 U/mL 0(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 0(L) Interview 13 176 - 382 U/mL 0(L) 410007102 58/M Interview 3 176 - 382 U/mL 304 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 10 176 - 382 U/mL 0(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 0(L) Interview 13 176 - 382 U/mL 0(L) 410008101 73/M Interview 3 176 - 382 U/mL 290 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 7 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 10 176 - 382 U/mL 0(L) Interview 11 176 - 382 U/mL 0(L) Planned overseas visits 111.01 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 0(L) Interview 13 176 - 382 U/mL 0(L) 458001101 44/M Interview 3 176 - 382 U/mL 242 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 10 176 - 382 U/mL 0(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 0(L) Interview 13 176 - 382 U/mL 0(L) 458002101 46/M Interview 3 176 - 382 U/mL 350 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 10 176 - 382 U/mL 0(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 0(L) Interview 13 176 - 382 U/mL 0(L) 458002103 43/F Interview 3 176 - 382 U/mL 278 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 458003101 39/M Planned overseas visits 101.01 176 - 382 U/mL 304 Interview 3 176 - 382 U/mL 236 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 10 176 - 382 U/mL 0(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 0(L) Interview 13 176 - 382 U/mL 0(L) 458003102 29/M Interview 3 176 - 382 U/mL 208 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 10 176 - 382 U/mL 2(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 Interview 13 616002101 21/F Interview 3 176 - 382 U/mL 311 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 702001102 47/M Interview 3 176 - 382 U/mL 267 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 10 Interview 11 724001101 48/F Interview 3 176 - 382 U/mL 256 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 10 176 - 382 U/mL 0(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 0(L) Interview 13 176 - 382 U/mL 0(L) 724002101 87/F Interview 3 176 - 382 U/mL 314 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 11 764004101 56/M Interview 3 176 - 382 U/mL 258 Interview 4 764005101 50/F Interview 3 Interview 4 792001103 21/F Interview 3 176 - 382 U/mL 381 Interview 4 176 - 382 U/mL 0(L) Interview 5 840001102 23/F Interview 3 176 - 382 U/mL 229 Interview 6 Ravelizumab 124001102 58/M Interview 3 176 - 382 U/mL 274 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 7 176 - 382 U/mL 0(L) Interview 9 124001103 21/M Interview 3 176 - 382 U/mL 350 Interview 4 176 - 382 U/mL 48(L) Interview 5 176 - 382 U/mL 37(L) Interview 7 176 - 382 U/mL 96(L) Interview 9 124001105 36/M Interview 3 158001101 34/M Interview 3 176 - 382 U/mL 196 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 1(L) Interview 10 176 - 382 U/mL 6(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 1(L) Interview 13 176 - 382 U/mL 6(L) Tv1r 176 - 382 U/mL 1(L) Planned overseas visits 215.01 158003101 66/M Interview 3 176 - 382 U/mL 228 Interview 4 176 - 382 U/mL 13(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 2(L) Interview 8 176 - 382 U/mL 1(L) Interview 9 Interview 10 158007101 20/M Interview 3 176 - 382 U/mL 257 Interview 4 176 - 382 U/mL 11(L) Interview 5 176 - 382 U/mL 1(L) Interview 6 176 - 382 U/mL 5(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 1(L) Interview 10 176 - 382 U/mL 6(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 4(L) Interview 13 176 - 382 U/mL 4(L) Planned overseas visits 113.01 392004101 75/M Interview 3 176 - 382 U/mL 303 Interview 4 Interview 5 410001102 62/M Interview 3 176 - 382 U/mL 384(H) Interview 4 176 - 382 U/mL 175(L) Interview 5 176 - 382 U/mL 62(L) Interview 6 176 - 382 U/mL 130(L) Interview 8 176 - 382 U/mL 61(L) Interview 9 176 - 382 U/mL 117(L) Interview 10 176 - 382 U/mL 158(L) Interview 11 176 - 382 U/mL 76(L) Visit 12 Interview 13 410001104 33/M Interview 3 176 - 382 U/mL 268 Interview 4 176 - 382 U/mL 13(L) Interview 5 176 - 382 U/mL 6(L) Interview 6 176 - 382 U/mL 9(L) Interview 8 176 - 382 U/mL 9(L) Interview 9 176 - 382 U/mL 11(L) Interview 10 176 - 382 U/mL 17(L) Interview 11 176 - 382 U/mL 7(L) Visit 12 176 - 382 U/mL 18(L) Interview 13 410003101 47/M Interview 3 176 - 382 U/mL 254 Interview 4 176 - 382 U/mL 10(L) Interview 5 176 - 382 U/mL 0(L) Interview 7 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 2(L) Interview 10 176 - 382 U/mL 8(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 3(L) Interview 13 176 - 382 U/mL 2(L) Tv1r 176 - 382 U/mL 1(L) Tv2r 176 - 382 U/mL 0(L) 410004101 67/M Interview 3 176 - 382 U/mL 290 Interview 4 176 - 382 U/mL 8(L) Interview 5 176 - 382 U/mL 2(L) Interview 6 176 - 382 U/mL 5(L) Interview 8 176 - 382 U/mL 2(L) Interview 9 176 - 382 U/mL 4(L) Interview 10 176 - 382 U/mL 8(L) Interview 11 176 - 382 U/mL 3(L) Visit 12 176 - 382 U/mL 9(L) Interview 13 176 - 382 U/mL 12(L) 410005101 20/F Interview 3 176 - 382 U/mL 275 Interview 4 176 - 382 U/mL 0(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 0(L) Interview 8 176 - 382 U/mL 0(L) Interview 9 176 - 382 U/mL 0(L) Interview 10 176 - 382 U/mL 0(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 0(L) Interview 13 176 - 382 U/mL 0(L) Planned overseas visits 214.01 176 - 382 U/mL 0(L) Planned overseas visits 215.01 176 - 382 U/mL 0(L) 410005103 23/F Interview 3 176 - 382 U/mL 248 Interview 4 176 - 382 U/mL 39(L) Interview 5 176 - 382 U/mL 4(L) Interview 6 176 - 382 U/mL 8(L) Interview 8 176 - 382 U/mL 1(L) Interview 9 176 - 382 U/mL 10(L) Interview 10 Interview 11 410008102 25/F Interview 3 176 - 382 U/mL 276 Interview 4 176 - 382 U/mL 8(L) Interview 5 176 - 382 U/mL 0(L) Interview 6 176 - 382 U/mL 1(L) Interview 8 176 - 382 U/mL 1(L) Interview 9 176 - 382 U/mL 2(L) Interview 10 176 - 382 U/mL 8(L) Interview 11 176 - 382 U/mL 0(L) Visit 12 176 - 382 U/mL 3(L) Interview 13 176 - 382 U/mL 21(L) Tv1r 176 - 382 U/mL 0(L) Tv2r 410008103 51/F Interview 3 176 - 382 U/mL 276 Planned overseas visits 103.02 176 - 382 U/mL 36(L) Interview 4 176 - 382 U/mL 23(L) Interview 5 176 - 382 U/mL 1(L) Interview 6 176 - 382 U/mL 19(L) Interview 8 176 - 382 U/mL 2(L) Interview 9 176 - 382 U/mL 9(L) Interview 10 176 - 382 U/mL 17(L) Interview 11 176 - 382 U/mL 1(L) Visit 12 176 - 382 U/mL 10(L) Interview 13 176 - 382 U/mL 15(L) 458001102 30/F Interview 3 176 - 382 U/mL 291 Interview 4 176 - 382 U/mL 19(L) Interview 5 176 - 382 U/mL 1(L) Interview 6 176 - 382 U/mL 24(L) Interview 8 176 - 382 U/mL 22(L) Interview 9 176 - 382 U/mL 18(L) Interview 10 176 - 382 U/mL 39(L) Interview 11 176 - 382 U/mL 3(L) Visit 12 176 - 382 U/mL 37(L) Interview 13 176 - 382 U/mL 45(L) Planned overseas visits 113.02 458002102 45/F Interview 3 176 - 382 U/mL 419(H) Interview 4 176 - 382 U/mL 130(L) Interview 5 176 - 382 U/mL 37(L) Interview 6 176 - 382 U/mL 142(L) Interview 8 176 - 382 U/mL 33(L) Interview 9 176 - 382 U/mL 66(L) Interview 10 176 - 382 U/mL 83(L) Interview 11 176 - 382 U/mL 12(L) Visit 12 176 - 382 U/mL 49(L) Interview 13 176 - 382 U/mL 99(L) Planned overseas visits 214.01 702001101 61/F Interview 3 176 - 382 U/mL 402(H) Interview 4 176 - 382 U/mL 27(L) Interview 5 176 - 382 U/mL 12(L) Interview 6 176 - 382 U/mL 24(L) Interview 8 176 - 382 U/mL 6(L) Interview 9 176 - 382 U/mL 37(L) Interview 10 176 - 382 U/mL 36(L) Interview 11 176 - 382 U/mL 9(L) Visit 12 724001102 20/F Interview 3 176 - 382 U/mL 257 Interview 4 176 - 382 U/mL 13(L) Interview 5 176 - 382 U/mL 3(L) Interview 6 Interview 8 764002101 36/F Interview 3 176 - 382 U/mL 343 Interview 4 176 - 382 U/mL 58(L) Interview 5 176 - 382 U/mL 19(L) Interview 6 176 - 382 U/mL 51(L) Interview 8 176 - 382 U/mL 26(L) 764002103 32/M Interview 3 176 - 382 U/mL 218 Interview 4 176 - 382 U/mL 20(L) Interview 5 176 - 382 U/mL 9(L) Interview 6 764004102 42/F Interview 3 176 - 382 U/mL 303 Interview 4 Example 8 : Viscosity Reducer in Co-formulation Containing Cemdisiran & REGN3918

This study was initiated to evaluate the effect of potential excipients on viscosity. Two base co-formulations were prepared in the presence of potential viscosity-lowering agents, one containing 120 mg/mL cemdisiran, 120 mg/mL paslimab, 15 mM histidine, pH 6.2, and the other containing 75 mg/mL cemdisiran, 150 mg/mL paslimab, 15 mM histidine, pH 6.2. The list of viscosity reducers and tested concentrations are as follows •75 mM arginine hydrochloride •5 mM sodium adipate •75 mM sodium chloride •75 mM lysine hydrochloride •75 mM sodium aspartate •75 mM proline •35 mM histidine, added to a total of 50 mM histidine in the final co-formulation •50 mM caffeine •50 mM phenylalanine •75 mM triethyl citrate

Co-formulations without additional excipients were also prepared and used as controls in this study.

The viscosity of all co-formulations at 20°C was measured by an automatic viscometer. Table 8-1 shows the reduction in viscosity of each co-formulation compared to the control. A maximum reduction in viscosity of about one-third was observed. All excipients tested were effective viscosity reducers for co-formulations containing 120 mg/mL Cemdisiran and 120 mg/mL Paselimab, while only some were effective for co-formulations containing 75 mg/mL Cemdisiran and 150 mg/mL Paselimab. For co-formulations containing 75 mg/mL Cemdisiran and 150 mg/mL Paselimab, a common property of ineffective viscosity reducers was a ring structure, while effective viscosity reducers were in salt form. Given the availability of sodium chloride and amino acid salt forms (Na ⁺ or HCl) for both co-formulations, the intermolecular interactions may be dominated by electrostatics.

The purity of Pazelimumab and Cemdisiran was measured after storage for ≥1 month at 2-8°C and compared with the source materials used to make the co-formulations. Size exclusion ULPA was performed using a fluorescent detector to assess the stability of Pazelimab. See Table 8-2. Denaturing anion exchange ULPA was performed to assess the stability of Cemdisiran. See Table 8-3. The purity of all formulations showed no significant change. Table 8-1. Viscosity of Cemdisiran & Pazelimab plus different excipients (viscosity was measured ( at 20 °C ) and the results were compared with the control ( no viscosity reducer ) ) Viscosity reducer 1:1 base formulation: 120 mg/mL Cemdisiran , 120 mg/mL Pasqualimumab, 15 mM Histidine, pH 6.2 1:2 base formulation: 75 mg/mL Cemdisiran , 150 mg/mL Pasqualimumab, 15 mM Histidine, pH 6.2 Viscosity at 20℃(cP) Reduction % compared to control Viscosity at 20℃(cP) Reduction % compared to control None (Comparison) 29.1 NA 29.8 NA 75 mM Arginine HCl 19.7 -32 20.8 -30* 75 mM Sodium adipate 18.6 -36 21.3 -29* 75 mM Sodium chloride 18.7 -36 19.8 -34* 75 mM Lysine hydrochloride 19.6 -33 20.9 -30* 75 mM Sodium Aspartate 19.9 -32 21.7 -27* 75 mM Proline 22.7 -twenty two 30.0 +1 50 mM Histidine (total) 24.5 -16 30.4 +2 50 mM caffeine 24.7 -15 32.0 +7 50 mM Phenylalanine 24.7 -15 30.7 +3 75 mM triethyl citrate 27.0 -7 30.9 +4 * The intermolecular interactions may be dominated by electrostatics, as salts effectively reduce viscosity. Table 8-2. SEC-FLR-UPLC ( size exclusion ultra-high performance liquid chromatography with fluorescent detector ) analysis to evaluate the stability of REGN3918 Viscosity reducer 1:1 base formulation: 120 mg/mL Cemdisiran , 120 mg/mL Pasqualimumab, 15 mM Histidine, pH 6.2 1:2 base formulation: 75 mg/mL Cemdisiran , 150 mg/mL Pasqualimumab, 15 mM Histidine, pH 6.2 REGN3918 Purity (%) Relative to the control Δ REGN3918 Purity (%) Relative to the control Δ 75 mM Arginine HCl 96.9 0.6 96.7 0.4 75 mM Sodium adipate 96.5 0.3 96.5 0.3 75 mM Sodium chloride 96.6 0.4 96.7 0.5 75 mM Lysine hydrochloride 96.8 0.5 96.9 0.6 75 mM Sodium Aspartate 96.7 0.4 96.6 0.3 75 mM Proline 96.6 0.3 96.8 0.5 50 mM Histidine (total) 96.4 0.2 96.7 0.4 50 mM caffeine 96.6 0.4 96.7 0.4 50 mM Phenylalanine 96.2 0.0 96.3 0.1 75 mM triethyl citrate 96.5 0.3 96.7 0.4 Comparison (compared to source materials used to make formulations) 96.2 NA 96.2 NA Table 8-3. dAEX-UPLC ( denaturing anion exchange ultra-high performance liquid chromatography ) analysis to evaluate the purity of Cemdisiran Viscosity reducer 1:1 base formulation: 120 mg/mL Cemdisiran , 120 mg/mL Pasqualimumab, 15 mM Histidine, pH 6.2 1:2 base formulation: 75 mg/mL Cemdisiran , 150 mg/mL Pasqualimumab, 15 mM Histidine, pH 6.2 Cemdisiran Purity (%) Relative to the control Δ Cemdisiran Purity (%) Relative to the control Δ 75 mM Arginine HCl 94.4 -1.0 94.7 -0.7 75 mM Sodium adipate 94.8 -0.5 94.7 -0.6 75 mM Sodium chloride 94.5 -0.8 94.3 -1.1 75 mM Lysine hydrochloride 94.5 -0.9 94.1 -1.3 75 mM Sodium Aspartate 94.8 -0.5 94.6 -0.7 75 mM Proline 94.7 -0.7 94.0 -1.4 50 mM Histidine (total) 94.7 -0.6 95.3 -0.1 50 mM caffeine 94.8 -0.5 94.6 -0.7 50 mM Phenylalanine 94.6 -0.7 94.6 -0.8 75 mM triethyl citrate 94.7 -0.6 94.6 -0.8 Comparison (compared to source materials used to make formulations) 95.4 NA 95.4 NA

All references cited herein are incorporated by reference to the same extent as if each individual publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent was specifically and individually indicated as incorporated by reference. Applicants intend that each and every individual publication, database entry (e.g., Genbank sequence or GeneID entry), patent application, or patent be associated by a statement of incorporation by reference, each of which is clearly identified, even if such reference is not immediately adjacent to the statement of incorporation by reference. The inclusion of a specific statement of incorporation by reference in the specification does not in any way diminish such general statement of incorporation by reference, if any. Citation of a reference herein does not constitute an admission that the reference is relevant prior art, nor is it to be regarded as an admission as to the contents or date of these publications or documents.

The scope of the invention is not limited to the scope of the specific embodiments described herein. In fact, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and the accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.

The length of the following sequence is less than the minimum length allowed by the ST.26 format: SEQ ID NO sequence 13 aaggcgtct 14 KAS 29 gatgcatcc 30 DAS 45 aaggcgtct 46 KAS 61 gctgcatcc 62 AAS 77 gctgcatcc 78 AAS 93 gatgcatcg 94 DAS 109 gctgcatcc 110 AAS 117 gctgcatcc 118 AAS 133 gctgcatcc 134 AAS 165 actgcatcc 166 TAS 181 actgcatcc 182 TAS 197 gatgcatcc 198 DAS 213 aaggcgtct 214 KAS 229 gctgcatcc 230 AAS 245 gatgcatcc 246 DAS 261 gctgcatcc 262 AAS 301 gctgcatcc 302 AAS 317 gatgcatcc 318 DAS 333 ggtgcatcc 334 GAS 349 gatgcatcc 350 DAS

without

Figure 1 : Cemdisiran structure. Duplex RNA sense and antisense strands with modified nucleotides linking the sense strand to the ligand (L96).

Figure 2 : Cemdisiran (total impurities #1 and #2) stability over time at 5°C for 75:100 and 100:100 co-formulations (Cemdisiran:Pasirimab concentration (mg/ml)).

Figure 3 : Stability of Cemdisiran (total impurities #1 and #2) over time at 40°C for 75:100 and 100:100 co-formulations (Cemdisiran:Pazerimab concentrations (mg/ml)) and Cemdisiran alone control.

Figure 4 : Chromatograms of dIPRP analysis of 100:100, 75:100 (Cemdisiran:Pazerimab concentration (mg/ml)) and Cemdisiran only samples stored at 40°C for 3 months.

Figure 5 : Structure of Cemdisiran isoform 1 lacking one GalNAc residue (wavy lines indicate double-stranded RNA).

Figure 6 : Cemdisiran purity by dIPRP for co-formulations 75:100 and 100:100 (Cemdisiran:Paszelimab concentration (mg/ml)) made from Paszelimab Process 1 and 2 materials and stored at 40°C.

Figure 7 : Chromatograms of dIPRP analysis of two formulations containing Cemdisiran alone (±10 μg/ml β-hexosaminidase) after 0.5 month at 40°C.

Figure 8 : Total impurities (Cemdisiran:Pasirimab concentration (mg/ml)) over time for two 50:100 co-formulations at pH 5.9 or pH 6.6 at all three temperatures (left to right: 40°C, 25°C, and 5°C) (Cemdisiran impurities #1, #2, and #3).

Figure 9 : Total impurities (Cemdisiran:Paszelimab concentration (mg/ml)) over time for two 100:100 and two 50:100 co-formulations made from Paszelimab batch 3 or 4 stored at 40°C at pH 6.0 (Cemdisiran impurities #1, #2 and #3). The degradation progress was fit to a curve with the equation shown.

Figure 10 : Variation of characteristics (pH, sucrose, arginine, paslimumab (REGN3918), cemdisiran, histidine; and desirability) in the 50:100 co-formulations evaluated in the DOE (design of experiments) experiment.

Figure 11 : Variation of characteristics of 100:100 co-formulations evaluated in DOE (design of experiments) experiments (pH, sucrose, arginine, paslimab (REGN3918), cemdisiran, histidine; and desirability).

Figure 12 : Percent change of high molecular weight species of Pazelimab after stirring at different concentrations of polysorbate 80 with two co-formulations (100:100 and 50:100) (Cemdisiran:Pazelimab concentration (mg/ml)).

Figure 13 : Total impurities (Cemdisiran impurities #1, #2 and #3) over time for two co-formulations (50:100 and 100:100) at pH 6.0 and two co-formulations (50:100 and 100:100) at pH 6.5 (Cemdisiran:Pasirimab concentration (mg/ml)) stored at 40°C.

Figure 14 : Quantification of β-hex in different batches of pazelimab (ng/ml).

Figure 15 : Analysis calibration curve.

Figure 16 : Dilution curve.

Figure 17 : Schematic diagram showing the dosing regimen of Paszelimab + Cemdisiran for patients previously treated with Paszelimab monotherapy, as described in Example 4.

Figure 18 : Graph showing individual LDH (× ULN) values over time for patients in Group 1 of the study described in Example 4 (Pazerimab Q4W + Cemdisiran).

Figure 19 : Graph showing individual LDH (× ULN) values over time for patients in Group 2 of the study described in Example 4 (Pazerimab Q2W + Cemdisiran).

Figure 20 : Graph showing individual hemoglobin values over time for patients in Group 1 (Pazelimab Q4W + Cemdisiran) and Group 2 (Pazelimab Q2W + Cemdisiran) of the study described in Example 4. Each line represents an individual patient.

Figure 21 : Graphs showing patient reported outcomes over time for patients in the study described in Example 4. Figure 21A is a graph showing FACIT-Fatigue scores, Figure 21B is a graph showing EORTC-QLQ-C30 Physical Function scores, and Figure 21C is a graph showing EORTC-QLQ-C30 GHS/QoL scores.

Figure 22 : Graph showing individual LDH (× ULN) values by visit for patients in the study described in Example 5. Each line represents an individual patient.

Figure 23 : Individual patient LDH values by visit for patients in the study described in Example 5.

Figure 24 : Individual patient hemoglobin values by visit for patients in the study described in Example 5.

Figure 25 : Research flow chart for the study described in Example 5.

Figure 26 : Research flow chart for the study described in Example 6.

Figure 27 : Research flow chart for the study described in Example 7.

Figure 28 : Italy Graph: LDH to ULN ratio (LDH/ULN) results by visit (full analysis set), Pazelimumab q2w + Cemdisiran q4w, and Pazelimumab q4w + Cemdisiran q4w.

Figure 29 : Italy Graph: CH50 results by visit (full analysis set), Pazelimumab q2w + Cemdisiran q4w, and Pazelimumab q4w + Cemdisiran q4w.

Figure 30 : Italy Plot: LDH (×ULN) results by visit from baseline visit 2 (Day 1) to Day 225 (full analysis set), showing 1.5XULN and 1XULN.

Figure 31 : Individual LDH values by visit (5 patients completed OLTP). Each line represents an individual patient. LDH, lactate dehydrogenase; ULN, upper limit of normal.

Figure 32 : Individual hemoglobin values by visit (5 patients completed OLTP). Each line represents an individual patient.

Figure 33 : Percentage of patients with LDH ≤ 1.5 × ULN over time (at data cutoff, all 24 randomized patients completed the OLTP, and 23 patients entered the optional OLEP). Group 1: pazelimab 400 mg SC Q4W + cemdisiran 200 mg SC Q4W. Group 2: pazelimab 400 mg SC Q2W + cemdisiran 200 mg SC Q4W. LDH, lactate dehydrogenase; Q2W, every 2 weeks; Q4W, every 4 weeks; SC, subcutaneous; ULN, upper limit of normal.

Figure 34 : Hemoglobin over time (At data cutoff, all 24 randomized patients completed the OLTP, and 23 patients entered the optional OLEP). Group 1: pazelimab 400 mg SC Q4W + cemdisiran 200 mg SC Q4W. Group 2: pazelimab 400 mg SC Q2W + cemdisiran 200 mg SC Q4W. SC, subcutaneous; SE, standard deviation; Q2W, every 2 weeks; Q4W, every 4 weeks.

Figure 35 : Mean percent change in lactate dehydrogenase excretion rate from baseline (U/L) over time in patients (pazelimumab 400 mg SC Q4W + cemdisiran 200 mg SC Q4W and ravulizumab patients) by visit (week).

Figure 36 : Italian graph of LDH/ULN results by visit in patients (pazelimumab 400 mg SC Q4W + cemdisiran 200 mg SC Q4W and ravlizumab patients) - 1.5 and 1 × ULN levels are shown. The dose of combination or ravlizumab is shown.

Figure 37 : LDH/ULN results by visit in the five patients who did not achieve adequate control of LDH by Week 8 (pazelimumab 400 mg SC Q4W + cemdisiran 200 mg SC Q4W and ravlizumab patients) - Italian diagram showing 1.5 and 1 × ULN levels. Dose of combination or ravlizumab is shown.

Figure 38 : Italian graph of CH50 (U/ml) by visit over time in patients (pazelimab 400 mg SC Q4W + cemdisiran 200 mg SC Q4W and ravlizumab patients). Dose and CH50 measurement results for the combination or ravlizumab are shown.

Figure 39 : Italian graph of CH50 (U/ml) by visit over time in patients with inadequate response (pazelimab 400 mg SC Q4W + cemdisiran 200 mg SC Q4W and ravulizumab patients). Patients who crossed over to trial R3918-PNH-2050 are shown.

Figure 40 : LDH over time in inadequate responders in the ravulizumab group before and after switching to the combination.

Figure 41 : Study with per-protocol switch between groups. One patient in each group met the protocol definition for switch but did not undergo the switch.

Figure 42 : Italian graph of red blood cell hemoglobin (g/l) according to visit in patients completing week 26. Hb = hemoglobin; reference range (g/L): 110 to 155 in women, 125 to 170 in men.

Figure 43 : Italian graph of LDH (×ULN) by visit in patients with a history of aplastic anemia (AA) or myelodysplastic syndrome (MDS). The solid line represents patients with AA, while the dashed line represents patients with MDS.

Figure 44 : Chemical structures of the viscosity reducers tested. Effect on viscosity in a 1:1 base formulation (120 mg/mL Cemdisiran, 120 mg/mL Pasqualimumab, 15 mM Histidine, pH 6.2) and a 1:2 base formulation (75 mg/mL Cemdisiran, 150 mg/mL Pasqualimumab, 15 mM Histidine, pH 6.2) relative to a control formulation lacking the viscosity reducer (shown in parentheses).

without

TW202417627A_112141079_SEQL.xml

Claims (107)

A co-formulation comprising: C5 iRNA bound to a ligand comprising one or more terminal N-acetylgalactosamine (GalNAc) and/or N-acetylglucosamine (GlcNAc) residues; an antibody or antigen-binding fragment thereof that specifically binds to C5 (anti-C5) and is isolated from a mammalian host cell; having a pH greater than or less than about 6; and a pharmaceutically acceptable carrier. A co-formulation comprising: C5 iRNA; an antibody or an antigen-binding fragment thereof that specifically binds to C5; a buffer; a viscosity reducer; a stabilizer; and a non-ionic surfactant, and a pH greater than or less than about 6. The co-formulation of any one of claims 1 to 2, wherein the pH is within 0.5 of not less than 6.0. A co-formulation as claimed in any one of claims 1 to 3, comprising a buffer of a histidine-based buffer, a citrate-based buffer, a phosphate-based buffer and/or an acetate-based buffer. The co-formulation of any one of claims 1 to 4, comprising about 10-35, 35-45, 20-50, 20, 25, 30, 35, 40, 45 or 50 mM buffer. A co-formulation according to any one of claims 1 to 5, comprising a viscosity reducing agent of an inorganic salt and/or an amino acid. A co-formulation as claimed in any one of claims 1 to 6, comprising a viscosity reducer, which is (D- or L-) arginine, L-arginine HCl, (D- or L-) alanine, proline, (D- or L-) valine, glycine, (D- or L-) serine, (D- or L-) phenylalanine, (D- or L-) lysine and (D- or L-) glutamine, and salts thereof; inorganic salts, pyridoxamine; L-ornithine; thiamine phosphate chloride dihydrate, benzenesulfonic acid and/or pyridoxine. The co-formulation of any one of claims 1 to 7, comprising about 20-140, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135 or 140 mM viscosity reducing agent. The co-formulation of any one of claims 1 to 8, comprising a stabilizer, wherein the stabilizer is a polyol or a sugar. The co-formulation of any one of claims 1 to 9, comprising a stabilizer, which is trehalose, sorbitol, mannitol, taurine, propanesulfonic acid, L-proline, sucrose, glycerol, threitol, maltitol, polyethylene glycol (PEG) and/or EG3350. The co-formulation of any one of claims 1 to 10, comprising about 0.8-3.6, 0.8, 0.9, 1.0, 1.25, 1.50, 2.0, 2.25, 2.50, 2.75, 3.00, 3.1, 3.2, 3.3, 3.4, 3.5 or 3.6% (w/v) stabilizer. A co-formulation as claimed in any one of claims 1 to 11, comprising a non-ionic surfactant, which is a polyoxyethylene glycol alkyl ether; a glucoside alkyl ether; a polyoxyethylene glycol octylphenol ether; a polyoxyethylene glycol alkylphenol ether; a glycerol alkyl ester; a polyoxyethylene glycol sorbitan alkyl ester; a sorbitan alkyl ester; a block copolymer of polypropylene glycol; a block copolymer of polyethylene glycol; and/or a polysorbate. A co-formulation as claimed in any one of claims 1 to 12, comprising a non-ionic surfactant, which is octaethylene glycol monododecyl ether; pentaethylene glycol monododecyl ether; polyoxypropylene glycol alkyl ether; decyl glucoside, lauryl glucoside, octyl glucoside; triton X-100; nonoxynol-9; glyceryl laurate; cocamide MEA, cocamide DEA, dodecyl dimethyl amine oxide; poloxamer; polyethoxylated tallow amine (PPOEA); polysorbate 20 (PS20) and/or polysorbate 80 (PS80). The co-formulation of any one of claims 1 to 13, comprising about 0.025, 0.05, 0.075, 0.1, 0.125, 0.15, 0.175% (w/v) non-ionic surfactant. The co-formulation of any one of claims 1 to 14, further comprising one or more viscosity reducing agents. The co-formulation of any one of claims 1 to 15, further comprising one or more viscosity reducing agents each at a concentration of about 5 mM to about 100 mM. The co-formulation of any one of claims 1 to 16, further comprising one or more viscosity reducing agents each at a concentration of about 50 mM to about 75 mM. A co-formulation as claimed in any one of claims 15 to 17, wherein the viscosity reducing agent is one or more of the following: an amino acid, a dicarboxylic acid, an inorganic salt, a citrate and/or a xanthine. A co-formulation as claimed in any one of claims 15 to 18, wherein the viscosity reducing agent is one or more of the following: arginine; adipate; NaCl; lysine; proline; histidine; caffeine; phenylalanine; and/or triethyl citrate. The co-formulation of any one of claims 15 to 19, wherein the viscosity reducing agent is an amino acid, and it is its L-enantiomer or its D-enantiomer. The co-formulation of any one of claims 15 to 20, wherein the viscosity reducing agent is a conjugate base of an acid viscosity reducing agent or a salt thereof. The co-formulation of any one of claims 1 to 21, wherein the purity of the anti-C5 antibody or antigen-binding fragment is about 96% or greater as assessed by size exclusion analysis after about 1 month at 2-8°C. The co-formulation of any one of claims 10 to 22, wherein the purity of the C5 iRNA is about 94% or greater as assessed by anion exchange chromatography after about 1 month at 2-8°C. A co-formulation as in any one of claims 1 to 23, comprising C5 iRNA and anti-C5 antibody or antigen-binding fragment at a mg/mL concentration ratio of 1:1. The co-formulation of claim 24, wherein the viscosity reducing agent is arginine, adipate, NaCl, lysine, aspartic acid, proline, histidine, caffeine, phenylalanine and/or triethyl citrate. The co-formulation of claim 25, wherein the viscosity reducing agent is 75 mM arginine, 75 mM adipate, 75 mM NaCl, 75 mM lysine, 75 mM aspartic acid, 75 mM proline, 50 mM histidine (wherein, if the buffer is histidine-based, the total histidine concentration of the co-formulation is 50 mM), 50 mM caffeine, 50 mM phenylalanine and/or 75 mM triethyl citrate. A co-formulation as in any one of claims 1 to 26, comprising C5 iRNA and anti-C5 antibody or antigen-binding fragment at a mg/mL concentration ratio of 1:2. The co-formulation of claim 27, wherein the viscosity reducing agent is arginine, adipate, NaCl, lysine and/or aspartic acid. The co-formulation of claim 28, wherein the viscosity reducing agent is 75 mM arginine, 75 mM adipate, 75 mM NaCl, 75 mM lysine and/or 75 mM aspartic acid. A co-formulation as in any one of claims 1 to 29, wherein the antibody or antigen-binding fragment thereof that specifically binds to C5 (anti-C5) comprises: (1) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 2, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 10; (2) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 18, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 26; (3) a HCVR comprising a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 19; HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 34, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: 42; (4) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 50, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: 58; (5) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 66, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: (6) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 82, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 90; (7) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 98, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 106; (8) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 98, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 106; HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 98, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: 114; (9) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 122, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: 106; (10) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 98, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: (11) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 138, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 106; (12) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 106; (13) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 106; 122, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 130; (14) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 114; (15) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: (16) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 138, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 130; (17) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 154, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 162; (18) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 138, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 130; HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 170, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: 178; (19) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 186, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: 194; (20) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 202, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: (22) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 234, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 242; (23) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 234, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 242; HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 250, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 258; (24) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 266, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 258; (25) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 274, and a LCVR comprising a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: (26) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 290, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 298; (27) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 306, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 314; (28) a HCVR comprising SEQ ID NO: 314; HCVRs comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 322, and LCVRs comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 330; and/or (29) HCVRs comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 338, and LCVRs comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 346. A co-formulation as in any one of claims 1 to 30, wherein the antibody or antigen-binding fragment thereof that specifically binds to C5 comprises: (i) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 4, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 6, and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 8, and the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 12, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 14, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 16; (ii) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 20, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 22, and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 24, and the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 28, and LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 29. (iii) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 36, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 38, and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 40, and the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 44, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 46, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 48; (iv) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 52, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 54, and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 56, and the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 60, and LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 61. NO: 62, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 62, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 64; (v) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 68, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 70, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 72, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 76, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 78, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 80; (vi) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 84, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 86, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 88, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 92, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 96, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 98; NO: 94, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 94, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 96; (vii) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 100, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 102, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 104, and the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 110, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 112; (viii) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 100, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 102, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 104, and the light chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 110, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 112. NO: 116, LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 118, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 118, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 120; (ix) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 124, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 126, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 128, and the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 110, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 112; (x) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 100, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 102, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 113. NO: 104, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 132, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 134, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 136; (xi) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 140, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 142, and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 144, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 110, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 112; (xii) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 148, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 149, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 150; NO: 150, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 150, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 152, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 108, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 110, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 112; (xiii) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 124, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 126, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 128, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 132, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 134, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 136; (xiv) the heavy chain variable region comprises a NO: 148, HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 148, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 150, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 152, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 116, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 118, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 120; (xv) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 148, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 150, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 152, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 132, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 134, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 136; (xvi) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 140, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 142, and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 144, and the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 132, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 134, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 136; (xvii) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 156, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 158, and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 160, and the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 164, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 166, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: NO: 168; (xviii) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 172, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 174, and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 176, and the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 180, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 182, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 184; (xix) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 188, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 190, and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 192, and the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 196, and LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 197. NO: 198, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 198, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 200; (xx) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 204, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 206, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 208, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 212, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 214, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 216; (xxi) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 220, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 222, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 224, the light chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 224, NO: 228, LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 228, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 230, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 232; (xxii) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 236, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 238, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 240, and the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 244, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 246, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 248; (xxiii) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 252, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 254, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 256; NO: 256, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 260, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 262, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 264; (xxiv) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 268, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 270, and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 272, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 260, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 262, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 264; (xxv) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 276, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 277; NO: 278, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 278, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 280, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 284, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 286, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 288; (xxvi) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 292, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 294, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 296, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 300, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 302, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 304; (xxvii) the heavy chain variable region comprises a 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5-mer 5 NO: 308, HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 308, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 310, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 312, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 316, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 318, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 320; (xxviii) the heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 324, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 326, HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 328, the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 332, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 334, LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 336; or (xxix) The heavy chain variable region comprises HCDR1 comprising the amino acid sequence shown in SEQ ID NO: 340, HCDR2 comprising the amino acid sequence shown in SEQ ID NO: 342, and HCDR3 comprising the amino acid sequence shown in SEQ ID NO: 344, and the light chain variable region comprises LCDR1 comprising the amino acid sequence shown in SEQ ID NO: 348, LCDR2 comprising the amino acid sequence shown in SEQ ID NO: 350, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO: 352. A co-formulation as in any one of claims 1 to 31, wherein the antibody or antigen-binding fragment thereof that specifically binds to C5 comprises: (1) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 2, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 10; (2) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 18, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 26; (3) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 34, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 42; (4) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 50, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 58; (5) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 66, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: NO:74; (6) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:82, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:90; (7) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:98, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:106; (8) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:98, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:114; (9) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:122, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO:106; (10) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO:98, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: NO: 130; (11) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 138, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 106; (12) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 146, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 106; (13) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 122, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 130; (14) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 146, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 114; (15) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 146, and a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: NO: 130; (16) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 138, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 130; (17) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 154, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 162; (18) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 170, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 178; (19) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 186, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 194; (20) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 202, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: NO: 210; (21) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 218, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 226; (22) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 234, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 242; (23) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 250, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 258; (24) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 266, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 258; (25) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 274, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: NO: 282; (26) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 290, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 298; (27) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 306, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 314; (28) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 322, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 330; or (29) a heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 338, a light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 346. The co-formulation of any one of claims 1 to 32, comprising about 90 to about 275 mg/ml; or about 90; 91; 92; 93; 94; 95; 96; 97; 98; 99; 100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 147 7; 148; 149; 150; 151; 152; 153; 154; 155; 156; 157; 158; 159; 160; 161; 162; 163; 164; 165; 166; 167; 168; 169; 170; 171; 172; 173; 174; 175; 176; 177; 178; 179; 180; 181; 182; 183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 211, 220, 242, or 274 mg/mL; or at least about 150 mg/ml, at least about 175 mg/ml, at least about 200 mg/ml, at least about 211 mg/ml, at least about 220 mg/ml, at least about 242 mg/ml or at least about 274 mg/ml of an antibody or antigen-binding fragment that specifically binds to C5. A co-formulation as claimed in any one of claims 1 to 33, wherein the C5 iRNA is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises a complementary region comprising at least 17 consecutive nucleotides that differ from the nucleotide sequence of 5'-UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 364) by no more than 3 nucleotides, and wherein the dsRNA agent comprises at least one modified nucleotide. The co-formulation of any one of claims 1 to 34, wherein the C5 iRNA is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO: 406) and the antisense strand comprises 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO: 369), wherein a, g, c and u are 2'-0-methyl (2'-OMe) A, G, C and U, respectively; Af, Gf, Cf and Uf are 2'-fluoro A, G, C and U, respectively; dT is a deoxythymidine nucleotide; s is a phosphorothioate linkage; and wherein the sense strand is joined to a ligand at its 3' end . The co-formulation of any one of claims 1 to 35, wherein the C5 iRNA is Cemdisiran or its Na ⁺ salt form. The co-formulation of any one of claims 1 to 36, comprising a C5 iRNA, wherein the C5 iRNA is Cemdisiran, and one or more of Cemdisiran Impure 1, Cemdisiran Impure 2, and Cemdisiran Impure 3. The co-formulation of any one of claims 1 to 37, comprising about 20-100, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 130, 140, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210 350, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg/ml C5 iRNA. The co-formulation of any one of claims 1 to 38, having a viscosity of < 30 cP at 20°C; and/or an osmotic pressure of 240-450 mOsm/kg. The co-formulation of claim 39, wherein the viscosity at 20°C is ≦20 cP. A co-formulation as claimed in any one of claims 1 to 40, comprising: double-stranded C5 iRNA; and anti-C5 antibody or antigen-binding fragment thereof, pH higher or lower than 6.0 (different by at least 0.5); C5 iRNA, anti-C5 antibody or antigen-binding fragment thereof, buffer, viscosity reducer, stabilizer, and non-ionic surfactant; C5 iRNA, anti-C5 antibody or antigen-binding fragment thereof, histidine-based buffer, L-arginine, stabilizer, and non-ionic surfactant; C5 iRNA, anti-C5 antibody or antigen-binding fragment thereof, histidine-based buffer, L-arginine, sugar or polyol, and non-ionic surfactant; cemdisiran, pozelimab, histidine-based buffer, L-arginine, stabilizer, and non-ionic surfactant, pH about 6.5; cemdisiran, pozelimab, histidine-based buffer, L-arginine, sucrose, and polysorbate 80, pH about 6.5; 100 (±10) mg/mL C5 iRNA, 100 (±10) mg/mL anti-C5 antibody or antigen-binding fragment thereof, 50 (±5) mM viscosity reducer, 10 (±1) mM buffer, 1.0 (±0.1)% stabilizer, 0.075 (±0.0075)% non-ionic surfactant, pH 6.5; 75 (±7.5) mg/mL C5 iRNA, 150 (±15) mg/mL anti-C5 antibody or its antigen-binding fragment, 75 (±7.5) mM viscosity reducer, 15 (±1.5) mM buffer, 1.5(±0.15)% stabilizer, 0.1125 (±0.01125)% non-ionic surfactant, pH 6.5; 50 (±5) mg/mL C5 iRNA, 100 (±10) mg/mL anti-C5 antibody or its antigen-binding fragment, 75 mM (±7.5) viscosity reducer, 15 (±1.5) mM buffer, 1.5 (±0.15)% stabilizer, 0.1125 (±0.01125)% non-ionic surfactant; pH 6.5; 50 (±5) mg/mL C5 iRNA, 100 (±10) mg/mL anti-C5 antibody or antigen-binding fragment thereof, 75 (±7.5) mM viscosity reducer, 35 (±3.5) mM buffer, 1.5 (±0.15)% stabilizer, 0.1125 (±0.01125)% non-ionic surfactant, pH 6.5; 100 (±10) mg/mL C5 iRNA, 100 (±10) mg/mL anti-C5 antibody or its antigen-binding fragment, 50 (±5) mM viscosity reducer, 30 (±3) mM buffer, 1 (±0.1)% stabilizer, 0.075 (±0.0075)% non-ionic surfactant, pH 6.5; 50 (±5) mg/mL C5 iRNA, 100 (±10) mg/mL anti-C5 antibody or its antigen-binding fragment, 90 (±9) mM viscosity reducer, 30 (±3) mM buffer, 1 (±0.1)% stabilizer, 0.075 (±0.0075)% non-ionic surfactant, pH 6.5; 100 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 50 mM L-arginine, 30 mM histidine-based buffer, 1% (w/v) sucrose, 0.075% (w/v) PS80, pH 6.5; 50 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 90 mM L-arginine, 30 mM histidine-based buffer, 1% (w/v) sucrose, 0.075% (w/v) PS80, pH 6.5; 100 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 50 mM L-arginine, 10 mM Histidine-based buffer, 1.0% sucrose, 0.075% PS80, pH 6.5; 75 mg/mL Cemdisiran, 150 mg/mL Paselimab, 75 mM L-arginine, 15 mM Histidine-based buffer, 1.5% sucrose, 0.1125% PS80, pH 6.5; 50 mg/mL Cemdisiran, 100 mg/mL Paselimab, 75 mM L-arginine, 15 mM Histidine-based buffer, 1.5% sucrose, 0.1125% PS80, pH 6.5; 50 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 75 mM L-arginine, 35 mM histidine-based buffer, 1.5% sucrose, 0.1125% PS80, pH 6.5; 100 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 50 mM L-arginine, 30 mM histidine-based buffer, 1% sucrose, 0.075% PS80, pH 6.5; 50 mg/mL Cemdisiran, 100 mg/mL Pazelimumab, 90 mM L-arginine, 30 mM histidine-based buffer, 1% sucrose, 0.075% PS80, pH 6.5; further comprising GalNAc and/or GlcNAc as appropriate; 120 mg/mL C5 iRNA, 120 mg/mL anti-C5 antibody or antigen-binding fragment, viscosity reducer; 15 mM histidine, pH 6.2; 75 mg/mL C5 iRNA, 150 mg/mL anti-C5 antibody or antigen-binding fragment, viscosity reducer; 15 mM histidine, pH 6.2; 120 mg/mL C5 iRNA, 120 mg/mL anti-C5 antibody or antigen-binding fragment, 15 mM histidine, pH 6.2; 75 mg/mL C5 iRNA, 150 mg/mL anti-C5 antibody or antigen-binding fragment, 15 mM histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 15 mM Histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM Arginine, 15 mM Histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM Adipate, 15 mM Histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM Sodium Chloride, 15 mM Histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM Sodium Chloride, 15 mM Histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM lysine, 15 mM histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM aspartic acid, 15 mM histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 75 mM proline, 15 mM histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 50 mM histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 50 mM caffeine, 15 mM histidine, pH 6.2; 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 50 mM Phenylalanine, 15 mM Histidine, pH 6.2 120 mg/mL Cemdisiran, 120 mg/mL Pazelimumab, 50 mM Triethyl Citrate, 15 mM Histidine, pH 6.2; 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 15 mM Histidine, pH 6.2; 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 75 mM Arginine, 15 mM Histidine, pH 6.2; 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 75 mM Arginine, 15 mM Histidine, pH 6.2; 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 75 mM adipate, 15 mM histidine, pH 6.2; 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 75 mM NaCl, 15 mM histidine, pH 6.2; 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 75 mM lysine, 15 mM histidine, pH 6.2; or 75 mg/mL Cemdisiran, 150 mg/mL Pazelimumab, 75 mM aspartic acid, 15 mM histidine, pH 6.2. A co-formulation of any one of claims 1 to 41, wherein the C5 iRNA is Cemdisiran; the antibody or antigen-binding fragment is Pasirimab; the viscosity reducer is L-arginine; the buffer is a histidine-based buffer; the stabilizer is sucrose; the non-ionic surfactant is polysorbate 80; and the pH is about 6.5. A co-formulation as claimed in any one of claims 1 to 42, wherein • the C5 iRNA is conjugated to a ligand comprising one or more terminal N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc) residues; • has a pH of about 0.5 that is not less than about 6; and/or • a pH of about 6.5. A co-formulation as claimed in any one of claims 1 to 43, which • comprises β-hexosaminidase; • comprises an antibody or an antigen-binding fragment thereof expressed and isolated from a mammalian host cell containing β-hexosaminidase; • comprises an antibody or an antigen-binding fragment thereof expressed and isolated from a Chinese hamster ovary cell; • comprises no more than about 1% Cemdisiran impurity 1 relative to total Cemdisiran; • comprises not less than about 80% Cemdisiran relative to total Cemdisiran after storage at 2-8°C for 2 years; • has about 91% Cemdisiran before storage (at t=0); • has not less than about 80% Cemdisiran after storage at 2-8°C for 1, 1½, 2, 2½ or 3 years; • has about 80% to about 91% Cemdisiran; • Cemdisiran purity (%) based on dIPRP was approximately 90.5% at t=0; 91.1% after 1 month at 2-8°C; 90.8% after 3 months at 2-8°C; 90% after 6 months at 2-8°C; 88.8% after 9 months at 2-8°C; 88.7% after 12 months at 2-8°C; 89% after 18 months at 2-8°C; and/or 89.4% after 24 months at 2-8°C; • The purity (%) of Cemdisiran was approximately 90.8% according to dIPRP at t=0, 90.6% after 1 month storage at 2-8℃; 90.5% after 3 months storage at 2-8℃; 89.4% after 6 months storage at 2-8℃; 88.3% after 9 months storage at 2-8℃; 87.8% after 12 months storage at 2-8℃; 87.8% after 18 months storage at 2-8℃; and/or 89.4% after 24 months storage at 2-8℃; • The purity (%) of Cemdisiran was approximately 90.5% according to dIPRP at t=0; 90.2% after 1 month storage at 25℃ and 60% RH; 89.4% after 24 months storage at 2-8℃; 87.8% after 3 months storage at 25℃ and 60% RH; 85.1% after 6 months storage at 25℃ and 60% RH; 90% after 0.5 month storage at 40℃ and 75% RH; 88.9% after 1 month storage at 40℃ and 75% RH; 85.8% after 3 months storage at 40℃ and 75% RH; • At t=0, the purity (%) of Cemdisiran according to dIPRP was about 90.8%, 88.8% after 1 month storage at 25℃ and 60% RH; 85.9% after 3 months storage at 25℃ and 60% RH; 82.3% after 6 months storage at 25℃ and 60% RH; 88.9% after 0.5 month storage at 40℃ and 75% RH; 85.8% after 3 months storage at 40℃ and 75% RH; • At t=0, the purity (%) of Cemdisiran according to dIPRP was about 90.8%, 88.8% after 1 month storage at 25℃ and 60% RH; 85.9% after 3 months storage at 25℃ and 60% RH; 82.3% after 6 months storage at 25℃ and 60% RH; 88.9% after 0.5 month storage at 40℃ and 75% RH; 85.8% after 3 months storage at 40℃ and 75% RH; RH for 1 month; 87.3% after 3 months at 40℃ and 75% RH; 82.3% after 3 months at 40℃ and 75% RH; •Cemdisiran purity (%) at t=0 according to dIPRP is about 90.9%; about 90.1% after 1 month at 25℃ and 60% RH; about 90.9% after 3 months at 25℃ and 60% RH; about 90.4% after 6 months at 25℃ and 60% RH; about 89.9% after 0.5 month at 40℃ and 75% RH; about 89.7% after 1 month at 40℃ and 75% RH; and/or about 89.5% after 3 months at 40℃ and 75% RH; • At t=0, the purity of Cemdisiran according to dIPRP was about 90.8%; after 1 month storage at 25℃, 60% RH, about 90.2%; after 3 months storage at 25℃, 60% RH, about 90.8%; after 6 months storage at 25℃, 60% RH, about 90.3%; after 0.5 month storage at 40℃, 75% RH, about 89.5%; after 1 month storage at 40℃, 75% RH, about 89.6%; and/or after 3 months storage at 40℃, 75% RH, about 89.1%; • At t=0, the purity of Cemdisiran according to dIPRP was about 90.5%; after 25℃, 60% RH for 1 month; 90.8% for 3 months at 25℃, 60% RH; 90.4% for 6 months at 25℃, 60% RH; 90.1% for 0.5 month at 40℃, 75% RH; 89.6% for 1 month at 40℃, 75% RH; and/or 89.9% for 3 months at 40℃, 75% RH; and/or • At t=0, the purity (%) of Cemdisiran according to dIPRP was about 91.1%; 90% for 1 month at 25℃, 60% RH; 91% for 3 months at 25℃, 60% RH; and 91% for 4 months at 25℃, 60% RH. RH for 6 months: about 90.7%; 40℃, 75% RH for 0.5 months: about 90%; 40℃, 75% RH for 1 month: about 89.7%; and/or 40℃, 75% RH for 3 months: about 89.9%. A co-formulation as claimed in any one of claims 1 to 44, comprising: • a molar ratio of no more than about 2.1 parts per million (ppm) of β-hexosaminidase and an antibody or antigen-binding fragment; • comprising no more than about 0.170 micrograms/ml β-hexosaminidase, • comprising no more than about 0.04 micrograms/ml β-hexosaminidase; and/or • about 0.04; 0.05; 0.06; 0.06; 0.0605; 0.0605; 0.0605; 0.063; 0.07; 0.07; 0.0765; 0.078; 0.08; 0.14; 0.141; 0.15; 0.1525; 0.166; or 0.17 micrograms/ml β-hexosaminidase; or no more than any of these concentrations. A method of administering the co-formulation of any one of claims 1 to 45 to a subject, comprising introducing the co-formulation into the subject. The method of claim 46, wherein the co-formulation is administered by injection into the subject. The method of claim 47, wherein the co-formulation is administered by intramuscular, subcutaneous, intravenous, intraocular and/or intravitreal injection. A method for treating or preventing a C5-related disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a co-formulation of any one of claims 1 to 48. The method of claim 49, wherein the disease or condition is: a condition of inappropriate or undesirable complement activation; a complication of hemodialysis; a lung disease or condition; a neurological disease; a parasitic disease; a post-ischemic reperfusion condition; a proteinuric kidney disease; a nephropathy; an adult respiratory distress syndrome; an adult respiratory distress syndrome (ARDS); an age-related macular degeneration (AMD); an allergy; Alport syndrome; Alzheimer's disease; an autoimmune disease or; an immune complex disorder; an inflammatory disorder; an eye disease; an organic dust disease; disease); vascular thrombosis and protein-deficient enteropathy); asthma; asthma; atherosclerosis; bronchoconstriction; bullous pemphigoid; C3 glomerulopathy; capillary leak syndrome; CHAPLE disease (CD55 deficiency with overactivation of complements; chemical injury caused by irritants and/or chemicals; chronic obstructive pulmonary disease (COPD); complement activation caused by burns; complement activation caused by frostbite; obesity-induced induced complement activation; sepsis-induced complement activation; Crohn's disease; diabetes; diabetic macular edema (DME); diabetic nephropathy; diabetic retinopathy; dry AMD; dyspnea; emphysema; epilepsy; fibrosis; geographic atrophy (GA); glomerulopathy; Goodpasture's syndrome; Guillain-Barré syndrome; hemolytic anemia; hemoptysis; hereditary vascular edema; hyperacute allograft rejection; allergic pneumonitis; immune Complex-related inflammation; infectious diseases; inflammation in autoimmune diseases; inherited CD59 deficiency; injury caused by inert dusts and/or minerals; IL-2-induced toxicity during interleukin-2 therapy; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative nephritis; mesenteric artery reperfusion after aortic reconstruction; multiple sclerosis; myasthenia gravis; myocardial infarction; neuromyelitis optica; ocular angiogenesis; Parkinson's disease; pneumonia; progressive renal failure; Pityriasis; pulmonary embolism and infarction; pulmonary fibrosis; pulmonary vasculitis; renal ischemia; renal ischemia-reperfusion injury; rheumatoid arthritis; schizophrenia; SLE nephritis; smoke injury; stroke; systemic inflammatory response to post-pump syndrome due to cardiopulmonary bypass or renal bypass; systemic lupus erythematosus (SLE); thermal injury; traumatic brain injury; uveitis; vasculitis; wet AMD; paroxysmal nocturnal hemoglobinuria (PNH); and/or xenograft rejection. The method of any one of claims 46 to 50, wherein one or more additional therapeutic agents are administered to the subject. The method of claim 51, wherein the additional chemotherapeutic agent is androgen, anticoagulant, anti-inflammatory drug, antihypertensive agent, immunosuppressant, fibrinolytic agent, lipid-lowering agent, anti-CD20 agent, anti-TNFα agent, C3 inhibitor, antithrombotic agent, corticosteroid, nonsteroidal anti-inflammatory drug, angiotensin converting enzyme inhibitor, hydroxymethylglutaryl CoA reductase inhibitor and/or anti-epileptic agent. The method of claim 52, wherein the additional chemotherapy agent is warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux, and a thrombin inhibitor (such as argatroban, lepirudin, bivalirudin, dabigatran, vincristine, cyclosporine A, methotrexate, ancrod, epsilon-aminocaproic acid, anticytosine-a1, prostacyclin, defibrotide, rituximab, infliximab, and/or magnesium sulfate). A method for increasing RNA stability or reducing β-hexosaminidase activity in a composition comprising RNA bound to a ligand and β-hexosaminidase, wherein the ligand comprises one or more terminal N-acetylgalactosamine (GalNAc) residues and/or N-acetylglucosamine (GlcNAc) residues; the method comprising (i) adding GalNAc and/or GlcNAc to the composition, and/or (ii) increasing or decreasing the pH of the composition relative to about 6. The method of claim 54, wherein the composition comprises: RNA, which is C5 iRNA; an antibody or an antigen-binding fragment thereof expressed and isolated from a mammalian host cell containing β-hexosaminidase; and optionally, a buffer; a viscosity reducer; a stabilizer; and a non-ionic surfactant. The method of any one of claims 54 to 55, wherein the composition comprises an antibody expressed in Chinese hamster ovary (CHO) cells. The method of any one of items 54 to 56, wherein the RNA is a double-stranded RNA, optionally comprising an overhang of 1 or 2 nucleotides at one or both ends. The method of any one of items 54 to 57, wherein the RNA is chemically synthesized. A method of making a co-formulation as claimed in any one of claims 1 to 45, comprising combining RNAi with an antibody or antigen binding fragment, and (i) adding GalNAc to the co-formulation and/or (ii) adjusting the pH of the co-formulation to about 6 or below. A co-formulation which is the product of the method of claim 59. A method of administering an antibody or antigen-binding fragment thereof that specifically binds to C5 (anti-C5) and a C5 iRNA to an individual comprises introducing the antibody or fragment and the iRNA into the individual. A method as claimed in claim 61, wherein the antibody or fragment and the iRNA are introduced by subcutaneous injection or intravenous infusion of a co-formulation comprising the antibody or fragment and the iRNA; or Subcutaneous injection or intravenous infusion of a separate formulation each comprising the antibody or fragment or the iRNA. A method for treating or preventing a C5-related disease or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to C5 and a C5 iRNA, either in a single co-formulation or in separate formulations. The method of any one of claims 61 to 63, further comprising one or more initial intravenous or subcutaneous loading doses of the antibody or antigen-binding fragment and/or iRNA. A method as claimed in any one of claims 61 to 64, comprising administering one or more of the following: (1) about 400 mg of an anti-C5 antibody or antigen-binding fragment; and (2) about 200 mg of a C5 iRNA. A method as claimed in any one of claims 61 to 65, wherein: About 400 mg of anti-C5 antibody or antigen-binding fragment is administered approximately every 2, 3 or 4 weeks (±3); and About 200 mg of C5 iRNA is administered approximately every 4 weeks (±3 days). The method of any one of claims 61 to 66, wherein the subject is administered: (i) about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously about every 2 weeks (±3, 4, 5, 6 or 7 days), and about 200 mg of C5 iRNA subcutaneously about every 4 weeks (±3, 4, 5, 6 or 7 days); (ii) about 400 mg of anti-C5 antibody or antigen-binding fragment subcutaneously about every 4 weeks (±3, 4, 5, 6 or 7 days), and about 200 mg of C5 iRNA subcutaneously every 4 weeks (±3, 4, 5, 6 or 7 days); (iii) an intravenous loading dose of anti-C5 antibody or antigen-binding fragment, subcutaneous administration of about 400 mg of anti-C5 antibody or antigen-binding fragment, and subcutaneous administration of about 200 mg of C5 iRNA; and then, approximately every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, approximately 400 mg of anti-C5 antibody or antigen-binding fragment and approximately 200 mg of C5 iRNA are subcutaneously administered; (iv) approximately 30 or 60 mg/kg of intravenous loading dose of anti-C5 antibody or antigen-binding fragment, approximately 400 mg of anti-C5 antibody or antigen-binding fragment are subcutaneously administered, and approximately 200 mg of C5 iRNA are subcutaneously administered; and then, approximately every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, approximately 400 mg of anti-C5 antibody or antigen-binding fragment are subcutaneously administered, and approximately 200 mg of C5 iRNA are subcutaneously administered; (v) approximately 30 or 60 mg/kg intravenous loading dose of anti-C5 antibody or antigen-binding fragment, followed by one or more weekly subcutaneous doses of about 800 mg of anti-C5 antibody or antigen-binding fragment, and then, depending on the situation, about 400 mg of anti-C5 antibody or antigen-binding fragment and about 200 mg of C5 iRNA are subcutaneously administered after a 1-week period; and then, about 400 mg of anti-C5 antibody or antigen-binding fragment and about 200 mg of C5 iRNA are subcutaneously administered about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter; (vi) (a) intravenous administration of one dose of eculizumab and subcutaneous administration of about 200 mg of C5 iRNA; (b) up to about 14 days (±3, 4, 5, 6 or 7 days) later, a dose of eculizumab; and (c) about another 14 or 15 days (±3, 4, 5, 6 or 7 days) later, intravenous administration of 30 or 60 mg/kg body weight of anti-C5 antibody or antigen-binding fragment, subcutaneous administration of about 400 mg of anti-C5 antibody or antigen-binding fragment, and subcutaneous administration of about 200 mg of C5 iRNA, and (d) about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, subcutaneous administration of a dose of about 400 mg of anti-C5 antibody or antigen-binding fragment and subcutaneous administration of about 200 mg of C5 iRNA; or (vii) (a) about 200 mg SC dose of C5 iRNA; (b) about 28 days (±3, 4, 5, 6, or 7 days) later, a 30 or 60 mg/kg IV loading dose of anti-C5 antibody or antigen-binding fragment, a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment, and a 200 mg SC dose of C5 iRNA; and (c) about 29 days (±3, 4, 5, 6, or 7 days) later and about every 4 weeks (±3, 4, 5, 6, or 7 days) thereafter, a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and a 200 mg SC dose of C5 iRNA; or (viii) (a) about 4 weeks (±3, 4, 5, 6, or 7 days) after administration of ravulizumab, a 200 mg SC dose of C5 iRNA; (b) approximately 28 days (±3, 4, 5, 6, or 7 days) later, a 30 or 60 mg/kg IV loading dose of anti-C5 antibody or antigen-binding fragment, a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment, and a 200 mg SC dose of C5 iRNA; and (c) approximately 29 days (±3, 4, 5, 6, or 7 days) later and approximately every 4 weeks (±3, 4, 5, 6, or 7 days) thereafter, a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and a 200 mg SC dose of C5 iRNA. A method as claimed in any one of claims 61 to 67, wherein: Anti-C5 antibody or antigen-binding fragment and C5 iRNA are subcutaneously administered as a single injection of a co-formulation comprising anti-C5 antibody or antigen-binding fragment and C5 iRNA approximately every 4 weeks (±3, 4, 5, 6 or 7 days); and Anti-C5 antibody or antigen-binding fragment is subcutaneously administered again approximately every 4 weeks (±3, 4, 5, 6 or 7 days). A method as claimed in any one of claims 61 to 67, wherein: Anti-C5 antibody or antigen-binding fragment and C5 iRNA are administered subcutaneously approximately every 4 weeks (±3, 4, 5, 6 or 7 days) as separate injections of separate formulations, wherein one formulation comprises anti-C5 antibody or antigen-binding fragment and the other formulation comprises C5 iRNA; and Anti-C5 antibody or antigen-binding fragment is administered subcutaneously again approximately every 4 weeks (±3, 4, 5, 6 or 7 days). A method as claimed in any one of claims 61 to 67, wherein: Anti-C5 antibody or antigen-binding fragment and C5 iRNA are subcutaneously administered as a single injection of a co-formulation comprising anti-C5 antibody or antigen-binding fragment and C5 iRNA approximately every 4 weeks (±3, 4, 5, 6 or 7 days); and Anti-C5 antibody or antigen-binding fragment is subcutaneously administered again approximately every 2 weeks (±3, 4, 5, 6 or 7 days). A method as claimed in any one of claims 61 to 67, wherein: Anti-C5 antibody or antigen-binding fragment and C5 iRNA are administered subcutaneously approximately every 4 weeks (±3, 4, 5, 6 or 7 days) as separate injections of separate formulations, wherein one formulation comprises anti-C5 antibody or antigen-binding fragment and the other formulation comprises C5 iRNA; and Anti-C5 antibody or antigen-binding fragment is administered subcutaneously again approximately every 2 weeks (±3, 4, 5, 6 or 7 days). The method of any one of claims 61 to 70, wherein the individual has previously been treated with ravulizumab and/or eculizumab. The method of claim 72, wherein the administration of ravlizumab is intravenous or subcutaneous. The method of claim 72, wherein the amount of eculizumab administered intravenously is about 900 mg. The method of any one of claims 61 to 74, wherein the individual has previously received treatment with pasirimab monotherapy. The method of any one of claims 61 to 71, wherein the subject has not been treated with a complement inhibitor. A method as claimed in any one of claims 61 to 72 and 74 for treating or preventing a C5-related disease or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the individual has previously received eculizumab, wherein the individual: (i) is administered a dose of eculizumab intravenously and 200 mg of C5 iRNA is administered subcutaneously; (ii) up to about 14 days (±3, 4, 5, 6 or 7 days) later (about day 15) a dose of eculizumab; (iii) about 14 or 15 days (±3, 4, 5, 6 or 7 days) later (about day 29), an anti-C5 antibody or antigen-binding fragment is administered intravenously at a dose of about 60 mg/kg body weight, and about 400 mg/kg of C5 iRNA is administered subcutaneously; mg of anti-C5 antibody or antigen-binding fragment and about 200 mg of C5 iRNA subcutaneously; and (iv) starting about 28 days (±3, 4, 5, 6 or 7 days) later (about day 57) and about every about 28 days (±3, 4, 5, 6 or 7 days) thereafter, about 400 mg of anti-C5 antibody or antigen-binding fragment and about 200 mg of C5 iRNA subcutaneously administered. A method as claimed in any one of claims 61 to 73 for treating or preventing a C5-related disease or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the individual has previously received revlizumab, wherein the individual: (i) is administered a SC dose of about 200 mg of C5 iRNA approximately 28 days (±3, 4, 5, 6 or 7 days) after the last administration of revlizumab; (ii) is administered an IV dose of about 60 mg/kg of anti-C5 antibody or antigen-binding fragment, an SC dose of about 400 mg of anti-C5 antibody or antigen-binding fragment, and an SC dose of about 200 mg of C5 iRNA approximately 28 days (±3, 4, 5, 6 or 7 days) later (approximately day 29); (iii) starting about 28 days (±3, 4, 5, 6 or 7 days) later (about day 57) and about every about 28 days (±3, 4, 5, 6 or 7 days) thereafter, administering about 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and about 200 mg SC dose of C5 iRNA. A method as claimed in any of claims 61 to 71 and 76 for treating or preventing a C5-related disease or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the individual has not previously received or has not recently received a complement inhibitor treatment, wherein the individual: (i) is administered an intravenous dose of about 30 mg/kg of the anti-C5 antibody or antigen-binding fragment, an intravenous dose of about 400 mg of the antibody or fragment, and an intravenous dose of about 200 mg of the C5 iRNA on about day 1; and (ii) beginning about 28 days (±3, 4, 5, 6 or 7 days) later and about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, administering about 400 mg of SC anti-C5 antibody or antigen-binding fragment and approximately 200 mg SC C5 iRNA. A method for treating or preventing a C5-related disease or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the individual has previously received monotherapy with the anti-C5 antibody or antigen-binding fragment: (i) administering about 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and about 200 mg SC dose of C5 iRNA starting about 7 to 8 days (±3 days) after the last dose of anti-C5 antibody or antigen-binding fragment monotherapy or when the next dose of monotherapy is due and about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter; or (ii) Starting approximately 7 to 8 days (±3 days) after the last dose of anti-C5 antibody or antigen-binding fragment monotherapy or at the expiration of the next dose of monotherapy: approximately 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and approximately every 2 weeks (±3, 4, 5, 6, or 7 days) thereafter; and approximately 200 mg SC dose of C5 iRNA and approximately every 4 weeks (±3, 4, 5, 6, or 7 days) thereafter. A method for treating or preventing a C5-related disease or condition in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the individual has received one or more doses of a non-competitive anti-C5 antibody or antigen-binding fragment: (i) an intravenous loading dose of pasorizumab, and a dose of pasorizumab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W; then (2) beginning approximately 4 weeks thereafter (and continuing every 4 weeks thereafter), pasorizumab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W; or (1) after having received a dose of N/C One dose of C5 iRNA approximately 4 weeks after Ab and before the intravenous loading dose of pazelimab, and one dose of pazelimab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W; then (2) starting approximately 4 weeks thereafter (and continuing every 4 weeks thereafter), pazelimab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W; or (1) on the day the N/C Ab dose expires, one dose of C5 iRNA and a noncompetitive antibody or fragment (N/C Ab); (2) on the day the dose expires, the next dose of N/C Ab; (3) approximately 1-2 half-lives of the N/C Ab or when the next dose of N/C Ab expires, pazelimab 60 mg/kg IV loading dose, and pazelimumab 400 mg SC and cemdisiran 200 mg SC; (4) beginning 4 weeks thereafter (and continuing every 4 weeks thereafter), pazelimumab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W; or (1) approximately 1-2 half-lives after the last dose of N/C Ab; or on the day the next dose of N/C Ab is due; or after half the dose interval from the last dose of N/C Ab, a dose of C5 iRNA; (2) approximately another 1-2 half-lives after the N/C Ab, pazelimumab 60 mg/kg IV loading dose, pazelimumab 400 mg SC and cemdisiran 200 mg SC; and (3) Starting 4 weeks thereafter (and continuing every 4 weeks thereafter), pazelimab 400 mg SC Q4W and cemdisiran 200 mg SC Q4W. The method of claim 81, wherein: The C5 iRNA is Cemdisiran and the dose is 200 mg SC The C5 iRNA is Cemdisiran; The anti-C5 antibody or antigen-binding fragment thereof is Pazerizumab; The intravenous loading dose of Pazerizumab is 30 or 60 mg/kg; The non-competitive anti-C5 antibody or antigen-binding fragment is Eculizumab; The non-competitive anti-C5 antibody or antigen-binding fragment is Eculizumab and the dose expires every 1, 2, 3, or 4 weeks; The non-competitive anti-C5 antibody or antigen-binding fragment is Ravelizumab; The non-competitive anti-C5 antibody or antigen-binding fragment is Ravelizumab and the dose expires every 4 or 8 weeks; The half-life of the non-competitive antibody is about 11 days; and/or The half-life of the non-competitive antibody is about 32 days. The method of any of claims 46 to 53 and 61 to 82, wherein during treatment, the individual achieves or achieves and maintains one or more of the following: • Hemoglobin stabilization; • No red blood cell transfusion; • Hemoglobin did not decrease by ≥ 2 g/dL; • No breakthrough hemolysis; CH50 levels in the blood were completely suppressed relative to baseline (0 kIU/L) before treatment and/or during any breakthrough hemolysis event; • Lack of treatment-emergent adverse events; • Fatigue improved relative to pre-treatment; • FACIT-fatigue score improved by > 5 points relative to pre-treatment; • Improved according to the European Physical Functioning Scale; • European; organization for Research and Treatment of Cancer: Quality of Life Questionnaire Core 30 items (European; organization for Research and Treatment of Cancer: • Compared with before treatment, the physical function score of the Global Health Status/QOL Scale (GHS) was improved; • Compared with before treatment, the lactate dehydrogenase (LDH) content decreased; • Compared with before treatment, LDH ≦ 1.5 × upper limit of normal (ULN) was achieved; • LDH ≦ 1.0 × ULN was achieved and maintained; • Compared with before treatment, the blood bilirubin content decreased; • Compared with before treatment, the reticulocyte count decreased; • Compared with before treatment, the alternative pathway hemolytic activity analysis (AH50) decreased; • Decreased red blood cells and/or granulocytes in PNH compared to before treatment; • Improved fatigue, shortness of breath, muscle weakness, headache, abdominal pain, back/leg pain, chest discomfort, difficulty sleeping, difficulty thinking clearly, and/or difficulty swallowing compared to before treatment; • Improved kidney function as measured by estimated glomerular filtration rate (eGFR) compared to before treatment; • Decreased free hemoglobin in the blood compared to before treatment; • Decreased total C5 in the blood compared to before treatment; • Decreased PNH clone size compared to before treatment; and/or • Increased haptoglobin compared to before treatment. The method of any of claims 61 to 83, wherein the C5-related disease or condition is a condition in which complement activation is inappropriate or undesirable; a complication of hemodialysis; a lung disease or condition; a neurological disease; a parasitic disease; a post-ischemic reperfusion condition; a proteinuric kidney disease; a nephropathy; an adult respiratory distress syndrome; an adult respiratory distress syndrome (ARDS); age-related macular degeneration (AMD); an allergy; Alport syndrome; Alzheimer's disease; an autoimmune disease or; an immune complex disorder; an inflammatory disorder; an eye disease; an organic dust disease; an angiothrombotic thrombosis and a protein deficiency enteropathy); asthma; asthma; atherosclerosis; bronchoconstriction; bullous pemphigoid; C3 glomerulopathy; capillary leak syndrome; CHAPLE disease (CD55 deficiency with complement hyperactivation; chemical injury caused by irritants and/or chemicals; chronic obstructive pulmonary disease (COPD); complement activation caused by burns; complement activation caused by frozen sores; complement activation caused by obesity; complement activation caused by sepsis; Crohn's disease; diabetes mellitus; diabetic macular edema (DME); diabetic nephropathy; diabetic retinopathy; dry AMD; dyspnea ; emphysema; epilepsy; fibrosis; geographic atrophy (GA); glomerulopathy; Goodpasture's syndrome; Guillain-Barré syndrome; hemolytic anemia; hemoptysis; hereditary vascular edema; hyperacute allograft rejection; allergic pneumonitis; immune complex-associated inflammation; infectious diseases; inflammation in autoimmune diseases; hereditary CD59 deficiency; injury caused by inert dust and/or mineral substances; IL-2-induced toxicity during interleukin-2 therapy; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative nephritis; enteroarterial reperfusion after aortic reconstruction; multiple sclerosis; myasthenia gravis; myocardial infarction; neuromyelitis optica; ocular angiogenesis; Parkinson's disease; pneumonia; progressive renal failure; eczema; pulmonary embolism and infarction; pulmonary fibrosis; pulmonary vasculitis; renal ischemia; renal ischemia-reperfusion injury; rheumatoid arthritis; schizophrenia; SLE nephritis; smoke injury; stroke; systemic inflammatory response to post-pump syndrome with cardiopulmonary bypass or renal bypass; systemic lupus erythematosus (SLE); thermal injury; traumatic brain injury; uveitis; vasculitis; wet AMD; paroxysmal nocturnal hemoglobinuria (PNH); and/or xenograft rejection. The method of any one of claims 46 to 53 and 61 to 84, wherein the C5 iRNA and the anti-C5 antibody or antigen-binding fragment are co-formulated as a co-formulation, and both the antibody or fragment and the C5 iRNA are administered by a single injection of the co-formulation. The method of claim 85, wherein the pH of the co-formulation is about 6.5. The method of any one of claims 46 to 53 and 61 to 86, wherein the C5 iRNA and the anti-C5 antibody or antigen-binding fragment are co-formulated as a co-formulation comprising 100 mg/ml Cemdisiran and 100 mg/ml Paslimab; or 50 mg/ml Cemdisiran and 100 mg/ml Paslimab. The method of any of claims 46 to 53 and 61 to 87, wherein the co-formulation comprises: Cemdisiran; Paszelimumab expressed and isolated by mammalian host cells comprising β-hexosaminidase; a buffer; a viscosity reducer; a stabilizer; and a nonionic surfactant; the pH is about 6.5. The method of any one of claims 46 to 53 and 61 to 88, wherein the subcutaneous injection is performed using a prefilled syringe. The method of any one of claims 46 to 53 and 61 to 89, wherein the individual suffers from aplastic anemia and/or myelodysplastic syndrome. The method of any of claims 46 to 53 and 61 to 90, wherein the individual has previously received or further comprises administering to the individual: • one or more subcutaneous or intravenous doses of pazelimab; • one or more 400 mg subcutaneous doses of pazelimab; • one or more subcutaneous or intravenous doses of anti-C5 antibody or antigen-binding fragment prior to (any of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days prior to) , after or during administration of 400 mg subcutaneous pazelimab and 200 mg subcutaneous cemdisiran; • One or more subcutaneous or intravenous doses of eculizumab; • One or more subcutaneous or intravenous doses of ravulizumab; • One or more subcutaneous or intravenous doses of cemdisiran; • One or more subcutaneous or intravenous doses of C5 iRNA; • One or more subcutaneous doses of 800 mg of paselimab; • One or more subcutaneous doses of 800 mg of an anti-C5 antibody or antigen-binding fragment; • One or more intravenous doses of 30 mg/kg body weight of paselimab; • One or more intravenous doses of 30 mg/kg body weight of an anti-C5 antibody or antigen-binding fragment; • One or more intravenous doses of about 60 mg/kg body weight of paselimab; • one or more intravenous doses of about 60 mg/kg body weight of an anti-C5 antibody or antigen-binding fragment; • one or more subcutaneous doses of about 800 mg of paslimab; • one or more subcutaneous doses of about 800 mg of an anti-C5 antibody or antigen-binding fragment; • one intravenous dose of about 60 mg/kg body weight of paslimab, followed by one or more subcutaneous doses of about 800 mg of paslimab; • one intravenous dose of about 60 mg/kg body weight of an anti-C5 antibody or antigen-binding fragment, followed by one or more subcutaneous doses of about 800 mg of an anti-C5 antibody or antigen-binding fragment; • One or more intravenous doses of ≧300, ≧600, ≧900 or ≧1200 mg of eculizumab; • One or more subcutaneous doses of 200 mg of cemdisiran; and/or • One or more subcutaneous doses of 200 mg of C5 iRNA. A method as in any of claims 46 to 53 and 61 to 91, wherein: • The intravenous administration of the anti-C5 antibody or antigen-binding fragment is separated from the subcutaneous administration of the anti-C5 antibody or antigen-binding fragment or C5 iRNA by about 30 minutes; • The subcutaneous administration of the anti-C5 antibody or antigen-binding fragment and C5 iRNA is followed by an observation period of about 30 minutes, 1 hour or 2 hours; and/or • The subcutaneous administration of the C5 iRNA is followed by an observation period of about 30 minutes, 1 hour or 2 hours. The method of any of claims 46 to 53 and 61 to 92, wherein the individual is further treated with intensified treatment comprising one or more 30 mg/kg IV doses of an anti-C5 antibody or antigen-binding fragment if the individual exhibits one or more of the following criteria: • breakthrough hemolysis not due to complement activation disorder; and/or • increase in LDH ≧2 × ULN due to complement activation disorder. The method of any of claims 46 to 53 and 61 to 94, wherein the individual receives a boost if the individual exhibits one or more of the following criteria: • breakthrough hemolysis not due to complement activation conditions; and/or • increase in LDH ≥ 2 × ULN due to complement activation conditions, wherein: (1) if the individual has received a treatment regimen comprising subcutaneous administration of about 400 mg of an anti-C5 antibody or antigen conjugate approximately every 4 weeks (±3, 4, 5, 6, or 7 days) and subcutaneous administration of about 200 mg of a C5 iRNA approximately every 4 weeks (±3, 4, 5, 6, or 7 days); then a single 30 mg/kg dose on the day of the boost IV dose of anti-C5 antibody or antigen-binding fragment, and a booster regimen of about 400 mg of anti-C5 antibody or antigen-binding fragment administered subcutaneously approximately every 2 weeks (±3, 4, 5, 6, or 7 days) and about 200 mg of C5 iRNA administered subcutaneously approximately every 4 weeks (±3, 4, 5, 6, or 7 days) starting on the day of the booster; or (2) if the individual has received a treatment regimen comprising about 400 mg of anti-C5 antibody or antigen-binding fragment administered subcutaneously approximately every 2 weeks (±3, 4, 5, 6, or 7 days) and about 200 mg of C5 iRNA administered subcutaneously approximately every 4 weeks (±3, 4, 5, 6, or 7 days); then a single 30 mg/kg dose on the day of the booster IV dose of anti-C5 antibody or antigen-binding fragment, and reinitiate on the day of boost a treatment regimen comprising subcutaneous administration of about 400 mg of anti-C5 antibody or antigen-binding fragment approximately every 2 weeks (±3, 4, 5, 6, or 7 days) and subcutaneous administration of about 200 mg of C5 iRNA approximately every 4 weeks (±3, 4, 5, 6, or 7 days). The method of any one of claims 46 to 53 or 61 to 94, wherein the anti-C5 antibody or antigen-binding fragment or Pasqualimab is expressed in a mammalian host cell and the iRNA or Cemdisiran is chemically synthesized. The method of claim 95, wherein the host cell is a Chinese hamster ovary cell. A method as claimed in any one of claims 46 to 53 or 61 to 96, wherein the anti-C5 antibody or antigen-binding fragment and C5 iRNA are co-formulated as a co-formulation comprising • a molar ratio of no more than about 2.1 parts per million (ppm) of β-hexosaminidase to the antibody or antigen-binding fragment; • including no more than about 0.170 micrograms/ml β-hexosaminidase, • including no more than about 0.04 micrograms/ml β-hexosaminidase; and/or • about 0.04; 0.05; 0.06; 0.0605; 0.063; 0.07; 0.0765; 0.078; 0.08; 0.14; 0.141; 0.15; 0.1525; 0.166; or 0.17 micrograms/ml β-hexosaminidase; or no more than any of these concentrations. The method of any one of claims 61 to 97, wherein the antibody or antigen-binding fragment thereof is (1) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 2, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 10; (2) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 18, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 26; (3) a HCVR comprising a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 1 HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 34, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: 42; (4) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 50, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: 58; (5) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 66, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: (6) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 82, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 90; (7) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 98, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 106; (8) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 98, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 106; HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 98, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: 114; (9) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 122, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: 106; (10) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 98, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: (11) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 138, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 106; (12) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 106; (13) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 106; 122, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 130; (14) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 114; (15) a HCVR comprising HCDR1, HCDR2, and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 146, and a LCVR comprising LCDR1, LCDR2, and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: (16) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 138, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 130; (17) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 154, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 162; (18) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 138, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 130; HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 170, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: 178; (19) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 186, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: 194; (20) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) having an amino acid sequence as shown in SEQ ID NO: 202, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) having an amino acid sequence as shown in SEQ ID NO: (22) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 234, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 242; (23) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 234, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 242; HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 250, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 258; (24) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 266, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 258; (25) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 274, and a LCVR comprising a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: (26) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 290, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 298; (27) a HCVR comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 306, and a LCVR comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 314; (28) a HCVR comprising SEQ ID NO: 314; HCVRs comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 322, and LCVRs comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 330; and/or (29) HCVRs comprising HCDR1, HCDR2 and HCDR3 of a heavy chain variable region (HCVR) comprising the amino acid sequence shown in SEQ ID NO: 338, and LCVRs comprising LCDR1, LCDR2 and LCDR3 of a light chain variable region (LCVR) comprising the amino acid sequence shown in SEQ ID NO: 346. The method of any one of claims 46 to 53 and 61 to 98, wherein the C5 iRNA comprises an RNA strand complementary to an mRNA transcribed from the sense strand DNA sequence of the C5 gene AAGCAAGATATTTTTATAATA (nucleotides 782-802 of SEQ ID NO: 360). The method of any one of claims 46 to 53 and 61 to 99, wherein the C5 iRNA is a double-stranded RNA (dsRNA) agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises a complementary region comprising at least 17 consecutive nucleotides that differ from the nucleotide sequence of 5'- UAUUAUAAAAAUAUCUUGCUUUU-3' (SEQ ID NO: 364) by no more than 3 nucleotides, and wherein the dsRNA agent comprises at least one modified nucleotide. The method of any one of claims 46 to 53 and 61 to 100, wherein the C5 iRNA is a double-stranded RNA (dsRNA) agent comprising a sense strand and an antisense strand, wherein the sense strand comprises 5'-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3' (SEQ ID NO: 406) and the antisense strand comprises 5'-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3' (SEQ ID NO: 369), wherein a, g, c and u are 2'-0-methyl (2'-OMe) A, G, C and U, respectively; Af, Gf, Cf and Uf are 2'-fluoro A, G, C and U, respectively; dT is a deoxythymidine nucleotide; s is a phosphorothioate linkage; and wherein the sense strand is bound to a ligand at the 3' end . The method of any one of claims 61 to 101, wherein the C5 iRNA and the antibody or antigen-binding fragment thereof that specifically binds to C5 are in the form of a co-formulation of any one of claims 1 to 45. The method of any one of claims 46 to 53 and 61 to 102, wherein the C5 iRNA and the anti-C5 antibody or antigen-binding fragment thereof are in the form of a single co-formulation, and when administered subcutaneously, the co-formulation is administered in one or two or more injections. The method of any one of claims 46 to 53 and 61 to 103, wherein the C5 iRNA and the anti-C5 antibody or antigen-binding fragment thereof are in the form of a single co-formulation, and when administered subcutaneously, the co-formulation is administered as two injections. The method of any one of claims 46 to 104, wherein the C5 iRNA is Cemdisiran. The method of claim 105, wherein Cemdisiran is in the form of a Na ⁺ salt. The method of any one of claims 46 to 106, wherein the anti-C5 antibody or antigen-binding fragment thereof is paslimab.