Nothing Special   »   [go: up one dir, main page]

WO2021025899A1 - Compositions pharmaceutiques à base d'oligomères morpholino phosphorodiamidate - Google Patents

Compositions pharmaceutiques à base d'oligomères morpholino phosphorodiamidate Download PDF

Info

Publication number
WO2021025899A1
WO2021025899A1 PCT/US2020/043824 US2020043824W WO2021025899A1 WO 2021025899 A1 WO2021025899 A1 WO 2021025899A1 US 2020043824 W US2020043824 W US 2020043824W WO 2021025899 A1 WO2021025899 A1 WO 2021025899A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
golodirsen
casimersen
potassium
another embodiment
Prior art date
Application number
PCT/US2020/043824
Other languages
English (en)
Inventor
Thomas Holt
Original Assignee
Sarepta Therapeutics, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sarepta Therapeutics, Inc. filed Critical Sarepta Therapeutics, Inc.
Publication of WO2021025899A1 publication Critical patent/WO2021025899A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system

Definitions

  • Antisense technology provides a means for modulating the expression of one or more specific gene products, including alternative splice products, and is uniquely useful in a number of therapeutic, diagnostic, and research applications.
  • the principle behind antisense technology is that an antisense compound, e.g., an oligonucleotide, which hybridizes to a target nucleic acid, modulates gene expression activities such as transcription, splicing or translation through any one of a number of antisense mechanisms.
  • the sequence specificity of antisense compounds makes them attractive as tools for target validation and gene functionalization, as well as therapeutics to selectively modulate the expression of genes involved in disease.
  • Duchenne muscular dystrophy is caused by a defect in the expression of the protein dystrophin.
  • the gene encoding the protein contains 79 exons spread out over more than 2 million nucleotides of DNA. Any exonic mutation that changes the reading frame of the exon, or introduces a stop codon, or is characterized by removal of an entire out of frame exon or exons, or duplications of one or more exons, has the potential to disrupt production of functional dystrophin, resulting in DMD.
  • SSOs splice switching oligonucleotides
  • Golodirsen is a phosphorodiamidate morpholino oligomer (PMO) designed to skip exon 53 of the human dystrophin gene in patients with DMD who are amendable to exon 53 skipping to restore the read frame and produce a functional shorter form of the dystrophin protein.
  • PMO phosphorodiamidate morpholino oligomer
  • Casimersen is a phosphorodiamidate morpholino oligomer (PMO) designed to skip exon 45 of the human dystrophin gene in patients with DMD who are amendable to exon 45 skipping to restore the read frame and produce a functional shorter form of the dystrophin protein.
  • PMO phosphorodiamidate morpholino oligomer
  • Sarepta Therapeutics, Inc. submitted a New Drug Application (NDA) to the United States Food and Drug Administration (FDA) seeking approval for the treatment of DMD in patients amendable to exon 45 skipping.
  • NDA New Drug Application
  • FDA United States Food and Drug Administration
  • compositions comprising golodirsen wherein the concentration of golodirsen is about 50 mg/mL of the pharmaceutical composition. Also provided herein are methods of treating a muscle disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of the disclosure.
  • a pharmaceutical composition comprising: a) golodirsen; b) sodium chloride; c) potassium chloride; d) potassium phosphate monobasic; e) sodium phosphate dibasic; and
  • a pharmaceutical composition comprising: a) 40-60 mg of golodirsen; b) 6.4-9.6 mg of sodium chloride; c) 0.16-0.24 mg of potassium chloride; d) 0.16-0.24 mg of potassium phosphate monobasic; e) 0.91-1.37 mg of sodium phosphate dibasic; and 1) water.
  • a pharmaceutical composition comprising: a) 80-120 mg of golodirsen; b) 12.8-19.2 mg of sodium chloride; c) 0.32-0.48 mg of potassium chloride; d) 0.32-0.48 mg of potassium phosphate monobasic; e) 1.82-2.74 mg of sodium phosphate dibasic; and 1) water.
  • a pharmaceutical composition comprising: a) 400-600 mg of golodirsen; b) 64-96 mg of sodium chloride; c) 1.6-2.4 mg of potassium chloride; d) 1.6-2.4 mg of potassium phosphate monobasic; e) 9.1-13.7 mg of sodium phosphate dibasic; and 1) water.
  • compositions of the disclosure comprise a concentration of golodirsen of about 50 mg/mL of the pharmaceutical composition.
  • compositions comprising casimersen wherein the concentration of casimersen is about 50 mg/mL of the pharmaceutical composition. Also provided herein are methods of treating a muscle disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of the disclosure.
  • a pharmaceutical composition comprising: a) casimersen; b) sodium chloride; c) potassium chloride; d) potassium phosphate monobasic; e) sodium phosphate dibasic; and 1) water, wherein the concentration of casimersen is about 50 mg/mL of the pharmaceutical composition.
  • a pharmaceutical composition comprising: a) 40-60 mg of casimersen; b) 6.4-9.6 mg of sodium chloride; c) 0.16-0.24 mg of potassium chloride; d) 0.16-0.24 mg of potassium phosphate monobasic; e) 0.91-1.37 mg of sodium phosphate dibasic; and 1) water.
  • a pharmaceutical composition comprising: a) 80-120 mg of casimersen; b) 12.8-19.2 mg of sodium chloride; c) 0.32-0.48 mg of potassium chloride; d) 0.32-0.48 mg of potassium phosphate monobasic; e) 1.82-2.74 mg of sodium phosphate dibasic; and 1) water.
  • a pharmaceutical composition comprising: a) 400-600 mg of casimersen; b) 64-96 mg of sodium chloride; c) 1.6-2.4 mg of potassium chloride; d) 1.6-2.4 mg of potassium phosphate monobasic; e) 9.1-13.7 mg of sodium phosphate dibasic; and 1) water.
  • compositions of the disclosure comprise a concentration of casimersen of about 50 mg/mL of the pharmaceutical composition.
  • provided herein is a method of treating a muscle disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition provided herein.
  • Fig. 1 and Fig. 2 show a representative analytical high performance liquid chromatography (HPLC) chromatogram of a synthesized and deprotected golodirsen (SRP- 4053) crude drug substance (see Example 1).
  • HPLC high performance liquid chromatography
  • Fig.3 and Fig. 4 show a representative analytical HPLC chromatogram of a purified golodirsen drug substance solution (see Example 2).
  • Fig. 5 and Fig. 6 show a representative analytical HPLC chromatogram of a desalted and lyophilized golodirsen drug substance (see Example 2).
  • Fig. 7 and Fig. 8 show a representative analytical high performance liquid chromatography (HPLC) chromatogram of a synthesized and deprotected casimersen (SRP- 4045) crude drug substance (see Example 4).
  • HPLC high performance liquid chromatography
  • Fig.9 and Fig. 10 show a representative analytical HPLC chromatogram of a purified casimersen drug substance solution (see Example 5).
  • Fig. 11 and Fig. 12 show a representative analytical HPLC chromatogram of a desalted and lyophilized casimersen drug substance (see Example 5).
  • compositions comprising golodirsen or casimersen.
  • methods of treating a muscle disease in a subject in need thereof comprising administering to the subject a pharmaceutical composition of the disclosure.
  • the morpholino oligonucleotides described herein display stronger affinity for DNA and RNA without compromising sequence selectivity, relative to native or unmodified oligonucleotides.
  • the oligonucleotides of the disclosure minimize or prevent cleavage by RNase H.
  • the antisense oligonucleotides of the disclosure do not activate RNase H.
  • support-bound refers to a chemical moiety that is covalently linked to a support-medium.
  • support-medium refers to any material including, for example, any particle, bead, or surface, upon which an oligomer can be attached or synthesized upon, or can be modified for attachment or synthesis of an oligomer.
  • Representative substrates include, but are not limited to, inorganic supports and organic supports such as glass and modified or functionalized glass, plastics (including acrylics, polystyrene and copolymers of styrene and other materials, polypropylene, polyethylene, polybutylene, polyurethanes, TEFLON, etc.), polysaccharides, nylon or nitrocellulose, ceramics, resins, silica or silica- based materials including silicon and modified silicon, carbon, metals, inorganic glasses, plastics, optical fiber bundles, and a variety of other polymers.
  • Particularly useful solid supports and solid surfaces for some embodiments are located within a flow cell apparatus.
  • the support-medium comprises polystyrene with 1% crosslinked divinylbenzene.
  • representative support-medium comprise at least one reactive site for attachment or synthesis of an oligomer.
  • a support-medium of the disclosure comprises one or more terminal amino or hydroxyl groups capable of forming a chemical bond with an incoming nucleoside or other activated group for attaching or synthesizing an oligomer.
  • CPG controlled pore glass
  • oxalyl- controlled pore glass see, e.g., Alul et al., Nucleic Acids Research 1991, 19, 1527
  • silica- containing particles such as porous glass beads and silica gel such as that formed by the reaction of trichloro-[3-(4-chloromethyl)phenyl]propylsilane and porous glass beads (see Parr and Grohmann. Angew. Chem. Internal. Ed.
  • POROS cross-linked styrene/divinylbenzene copolymer beaded matrix
  • POROS cross-linked styrene/divinylbenzene copolymer beaded matrix
  • POROS cross-linked styrene/divinylbenzene copolymer beaded matrix
  • soluble support-medium such as polyethylene glycol PEG'S (see Bonora et al, Organic Process Research & Development 2000, 4, 225-231)
  • PEPS support which is a polyethylene (PE) film with pendant long-chain polystyrene (PS) grafts (see Berg et al, J. Am. Chem. Soc.
  • copolymers of dimethylacrylamide cross-linked withN,N'- bisacryloylethylenediamine, including a known amount of N-tertbutoxycarbonyl-beta-alanyl- N'-acryloylhexamethylenediamine see Atherton et al, J. Am. Chem. Soc. 1975, 97, 6584; Atherton et al, Bioorg. Chem. 1979, 8, 351; and Atherton et al, J. Chem. Soc. Perkin 11981, 538
  • glass particles coated with a hydrophobic cross-linked styrene polymer see Scott et al, J. Chrom.
  • flow cell apparatus refers to a chamber comprising a surface (e.g., solid surface) across which one or more fluid reagents (e.g., liquid or gas) can be flowed.
  • a surface e.g., solid surface
  • fluid reagents e.g., liquid or gas
  • treating comprises a treatment relieving, reducing or alleviating at least one symptom in a subject or effecting a delay of progression of a disease.
  • treatment can be the diminishment of one or several symptoms of a disorder or complete eradication of a disorder, such as muscular dystrophy, e.g., Duchenne muscular dystrophy.
  • the term “treat” also denotes to arrest, delay the onset (i.e., the period prior to clinical manifestation of a disease) or reduce the risk of developing or worsening a disease.
  • protection is used herein to mean prevent, delay, or treat, or all, as appropriate, development, continuance or aggravation of a disease in a subject, e.g., a mammal or human.
  • prevent comprises the prevention of at least one symptom associated with or caused by the state, disease or disorder being prevented.
  • subject or “patient” as used herein is intended to include animals, which are capable of suffering from or afflicted with a muscle disease or any disorder involving, directly or indirectly, a muscle disease.
  • subjects include mammals, e.g., humans, apes, monkeys, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals.
  • the subject is a human, e.g., a human suffering from, at risk of suffering from, or potentially capable of suffering from muscle diseases.
  • “Amendable to exon 53 skipping” as used herein with regard to a subject or patient is intended to include subjects and patients having various mutations in the dystrophin gene which are amenable to exon 53 skipping.
  • Non-limiting examples of mutations in the following exons of the dystrophin gene are amenable to exon 53 skipping include, e.g.: exons 3 to 52, 4 to 52, 5 to 52, 6 to 52, 9 to 52, 10 to 52, 11 to 52, 13 to 52, 14 to 52, 15 to 52, 16 to 52, 17 to 52, 19 to 52, 21 to 52, 23 to 52, 24 to 52, 25 to 52, 26 to 52, 27 to 52, 28 to 52, 29 to
  • Leiden Duchenne muscular dystrophy mutation database Leiden University Medical Center, The Netherlands. Determining whether a patient has a mutation in the dystrophin gene that is amenable to exon skipping is within the purview of one of skill in the art (see, e.g., Aartsma- Rus et al, HumMut 2009, 30, 293-299; Gurvich et ak, Hum Mutat. 2009; 30(4) 633-640, and Fletcher et al. (2010) Molecular Therapy 18(6) 1218-1223).
  • “Amendable to exon 45 skipping” as used herein with regard to a subject or patient is intended to include subjects and patients having various mutations in the dystrophin gene which are amenable to exon 45 skipping.
  • Non-limiting examples of mutations in the following exons of the dystrophin gene are amenable to exon 45 skipping include, e.g.: exons 7 to 42, 12 to 42, 18 to 42, 44 to 46, 44 to 47, 44 to 48, 44 to 49, 44 to 51, 44 to 53, 44 to 55, 44 to 57, or 44 to 59, or exon 44.
  • USP refers to United States Pharmacopeia, incorporated herein by reference in its entirety, and indicates that the material so identified conforms to USP specification.
  • NF refers to National Formulary, incorporated herein by reference in its entirety, and indicates that the material so identified conforms to NF specifications.
  • Morpholino-based oligomers are detailed, for example, in U.S. Patent Nos. 5,698,685, 5,217,866, 5,142,047, 5,034,506, 5,166,315, 5,185,444, 5,521,063, 5,506,337, 8,299,206, and 8,076,476, U.S. Patent Application Publication Nos. US 2016/0040162 and US 2019/0262375 Al, International Patent Application Publication Nos. WO/2009/064471 and WO/2012/043730, and Summerton et al, Antisense Nucleic Acid Drug Dev. 1997, 7, 187-195, each of which are hereby incorporated by reference in their entirety.
  • Golodirsen (see e.g., Example 2 of U.S. Patent Application Publication No. US 2016/0040162 , incorporated herein by reference in its entirety) has been the subject of clinical studies to test its safety and efficacy, and clinical development is ongoing.
  • Golodirsen is a phosphorodiamidate morpholino (PMO) antisense oligonucleotide.
  • the dystrophin therapeutic “golodirsen,” is also known as “SRP-4053.”
  • Golodirsen is a PMO having the base sequence 5'- -3' (SEQ ID NO: 1). Golodirsen is registered under CAS Registry Number 1422959-91-8.
  • RNA [P- deoxy-P-(dimethylamino)](2',3'-dideoxy-2',3'-imino-2',3'-seco)(2'a 5')(G-m5U-m5U-G-C- C-m5U-C-C-G-G-m5U-m5U-C-m5U-G-A-A-G-G-m5U-G-m5U-m5U-C), 5'-[P-[4-[[2-[2-(2- hydroxyethoxy)ethoxy]ethoxy]carbonyl]-l-piperazinyl]-N,N-dimethylphosphonamidate], all- P-iTMZ>o-[P,2',3'-trideoxy-P-(dimethylamino)-2',3'-imino-2',3'-seco](2'a®5')(G-T-T-G-C-C
  • Golodirsen has the following structure:
  • Casimersen (see e.g., Example 3 of U.S. Patent Application Publication No. US 2019/0262375, incorporated herein by reference in its entirety) has been the subject of clinical studies to test its safety and efficacy, and clinical development is ongoing.
  • Casimersen is a phosphorodiamidate morpholino (PMO) antisense oligonucleotide.
  • the dystrophin therapeutic “casimersen,” is also known as “SRP-4045.”
  • Casimersen is a PMO having the base sequence 5'- 3' (SEQ ID NO: 2). Casimersen is registered under CAS Registry Number 1422958-19-7.
  • Chemical names include: all-P-amb ⁇ ) - ⁇ P.2'.3'-trideo ⁇ y-P-(dimethylamino)-2'.3'-imino-2'.3'-seco
  • Casimersen has the following structure:
  • sequence of bases from the 5' end to the 3' end is:
  • the structural formulae of golodirsen and casimersen is a continuous structural formula from 5’ to 3’, and, for the convenience of depicting the entire formula in a compact form in the above structural formulae, Applicants have included various illustration breaks labeled “BREAK A,” “BREAK B,” and “BREAK C.” As would be understood by the skilled artisan, for example, each indication of “BREAK A” shows a continuation of the illustration of the structural formula at these points. The skilled artisan understands that the same is true for each instance of “BREAK B,” and “BREAK C” in the structural formulae of golodirsen and casimersen above. None of the illustration breaks, however, are intended to indicate, nor would the skilled artisan understand them to mean, an actual discontinuation of the structural formula of golodirsen and casimersen above.
  • Oligomeric compounds of the disclosure may have asymmetric centers, chiral axes, and chiral planes (as described, for example, in: E. L. Eliel and S. H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190, and March, J., Advanced Organic Chemistry, 3d. Ed., Chap. 4, John Wiley & Sons, New York (1985)), and may occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers. Oligomeric compounds of the disclosure herein specifically mentioned, without any indication of their stereochemistry, are intended to represent all possible isomers and mixtures thereof. Specifically, without wishing to be bound by any particular theory, oligomeric compounds of the disclosure are prepared, as discussed herein, from activated morpholino subunits including Compound C, Compound D, Compound E, and Compound F:
  • Each of Compound C, Compound D, Compound E, and Compound F may be prepared, for example, from the corresponding beta-D-ribofuranosyl as depicted below:
  • each morpholino subunit may otherwise be produced based on selection of, for example, an alpha-L- ribofuranosyl, alpha-D- ribofuranosyl, beta-L-ribofuranosyl, or beta-D-ribofuranosyl starting material.
  • oligomeric compounds of the disclosure comprise one or more phosphorous-containing intersubunit linkages, which create a chiral center at each phosphorus, each of which is designated as either an “Sp” or “Rp” configuration as understood in the art. Without wishing to be bound by any particular theory, this chirality creates stereoisomers, which have identical chemical composition but different three- dimensional arrangement of their atoms.
  • each phosphorous intersubunit linkage occurs randomly during synthesis of, for example, oligomeric compounds of the disclosure.
  • the synthesis process generates an exponentially large number of stereoisomers of an oligomeric compound of the disclosure because oligomeric compounds of the disclosure are comprised of numerous phosphorous-containing intersubunit linkages - with each phosphorous-containing intersubunit linkage having a random chiral configuration.
  • each intersubunit linkage of an additional morpholino subunit doubles the number of stereoisomers of the product, so that a conventional preparation of an oligomeric compound of the disclosure is in fact a highly heterogeneous mixture of 2 N stereoisomers, where N represents the number of phosphorous-containing intersubunit linkages.
  • compositions comprising golodirsen, or a pharmaceutically acceptable salt thereof, wherein the concentration of golodirsen is about 50 mg/mL of the pharmaceutical composition.
  • pharmaceutical compositions comprising casimersen, or a pharmaceutically acceptable salt thereof, wherein the concentration of casimersen is about 50 mg/mL of the pharmaceutical composition.
  • the compositions are suitable for use in treating a muscle disease.
  • a pharmaceutical composition comprising: a) golodirsen; b) sodium chloride; c) potassium chloride; d) potassium phosphate monobasic; e) sodium phosphate dibasic; and
  • a pharmaceutical composition comprising: a) 40-60 mg of golodirsen; b) 6.4-9.6 mg of sodium chloride; c) 0.16-0.24 mg of potassium chloride; d) 0.16-0.24 mg of potassium phosphate monobasic; e) 0.91-1.37 mg of sodium phosphate dibasic; and
  • the pharmaceutical composition comprises about 50 mg of golodirsen. In another embodiment of this aspect, the total volume of the pharmaceutical composition is about 1 mL.
  • a pharmaceutical composition comprising: a) about 50 mg of golodirsen; b) about 8 mg of sodium chloride; c) about 0.2 mg of potassium chloride; d) about 0.2 mg of potassium phosphate monobasic; e) about 1.14 mg of sodium phosphate dibasic; and
  • the total volume of the pharmaceutical composition is about 1 mL.
  • a pharmaceutical composition comprising: a) 50 mg of golodirsen; b) 8 mg of sodium chloride; c) 0.2 mg of potassium chloride; d) 0.2 mg of potassium phosphate monobasic; e) 1.14 mg of sodium phosphate dibasic; and 1) water.
  • the total volume of the pharmaceutical composition is 1 mL.
  • a pharmaceutical composition comprising: a) 80-120 mg of golodirsen; b) 12.8-19.2 mg of sodium chloride; c) 0.32-0.48 mg of potassium chloride; d) 0.32-0.48 mg of potassium phosphate monobasic; e) 1.82-2.74 mg of sodium phosphate dibasic; and 1) water.
  • the pharmaceutical composition comprises about 100 mg of golodirsen. In another embodiment of this aspect, the total volume of the pharmaceutical composition is about 2 mL.
  • a pharmaceutical composition comprising: a) about 100 mg of golodirsen; b) about 16 mg of sodium chloride; c) about 0.4 mg of potassium chloride; d) about 0.4 mg of potassium phosphate monobasic; e) about 2.28 mg of sodium phosphate dibasic; and 1) water.
  • the total volume of the pharmaceutical composition is about 2 mL.
  • a pharmaceutical composition comprising: a) 100 mg of golodirsen; b) 16 mg of sodium chloride; c) 0.4 mg of potassium chloride; d) 0.4 mg of potassium phosphate monobasic; e) 2.28 mg of sodium phosphate dibasic; and 1) water.
  • the total volume of the pharmaceutical composition is 2 mL.
  • a pharmaceutical composition comprising: a) 400-600 mg of golodirsen; b) 64-96 mg of sodium chloride; c) 1.6-2.4 mg of potassium chloride; d) 1.6-2.4 mg of potassium phosphate monobasic; e) 9.1-13.7 mg of sodium phosphate dibasic; and 1) water.
  • the pharmaceutical composition comprises about 500 mg of golodirsen. In another embodiment, the total volume of the pharmaceutical composition is about 10 mL.
  • a pharmaceutical composition comprising: a) about 500 mg of golodirsen; b) about 80 mg of sodium chloride; c) about 2 mg of potassium chloride; d) about 2 mg of potassium phosphate monobasic; e) about 11.4 mg of sodium phosphate dibasic; and 1) water.
  • the total volume of the pharmaceutical composition is about 10 mL.
  • a pharmaceutical composition comprising: a) 500 mg of golodirsen; b) 80 mg of sodium chloride; c) 2 mg of potassium chloride; d) 2 mg of potassium phosphate monobasic; e) 11.4 mg of sodium phosphate dibasic; and 1) water.
  • the total volume of the pharmaceutical composition is 10 mL.
  • the concentration of golodirsen is about 50 mg/mL of the pharmaceutical composition.
  • the concentration of golodirsen in the pharmaceutical composition ranges from about 45 mg/mL to about 55 mg/mL.
  • the concentration of golodirsen in the pharmaceutical composition ranges from 45 mg/mL to 55 mg/mL.
  • the concentration of golodirsen in the pharmaceutical composition ranges from about 47.5 mg/mL to about 52.5 mg/mL.
  • the concentration of golodirsen in the pharmaceutical composition ranges from
  • the concentration of golodirsen in the pharmaceutical composition is about 50 mg/mL ⁇ 10%. In some embodiments, the concentration of golodirsen in the pharmaceutical composition is 50 mg/mL ⁇ 10%. In certain embodiments, the concentration of golodirsen in the pharmaceutical composition is within ⁇ 10% of 50 mg/mL. In some embodiments, the concentration of golodirsen in the pharmaceutical composition is about 50 mg/mL ⁇ 5%. In some embodiments, the concentration of golodirsen in the pharmaceutical composition is 50 mg/mL ⁇ 5%.
  • the concentration of golodirsen in the pharmaceutical composition is within ⁇ % of 50 mg/mL. In some embodiments, the concentration of golodirsen ranges from about 45.5 mg/mL to 55 mg/mL, about 46 mg/mL to about 54.5 mg/mL, about 46.5 mg/mL to about 54 mg/mL, about 47 mg/mL to about 53.5 mg/mL, about
  • the concentration of golodirsen in the pharmaceutical composition is about 45 mg/mL, 45.5 mg/mL, 46 mg/mL, 46.5 mg/mL, 47 mg/mL, 47.5 mg/mL, 48 mg/mL, 48.5 mg/mL, 49 mg/mL, 49.5 mg/mL, 50 mg/mL, 50.5 mg/mL, 51 mg/mL, 51.5 mg/mL, 52 mg/mL, 52.5 mg/mL, 53 mg/mL, 53.5 mg/mL, 54 mg/mL, 54.5 mg/mL, or 55 mg/mL of the pharmaceutical composition.
  • the concentration of golodirsen is 45 mg/mL, 45.5 mg/mL, 46 mg/mL, 46.5 mg/mL, 47 mg/mL,
  • a pharmaceutical composition comprising: a) about 5 w/v % golodirsen; b) about 0.8 w/v % sodium chloride; c) about 0.02 w/v % potassium chloride; d) about 0.02 w/v % potassium phosphate monobasic; e) about 0.114 w/v % sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is about 1 mL. In another embodiment, the total volume of the composition is about 2 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is about 10 mL. In another embodiment, the total volume of the composition is 10 mL.
  • the pharmaceutical composition comprises about 50 mg of golodirsen. In some embodiments, the pharmaceutical composition comprises 50 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises about 100 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 100 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises about 500 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 500 mg of golodirsen.
  • a pharmaceutical composition comprising: a) 5 w/v % golodirsen; b) 0.8 w/v % sodium chloride; c) 0.02 w/v % potassium chloride; d) 0.02 w/v % potassium phosphate monobasic; e) 0.114 w/v % sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is 1 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is 10 mL. In another embodiment of this aspect that specifies certain w/v percentages, the pharmaceutical composition comprises 50 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 100 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 500 mg of golodirsen.
  • a pharmaceutical composition comprising: a) about 50 mg/mL golodirsen; b) about 8 mg/mL sodium chloride; c) about 0.2 mg/mL potassium chloride; d) about 0.2 mg/mL potassium phosphate monobasic; e) about 1.14 mg/mL sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is about 1 mL. In another embodiment, the total volume of the composition is about 2 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is about 10 mL. In another embodiment, the total volume of the composition is 10 mL.
  • the pharmaceutical composition comprises about 50 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 50 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises about 100 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 100 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises about 500 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 500 mg of golodirsen.
  • a pharmaceutical composition comprising: a) 50 mg/mL golodirsen; b) 8 mg/mL sodium chloride; c) 0.2 mg/mL potassium chloride; d) 0.2 mg/mL potassium phosphate monobasic; e) 1.14 mg/mL sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is 1 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is 10 mL. In another embodiment, the pharmaceutical composition comprises 50 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 100 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 500 mg of golodirsen.
  • a pharmaceutical composition comprising: a) about 50 mg of golodirsen; b) about 8 mg of sodium chloride; c) about 0.2 mg of potassium chloride; d) about 0.2 mg of potassium phosphate monobasic; e) about 1.14 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is about 1 mL.
  • a pharmaceutical composition comprising: a) 50 mg of golodirsen; b) 8 mg of sodium chloride; c) 0.2 mg of potassium chloride; d) 0.2 mg of potassium phosphate monobasic; e) 1.14 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is 1 mL.
  • a pharmaceutical composition comprising: a) about 100 mg of golodirsen; b) about 16 mg of sodium chloride; c) about 0.4 mg of potassium chloride; d) about 0.4 mg of potassium phosphate monobasic; e) about 2.28 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is about 2 mL.
  • a pharmaceutical composition comprising: a) 100 mg of golodirsen; b) 16 mg of sodium chloride; c) 0.4 mg of potassium chloride; d) 0.4 mg of potassium phosphate monobasic; e) 2.28 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is 2 mL.
  • a pharmaceutical composition comprising: a) about 500 mg of golodirsen; b) about 80 mg of sodium chloride; c) about 2 mg of potassium chloride; d) about 2 mg of potassium phosphate monobasic; e) about 11.4 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is about 10 mL.
  • a pharmaceutical composition comprising: a) 500 mg of golodirsen; b) 80 mg of sodium chloride; c) 2 mg of potassium chloride; d) 2 mg of potassium phosphate monobasic; e) 11.4 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is 10 mL.
  • a pharmaceutical composition comprising: a) 50 mg of golodirsen; b) 8 mg of sodium chloride, USP; c) 0.2 mg of potassium chloride, USP; d) 0.2 mg of potassium phosphate monobasic, NF; e) 1.14 mg of sodium phosphate dibasic anhydrous, USP; and 1) water for injection, USP, wherein the total volume of the pharmaceutical composition is 1 mL, the pH of the pharmaceutical composition is about 7.5, and the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • a pharmaceutical composition comprising: a) 100 mg of golodirsen; b) 16 mg of sodium chloride, USP; c) 0.4 mg of potassium chloride, USP; d) 0.4 mg of potassium phosphate monobasic, NF; e) 2.28 mg of sodium phosphate dibasic anhydrous, USP; and 1) water for injection, USP, wherein the total volume of the pharmaceutical composition is 2 mL, the pH of the pharmaceutical composition is about 7.5, and the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • a pharmaceutical composition comprising: a) 500 mg of golodirsen; b) 80 mg of sodium chloride, USP; c) 2 mg of potassium chloride, USP; d) 2 mg of potassium phosphate monobasic, NF; e) 11.4 mg of sodium phosphate dibasic anhydrous, USP; and 1) water for injection, USP, wherein the total volume of the pharmaceutical composition is 10 mL, the pH of the pharmaceutical composition is about 7.5, and the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • a pharmaceutical composition comprising: a) 50 mg of golodirsen; b) 8 mg of sodium chloride; c) 0.2 mg of potassium chloride; d) 0.2 mg of potassium phosphate monobasic; e) 1.14 mg of sodium phosphate dibasic anhydrous; and 1) water for injection, wherein the total volume of the pharmaceutical composition is 1 mL, the pH of the pharmaceutical composition is about 7.5, and the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • a pharmaceutical composition comprising: a) 100 mg of golodirsen; b) 16 mg of sodium chloride; c) 0.4 mg of potassium chloride; d) 0.4 mg of potassium phosphate monobasic; e) 2.28 mg of sodium phosphate dibasic anhydrous; and 1) water for injection, wherein the total volume of the pharmaceutical composition is 2 mL, the pH of the pharmaceutical composition is about 7.5, and the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • a pharmaceutical composition comprising: a) 500 mg of golodirsen; b) 80 mg of sodium chloride; c) 2 mg of potassium chloride; d) 2 mg of potassium phosphate monobasic; e) 11.4 mg of sodium phosphate dibasic anhydrous; and 1) water for injection, wherein the total volume of the pharmaceutical composition is 10 mL, the pH of the pharmaceutical composition is about 7.5, and the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • a pharmaceutical composition comprising: a) casimersen; b) sodium chloride; c) potassium chloride; d) potassium phosphate monobasic; e) sodium phosphate dibasic; and 1) water, wherein the concentration of casimersen is about 50 mg/mL of the pharmaceutical composition.
  • a pharmaceutical composition comprising: a) 40-60 mg of casimersen; b) 6.4-9.6 mg of sodium chloride; c) 0.16-0.24 mg of potassium chloride; d) 0.16-0.24 mg of potassium phosphate monobasic; e) 0.91-1.37 mg of sodium phosphate dibasic; and 1) water.
  • the pharmaceutical composition comprises about 50 mg of casimersen. In another embodiment of this aspect, the total volume of the pharmaceutical composition is about 1 mL.
  • a pharmaceutical composition comprising: a) about 50 mg of casimersen; b) about 8 mg of sodium chloride; c) about 0.2 mg of potassium chloride; d) about 0.2 mg of potassium phosphate monobasic; e) about 1.14 mg of sodium phosphate dibasic; and 1) water.
  • the total volume of the pharmaceutical composition is about 1 mL.
  • a pharmaceutical composition comprising: a) 50 mg of casimersen; b) 8 mg of sodium chloride; c) 0.2 mg of potassium chloride; d) 0.2 mg of potassium phosphate monobasic; e) 1.14 mg of sodium phosphate dibasic; and 1) water.
  • the total volume of the pharmaceutical composition is 1 mL.
  • a pharmaceutical composition comprising: a) 80-120 mg of casimersen; b) 12.8-19.2 mg of sodium chloride; c) 0.32-0.48 mg of potassium chloride; d) 0.32-0.48 mg of potassium phosphate monobasic; e) 1.82-2.74 mg of sodium phosphate dibasic; and 1) water.
  • the pharmaceutical composition comprises about 100 mg of casimersen. In another embodiment of this aspect, the total volume of the pharmaceutical composition is about 2 mL.
  • a pharmaceutical composition comprising: a) about 100 mg of casimersen; b) about 16 mg of sodium chloride; c) about 0.4 mg of potassium chloride; d) about 0.4 mg of potassium phosphate monobasic; e) about 2.28 mg of sodium phosphate dibasic; and 1) water.
  • the total volume of the pharmaceutical composition is about 2 mL.
  • a pharmaceutical composition comprising: a) 100 mg of casimersen; b) 16 mg of sodium chloride; c) 0.4 mg of potassium chloride; d) 0.4 mg of potassium phosphate monobasic; e) 2.28 mg of sodium phosphate dibasic; and 1) water.
  • the total volume of the pharmaceutical composition is 2 mL.
  • a pharmaceutical composition comprising: a) 400-600 mg of casimersen; b) 64-96 mg of sodium chloride; c) 1.6-2.4 mg of potassium chloride; d) 1.6-2.4 mg of potassium phosphate monobasic; e) 9.1-13.7 mg of sodium phosphate dibasic; and
  • the pharmaceutical composition comprises about 500 mg of casimersen. In another embodiment, the total volume of the pharmaceutical composition is about 10 mL.
  • a pharmaceutical composition comprising: a) about 500 mg of casimersen; b) about 80 mg of sodium chloride; c) about 2 mg of potassium chloride; d) about 2 mg of potassium phosphate monobasic; e) about 11.4 mg of sodium phosphate dibasic; and
  • the total volume of the pharmaceutical composition is about 10 mL.
  • a pharmaceutical composition comprising: a) 500 mg of casimersen; b) 80 mg of sodium chloride; c) 2 mg of potassium chloride; d) 2 mg of potassium phosphate monobasic; e) 11.4 mg of sodium phosphate dibasic; and
  • the total volume of the pharmaceutical composition is 10 mL.
  • the concentration of casimersen is about 50 mg/mL of the pharmaceutical composition. In some embodiments, the concentration of casimersen in the pharmaceutical composition ranges from about 45 mg/mL to about 55 mg/mL. In some embodiments, the concentration of casimersen in the pharmaceutical composition ranges from 45 mg/mL to 55 mg/mL. In certain embodiments, the concentration of casimersen in the pharmaceutical composition ranges from about 47.5 mg/mL to about 52.5 mg/mL. In certain embodiments, the concentration of casimersen in the pharmaceutical composition ranges from 47.5 mg/mL to 52.5 mg/mL.
  • the concentration of casimersen in the pharmaceutical composition is about 50 mg/mL ⁇ 10%. In some embodiments, the concentration of casimersen in the pharmaceutical composition is 50 mg/mL ⁇ 10%. In certain embodiments, the concentration of casimersen in the pharmaceutical composition is within ⁇ 10% of 50 mg/mL. In some embodiments, the concentration of casimersen in the pharmaceutical composition is about 50 mg/mL ⁇ 5%. In some embodiments, the concentration of casimersen in the pharmaceutical composition is 50 mg/mL ⁇ 5%.
  • the concentration of casimersen in the pharmaceutical composition is within ⁇ % of 50 mg/mL. In some embodiments, the concentration of casimersen ranges from about 45.5 mg/mL to 55 mg/mL, about 46 mg/mL to about 54.5 mg/mL, about 46.5 mg/mL to about 54 mg/mL, about 47 mg/mL to about 53.5 mg/mL, about 47.5 mg/mL to about 53 mg/mL, about 45.5 mg/mL to about 52.5 mg/mL, about 45.5 mg/mL to about 52 mg/mL, about 48 mg/mL to about 51.5 mg/mL, about 48.5 mg/mL to about 51 mg/mL, about 49 mg/mL to about 50.5 mg/mL, or about 49.5 mg/mL to about 50 mg/mL of the pharmaceutical composition.
  • the concentration of casimersen in the pharmaceutical composition is about 45 mg/mL, 45.5 mg/mL, 46 mg/mL, 46.5 mg/mL, 47 mg/mL, 47.5 mg/mL, 48 mg/mL, 48.5 mg/mL, 49 mg/mL, 49.5 mg/mL, 50 mg/mL, 50.5 mg/mL, 51 mg/mL, 51.5 mg/mL, 52 mg/mL, 52.5 mg/mL, 53 mg/mL, 53.5 mg/mL, 54 mg/mL, 54.5 mg/mL, or 55 mg/mL of the pharmaceutical composition.
  • the concentration of casimersen is 45 mg/mL, 45.5 mg/mL, 46 mg/mL, 46.5 mg/mL, 47 mg/mL, 47.5 mg/mL, 48 mg/mL, 48.5 mg/mL, 49 mg/mL, 49.5 mg/mL, 50 mg/mL, 50.5 mg/mL, 51 mg/mL, 51.5 mg/mL, 52 mg/mL, 52.5 mg/mL, 53 mg/mL, 53.5 mg/mL, 54 mg/mL, 54.5 mg/mL, or 55 mg/mL of the pharmaceutical composition.
  • a pharmaceutical composition comprising: a) about 5 w/v % casimersen; b) about 0.8 w/v % sodium chloride; c) about 0.02 w/v % potassium chloride; d) about 0.02 w/v % potassium phosphate monobasic; e) about 0.114 w/v % sodium phosphate dibasic; and 1) water.
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is about 1 mL. In another embodiment, the total volume of the composition is about 2 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is about 10 mL. In another embodiment, the total volume of the composition is 10 mL.
  • the pharmaceutical composition comprises about 50 mg of casimersen. In some embodiments, the pharmaceutical composition comprises 50 mg of casimersen. In another embodiment, the pharmaceutical composition comprises about 100 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 100 mg of casimersen. In another embodiment, the pharmaceutical composition comprises about 500 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 500 mg of casimersen.
  • a pharmaceutical composition comprising: a) 5 w/v % casimersen; b) 0.8 w/v % sodium chloride; c) 0.02 w/v % potassium chloride; d) 0.02 w/v % potassium phosphate monobasic; e) 0.114 w/v % sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is 1 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is 10 mL. In another embodiment of this aspect that specifies certain w/v percentages, the pharmaceutical composition comprises 50 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 100 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 500 mg of casimersen.
  • a pharmaceutical composition comprising: a) about 50 mg/mL casimersen; b) about 8 mg/mL sodium chloride; c) about 0.2 mg/mL potassium chloride; d) about 0.2 mg/mL potassium phosphate monobasic; e) about 1.14 mg/mL sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is about 1 mL. In another embodiment, the total volume of the composition is about 2 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is about 10 mL. In another embodiment, the total volume of the composition is 10 mL.
  • the pharmaceutical composition comprises about 50 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 50 mg of casimersen. In another embodiment, the pharmaceutical composition comprises about 100 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 100 mg of casimersen. In another embodiment, the pharmaceutical composition comprises about 500 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 500 mg of casimersen.
  • a pharmaceutical composition comprising: a) 50 mg/mL casimersen; b) 8 mg/mL sodium chloride; c) 0.2 mg/mL potassium chloride; d) 0.2 mg/mL potassium phosphate monobasic; e) 1.14 mg/mL sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is 1 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is 10 mL. In another embodiment, the pharmaceutical composition comprises 50 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 100 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 500 mg of casimersen.
  • a pharmaceutical composition comprising: a) about 50 mg of casimersen; b) about 8 mg of sodium chloride; c) about 0.2 mg of potassium chloride; d) about 0.2 mg of potassium phosphate monobasic; e) about 1.14 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is about 1 mL.
  • a pharmaceutical composition comprising: a) 50 mg of casimersen; b) 8 mg of sodium chloride; c) 0.2 mg of potassium chloride; d) 0.2 mg of potassium phosphate monobasic; e) 1.14 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is 1 mL.
  • a pharmaceutical composition comprising: a) about 100 mg of casimersen; b) about 16 mg of sodium chloride; c) about 0.4 mg of potassium chloride; d) about 0.4 mg of potassium phosphate monobasic; e) about 2.28 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is about 2 mL.
  • a pharmaceutical composition comprising: a) 100 mg of casimersen; b) 16 mg of sodium chloride; c) 0.4 mg of potassium chloride; d) 0.4 mg of potassium phosphate monobasic; e) 2.28 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is 2 mL.
  • a pharmaceutical composition comprising: a) about 500 mg of casimersen; b) about 80 mg of sodium chloride; c) about 2 mg of potassium chloride; d) about 2 mg of potassium phosphate monobasic; e) about 11.4 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is about 10 mL.
  • a pharmaceutical composition comprising: a) 500 mg of casimersen; b) 80 mg of sodium chloride; c) 2 mg of potassium chloride; d) 2 mg of potassium phosphate monobasic; e) 11.4 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is 10 mL.
  • a pharmaceutical composition comprising: a) 50 mg of casimersen; b) 8 mg of sodium chloride, USP; c) 0.2 mg of potassium chloride, USP; d) 0.2 mg of potassium phosphate monobasic, NF; e) 1.14 mg of sodium phosphate dibasic anhydrous, USP; and 1) water for injection, USP, wherein the total volume of the pharmaceutical composition is 1 mL, the pH of the pharmaceutical composition is about 7.5, and the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • a pharmaceutical composition comprising: a) 100 mg of casimersen; b) 16 mg of sodium chloride, USP; c) 0.4 mg of potassium chloride, USP; d) 0.4 mg of potassium phosphate monobasic, NF; e) 2.28 mg of sodium phosphate dibasic anhydrous, USP; and 1) water for injection, USP, wherein the total volume of the pharmaceutical composition is 2 mL, the pH of the pharmaceutical composition is about 7.5, and the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • a pharmaceutical composition comprising: a) 500 mg of casimersen; b) 80 mg of sodium chloride, USP; c) 2 mg of potassium chloride, USP; d) 2 mg of potassium phosphate monobasic, NF; e) 11.4 mg of sodium phosphate dibasic anhydrous, USP; and 1) water for injection, USP, wherein the total volume of the pharmaceutical composition is 10 mL, the pH of the pharmaceutical composition is about 7.5, and the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • a pharmaceutical composition comprising: a) 50 mg of casimersen; b) 8 mg of sodium chloride; c) 0.2 mg of potassium chloride; d) 0.2 mg of potassium phosphate monobasic; e) 1.14 mg of sodium phosphate dibasic anhydrous; and 1) water for injection, wherein the total volume of the pharmaceutical composition is 1 mL, the pH of the pharmaceutical composition is about 7.5, and the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • a pharmaceutical composition comprising: a) 100 mg of casimersen; b) 16 mg of sodium chloride; c) 0.4 mg of potassium chloride; d) 0.4 mg of potassium phosphate monobasic; e) 2.28 mg of sodium phosphate dibasic anhydrous; and 1) water for injection, wherein the total volume of the pharmaceutical composition is 2 mL, the pH of the pharmaceutical composition is about 7.5, and the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • a pharmaceutical composition comprising: a) 500 mg of casimersen; b) 80 mg of sodium chloride; c) 2 mg of potassium chloride; d) 2 mg of potassium phosphate monobasic; e) 11.4 mg of sodium phosphate dibasic anhydrous; and 1) water for injection, wherein the total volume of the pharmaceutical composition is 10 mL, the pH of the pharmaceutical composition is about 7.5, and the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • the pH of the pharmaceutical composition is about 7.5 or is 7.5. In some embodiments, the pH of the pharmaceutical composition is adjusted to about pH 7.5 with NaOH, NF, HC1, NF, or a combination thereof.
  • the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • the pH of the pharmaceutical composition is about 7.5 and the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • compositions of the disclosure may additionally comprise a carbohydrate as provided in Han et al, Nat. Comms. 2016, 7, 10981, the entirety of which is incorporated herein by reference.
  • pharmaceutical compositions of the disclosure may comprise 5% of a hexose carbohydrate.
  • pharmaceutical composition of the disclosure may comprise 5% glucose, 5% fructose, or 5% mannose.
  • pharmaceutical compositions of the disclosure may comprise 2.5% glucose and 2.5% fructose.
  • compositions of the disclosure may comprises a carbohydrate selected from: arabinose present in an amount of 5% by volume, glucose present in an amount of 5% by volume, sorbitol present in an amount of 5% by volume, galactose present in an amount of 5% by volume, fructose present in an amount of 5% by volume, xylitol present in an amount of 5% by volume, mannose present in an amount of 5% by volume, a combination of glucose and fructose each present in an amount of 2.5% by volume, and a combination of glucose present in an amount of 5.7% by volume, fructose present in an amount of 2.86% by volume, and xylitol present in an amount of 1.4% by volume.
  • a carbohydrate selected from: arabinose present in an amount of 5% by volume, glucose present in an amount of 5% by volume, sorbitol present in an amount of 5% by volume, galactose present in an amount of 5% by volume, fructose present in an amount of
  • kits for treating a muscle disease in a subject in need thereof comprising administering to the subject a pharmaceutical composition of the disclosure.
  • provided herein is a method of treating a muscle disease in a subject in need thereof, comprising administering to the subject a pharmaceutical composition disclosed herein.
  • the muscle disease is Duchenne muscular dystrophy.
  • the muscle disease is Duchenne muscular dystrophy.
  • a method for treating Duchenne muscular dystrophy in a subject in need thereof wherein the subject has a mutation of the dystrophin gene that is amenable to exon 53 skipping comprising administering to the subject a pharmaceutical composition of the disclosure comprising golodirsen.
  • a method for treating Duchenne muscular dystrophy in a subject in need thereof wherein the subject has a mutation of the dystrophin gene that is amenable to exon 45 skipping comprising administering to the subject a pharmaceutical composition of the disclosure comprising casimersen.
  • the subject considered herein is typically a human. However, the subject can be any mammal for which treatment is desired. Thus, the methods described herein can be applied to both human and veterinary applications.
  • compositions provided herein may be administered by any means known in the art.
  • the pharmaceutical compositions provided herein are more preferably delivered by intravenous, intra-arterial, intraperitoneal, intramuscular, or subcutaneous routes of administration.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 40-60 mg of golodirsen; b) 6.4-9.6 mg of sodium chloride; c) 0.16-0.24 mg of potassium chloride; d) 0.16-0.24 mg of potassium phosphate monobasic; e) 0.91-1.37 mg of sodium phosphate dibasic; and
  • the pharmaceutical composition comprises about 50 mg of golodirsen. In another embodiment of this method, the total volume of the pharmaceutical composition is about 1 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) about 50 mg of golodirsen; b) about 8 mg of sodium chloride; c) about 0.2 mg of potassium chloride; d) about 0.2 mg of potassium phosphate monobasic; e) about 1.14 mg of sodium phosphate dibasic; and
  • the total volume of the pharmaceutical composition is about 1 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 80-120 mg of golodirsen; b) 12.8-19.2 mg of sodium chloride; c) 0.32-0.48 mg of potassium chloride; d) 0.32-0.48 mg of potassium phosphate monobasic; e) 1.82-2.74 mg of sodium phosphate dibasic; and
  • the pharmaceutical composition comprises about 100 mg of golodirsen. In another embodiment of this method, the total volume of the pharmaceutical composition is about 2 mL. In another embodiment of this method, the total volume of the pharmaceutical composition is 2 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) about 100 mg of golodirsen; b) about 16 mg of sodium chloride; c) about 0.4 mg of potassium chloride; d) about 0.4 mg of potassium phosphate monobasic; e) about 2.28 mg of sodium phosphate dibasic; and
  • the total volume of the pharmaceutical composition is about 2 mL. In an embodiment of this method, the total volume of the pharmaceutical composition is 2 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 400-600 mg of golodirsen; b) 64-96 mg of sodium chloride; c) 1.6-2.4 mg of potassium chloride; d) 1.6-2.4 mg of potassium phosphate monobasic; e) 9.1-13.7 mg of sodium phosphate dibasic; and
  • the pharmaceutical composition comprises about 500 mg of golodirsen. In another embodiment, the total volume of the pharmaceutical composition is about 10 mL. In an embodiment of this method, the pharmaceutical composition comprises 500 mg of golodirsen. In another embodiment, the total volume of the pharmaceutical composition is 10 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) about 500 mg of golodirsen; b) about 80 mg of sodium chloride; c) about 2 mg of potassium chloride; d) about 2 mg of potassium phosphate monobasic; e) about 11.4 mg of sodium phosphate dibasic; and
  • the total volume of the pharmaceutical composition is about 10 mL. In an embodiment of this method, the total volume of the pharmaceutical composition is 10 mL.
  • the concentration of golodirsen is about 50 mg/mL of the pharmaceutical composition. In some embodiments, the concentration of golodirsen in the pharmaceutical composition ranges from about 45 mg/mL to about 55 mg/mL. In some embodiments, the concentration of golodirsen in the pharmaceutical composition ranges from 45 mg/mL to 55 mg/mL. In certain embodiments, the concentration of golodirsen in the pharmaceutical composition ranges from about 47.5 mg/mL to about 52.5 mg/mL. In certain embodiments, the concentration of golodirsen in the pharmaceutical composition ranges from 47.5 mg/mL to 52.5 mg/mL. For example, the concentration of golodirsen in the pharmaceutical composition ranges from
  • the concentration of golodirsen in the pharmaceutical composition is about 50 mg/mL ⁇ 10%. In some embodiments, the concentration of golodirsen in the pharmaceutical composition is 50 mg/mL ⁇ 10%. In certain embodiments, the concentration of golodirsen in the pharmaceutical composition is within ⁇ 10% of 50 mg/mL. In some embodiments, the concentration of golodirsen in the pharmaceutical composition is about 50 mg/mL ⁇ 5%. In some embodiments, the concentration of golodirsen in the pharmaceutical composition is 50 mg/mL ⁇ 5%.
  • the concentration of golodirsen in the pharmaceutical composition is within ⁇ 5% of 50 mg/mL. In some embodiments, the concentration of golodirsen ranges from about 45.5 mg/mL to 55 mg/mL, about 46 mg/mL to about 54.5 mg/mL, about 46.5 mg/mL to about 54 mg/mL, about 47 mg/mL to about 53.5 mg/mL, about 47.5 mg/mL to about 53 mg/mL, about 45.5 mg/mL to about 52.5 mg/mL, about 45.5 mg/mL to about 52 mg/mL, about 48 mg/mL to about 51.5 mg/mL, about 48.5 mg/mL to about 51 mg/mL, about 49 mg/mL to about 50.5 mg/mL, or about 49.5 mg/mL to about 50 mg/mL of the pharmaceutical composition.
  • the concentration of golodirsen in the pharmaceutical composition is about 45.5 mg/mL, 46 mg/mL, 46.5 mg/mL, 47 mg/mL, 47.5 mg/mL, 48 mg/mL, 48.5 mg/mL, 49 mg/mL, 49.5 mg/mL, 50 mg/mL, 50.5 mg/mL, 51 mg/mL, 51.5 mg/mL, 52 mg/mL, 52.5 mg/mL, 53 mg/mL, 53.5 mg/mL, 54 mg/mL, 54.5 mg/mL, or 55 mg/mL of the pharmaceutical composition.
  • the concentration of golodirsen is 45 mg/mL, 45.5 mg/mL, 46 mg/mL, 46.5 mg/mL, 47 mg/mL, 47.5 mg/mL, 48 mg/mL, 48.5 mg/mL, 49 mg/mL, 49.5 mg/mL, 50 mg/mL, 50.5 mg/mL, 51 mg/mL, 51.5 mg/mL, 52 mg/mL, 52.5 mg/mL, 53 mg/mL, 53.5 mg/mL, 54 mg/mL, 54.5 mg/mL, or 55 mg/mL of the pharmaceutical composition.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) about 5 w/v % golodirsen; b) about 0.8 w/v % sodium chloride; c) about 0.02 w/v % potassium chloride; d) about 0.02 w/v % potassium phosphate monobasic; e) about 0.114 w/v % sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is about 1 mL. In another embodiment, the total volume of the composition is about 2 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is about 10 mL. In another embodiment, the total volume of the composition is 10 mL. In another embodiment of this method that specifies certain w/v percentages, the pharmaceutical composition comprises about 50 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 50 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises about 100 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 100 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises about 500 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 500 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 500 mg of golodirsen.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 5 w/v % golodirsen; b) 0.8 w/v % sodium chloride; c) 0.02 w/v % potassium chloride; d) 0.02 w/v % potassium phosphate monobasic; e) 0.114 w/v % sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is 1 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is 10 mL. In another embodiment of this aspect that specifies certain w/v percentages, the pharmaceutical composition comprises 50 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 100 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 500 mg of golodirsen.
  • the pharmaceutical composition comprises about 50 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 50 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises about 100 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 100 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises about 500 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 500 mg of golodirsen.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) about 50 mg/mL golodirsen; b) about 8 mg/mL sodium chloride; c) about 0.2 mg/mL potassium chloride; d) about 0.2 mg/mL potassium phosphate monobasic; e) about 1.14 mg/mL sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is about 1 mL. In another embodiment, the total volume of the composition is about 2 mL. In another embodiment, the total volume of the composition is about 10 mL. In another embodiment, the pharmaceutical composition comprises about 50 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises about 100 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises about 500 mg of golodirsen.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 50 mg/mL golodirsen; b) 8 mg/mL sodium chloride; c) 0.2 mg/mL potassium chloride; d) 0.2 mg/mL potassium phosphate monobasic; e) 1.14 mg/mL sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is 1 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is 10 mL. In another embodiment, the pharmaceutical composition comprises 50 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 100 mg of golodirsen. In another embodiment, the pharmaceutical composition comprises 500 mg of golodirsen.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 50 mg of golodirsen; b) 8 mg of sodium chloride; c) 0.2 mg of potassium chloride; d) 0.2 mg of potassium phosphate monobasic; e) 1.14 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is 1 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 100 mg of golodirsen; b) 16 mg of sodium chloride; c) 0.4 mg of potassium chloride; d) 0.4 mg of potassium phosphate monobasic; e) 2.28 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is 2 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 500 mg of golodirsen; b) 80 mg of sodium chloride; c) 2 mg of potassium chloride; d) 2 mg of potassium phosphate monobasic; e) 11.4 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is 10 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 40-60 mg of casimersen; b) 6.4-9.6 mg of sodium chloride; c) 0.16-0.24 mg of potassium chloride; d) 0.16-0.24 mg of potassium phosphate monobasic; e) 0.91-1.37 mg of sodium phosphate dibasic; and 1) water.
  • the pharmaceutical composition comprises about 50 mg of casimersen. In another embodiment of this method, the total volume of the pharmaceutical composition is about 1 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) about 50 mg of casimersen; b) about 8 mg of sodium chloride; c) about 0.2 mg of potassium chloride; d) about 0.2 mg of potassium phosphate monobasic; e) about 1.14 mg of sodium phosphate dibasic; and
  • the total volume of the pharmaceutical composition is about 1 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 80-120 mg of casimersen; b) 12.8-19.2 mg of sodium chloride; c) 0.32-0.48 mg of potassium chloride; d) 0.32-0.48 mg of potassium phosphate monobasic; e) 1.82-2.74 mg of sodium phosphate dibasic; and
  • the pharmaceutical composition comprises about 100 mg of casimersen. In another embodiment of this method, the total volume of the pharmaceutical composition is about 2 mL. In another embodiment of this method, the total volume of the pharmaceutical composition is 2 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) about 100 mg of casimersen; b) about 16 mg of sodium chloride; c) about 0.4 mg of potassium chloride; d) about 0.4 mg of potassium phosphate monobasic; e) about 2.28 mg of sodium phosphate dibasic; and
  • the total volume of the pharmaceutical composition is about 2 mL. In an embodiment of this method, the total volume of the pharmaceutical composition is 2 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 400-600 mg of casimersen; b) 64-96 mg of sodium chloride; c) 1.6-2.4 mg of potassium chloride; d) 1.6-2.4 mg of potassium phosphate monobasic; e) 9.1-13.7 mg of sodium phosphate dibasic; and
  • the pharmaceutical composition comprises about 500 mg of casimersen. In another embodiment, the total volume of the pharmaceutical composition is about 10 mL. In an embodiment of this method, the pharmaceutical composition comprises 500 mg of casimersen. In another embodiment, the total volume of the pharmaceutical composition is 10 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) about 500 mg of casimersen; b) about 80 mg of sodium chloride; c) about 2 mg of potassium chloride; d) about 2 mg of potassium phosphate monobasic; e) about 11.4 mg of sodium phosphate dibasic; and
  • the total volume of the pharmaceutical composition is about 10 mL. In an embodiment of this method, the total volume of the pharmaceutical composition is 10 mL.
  • the concentration of casimersen is about 50 mg/mL of the pharmaceutical composition. In some embodiments, the concentration of casimersen in the pharmaceutical composition ranges from about 45 mg/mL to about 55 mg/mL. In some embodiments, the concentration of casimersen in the pharmaceutical composition ranges from 45 mg/mL to 55 mg/mL. In certain embodiments, the concentration of casimersen in the pharmaceutical composition ranges from about 47.5 mg/mL to about 52.5 mg/mL. In certain embodiments, the concentration of casimersen in the pharmaceutical composition ranges from 47.5 mg/mL to 52.5 mg/mL. For example, the concentration of casimersen in the pharmaceutical composition ranges from
  • the concentration of casimersen in the pharmaceutical composition is about 50 mg/mL ⁇ 10%. In some embodiments, the concentration of casimersen in the pharmaceutical composition is 50 mg/mL ⁇ 10%. In certain embodiments, the concentration of casimersen in the pharmaceutical composition is within ⁇ 10% of 50 mg/mL. In some embodiments, the concentration of casimersen in the pharmaceutical composition is about 50 mg/mL ⁇ 5%. In some embodiments, the concentration of casimersen in the pharmaceutical composition is 50 mg/mL ⁇ 5%.
  • the concentration of casimersen in the pharmaceutical composition is within ⁇ 5% of 50 mg/mL. In some embodiments, the concentration of casimersen ranges from about 45.5 mg/mL to 55 mg/mL, about 46 mg/mL to about 54.5 mg/mL, about 46.5 mg/mL to about 54 mg/mL, about 47 mg/mL to about 53.5 mg/mL, about 47.5 mg/mL to about 53 mg/mL, about 45.5 mg/mL to about 52.5 mg/mL, about 45.5 mg/mL to about 52 mg/mL, about 48 mg/mL to about 51.5 mg/mL, about 48.5 mg/mL to about 51 mg/mL, about 49 mg/mL to about 50.5 mg/mL, or about 49.5 mg/mL to about 50 mg/mL of the pharmaceutical composition.
  • the concentration of casimersen in the pharmaceutical composition is about 45.5 mg/mL, 46 mg/mL, 46.5 mg/mL, 47 mg/mL, 47.5 mg/mL, 48 mg/mL, 48.5 mg/mL, 49 mg/mL, 49.5 mg/mL, 50 mg/mL, 50.5 mg/mL, 51 mg/mL, 51.5 mg/mL, 52 mg/mL, 52.5 mg/mL, 53 mg/mL, 53.5 mg/mL, 54 mg/mL, 54.5 mg/mL, or 55 mg/mL of the pharmaceutical composition.
  • the concentration of casimersen is 45 mg/mL, 45.5 mg/mL, 46 mg/mL, 46.5 mg/mL, 47 mg/mL, 47.5 mg/mL, 48 mg/mL, 48.5 mg/mL, 49 mg/mL, 49.5 mg/mL, 50 mg/mL, 50.5 mg/mL, 51 mg/mL, 51.5 mg/mL, 52 mg/mL, 52.5 mg/mL, 53 mg/mL, 53.5 mg/mL, 54 mg/mL, 54.5 mg/mL, or 55 mg/mL of the pharmaceutical composition.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) about 5 w/v % casimersen; b) about 0.8 w/v % sodium chloride; c) about 0.02 w/v % potassium chloride; d) about 0.02 w/v % potassium phosphate monobasic; e) about 0.114 w/v % sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is about 1 mL. In another embodiment, the total volume of the composition is about 2 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is about 10 mL. In another embodiment, the total volume of the composition is 10 mL. In another embodiment of this method that specifies certain w/v percentages, the pharmaceutical composition comprises about 50 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 50 mg of casimersen. In another embodiment, the pharmaceutical composition comprises about 100 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 100 mg of casimersen. In another embodiment, the pharmaceutical composition comprises about 500 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 500 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 500 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 500 mg of casimersen.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 5 w/v % casimersen; b) 0.8 w/v % sodium chloride; c) 0.02 w/v % potassium chloride; d) 0.02 w/v % potassium phosphate monobasic; e) 0.114 w/v % sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is 1 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is 10 mL. In another embodiment of this aspect that specifies certain w/v percentages, the pharmaceutical composition comprises 50 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 100 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 500 mg of casimersen.
  • the pharmaceutical composition comprises about 50 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 50 mg of casimersen. In another embodiment, the pharmaceutical composition comprises about 100 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 100 mg of casimersen. In another embodiment, the pharmaceutical composition comprises about 500 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 500 mg of casimersen.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) about 50 mg/mL casimersen; b) about 8 mg/mL sodium chloride; c) about 0.2 mg/mL potassium chloride; d) about 0.2 mg/mL potassium phosphate monobasic; e) about 1.14 mg/mL sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is about 1 mL. In another embodiment, the total volume of the composition is about 2 mL. In another embodiment, the total volume of the composition is about 10 mL. In another embodiment, the pharmaceutical composition comprises about 50 mg of casimersen. In another embodiment, the pharmaceutical composition comprises about 100 mg of casimersen. In another embodiment, the pharmaceutical composition comprises about 500 mg of casimersen.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 50 mg/mL casimersen; b) 8 mg/mL sodium chloride; c) 0.2 mg/mL potassium chloride; d) 0.2 mg/mL potassium phosphate monobasic; e) 1.14 mg/mL sodium phosphate dibasic; and
  • the total volume of the composition is 1-10 mL. In another embodiment, the total volume of the composition is 1 mL. In another embodiment, the total volume of the composition is 2 mL. In another embodiment, the total volume of the composition is 10 mL. In another embodiment, the pharmaceutical composition comprises 50 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 100 mg of casimersen. In another embodiment, the pharmaceutical composition comprises 500 mg of casimersen.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 50 mg of casimersen; b) 8 mg of sodium chloride; c) 0.2 mg of potassium chloride; d) 0.2 mg of potassium phosphate monobasic; e) 1.14 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is 1 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 100 mg of casimersen; b) 16 mg of sodium chloride; c) 0.4 mg of potassium chloride; d) 0.4 mg of potassium phosphate monobasic; e) 2.28 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is 2 mL.
  • methods of the disclosure comprise administering to the subject a pharmaceutical composition, the pharmaceutical composition comprising: a) 500 mg of casimersen; b) 80 mg of sodium chloride; c) 2 mg of potassium chloride; d) 2 mg of potassium phosphate monobasic; e) 11.4 mg of sodium phosphate dibasic; and 1) water, wherein the total volume of the pharmaceutical composition is 10 mL.
  • the pH of the pharmaceutical composition is about 7.5 or is 7.5. In some embodiments, the pH of the pharmaceutical composition is adjusted to about pH 7.5 with NaOH, NF, HC1, NF, or a combination thereof.
  • the osmolality of the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • the pH of the pharmaceutical composition is about 7.5 and the pharmaceutical composition ranges from about 260 mOsm to about 320 mOsm.
  • compositions of the disclosure may be co-administered with a carbohydrate in the methods of the disclosure, either in the same formulation or is a separate formulation, as provided in Han et al, Nat. Comms. 2016, 7, 10981, the entirety of which is incorporated herein by reference.
  • pharmaceutical compositions of the disclosure may be co-administered with 5% of ahexose carbohydrate.
  • pharmaceutical compositions of the disclosure may be co- administered with 5% glucose, 5% fructose, or 5% mannose.
  • pharmaceutical compositions of the disclosure may be co-administered with 2.5% glucose and 2.5% fructose.
  • composition of the disclosure may be co-administered with a carbohydrate selected from: arabinose present in an amount of 5% by volume, glucose present in an amount of 5% by volume, sorbitol present in an amount of 5% by volume, galactose present in an amount of 5% by volume, fructose present in an amount of 5% by volume, xylitol present in an amount of 5% by volume, mannose present in an amount of 5% by volume, a combination of glucose and fructose each present in an amount of 2.5% by volume, and a combination of glucose present in an amount of 5.7% by volume, fructose present in an amount of 2.86% by volume, and xylitol present in an amount of 1.4% by volume.
  • a carbohydrate selected from: arabinose present in an amount of 5% by volume, glucose present in an amount of 5% by volume, sorbitol present in an amount of 5% by volume, galactose present in an amount of 5% by volume, fructos
  • kits are provided.
  • Kits according to the disclosure include package(s) comprising golodirsen or casimersen, or pharmaceutical compositions of the disclosure.
  • kits comprise golodirsen, or a pharmaceutically acceptable salt thereof.
  • kits comprise casimersen, or a pharmaceutically acceptable salt thereof.
  • packaging means any vessel containing oligonucleotides or compositions presented herein.
  • the package can be a box or wrapping.
  • Packaging materials for use in packaging pharmaceutical products are well-known to those of skill in the art. Examples of pharmaceutical packaging materials include, but are not limited to, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • the kit can also contain items that are not contained within the package, but are attached to the outside of the package, for example, pipettes.
  • Kits can further contain instructions for administering golodirsen, casimersen, or pharmaceutical compositions of the disclosure to a patient. Kits also can comprise instructions for approved uses of golodirsen or casimersen by regulatory agencies, such as the United States Food and Drug Administration. Kits can also contain labeling or product inserts for golodirsen or casimersen. The package(s) or any product insert(s), or both, may themselves be approved by regulatory agencies.
  • the kits can include golodirsen or casimersen in the solid phase or in a liquid phase (such as buffers provided) in a package. The kits can also include buffers for preparing solutions for conducting the methods, and pipettes for transferring liquids from one container to another.
  • Anchor Loaded Resin 750 g of Anchor Loaded Resin and 10.5 L of NMP were charged to a 50 L silanized reactor and stirred for 3 hours. The NMP was drained and the Anchor Loaded Resin was washed twice with 5.5L each of DCM and twice with 5.5 L each of 30% TFE/DCM.
  • the Anchor Loaded Resin was washed three times with 5.5 L each of 30% TFE/DCM and drained, washed with 5.5 L of CYFTA solution for 15 minutes and drained, and again washed with 5.5 L of CYTFA Solution for 15 minutes without draining to which 122 mL of 1 : 1 NEM/DCM was charged and the suspension stirred for 2 minutes and drained.
  • the resin was washed once with 5.5L Neutralization Solution for 10 minutes and drained, twice with 5.5 L of Neutralization Solution for 5 minutes and drained, then twice with 5.5 L each of DCM and drained.
  • the resin Prior to each coupling cycle as described in Table 3, the resin was: 1) washed with 30% TFE/DCM; 2) a) treated with CYTFA Solution 15 minutes and drained, and b) treated with CYTFA solution for 15 minutes to which was added 1:1 NEM/DCM, stirred, and drained; 3) stirred three times with Neutralization Solution; and 4) washed twice with DCM. See Table 3. ii. Post Coupling Treatments
  • the resin was washed 8 times with 19.5 L each of IP A, and dried under vacuum at room temperature for about 63.5 hours to a dried weight of 4857.9 g.
  • the above resin bound golodirsen Crude Drug Substance was divided into two lots, each lot was treated as follows.
  • a 1619.3g lot of resin was: 1) stirred with 10L of NMP for 2hrs, then the NMP was drained; 2) washed tree times with 10L each of 30% TFE/DCM; 3) treated with 10L CYTFA Solution for 15 minutes; and 4) 10L of CYTFA Solution for 15 minutes to which 130ml 1:1 NEM/DCM was then added and stirred for 2 minutes and drained.
  • the resin was treated three times with 10L each of Neutralization Solution, washed six times with 10L of DCM, and eight times with 10L each of NMP.
  • the resin was treated with a Cleaving Solution of 1530.4g DTT and 2980 DBU in 6.96L NMP for 2 hours to detach the golodirsen Crude Drug Substance from the resin.
  • the Cleaving Solution was drained and retained in a separate vessel.
  • the reactor and resin were washed with 4.97L of NMP which was combined with the Cleaving Solution.
  • the combined Cleaving Solution and NMP wash were transferred to a pressure vessel which was added 39.8L of NEEOH (NEb ⁇ EhO) that had been chilled to a temperature of - 10° to -25° C in a freezer.
  • the pressure vessel was sealed and heated to 45° C for 16hrs then allowed to cool to 25° C.
  • This deprotection solution containing the golodirsen crude drug substance was diluted 3:1 with purified water prior to solvent removal. During solvent removal, the deprotection solution was pH adjusted to 3.0 with 2M phosphoric acid, then to pH 8.03 with NH 4 OH.
  • HPLC C18 77.552% (Fig. 1) and SCX-1073.768% (Fig. 2).
  • Example 1 The deprotection solution from Example 1, part E, containing the golodirsen crude drug substance was loaded onto a column of ToyoPearl Super-Q 650S anion exchange resin (Tosoh Bioscience) and eluted with a gradient of 0-35% B over 17 column volume (Buffer A: 10 mM sodium hydroxide; Buffer B: 1 M sodium chloride in 10 mM sodium hydroxide) and fractions of acceptable purity (Cl 8 and SCX HPLC) were pooled to a purified drug product solution. HPLC: 93.571% (C18; Fig. 3) 88.270% (SCX; Fig. 4).
  • the purified drug substance solution was desalted and lyophilized to 1450.72 g purified golodirsen drug substance. Yield 54.56 %; HPLC: 93.531% (Fig. 5; C18) 88.354% (Fig. 6; SCX).
  • the amount of water present is sufficient to achieve a concentration of golodirsen of about 50 mg/mL of the pharmaceutical composition.
  • the pH of the Exemplary Compositions is about 7.5, and the osmolality of the Exemplary Compositions ranges from about 260 mOsm to about 320 mOsm.
  • the materials, including the starting materials and the solutions used for solid phase oligomer synthesis of casimersen crude drug substance are the same as those used above in Example 1 for solid phase oligomer synthesis of golodirsen crude drug substance and described above in Table 1 and Table 2.
  • Anchor Loaded Resin 750 g of Anchor Loaded Resin and 10.5 L of NMP were charged to a 50 L silanized reactor and stirred for 3 hours. The NMP was drained and the Anchor Loaded Resin was washed twice with 5.5L each of DCM and twice with 5.5 L each of 30% TFE/DCM.
  • the Anchor Loaded Resin was washed three times with 5.5 L each of 30% TFE/DCM and drained, washed with 5.5 L of CYFTA solution for 15 minutes and drained, and again washed with 5.5 L of CYTFA Solution for 15 minutes without draining to which 122 mL of 1 : 1 NEM/DCM was charged and the suspension stirred for 2 minutes and drained.
  • the resin was washed once with 5.5L Neutralization Solution for 10 minutes and drained, twice with 5.5 L of Neutralization Solution for 5 minutes and drained, then twice with 5.5 L each of DCM and drained.
  • a solution of 374.8 g of benzoic anhydride and 195 mL NEM in 2680 mL NMP was charged and stirred for 15 minutes and drained.
  • the resin was washed once with 5.5 L of Neutralization Solution for 10 minutes and drained, once with 5.5 L of Neutralization Solution for 5 minutes and drained, and once with 5.5 L of DCM and drained and twice with 5.5 L each of 30% TFE/DCM.
  • the resin was suspended in 5.5 L of 30% TFE/DCM and held for 14 hours.
  • the resin Prior to each coupling cycle as described in Table 6, the resin was: 1) washed with 30% TFE/DCM; 2) a) treated with CYTFA Solution 15 minutes and drained, and b) treated with CYTFA solution for 15 minutes to which was added 1:1 NEM/DCM, stirred, and drained; 3) stirred three times with Neutralization Solution; and 4) washed twice with DCM. See Table 6. ii. Post Coupling Treatments
  • the resin was washed 8 times with 19.5 L each of IP A, and dried under vacuum at room temperature for about 63.5 hours to a dried weight of 4523 g.
  • the above resin bound Casimersen Crude Drug Substance was divided into two lots, each lot was treated as follows. Two 2261.5 g lots of resin were each: 1) stirred with 10L of NMP for 2hrs, then the NMP was drained; 2) washed tree times with 10L each of 30% TFE/DCM; 3) treated with 10L CYTFA Solution for 15 minutes; and 4) 10L of CYTFA Solution for 15 minutes to which 130ml 1:1 NEM/DCM was then added and stirred for 2 minutes and drained. The resin was treated three times with 10L each of Neutralization Solution, washed six times with 10L of DCM, and eight times with 10L each of NMP.
  • the resin was treated with a Cleaving Solution of 1530.4g DTT and 2980 DBU in 6.96L NMP for 2 hours to detach the Casimersen Crude Drug Substance from the resin.
  • the Cleaving Solution was drained and retained in a separate vessel.
  • the reactor and resin were washed with 4.97L of NMP which was combined with the Cleaving Solution. Table 6:
  • the combined Cleaving Solution and NMP wash were transferred to a pressure vessel to which was added 39.8L of NFEOH (NFE ⁇ FEO) that had been chilled to a temperature of - 10° to -25° C in a freezer.
  • the pressure vessel was sealed and heated to 45° C for 16hrs then allowed to cool to 25° C.
  • This deprotection solution containing the Casimersen crude drug substance was diluted 3:1 with purified water prior to solvent removal. During solvent removal, the deprotection solution was pH adjusted to 3.0 with 2M phosphoric acid, then to pH 8.03 with UOH.
  • HPLC C18 80.93% (Fig. 7) and SCX-10 84.4% (Fig. 8).
  • Example 5 Purification of Casimersen Crude Drug Substance
  • the deprotection solution from Example 4, part E, containing the Casimersen crude drug substance was loaded onto a column of ToyoPearl Super-Q 650S anion exchange resin (Tosoh Bioscience) and eluted with a gradient of 0-35% B over 17 column volume (Buffer A: 10 mM sodium hydroxide; Buffer B: 1 M sodium chloride in 10 mM sodium hydroxide) and fractions of acceptable purity (Cl 8 and SCX HPLC) were pooled to a purified drug product solution.
  • HPLC 97.74% (C18; Fig. 9) 94.58% (SCX; Fig. 10).
  • the amount of water present is sufficient to achieve a concentration of casimersen of about 50 mg/mL of the pharmaceutical composition.
  • the pH of the Exemplary Compositions is about 7.5, and the osmolality of the Exemplary Compositions ranges from about 260 mOsm to about 320 mOsm.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques comprenant du golodirsen ou du casimersen. L'invention concerne également des méthodes de traitement d'une maladie musculaire chez un sujet en ayant besoin, qui consistent à administrer au sujet une composition pharmaceutique de l'invention.
PCT/US2020/043824 2019-08-02 2020-07-28 Compositions pharmaceutiques à base d'oligomères morpholino phosphorodiamidate WO2021025899A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201962881996P 2019-08-02 2019-08-02
US62/881,996 2019-08-02
US202063056772P 2020-07-27 2020-07-27
US63/056,772 2020-07-27

Publications (1)

Publication Number Publication Date
WO2021025899A1 true WO2021025899A1 (fr) 2021-02-11

Family

ID=72047147

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2020/043824 WO2021025899A1 (fr) 2019-08-02 2020-07-28 Compositions pharmaceutiques à base d'oligomères morpholino phosphorodiamidate

Country Status (1)

Country Link
WO (1) WO2021025899A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4230196A1 (fr) 2022-02-21 2023-08-23 Som Innovation Biotech, S.A. Composés à utiliser dans le traitement des dystrophinopathies

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1990002749A1 (fr) 1988-09-01 1990-03-22 Forskningscenter Risø Procede de synthese de peptides et support solide de realisation dudit procede
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US5142047A (en) 1985-03-15 1992-08-25 Anti-Gene Development Group Uncharged polynucleotide-binding polymers
US5166315A (en) 1989-12-20 1992-11-24 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
US5185444A (en) 1985-03-15 1993-02-09 Anti-Gene Deveopment Group Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages
US5217866A (en) 1985-03-15 1993-06-08 Anti-Gene Development Group Polynucleotide assay reagent and method
US5506337A (en) 1985-03-15 1996-04-09 Antivirals Inc. Morpholino-subunit combinatorial library and method
US5521063A (en) 1985-03-15 1996-05-28 Antivirals Inc. Polynucleotide reagent containing chiral subunits and methods of use
WO2009064471A1 (fr) 2007-11-15 2009-05-22 Avi Biopharma, Inc. Procédé de synthèse d'oligomères morpholino
US8067571B2 (en) 2005-07-13 2011-11-29 Avi Biopharma, Inc. Antibacterial antisense oligonucleotide and method
US8076476B2 (en) 2007-11-15 2011-12-13 Avi Biopharma, Inc. Synthesis of morpholino oligomers using doubly protected guanine morpholino subunits
WO2012043730A1 (fr) 2010-09-30 2012-04-05 日本新薬株式会社 Dérivé d'acide morpholino nucléique
US8299206B2 (en) 2007-11-15 2012-10-30 Avi Biopharma, Inc. Method of synthesis of morpholino oligomers
WO2013082551A1 (fr) 2011-11-30 2013-06-06 Sarepta Therapeutics, Inc. Inclusion d'exon induite pour l'amyotrophie spinale
US20160040162A1 (en) 2013-03-14 2016-02-11 Sarepta Therapeutics, Inc. Exon skipping compositions for treating muscular dystrophy
WO2017205880A1 (fr) 2016-05-24 2017-11-30 Sarepta Therapeutics, Inc. Procédés de préparation d'oligomères morpholino de phosphorodiamidate
WO2018005805A1 (fr) * 2016-06-30 2018-01-04 Sarepta Therapeutics, Inc. Sauts d'exons oligomères pour la dystrophie musculaire
WO2020198268A1 (fr) * 2019-03-28 2020-10-01 Sarepta Therapeutics, Inc. Procédés de traitement de la dystrophie musculaire avec casimersen

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
US5142047A (en) 1985-03-15 1992-08-25 Anti-Gene Development Group Uncharged polynucleotide-binding polymers
US5185444A (en) 1985-03-15 1993-02-09 Anti-Gene Deveopment Group Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages
US5217866A (en) 1985-03-15 1993-06-08 Anti-Gene Development Group Polynucleotide assay reagent and method
US5506337A (en) 1985-03-15 1996-04-09 Antivirals Inc. Morpholino-subunit combinatorial library and method
US5521063A (en) 1985-03-15 1996-05-28 Antivirals Inc. Polynucleotide reagent containing chiral subunits and methods of use
US5698685A (en) 1985-03-15 1997-12-16 Antivirals Inc. Morpholino-subunit combinatorial library and method
WO1990002749A1 (fr) 1988-09-01 1990-03-22 Forskningscenter Risø Procede de synthese de peptides et support solide de realisation dudit procede
US5166315A (en) 1989-12-20 1992-11-24 Anti-Gene Development Group Sequence-specific binding polymers for duplex nucleic acids
US8067571B2 (en) 2005-07-13 2011-11-29 Avi Biopharma, Inc. Antibacterial antisense oligonucleotide and method
WO2009064471A1 (fr) 2007-11-15 2009-05-22 Avi Biopharma, Inc. Procédé de synthèse d'oligomères morpholino
US8076476B2 (en) 2007-11-15 2011-12-13 Avi Biopharma, Inc. Synthesis of morpholino oligomers using doubly protected guanine morpholino subunits
US8299206B2 (en) 2007-11-15 2012-10-30 Avi Biopharma, Inc. Method of synthesis of morpholino oligomers
WO2012043730A1 (fr) 2010-09-30 2012-04-05 日本新薬株式会社 Dérivé d'acide morpholino nucléique
WO2013082551A1 (fr) 2011-11-30 2013-06-06 Sarepta Therapeutics, Inc. Inclusion d'exon induite pour l'amyotrophie spinale
US20160040162A1 (en) 2013-03-14 2016-02-11 Sarepta Therapeutics, Inc. Exon skipping compositions for treating muscular dystrophy
WO2017205880A1 (fr) 2016-05-24 2017-11-30 Sarepta Therapeutics, Inc. Procédés de préparation d'oligomères morpholino de phosphorodiamidate
WO2018005805A1 (fr) * 2016-06-30 2018-01-04 Sarepta Therapeutics, Inc. Sauts d'exons oligomères pour la dystrophie musculaire
US20190262375A1 (en) 2016-06-30 2019-08-29 Sarepta Therapeutics, Inc. Exon skipping oligomers for muscular dystrophy
WO2020198268A1 (fr) * 2019-03-28 2020-10-01 Sarepta Therapeutics, Inc. Procédés de traitement de la dystrophie musculaire avec casimersen

Non-Patent Citations (23)

* Cited by examiner, † Cited by third party
Title
AARTSMA-RUS ET AL., HUM MUT, vol. 30, 2009, pages 293 - 299
ALUL ET AL., NUCLEIC ACIDS RESEARCH, vol. 19, 1991, pages 1527
ANNEMIEKE AARTSMA-RUS ET AL: "Development of Exon Skipping Therapies for Duchenne Muscular Dystrophy: A Critical Review and a Perspective on the Outstanding Issues", NUCLEIC ACID THERAPEUTICS, vol. 27, no. 5, 1 October 2017 (2017-10-01), US, pages 251 - 259, XP055699369, ISSN: 2159-3337, DOI: 10.1089/nat.2017.0682 *
ATHERTON ET AL., BIOORG. CHEM., vol. 8, 1979, pages 351
ATHERTON ET AL., J. AM. CHEM. SOC., vol. 97, 1975, pages 6584
ATHERTON ET AL., J. CHEM. SOC. PERKIN 1, vol. 538, 1981
BAYERJUNG, TETRAHEDRON LETT., vol. 51, 1970, pages 4503
BERG ET AL., J. AM. CHEM. SOC., vol. 111, 1989, pages 8024
BONORA ET AL., ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 4, 2000, pages 225 - 231
DANIELS ET AL., TETRAHEDRON LETT., vol. 30, 1989, pages 4345
E. L. ELIELS. H. WILEN: "Stereochemistry of Carbon Compounds", 1994, JOHN WILEY & SONS, pages: 1119 - 1190
FLETCHER ET AL., MOLECULAR THERAPY, vol. 18, no. 6, 2010, pages 1218 - 1223
GEYSEN ET AL., PROC. NATL. ACAD. SCI. USA, vol. 81, 1984, pages 3998
GURVICH ET AL., HUM MUTAT., vol. 30, no. 4, 2009, pages 633 - 640
HAN ET AL., NAT. COMMS., vol. 7, 2016, pages 10981
HOUGHTEN, PROC. NATL. ACAD. SCI. USA, vol. 82, 1985, pages 5131
KENTMERRIFIELD, ISRAEL J. CHEM., vol. 17, 1978, pages 243
MARCH, J.: "Advanced Organic Chemistry", 1985, JOHN WILEY & SONS
PARRGROHMANN, ANGEW. CHEM. INTERNAL. ED., vol. 11, 1972, pages 314
RIETSCHOTEN: "Peptides", 1974, WILEY AND SONS, pages: 113 - 116
SCOTT ET AL., J. CHROM. SCI., vol. 9, 1971, pages 577
SUMMERTON ET AL., ANTISENSE NUCLEIC ACID DRUG DEV., vol. 7, 1997, pages 187 - 195
WRIGHT ET AL., TETRAHEDRON LETT., vol. 34, 1993, pages 3373

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4230196A1 (fr) 2022-02-21 2023-08-23 Som Innovation Biotech, S.A. Composés à utiliser dans le traitement des dystrophinopathies
WO2023156645A1 (fr) 2022-02-21 2023-08-24 Som Innovation Biotech, S.A. Composés destinés à être utilisés dans le traitement de dystrophinopathies

Similar Documents

Publication Publication Date Title
TWI737736B (zh) 製備磷醯二胺嗎啉代寡聚物之方法
US11384105B2 (en) Processes for preparing oligomers
WO2017213854A1 (fr) Composition pharmaceutique comprenant de l'éteplirsen
WO2012075117A2 (fr) Conjugués de petite molécule-polymère et procédés pour leur préparation
AU2017270598B2 (en) Processes for preparing phosphorodiamidate morpholino oligomers
WO2021025899A1 (fr) Compositions pharmaceutiques à base d'oligomères morpholino phosphorodiamidate
BR112018074330B1 (pt) Processo para preparar um composto oligomérico e compostos oligômeros morfolino fosforodiamidato
JP7218361B2 (ja) 高速流動合成を介してホスホロジアミデートモルホリノオリゴマーを調製するための方法
EP3805242A1 (fr) Procédé de production d'une molécule d'adn catalytiquement active présentant une activité améliorée et son utilisation dans un procédé de traitement de l'asthme
BR122024017733A2 (pt) Compostos oligômeros morfolino fosforodiamidato e processos para preparar os mesmos

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20754571

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20754571

Country of ref document: EP

Kind code of ref document: A1