WO2020039401A1

WO2020039401A1 - Treatment comprising il-1βeta binding antibodies and combinations thereof

Info

Publication number: WO2020039401A1
Application number: PCT/IB2019/057121
Authority: WO
Inventors: Shalini CHATURVEDI; Hans Menssen; Thomas Radimerski; Paul Ridker
Original assignee: Novartis Ag
Priority date: 2018-08-24
Filing date: 2019-08-23
Publication date: 2020-02-27

Abstract

The present invention relates to IL-1β binding antibodies or functional fragments thereof for treating, preventing or reducing the incidence of anemia. The present invention also relates topharmaceutical combinations comprising such IL-1β binding antibodies or functional fragment thereof and b) at least one further therapeutic agent, preferably ruxolitinib or a pharmaceutically acceptable salt thereof.

Description

TREATMENT COMPRISING IL-l BETA BINDING ANTIBODIES AND COMBINATIONS

THEREOF

FIELD OF THE INVENTION

[0001] The present invention relates to IL-l b binding antibodies and functional fragments thereof for use in methods of treating or preventing anemia. The present invention also relates to methods of treating or preventing anemia by administering to a subject in need thereof a therapeutically effective amount of an IL- l b-binding antibody or functional fragment thereof.

[0002] The present invention also relates to combination therapies comprising a) an anti-IL- 1 b antibody or antigen-binding fragment thereof and b) a JAK inhibitor.

BACKGROUND OF THE INVENTION

[0003] Anemia is a frequent finding in cancer patients. In patients treated with chemotherapy, the incidence of anemia may be 90%. Anemia exerts a negative influence on the quality' of life of cancer patients as it may contribute to cancer-induced fatigue. Anemia has also been identified as an adverse prognostic factor in cancer diseases.

[0004] Myeloproliferative neoplasms (MPNs) are a unique and heterogeneous group of hemopathies characterized by proliferation and accumulation of mature myeloid cells, including myelofibrosis (MF), essential thrombocythemia (ET) and polycythemia vera (PV). Importantly, MF is the most severe form of Philadelphia chromosome-negative (i.e. BCR-ABL1 -negative) myeloproliferative neoplasms, with a prevalence estimated to be 2.2 per 100,000 population. Myelofibrosis (MF) can present as a de novo disorder (PMF) or evolve from previous PV or ET (PPV-MF or PET-MF). The range of reported frequencies for post-PV MF are 4.9-6% at 10 years and 6-14% at 15 years, respectively, and 0.8-4.9% for post-ET MF at 10 years and 4-11% at 15 years, respectively (S Cerquozzi and A Tefferi, Blood Cancer Journal (2015) 5, e366).

[0005] Regardless of whether MF developed from PV, ET or as a primary disorder, it is characterized by a clonal stem cell proliferation associated with production of elevated levels of several inflammatory and proangiogenic cytokines resulting in a bone marrow stromal reaction that includes varying degrees of reticulin and/or collagen fibrosis, osteosclerosis and angiogenesis, some degree of megakaryocyte atypia and a peripheral blood smear showing a leukoerythroblastic pattern with varying degrees of circulating progenitor cells. The abnormal bone marrow milieu results in release of hematopoietic stem cells into the blood, extramedullary hematopoiesis, and organomegaly at these sites. Clinically, MF is characterized by progressive anemia, leukopenia or leukocytosis, thrombocytopenia or thrombocythemia and multi-organ extramedullary hematopoiesis, which most prominently involves the spleen leading to massive splenomegaly, severe constitutional symptoms, a hypermetabolic state, cachexia, and premature death.

[0006] A considerable number of cytokine and growth factor receptors utilize non-receptor tyrosine kinases, the Janus kinases (JAKs), to transmit extracellular ligand binding into an intracellular response. For example, erythropoietin, thrombopoietin and granulocyte monocyte colony stimulating factor are all known to signal through receptors that utilize JAK2. JAKs activate a number of downstream pathways implicated in proliferation and survival, including the STATs (signal transducers and activators of transcription), a family of important latent transcription factors.

[0007] Myelofibrosis is now known to be a clonal stem cell disease characterized by molecular (JAK2\6 \ 7F, A7/7.W515L/K) and cytogenetic (l3q-,20q-) markers (Pikman Y, Lee BH, Mercher T, et al. PLoS Med. 2006;3(7):e270; Scott LM, Tong W, Levine RL, et al. N Engl J Med. 2007;356:459-468). The JAK2V611F mutation has been identified in over 95% of patients with PV and approximately 50% of patients with ET and PMF. Furthermore, in a preclinical setting, animal studies have demonstrated that this mutation can lead to an MF-like syndrome. The JAK2V 617F mutation alters the JAK2 tyrosine kinase making it constitutively active. As a result, polycythemia, thrombocythemia and leukocytosis can develop independently from growth factor regulation. Even in patients lacking a confirmed JAK2 mutation, the detection of STAT activation suggests dysregulated JAK activity. In fact, regardless of the mutational status of JAK2, the malignant cells appear to retain their responsiveness to JAK activating cytokines and/or growth factors; hence, they may benefit from JAK inhibition. Although several JAKs inhibitors, including ruxolitinib (approved under the name Jakavi®/Jakafi™) have been approved for the treatment of MF, they have only demonstrated effect in treatment of symptoms. Progression of the disease is not halted and eventually patients may die prematurely.

[0008] IL-l b secreted by the MPN clone has been shown to remodel the stem cell niche in a murine disease model and to support the growth of the malignant clone. In a mouse model of disease it was shown that blockade of IL-l signaling using the recombinant IL-l receptor antagonist (IL- lRa) anakinra reduced platelet counts and increased BM MSC frequency (Arranz et al Nature. 2014 Aug 7;512(7512):78-81).

[0009] In MF patients, level of IL-l b and mean number of circulating CD34+ cells were shown to be increased regardless of mutational status and behavior of the MF-derived HSPCs in vitro can be upregulated by cooperation between various pro-inflammatory factors in the inflammatory microenvironment, which appears to select for the malignant clone (Sollazzo et al Oncotarget. 2016; 7:43974-43988).

[0010] Myelofibrosis (MF) is defined by progressive bone marrow (BM) fibrosis and a consecutive reduction of blood cells. The disruption of the medullary erythropoietic niche is the primary mechanism governing the bone marrow failure and anemia, which typify MF. Nearly 40% of MF patients have hemoglobin (Hb) levels < 10 g/dL at diagnosis. Furthermore, anemia is the disease feature most consistently associated with poor prognosis in MF. Ruxolitinib demonstrates improvements in splenomegaly and constitutional symptoms, however, does not improve anemia.

[0011] Despite current treatment options for treating or preventing diseases and disorders associated anemia and/or myelofibrosis and its associated disease features, there remains a need for improved methods of treatment of anemia and/or myelofibrosis and its associated disease features which are effective and well-tolerated.

SUMMARY OF THE INVENTION

[0012] The present invention relates, in part, to the finding that direct inhibition of inflammation by administration of IL-l b binding antibodies reduces anemia.

[0013] Accordingly, the present invention is directed to an IL- l b-binding antibody or functional fragment thereof for use in treating or preventing anemia in a subject in need thereof. The present invention is also directed to methods of treating or preventing anemia by administering to a subject in need thereof a therapeutically effective amount of an IL- l b-binding antibody or functional fragment thereof.

[0014] The invention also relates to pharmaceutical combinations comprising a) an IL-l b-binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab, and b) a JAK inhibitor, suitably ruxolitinib, or a pharmaceutically acceptable salt thereof

[0015] Further features and advantages of the invention will become apparent from the following detailed description of the invention. BRIEF DESCRIPTION OF THE FIGURES

Figure 1. CANTOS Trial Diagram.

Figure 2. Clinical efficacy of canakinumab as compared to placebo for incident anemia according to subgroups based on baseline clinical characteristics. Data are shown as hazard ratios for combined canakinumab doses (50 mg, 150 mg, and 300 mg) as compared to placebo.

Figure 3. Incidence of anemia in the placebo and the canakinumab groups at > 65 years of age or < 65 years of age.

Figure 4. Cumulative incidence of anemia in patients treated with canakinumab (all doses) compared to placebo in participants greater than 65 years of age and less than 65 years of age.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0016] All patents, published patent applications, publications, references and other material referred to herein are incorporated by reference herein in their entirety.

[0017] As used herein, the term“comprising” encompasses“including” as well as“consisting of’ e.g. a composition“comprising” X may consist exclusively of X or may include something additional, e.g., X + Y.

[0018] As used herein, the articles "a" and "an" refer to one or to more than one (e.g., to at least one) of the grammatical object of the article.

[0019] The term "or" is used herein to mean, and is used interchangeably with, the term "and/or", unless context clearly indicates otherwise.

[0020] As used herein, the term“baseline” refers to a subject’s state or the degree of a condition, e.g. a disease, or one or more parameters associated with the state of a patient, observed before treatment, e.g., before administration of a compound, e.g., before administration of the IL- 1 b binding antibody or fragment thereof and/or standard of care agent and/or a JAK inhibitor according to the present invention.

[0021 ] As used herein, the term“administering” in relation to a compound, e.g., the IL-l b binding antibody or fragment thereof or standard of care agent or a JAK inhibitor, is used to refer to delivery of that compound by any route of delivery. [0022] As used herein, the term“about” in relation to a numerical value x means, for example, +/- 10%.

[0023] As used herein, the word “substantially” does not exclude “completely,” e.g., a composition which is“substantially free” from Y may be completely free from Y. Where necessary, the word“substantially” may be omitted from the definition of the disclosure.

[0024] As used herein, the term“approximately” means that the indicated time in weeks or months may vary by ±5 days or ±10 days.

[0025] The term "treating or preventing" includes the administration of a compound, e.g., the IL- 1 b binding antibody, or fragment thereof, or standard of care agent to prevent or delay the onset of the symptoms, complications, or biochemical indicia of a disease (e.g., anemia), alleviating the symptoms or arresting or inhibiting further development of the disease, condition, or disorder. Treatment may be prophylactic (to prevent or delay the onset of the disease, or to prevent the manifestation of clinical or subclinical symptoms thereof) or therapeutic suppression or alleviation of symptoms after the manifestation of the disease.

[0026] As used herein, the term“prevent”,“preventing” or "prevention" in connection to a disease or disorder refers to the prophylactic treatment of a subject who is at risk of developing a condition (e.g., a specific disease or disorder or clinical symptom thereof such as anemia) resulting in a decrease in the probability that the subject will develop the condition.

[0027] The terms“treat” and“treatment” refer to both therapeutic treatment and prophylactic or preventive measures, wherein the object is to prevent or slow down an undesired physiological change or disorder. For the purpose of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. In other embodiments the terms“treat”,“treatment” and“treating” refer to the inhibition of the progression of a disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.

[0028] An“effective amount” refers to an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A“therapeutically effective amount” of a therapeutic compound (i.e., an effective dosage) depends on the therapeutic compounds selected. The compositions can be administered from one or more times per day to one or more times per week, and also include less frequent administration, e.g., as described herein. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the therapeutic compounds described herein can include a single treatment or a series of treatments.

[0029] The term "therapeutically effective amount" refers to an amount of a drug or a therapeutic agent that will elicit the desired biological and/or medical response of a tissue, system or an animal (including man) that is being sought by a researcher or clinician.

[0030] The term“anemia”, as used herein, refers to hemoglobin level, in blood specimen laboratory test, of less than 13 gram/lOO ml (13 g/dL) in men and hemoglobin level of less than 12.0 gram/lOO ml (12 g/dL) in non-pregnant women, according to criteria set by the World Health Organization (WHO). The term“mild anemia”, as used herein, refers to hemoglobin level, in blood specimen laboratory test, of between 11.0 and 12.9 g/dL in men and hemoglobin level of between 11 and 11.9 g/dL in non -pregnant women, while the term“moderate anemia”, as used herein, refers to hemoglobin level, in blood specimen laboratory test, of between 8.0 and 10.9 g/dL in men and non-pregnant women, according to criteria set by the World Health Organization (WHO).“Severe anemia”, as used herein, refers to hemoglobin level, in blood specimen laboratory test, of between less than 8 g/dL in men and non-pregnant women, according to criteria set by the World Health Organization (WHO) (WHO. Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. Geneva, World Health Organization, 2011 (WHO/NMH/NHD/MNM/l 1.1)

(http://www.who.int/vmnis/indicators/haemoglobin. pdf, accessed August 2019). The term “treatment of anemia”, as used herein, refers to“stabilizing anemia” or“improving anemia”, for example, in comparison to pre-treatment situation or in comparison to standard of treatment. The term“stabilizing anemia” refers, for example, to prevent increase in severity of anemia (e.g., preventing that a“transfusion-independent” patient becomes a“transfusion-dependent” patient or preventing anemia grade 2 becomes anemia grade 3). The term“improving anemia” refers to a decrease in severity of anemia or improvement (e.g. increase) of hemoglobin level.

[0031] As used herein, the term "antibody" as referred to herein includes whole antibodies and any antigen binding fragment or single chains thereof (i.e., "functional fragment"). A naturally occurring "antibody" is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised ofthree domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs arranged from amino -terminus to carboxy-terminus in the following order: FR1 , CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.

[0032] As used herein, the term "functional fragment" of an antibody as used herein, refers to portions or fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., IL- 1 b). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term "functional fragment" of an antibody include a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; a Fd fragment consisting of the VH and CH1 domains; a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a dAb fragment (Ward et al., 1989), which consists of a VH domain; and an isolated complementarity determining region (CDR). Although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see, e.g., Bird et al., 1988; and Huston et al, 1988). Such single chain antibodies are also intended to be encompassed within the term "functional fragments" of an antibody. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.

[0033] As used herein, the terms "monoclonal antibody" or "monoclonal antibody composition" as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

[0034] As used herein, the term "human antibody", as used herein, is intended to include antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Furthermore, if the antibody contains a constant region, the constant region also is derived from such human sequences, e.g., human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis as described in Knappik, et al. A“human antibody” need not be produced by a human, human tissue or human cell. The human antibodies of the disclosure may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0035] As used herein, the term "KD", as used herein, is intended to refer to the dissociation constant, which is obtained from the ratio of K_d to K_a (i.e. K_d/K_a) and is expressed as a molar concentration (M). KD values for antibodies can be determined using methods well established in the art. A method for determining the KD of an antibody is by using surface plasmon resonance, or using a biosensor system such as a Biacore® system.

[0036] As used herein, the terms“subject” or“subjects” refers to a human being, who is diseased with the condition (i.e. disease or disorder) of interest and who would benefit from the treatment, e.g. a patient.

[0037] As used herein, a subject is“in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment. [0038] As used herein, the term“patient” is used interchangeably with the term“subject” and refers to a human patient.

[0039] As used herein, an antibody that "inhibits" one or more of these IL-l b functional properties (e.g., biochemical, immunochemical, cellular, physiological or other biological activities, or the like) as determined according to methodologies known to the art and described herein, will be understood to relate to a statistically significant decrease in the particular activity relative to that seen in the absence of the antibody (or when a control antibody of irrelevant specificity is present). An antibody that inhibits IL- l b activity affects a statistically significant decrease, e.g., by at least 10% of the measured parameter, by at least 50%, 80% or 90%, and in certain embodiments an antibody of the disclosure may inhibit greater than 95%, 98% or 99% of IL-l b functional activity.

[0040] As used herein, the terms“C-reactive protein” and“CRP” refers to serum C-reactive protein, which is used as an indicator of the acute phase response to inflammation. In certain embodiments of the uses and methods described herein, hsCRP levels are assessed in a biological sample, e.g., blood, obtained from the patient. A biological sample from the patient is assayed for the level of hsCRP. As used herein, the term“hsCRP” refers to the level of CRP in the blood as measured by high sensitivity CRP testing. The level of CRP or hsCRP in plasma may be given in any concentration, e.g., mg/dl, mg/L, nmol/L. Levels of CRP or hsCRP may be measured by a variety of well-known methods, e.g., radial immunodiffusion, electro immunoassay, immunoturbidimetry, ELISA, turbidimetric methods, fluorescence polarization immunoassay, and laser nephelometry. Testing for CRP may employ a standard CRP test or a high sensitivity CRP (hsCRP) test (i.e., a high sensitivity test that is capable of measuring low levels of CRP in a sample, e.g., using laser nephelometry). Kits for detecting levels of CRP or hsCRP may be purchased from various companies, e.g., Calbiotech, Inc, Cayman Chemical, Roche Diagnostics Corporation, Abazyme, DADE Behring, Abnova Corporation, Aniara Corporation, Bio-Quant Inc., Siemens Healthcare Diagnostics, etc.

[0041] The term“assaying” is used to mean that a sample may be tested (either directly or indirectly) for either the presence or level of a given marker (e.g., hsCRP and/or hemoglobin). It will be understood that, in a situation where the level of a substance denotes a probability, then the level of such substance may be used to guide a therapeutic decision. For example, one may determine the level of hsCRP and/or hemoglobin in a patient by assaying for its presence by quantitative or relatively-quantitative means (e.g., levels relative to the levels in other samples). [0042] As used herein, the term “myocardial infarction (MI)” refers to “acute myocardial infarction”: the term myocardial infarction (MI) is used when there is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. The term MI includes an ST- elevated MI (STEM!) or a non-ST-elevated MI (NSTEMI).

[0043] The term“combination” or“pharmaceutical combination” used herein, refers to a non- fixed combination wherein the IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab, and a JAK inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof, may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g. synergistic effect. The terms“co-administration” or“combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g. a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time as separate entities either simultaneously or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.

Methods and uses

[0044] The present invention arose from analysis of the data generated from the CANTOS trial (Ridker PM et al, Am Heart J. 201 l;l62(4):597-605, Ridker PM et al, N Engl J Med 2017; 377: 1119-1131 and as disclosed in WO2013/049278, the contents of which are hereby incorporated by reference in their entirety), a randomized, double-blind, placebo-controlled, event- driven trial, designed to evaluate whether the administration of quarterly subcutaneous canakinumab can prevent recurrent cardiovascular events among stable post-myocardial infarction patients with elevated hsCRP. The enrolled 10,061 patients with myocardial infarction and inflammatory atherosclerosis had high sensitivity C-reactive protein (hsCRP) of > 2 mg/L. Three escalating canakinumab doses (50 mg, 150 mg, and 300 mg given subcutaneously every 3 months) were compared to placebo.

[0045] Canakinumab (international nonproprietary name (INN) number 8836) is disclosed in WO02/16436, which is hereby incorporated by reference in its entirety. Canakinumab is a fully human monoclonal anti-human IL- 1 b antibody of the IgGl/k isotype, being developed for the treatment of IL-l p driven inflammatory diseases. It is designed to bind to human IL- 1 b, and thereby blocking the interaction of the cytokine with its receptors.

[0046] Gevokizumab (international nonproprietary name (INN) number 9310) is disclosed in W02007/002261, which is hereby incorporated by reference in its entirety. Gevokizumab is a humanized monoclonal anti-human IL- 1 b antibody of the IgG2 isotype, being developed for the treatment of IL-lp driven inflammatory diseases.

[0047] The inventors have now found that treatment with the IL- 1 b-binding antibody canakinumab significantly reduces the risk of incident anemia in stable post-myocardial patients with elevated hsCRP. The IL-1 b-binding antibody or fragments thereof can be used according to the present invention to treat or prevent anemia.

[0048] In one embodiment, provided are methods of treating or preventing anemia by administering to a subject in need thereof a therapeutically effective amount of an IL-1 b-binding antibody or functional fragment thereof as disclosed herein. Also provided is an IL-1 b-binding antibody or functional fragment thereof for use in treating or preventing anemia in a subject in need thereof.

[0049] As used herein, the term“anemia” includes, but is not limited to: anemia of inflammation (also known as“anemia of chronic inflammation” or“anemia of chronic disease” (ACD)), anemia of (e.g., associated with) chronic kidney disease (CKD), anemia of (e.g., associated with) cancer, anemia associated with cancer having at least a partial inflammatory basis, anemia of (e.g. associated with) hematological malignancy, anemia of (e.g. associated with) myelofibrosis, erythropoiesis stimulating agent (ESA) resistant anemia (e.g., erythropoietin (EPO) resistant anemia, ESA hyporesponsive anemia (e.g., EPO hyporesponsive anemia), functional iron- deficiency anemia, iron-restricted anemia, anemia associated with a decline or loss of kidney function (chronic renal failure), anemia associated with myelosuppressive therapy (e.g., chemotherapy or anti-virals), anemia associated with the progression of non-myeloid cancers, anemia associated with viral infections, anemia associated with relative erythropoietin deficiency, anemia associated with congestive heart failure and/or anemia of chronic disease such as autoimmune disease (e.g., rheumatoid arthritis).

[0050] As used herein, the term“anemia of (e.g., associated with) cancer” refers to a finding of anemia in a cancer patient. Anemia can result from the cancer itself or from a cancer treatment. Anemia is for instance a common complication in patients with hematologic malignancies wherein the cancer causes malfunctioning of the bone marrow so that the bone marrow produces less red blood cells or stops producing red blood cells.“Anemia of a hematological malignancy” as used herein refers to a patient with a hematologic malignancy having anemia. Hematological malignancies or hematologic cancer or blood cancer (terms used interchangeably herein), refers to a cancer that begins in blood-forming tissue, such as the bone marrow, or in the cells of the immune system. Examples of hematologic cancer are leukemia, lymphoma, and multiple myeloma. In one embodiment the hematological malignancy is myelofibrosis.

[0051] Cancer treatments can cause anemia, for instance surgery can cause blood loss, radiation may affect the bone marrow or numerous chemotherapeutic drugs also suppress the blood cell production.

[0052] As used herein, cancers, comprising cancers having at least a partial inflammatory basis include, but are not limited to lung cancer, especially non-small cell lung cancer (NSCLC), colorectal cancer, melanoma, gastric cancer (including gastric and intestinal cancer, cancer of the esophagus, particularly the lower part of the esophagus, renal cell carcinoma (RCC), breast cancer, prostate cancer, head and neck cancer (including HPV, EBV and tobacco/alcohol induced head and neck cancer), bladder cancer, hepatocellular carcinoma (HCC), pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, neuroendocrine cancer and biliary tract cancer (including bile duct and gallbladder cancers) as well as hematologic cancers such as acute myeloblastic leukemia (AML), myelofibrosis and multiple myeloma (MM).

[0053] As used herein, the term“anemia of inflammation” refers to mild to moderate anemia that is often associated with inflammation, including but not limited to: trauma; infectious inflammation; noninfectious inflammation, such as may be associated with rheumatoid arthritis (RA), inflammatory bowel disease (IBD), lupus (including systemic lupus erythematosus or SLE), multiple sclerosis (MS), congestive heart failure (CHF), cardiovascular inflammation, and neoplastic diseases. Typically and preferably inflammation is defined by the level of hsCRP. A subject has inflammation if his base line hsCRP level of >2 mg/L, >3 mg/L, >4 mg/L or >5 mg/L.

[0054] The present invention relates to methods of treating or preventing a disease or disorder associated with increased IL-1 b activity by administering to a subject in need thereof a therapeutically effective amount of an IL- 1 b-binding antibody or fragment thereof. The present invention also provides an IL- 1 b-binding antibody or fragment thereof for use in treating or preventing anemia in a subject in need thereof. In one embodiment of any method or use of the disclosure, said IL-1 b binding antibody or functional fragment thereof is an IL-1 b binding antibody. In some embodiments of any and/or all of the methods or uses described herein, the IL- 1b binding antibody or functional fragment thereof is a neutralizing antibody. In some embodiments of any of the method or use described herein, the antibody or fragment binds to human IL- 1b with a dissociation constant of about 50 pM or less. In some embodiments, the antibody or fragment binds to human Iί-ΐb with a dissociation constant of about 500 pM or less. In some embodiments, the Iί-ΐ b binding antibody or functional fragment thereof binds to human Gί-ΐ b with a dissociation constant of about 250 pM or less. In some embodiments, the IL-Ib binding antibody or functional fragment thereof binds to human IL-l b with a dissociation constant of about 100 pM or less. In some embodiments of any of the methods described above, the IL-l b binding antibody or functional fragment thereof binds to human IL- 1b with a dissociation constant of about 5 pM or less. In some embodiments, the IL-Ib binding antibody or functional fragment thereof binds to human IL- 1b with a dissociation constant of about 1 pM or less. In some embodiments, the Iί-ΐ b binding antibody or functional fragment thereof binds to human IL- 1 b with dissociation constant of about 0.3 pM or less.

[0055] In one embodiment of any method or use described herein, said IL-l b binding antibody or functional fragment thereof is capable of inhibiting the binding of IL-l b to its receptor and has a K_D for binding to IL-l b of about 50 pM or less. In one embodiment of any method or use described herein said Iί-ΐ b binding antibody an I L- 1 b binding antibody directed to an antigenic epitope of human IL-l b which includes the loop comprising the Glu64 residue of the mature IL-l b, wherein said IL-l b binding antibody is capable of inhibiting the binding of IL-l b to its receptor, and further wherein said IL- 1 b binding antibody has a K_D for binding to IL-1 b of about 50 pM or less.

[0056] In a preferred embodiment of any method or use described herein, said Iί-ΐ b binding antibody is canakinumab.

[0057] In other embodiments of any method or use described herein, said Iί-ΐ b binding antibody or functional fragment thereof is selected from the group consisting of XOMA 052 or gevokizumab, LY-2189102, AMG-108, CDP-484 and IL-l Affibody (SOBI 006).

[0058] In other preferred embodiments of any use or method described herein, said Iί-ΐb binding antibody is gevokizumab. Gevokizumab (XOMA-052) is a high-affinity, humanized monoclonal antibody of the IgG2 isotype to interleukin-^, developed for the treatment of IL- 1 b driven inflammatory diseases. Gevokizumab modulates Iί-ΐ b binding to its signaling receptor. Gevokizumab is disclosed in W02007/002261 which is hereby incorporated by reference in its entirety.

[0059] In one embodiment said IL-1 b binding antibody is LY-2189102, which is a humanised interleukin-l beta (IL- 1 b) monoclonal antibody.

[0060] In one embodiment said IL- 1 b binding antibody or a functional fragment thereof is CDP- 484 (Celltech), which is an antibody fragment blocking IL-l b.

[0061] In one embodiment said IL-1 b binding antibody or a functional fragment thereof is IL-l Affibody (SOBI 006, Z-FC (Swedish Orphan Biovitrum/Affibody)).

[0062] In one embodiment of any method or use described herein, said anemia is anemia of chronic disease. In one embodiment of any method or use described herein, said anemia is anemia of chronic kidney disease. In one embodiment of any method or use described herein, said anemia is anemia of cancer. In one embodiment of any method or use described herein, said anemia is anemia of cancer with partial inflammatory basis. In one embodiment of any method or use described herein, said anemia is anemia of inflammation. Accordingly, in one embodiment provided is a method of treating or preventing anemia, comprising administering a therapeutically effective dose of an Iί-ΐ b binding antibody or functional fragment thereof to a subject in need thereof. In one embodiment provided is a method of treating or preventing anemia of inflammation, comprising administering a therapeutically effective dose of an Iί-ΐ b binding antibody or functional fragment thereof to a subject in need thereof. In another embodiment, provided is a method of treating or preventing anemia of cancer, comprising administering a therapeutically effective dose of an Iί-ΐb binding antibody or functional fragment thereof to a subject in need thereof. In another embodiment, provided is a method of treating or preventing anemia of cancer with partial inflammatory basis, comprising administering a therapeutically effective dose of an Iί-ΐ b binding antibody or functional fragment thereof to a subject in need thereof. In one embodiment provided is a method of treating or preventing anemia, comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof. In one embodiment provided is a method of treating or preventing anemia of inflammation, comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof. In another embodiment, provided is a method of treating or preventing anemia of cancer, comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof. In another embodiment, provided is a method of treating or preventing anemia of cancer with partial inflammatory basis, comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof. In one embodiment provided is a method of treating or preventing anemia, comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof. In one embodiment provided is a method of treating or preventing anemia of inflammation, comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof. In another embodiment, provided is a method of treating or preventing anemia of cancer, comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof. In another embodiment, provided is a method of treating or preventing anemia of cancer with partial inflammatory basis, comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof. In one embodiment provided is a method of treating or preventing anemia associated with myelofibrosis, comprising administering a therapeutically effective dose of an IL-l b binding antibody or functional fragment thereof to a subject in need thereof. In one embodiment provided is a method of treating or preventing anemia associated with myelofibrosis, comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof. In one embodiment provided is a method of treating or preventing anemia associated with myelofibrosis, comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof. In another embodiment provided is an IL- l b binding antibody or functional fragment thereof for use in treating or preventing anemia associated with myelofibrosis, comprising administering a therapeutically effective dose of to a subject in need thereof. In one embodiment provided is canakinumab for use in treating or preventing anemia associated with myelofibrosis, comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof. In one embodiment provided is gevokizumab for use in treating or preventing anemia associated with myelofibrosis, comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof.

[0063] In another embodiment, the invention relates to methods for treating anemia associated with an elevated level of hepcidin, comprising administering a therapeutically effective dose of an Gί-ΐ b binding antibody or functional fragment thereof to a subject in need thereof. In one embodiment, provided is a method for treating anemia associated with an elevated level of hepcidin, comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof. In another embodiment, provided is a method for treating anemia associated with an elevated level of hepcidin, comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof.

[0064] In one embodiment of any use or method described herein, said patient has hsCRP level of >2 mg/L before administration of the IL-l b binding antibody or functional fragment thereof.

[0065] In one embodiment, provided is a method of treating or preventing anemia, comprising administering a therapeutically effective dose of an IL-l b binding antibody or functional fragment thereof to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of said IL-l b binding antibody or functional fragment thereof. In one embodiment, provided is a method of treating or preventing anemia, comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of canakinumab. In another embodiment, provided is a method of treating or preventing anemia, comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of gevokizumab.

[0066] In one embodiment, provided is a method of treating or preventing anemia of inflammation, comprising administering a therapeutically effective dose of an IL- l b-binding antibody or fragment thereof to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of the IL- l b binding antibody or functional fragment thereof. In one embodiment, provided is a method of treating or preventing anemia of inflammation, comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of canakinumab. In one embodiment, provided is a method of treating or preventing anemia of inflammation, comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of gevokizumab.

[0067] In one embodiment, provided is a method of treating or preventing anemia of inflammation, comprising administering a therapeutically effective dose of an IL-l b-binding antibody or functional fragment thereof to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L, >3 mg/L, >4 mg/L or >5 mg/L before first administration of the IL-l b binding antibody or functional fragment thereof and wherein said subject has reduced hsCRP level of <5 mg/L, <4 mg/L, <3 mg/L, or <2 mg/L assessed after administration of the IL-l b-binding antibody or functional fragment thereof. In one embodiment, said hsCRP level is >5 mg/L before first administration of the IL- 1 b-binding antibody or functional fragment thereof and reduced to <5 mg/L assessed after administration of the IL- 1 b-binding antibody or functional fragment thereof. In one embodiment, said hsCRP level is >4 mg/L before first administration of the IL- 1 b-binding antibody or functional fragment thereof and reduced to <4 mg/L assessed after administration of the IL-l b-binding antibody or functional fragment thereof. In one embodiment, said hsCRP level is >3 mg/L before first administration of the IL-l b-binding antibody or functional fragment thereof and reduced to <3 mg/L assessed after administration of the IL-l b-binding antibody or functional fragment thereof. In one embodiment, said hsCRP level is >2 mg/L before first administration of the IL-l b-binding antibody or functional fragment thereof and reduced to <2 mg/L assessed after administration of the IL-1 b-binding antibody or functional fragment thereof. In one embodiment, said assessment of hsCRP after administration of the IL- 1 b-binding antibody or functional fragment thereof is performed at least approximately one month, at least approximately two months, at least approximately three months, at least approximately four months, at least approximately five months or at least approximately six months after administration of the IL-l b- binding antibody or functional fragment thereof In a preferred embodiment, said assessment of hsCRP level after administration of the IL-1 b-binding antibody or functional fragment thereof is performed at least approximately three months after first administration of the IL-1 b-binding antibody or functional fragment thereof.

[0068] In one embodiment, provided is a method of treating or preventing anemia of inflammation, comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L, >3 mg/L, >4 mg/L or >5 mg/L before first administration of canakinumab and wherein said subject has reduced hsCRP level of <5 mg/L, <4 mg/L, <3 mg/L, or <2 mg/L assessed after administration of canakinumab. In one embodiment, said hsCRP level is >5 mg/L before first administration canakinumab and reduced to <5 mg/L assessed after administration of canakinumab. In one embodiment, said hsCRP level is >4 mg/L before first administration of canakinumab and reduced to <4 mg/L assessed after administration of canakinumab. In one embodiment, said hsCRP level is >3 mg/L before first administration of canakinumab and reduced to <3 mg/L assessed after administration of canakinumab. In one embodiment, said hsCRP level is >2 mg/L before first administration of canakinumab and reduced to <2 mg/L assessed after administration of canakinumab. In one embodiment, said assessment of hsCRP after administration of canakinumab is performed at least approximately one month, at least approximately two months, at least approximately three months, at approximately about four months, at least approximately five months or at least approximately six months after administration of canakinumab. In a preferred embodiment, said assessment of hsCRP level after administration of canakinumab is performed at least approximately three months after first administration of canakinumab.

[0069] In one embodiment, provided is a method of treating or preventing anemia of inflammation, comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L, >3 mg/L, >4 mg/L or >5 mg/L before first administration of gevokizumab and wherein said subject has reduced hsCRP level of <5 mg/L, <4 mg/L, <3 mg/L, or <2 mg/L assessed after administration of gevokizumab. In one embodiment, said hsCRP level is >5 mg/L before first administration gevokizumab and reduced to <5 mg/L assessed after administration of gevokizumab. In one embodiment, said hsCRP level is >4 mg/L before first administration of gevokizumab and reduced to <4 mg/L assessed after administration of gevokizumab. In one embodiment, said hsCRP level is >3 mg/L before first administration of gevokizumab and reduced to <3 mg/L assessed after administration of gevokizumab. In one embodiment, said hsCRP level is >2 mg/L before first administration of gevokizumab and reduced to <2 mg/L assessed after administration of gevokizumab. In one embodiment, said assessment of hsCRP after administration of gevokizumab is performed at least approximately one month, at least approximately two months, at least approximately three months, at least approximately four months, at least approximately five months or at least approximately six months after administration of gevokizumab. In a preferred embodiment, said assessment of hsCRP level after administration of gevokizumab is performed at least approximately three months after first administration of gevokizumab.

[0070] In one embodiment, provided is a method of treating or preventing anemia in a subject with cancer, comprising administering a therapeutically effective dose of an IL-l b-binding antibody or functional fragment thereof to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of the IL- l b binding antibody or functional fragment thereof. In one embodiment, provided is a method of treating or preventing anemia in a subject with cancer, comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of canakinumab. In another embodiment, provided is a method of treating or preventing anemia in a subject with cancer, comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of gevokizumab. In one embodiment, provided is a method of treating or preventing anemia in a subject with cancer with partial inflammatory basis, comprising administering a therapeutically effective dose of an IL-1 b-binding antibody or fragment thereof to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of the IL- 1 b binding antibody or functional fragment thereof. In one embodiment, provided is a method of treating or preventing anemia in a subject with cancer with partial inflammatory basis, comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of canakinumab. In one embodiment, provided is a method of treating or preventing anemia in a subject with cancer having at least partial inflammatory basis, comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of gevokizumab.

[0071 ] In one embodiment, provided is a method of treating or preventing anemia in a subject with cancer, comprising administering a therapeutically effective dose of an IL-l b-binding antibody or functional fragment thereof to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of the IL- 1 b binding antibody or functional fragment thereof and wherein said subject has reduced hsCRP level compared to baseline assessed after administration of the IL-l b-binding antibody or functional fragment thereof. In one embodiment, said assessment of hsCRP after administration of the IL-1 b-binding antibody or functional fragment thereof is performed at least approximately one month, at least approximately two months, at least approximately three months, at least approximately four months, at least approximately five months or at least approximately six months after administration of the IL-l b-binding antibody or functional fragment thereof.

[0072] In one embodiment, provided is a method of treating or preventing anemia in a subject with cancer, comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of canakinumab and wherein said subject has reduced hsCRP level compared to baseline assessed after administration of canakinumab. In one embodiment, said assessment of hsCRP after administration of canakinumab is performed at least approximately one month, at least approximately two months, at least approximately three months, at least approximately four months, at least approximately five months or at least approximately six months after administration of canakinumab.

[0073] In one embodiment, provided is a method of treating or preventing anemia in a subject with cancer, comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof, wherein said subject has hsCRP level of >2 mg/L before administration of gevokizumab and wherein said subject has reduced hsCRP level compared to baseline assessed after administration of gevokizumab. In one embodiment, said assessment of hsCRP after administration of gevokizumab is performed at least approximately one month, at least approximately two months, at least approximately three months, at least approximately four months, at least approximately five months or at least approximately six months after administration of gevokizumab.

[0074] In one embodiment, provided is a method for treating or preventing anemia, comprising administering a therapeutically effective dose of an IL-l b binding antibody or functional fragment thereof, suitably canakinumab or gevokizumab, to a subject in need thereof, resulting in stabilizing anemia or improving anemia. In one embodiment, the present disclosure provides a method for treating or preventing anemia, comprising administering a therapeutically effective dose of an IL- 1 b binding antibody or functional fragment thereof, suitably canakinumab or gevokizumab, to a subject in need thereof, resulting in preventing that a“transfusion-independent” patient becomes a“transfusion-dependent” patient.

[0075] In another embodiment, said patient has previously suffered myocardial infarction (MI). In another embodiment, provided is a method for treating or preventing anemia in a patient that has suffered myocardial infarction (MI), comprising administering a therapeutically effective dose of the IL- l b binding antibody or functional fragment thereof, wherein said patient has a high sensitivity C-reactive protein (hsCRP) level of >2 mg/L assessed at least 28 days after MI and before first administration of said IL- l b binding antibody or functional fragment thereof.

[0076] In one embodiment, the subject is over 60 years of age. In one embodiment, the subject is male and over 60 years of age. In another embodiment, the subject is female and over 60 years of age. [0077] In one embodiment, the subject is over 65 years of age. In one embodiment, the subject is male and over 65 years of age. In another embodiment, the subject is female and over 65 years of age.

[0078] In one embodiment, the subject is over 70 years of age. In one embodiment, the subject is male and over 70 years of age. In another embodiment, the subject is female and over 70 years of age.

[0079] In one embodiment, the subject is over 75 years of age. In one embodiment, the subject is male and over 75 years of age. In another embodiment, the subject is female and over 75 years of age.

[0080] In other embodiments of any method or use described herein, said patient is concomitantly receiving one or more other therapies for the treatment of anemia including standard of care treatment or the treatment of the underlying disease or disorder causing the anemia, including standard of care treatment for the underlying disease or disorder.

Combination therapy

[0081] The present disclosure also provides a pharmaceutical combination comprising (a) an IL- 1 b binding antibody, or functional fragment thereof, suitably gevokizumab or canakinumab, and (b) JAKs inhibitor, suitably ruxolitinib, or a pharmaceutically acceptable salt thereof. The pharmaceutical combination may be used for the simultaneous, separate or sequential administration for the treatment of anemia of hematological malignancy, leukemia or myelofibrosis.

[0082] Allosteric inhibition of IL-l b in the hematopoietic stem cell niche prevents proliferation of myelofibrosis blasts and reduces genotoxic effects.

[0083] A considerable number of cytokine and growth factor receptors utilize non-receptor tyrosine kinases, the Janus kinases (JAKs), to transmit extracellular ligand binding into an intracellular response. For example, erythropoietin, thrombopoietin and granulocyte monocyte colony stimulating factor are all known to signal through receptors that utilize JAK2. JAKs activate a number of downstream pathways implicated in proliferation and survival, including the STATs (signal transducers and activators of transcription), a family of important latent transcription factors.

[0084] In one embodiment the JAKs is a JAK1/JAK2 inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof or momelotinib or a pharmaceutically acceptable salt thereof, more suitably ruxolitinib or a pharmaceutically acceptable salt, more suitably ruxolitinib phosphate.

[0085] Ruxolitinib represents a novel, potent, and selective inhibitor of JAK1 and JAK2. Ruxolitinib potently inhibits JAK1 and JAK2 [half maximal inhibitory concentration (IC50) 0.4 to 1.7 nM], yet it does not significantly inhibit (< 30% inhibition) a broad panel of 26 kinases when tested at 200 nM (approximately lOOx the average IC50 value for JAK enzyme inhibition) and does not inhibit JAK 3 at clinically relevant concentrations.

[0086] In one embodiment the JAKs is a JAK2 inhibitor, suitably pacritinib or a pharmaceutically acceptable salt thereof or fedratinib or a pharmaceutically acceptable salt thereof.

[0087] In one embodiment the JAKs inhibitor is a JAK2^V617F inhibitor, suitably gandotinib or a pharmaceutically acceptable salt thereof.

[0088] In one embodiment the JAKs inhibitor is a JAK2 inhibitor, suitably BMS-911543 or a pharmaceutically acceptable salt thereof.

[0089] In one embodiment the JAKs inhibitor is a JAK1 inhibitor, suitably itacitinib or a pharmaceutically acceptable salt thereof, in particular itacitinib adipate.

[0090] In one embodiment the JAKs inhibitor is a JAK2/Src inhibitor, suitably NS-018 or a pharmaceutically acceptable salt thereof.

[0091] As used herein, “ruxolitinib” is the JAK1/JAK2 inhibitor (R)-3-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-lH-pyrazol-l-yl)-3-cyclopentylpropanenitrile, also named 3 (R)-Cyclopentyl-3 - [4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-pyrazol-l -yl]propanenitrile, of formula:

which can be prepared, for example, as described in W02007/070514, which is incorporated herein by reference. As used herein,“ruxolitinib” refers to the free form, and any reference to“a pharmaceutically acceptable salt thereof’ refers to“a pharmaceutically acceptable acid addition salt thereof’, in particular ruxolitinib phosphate, which can be prepared, for example, as described in W02008/157208, which is incorporated herein by reference. Ruxolitinib is approved for the treatment of intermediate to high-risk myelofibrosis under the tradename Jakafi®/Jakavi®.

[0092] Ruxolitinib, or pharmaceutically acceptable salt thereof, in particular ruxolitinib phosphate, can be in a unit dosage form (e.g. tablet), which is administered orally. Suitably ruxolitinib is administered in an amount of from 5 mg twice daily to 25 mg twice daily, such as 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, 20 mg twice daily or 25 mg twice daily, depending on the patient’s blood count according to the prescribing information for Jakavi®/Jakafi® and the judgment of the treating physician.

[0093] In another embodiment, ruxolitinib or a pharmaceutically acceptable salt thereof is comprised in a sustained-release dosage form. A sustained release dosage form of ruxolitinib has been described in international patent application WO 14078486, the content of which is hereby incorporated in its entirety. In any embodiment of any of the disclosed dosing regimens described herein, ruxolitinib or a pharmaceutically acceptable salt thereof may be administered in a sustained-release dosage form, wherein said ruxolitinib, or pharmaceutically acceptable salt thereof, is present in said sustained-release dosage form in an amount of about 10 to about 60 mg on a free base basis. In another embodiment, said ruxolitinib, or pharmaceutically acceptable salt thereof, is present in said sustained-release dosage form in an amount of about 25 mg on a free base basis. Administration of such sustained-release form may be orally. Suitably, the sustained- release dosage form of ruxolitinib, or a pharmaceutically acceptable salt thereof, is administered once daily.

[0094] In one embodiment,“ruxolitinib” is also intended to represent isotopically labeled forms lsotopically labeled compounds have structures depicted by the formula above except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into ruxolitinib, for example, isotopes of hydrogen, namely the compound of formula:

wherein each Ri, R₂, R3, R4, R5, Re, R7, Rs, R9, Rio, R11, R12, R13, Ri4, R15, R½ and R17 is independently selected from H or deuterium; provided that there is at least one deuterium present in the compound. In other embodiments there are multiple deuterium atoms present in the compound. Suitable compounds are disclosed in US 9,249,149 B2, which is hereby incorporated in its entirety.

[0095] In one preferred embodiment, a deuterated ruxolitinib is selected from the group consisting

or a pharmaceutically acceptable salt of any of the foregoing.

[0096] In a preferred embodiment, a deuterated ruxolitinib is

, or a pharmaceutically acceptable salt thereof

[0097] As used herein,“itacitinib” refers to the JAK1/JAK2 inhibitor 2-(3-(4-(7H-pyrrolo(2,3- d)pyrimidin-4-yl)-lH-pyrazol-l-yl)-l-(l-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4- yl)azeti din-3 -yl)acetonitrile, also named 2-[l-[l-[3-fluoro-2-(trifluoromethyl)pyridine-4- carbonyl]piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-l-yl]azetidin-3- yl]acetonitrile of formula

, which can be prepared, for example, as described in

WO2011/112662, which is incorporated herein by reference. As used herein,“itacitinib” refers to the free form, and any reference to“a pharmaceutically acceptable salt thereof’ refers to“a pharmaceutically acceptable acid addition salt thereof’, in particular itacitinib adipate.

[0098] In one aspect provided is a pharmaceutical combination comprising, consisting essentially of or consisting of a) an IL- 1 b binding antibody, or functional fragment thereof, and b) a JAKs inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof. Suitably the pharmaceutical combination is for use in the treatment of myelofibrosis. [0099] Accordingly, in one aspect, provided is a pharmaceutical combination comprising a) an IL- 1 b binding antibody, or functional fragment thereof, suitably gevokizumab or canakinumab, and (b) ruxobtinib, or a pharmaceutically acceptable salt thereof.

[0100] In another aspect, provided is a pharmaceutical combination comprising a) gevokizumab and (b) ruxobtinib, or a pharmaceutically acceptable salt thereof.

[0101] In another aspect, provided is a pharmaceutical combination comprising a) canakinumab and (b) ruxobtinib, or a pharmaceutically acceptable salt thereof.

[0102] There is also provided a pharmaceutical composition comprising such a combination; a method of treating a subject having anemia of hematological malignancy, leukemia or myelofibrosis, comprising administration of said combination to a subject in need thereof; use of such combination for the treatment of proliferative disease; and a commercial package comprising such combination. Suitably the pharmaceutical combination is for use in the treatment of myelofibrosis in a subject in need thereof.

[0103] In one aspect, provided is gevokizumab for use in the treatment of myelofibrosis, wherein gevokizumab, is administered in combination with ruxobtinib or a pharmaceutically acceptable salt thereof, and wherein gevokizumab and ruxobtinib or a pharmaceutically acceptable salt thereof, are administered in jointly therapeutically effective amounts to a subject in need thereof.

[0104] In one aspect, provided is canakinumab for use in the treatment of myelofibrosis, wherein canakinumab, is administered in combination with ruxobtinib or a pharmaceutically acceptable salt thereof, and wherein canakinumab and ruxobtinib or a pharmaceutically acceptable salt thereof, are administered in jointly therapeutically effective amounts to a subject in need thereof.

[0105] In one aspect, provided is ruxobtinib, or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, wherein ruxobtinib or a pharmaceutically acceptable salt thereof, is administered in combination with gevokizumab, and wherein ruxobtinib or a pharmaceutically acceptable salt thereof, and gevokizumab, are administered in jointly therapeutically effective amounts to a subject in need thereof.

[0106] In one aspect, provided is ruxobtinib, or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, wherein ruxobtinib or a pharmaceutically acceptable salt thereof, is administered in combination with canakinumab, and wherein ruxobtinib, or a pharmaceutically acceptable salt thereof, and canakinumab, are administered in jointly therapeutically effective amounts to a subject in need thereof. [0107] In one aspect, provided is a pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxobtinib or a pharmaceutically acceptable salt thereof for use in the treatment of myelofibrosis.

[0108] Also provided is a pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxobtinib or a pharmaceutically acceptable salt thereof for use in the treatment of anemia of hematological malignancy.

[0109] Also provided is a pharmaceutical combination comprising a) the K-1 b binding antibody gevokizumab or functional fragment thereof and b) the JAK inhibitor ruxobtinib or a pharmaceutically acceptable salt thereof for use in the treatment of anemia of hematological malignancy.

[0110] Also provided is a pharmaceutical combination comprising a) the K-1 b binding antibody canakinumab or functional fragment thereof and b) the JAK inhibitor ruxobtinib or a pharmaceutically acceptable salt thereof for use in the treatment of anemia of hematological malignancy.

[0111] Also provided is a pharmaceutical combination comprising a) an K-1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxobtinib or a pharmaceutically acceptable salt thereof for use in the treatment of anemia associated with myelofibrosis.

[0112] Also provided is a pharmaceutical combination comprising a) the K-1 b binding antibody gevokizumab or functional fragment thereof and b) the JAK inhibitor ruxobtinib or a pharmaceutically acceptable salt thereof for use in the treatment of anemia associated with myelofibrosis.

[0113] Also provided is a pharmaceutical combination comprising a) the K-1 b binding antibody canakinumab or functional fragment thereof and b) the JAK inhibitor ruxobtinib or a pharmaceutically acceptable salt thereof for use in the treatment of anemia associated with myelofibrosis.

[0114] Also provided is a pharmaceutical combination comprising a) an K-1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof for use in the treatment associated with leukemia.

[0115] Myelofibrosis comprises primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera myelofibrosis (PPV-MF).

[0116] The term“primary myelofibrosis” (PMF), as used herein, is defined with reference to“The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia”, as published in Blood, 2016, 127:2391-2405. Primary myelofibrosis encompasses prefibrotic/early primary myelofibrosis (prePMF) and overt primary myelofibrosis (overt PMF). Diagnosis of prePMF requires meeting the following 3 major criteria, and at least 1 minor criterion according to the 2016 WHO classification for prePMF in Table 1 :

Table 1: Criteria for diagnosis of prePMF

[0117] Diagnosis of overt PMF requires meeting the following 3 major criteria, and at least 1 minor criterion according to the 2016 WHO classification for overt PMF in Table 2:

[0118] The term“bone marrow fibrosis”, as used herein, refers to bone marrow fibrosis graded according to the 2005 European consensus grading system (Thiele et. ah, Haematologica, 2005, 90(8), 1128-1132, in particular as defined in Table 3 and Figure 1 of page 1130 therein), such as: “fibrosis grade 0”: scattered linear reticulin with no intersections (cross-overs) corresponding to normal bone marrow;

“fibrosis grade 1”: loose network of reticulin with many intersections, especially in perivascular areas;

“fibrosis grade 2”: diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis;

“fibrosis grade 3”: diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis;

wherein the grading (i.e. grading of fiber density and quality) is made on the basis of bone marrow biopsy specimen assessment.

[0119] The term“essential thrombocythemia” (ET), as used herein, is defined with reference to “The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia”, as published in Blood, 2016, 127:2391 -2405. The term“post-essential thrombocythemia myelofibrosis” (PET-MF), as used herein, refers to MF secondary to ET (i.e. MF arising as a progression of ET), wherein ET is as defined herein above. According to the IWG- MRT criteria (Barosi G etal, Leukemia (2008) 22, 437-438), criteria for diagnosing post-essential thrombocythemia myelofibrosis are:

Table 3: Criteria for diagnosis of post-essential thrombocythemia myelofibrosis

[0120] The term“polycythemia vera” (PV), as used herein, is defined with reference to“The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia”, as published in Blood, 2016, 127:2391-2405. The term “post-polycythemia myelofibrosis” (PPV-MF), as used herein, refers to MF secondary to PV (i.e. MF arising as a progression of PV). According to the IWG-MRT criteria (Barosi G et al, Leukemia (2008) 22, 437-438), criteria for diagnosing post-polycythemia myelofibrosis are:

Table 4: Criteria for diagnosis of post-polycythemia myelofibrosis

[0121] As used herein, the following response criteria as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and the European Leukemia Net (ELN) response criteria for MF (Tefferi et al, Blood 2013 122: 1395-1398, which is incorporated by reference in its entirety) are used herein:

Table 5: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and the European Leukemia Net (ELN) response criteria for myelofibrosis

• EMH, extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology- or imaging study-proven nonhepatosplenic EMH); LCM, left costal margin; ETNL, upper normal limit.

• * Baseline and posttreatment bone marrow slides are to be interpreted at one sitting by a central review process.

• † Grading of MF is according to the European classification: Thiele etal. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica.

2005;90:l 128.

• | Immature myeloid cells constitute blasts + promyelocytes + myelocytes +

metamyelocytes + nucleated red blood cells. In splenectomized patients, <5% immature myeloid cells is allowed.

• § Increase in severity of anemia constitutes the occurrence of new transfusion

dependency or a >20 g/L decrease in hemoglobin level from pretreatment baseline that lasts for at least 12 weeks. Increase in severity of thrombocytopenia or neutropenia is defined as a 2-grade decline, from pretreatment baseline, in platelet count or absolute neutrophil count, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. In addition, assignment to Cl requires a minimum platelet count of >25 000 x lO(9)/L and absolute neutrophil count of >0.5 x lO(9)/L.

• || Applicable only to patients with baseline hemoglobin of <100 g/L. In patients not meeting the strict criteria for transfusion dependency at the time of treatment initiation, but have received transfusions within the previous month, the pre-transfusion hemoglobin level should be used as the baseline.

• Tf Transfusion dependency is defined as transfusions of at least 6 units of packed red blood cells (PRBC), in the 12 weeks prior to start of treatment initiation, for a hemoglobin level of <85 g/L, in the absence of bleeding or treatment-induced anemia. In addition, the most recent transfusion episode must have occurred in the 28 days prior to start of treatment initiation.

Response in transfusion-dependent patients requires absence of any PRBC transfusions during any consecutive“rolling” 12-week interval during the treatment phase, capped by a hemoglobin level of >85 g/L. • # In splenectomized patients, palpable hepatomegaly is substituted with the same measurement strategy.

• ** Spleen or liver responses must be confirmed by imaging studies where a >35% reduction in spleen volume, as assessed by MRI or CT, is required. Furthermore, a >35% volume reduction in the spleen or liver, by MRI or CT, constitutes a response regardless of what is reported with physical examination.

• †† Symptoms are evaluated by the MPN-SAF TSS. The MPN-SAF TSS is assessed by the patients themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all the individual scores (0-100 scale). Symptoms response requires >50% reduction in the MPN-SAF TSS.

[0122] Among patients, myelofibrosis frequently causes shortened survival due to disease transformation to acute leukemia, progression without acute transformation, cardiovascular complications or thrombosis, infection or portal hypertension. It is one of the aims of the present disclosure to improve the median survival of myelofibrosis patients.

[0123] As used herein, the term "median survival time" refers to the time of diagnosis or from the time of initiation of treatment according to the present disclosure that half of the patients in a group of patients diagnosed with the disease are still alive compared to patients receiving best available treatment or compared to patients receiving placebo and wherein patients belong to the same risk group of myelofibrosis, for example as described by Gangat et al (J Clin Oncol. 2011 Feb l;29(4):392-397), which is hereby incorporated by reference in its entirety.

[0124] Accordingly, in one embodiment the present disclosure provides an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab, in combination with a JAKs inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, especially primary MF, wherein median survival time is increased by at least 3 months in the group of high risk MF patients or by at least six months, preferably by at least 12 months in the group of medium risk MF patients.

[0125] As used herein, the term "newly diagnosed" refers to diagnosis of the disorder, e.g. myelofibrosis and said patient has not received any treatment. In one embodiment the present disclosure provides a pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxobtinib or a pharmaceutically acceptable salt thereof, for use in the treatment of a newly diagnosed myelofibrosis patient.

[0126] The term“triple-negative myelofibrosis patient”, as used herein, refers to a patient who lacks JAK2, CALR and MPL mutations. In one embodiment the present disclosure provides a pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxobtinib or a pharmaceutically acceptable salt thereof, for use in the treatment of triple-negative myelofibrosis patient.

[0127] The term“best available therapy”, as used herein, refers to any commercially available agent approved poor to August 2018 for the treatment of PMF, PET-MF or PPV-MF, as monotherapy, or in combination. Exemplary agents include, but are not limited to ruxobtinib or a pharmaceutically acceptable salt thereof, antineoplastic agents (e.g., hydroxyurea, anagrelide), glucocorticoids (e g., prednisone/prednisolone, metbylprednisoione), antianemia preparations (e.g., epoetin-alpha), immunomodulatory agents (e.g., thalidomide, ienalidomide), purine analogs (e.g., mereaptopurine, thioguanine), antigonadotropins (e.g., danazoi), interferons (e.g., PEG- mterferon -alpha 2a, interferon-alpha), nitrogen mustard analogs (e.g. melphalan), pyrimidine analogs (e.g., cytarabine).

[0128] The term“splenomegaly”, as used herein, refers to a palpably enlarged spleen (e.g. a spleen is palpable at > 5 cm below the left coastal margin) or to an enlarged spleen as detected by an imaging test (e.g. a computed tomography (CT) scan, MRI, X-rays or ultrasound), wherein the term“enlarged spleen” refers to a spleen greater in size than normal (e.g., median normal spleen volume of 200 cm³).

[0129] The term “treatment of splenomegaly”, as used herein, refers to “improvement of splenomegaly”, which means a decrease in splenomegaly, for example a reduction in spleen volume, as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and the European Leukemia Net (ELN) response criteria for MF in Table 5. In one embodiment, the disclosure provides a pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxobtinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of splenomegaly associated with myelofibrosis, resulting in, for example, >20%, >25%, >30% or >35% reduction in spleen volume as measured by magnetic resonance imaging (MRI) or computed tomography (CT) from pre treatment baseline to, for example, week 24 or week 48. In another embodiment, provided is a pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, wherein volume of the spleen does not increase. Spleen volume progression is considered as a spleen volume increase of 25% or more from baseline as determined by MRI/CT, as assessed, for example, in week 24 or in week 48.

[0130] The term“hepatomegaly”, as used herein, refers to a palpably enlarged liver or to an enlarged liver as detected by an imaging test (e.g. a computed tomography (CT) scan), wherein the term“enlarged liver” refers to a liver greater in size than normal (e.g., median normal liver volume of approximately 1500 cm³).

[0131] The term “treatment of hepatomegaly”, as used herein, refers to “improvement of hepatomegaly”, which means a decrease in hepatomegaly, for example a reduction in hepatomegaly, as defined according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and the European Leukemia Net (ELN) response criteria for MF in the preceding table. Accordingly, in one embodiment the present disclosure provides a pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of hepatomegaly associated with myelofibrosis, resulting in, for example, >20%, >25%, >30% or >35% reduction in liver volume as measured by magnetic resonance imaging (MRI) or computed tomography (CT) from pre-treatment baseline to, for example, week 24 or week 48.

[0132] The term“thrombocytopenia”, as used herein, refers to a platelet count, in blood specimen laboratory test, lower than normal. The term“severity of thrombocytopenia”, as used herein, refers, for example, to specific grade 1-4 of thrombocytopenia according to CTCAE (version 4.03).

[0133] The term “treatment of thrombocytopenia”, as used herein, refers to “stabilizing thrombocytopenia” or “improving thrombocytopenia”, in comparison to the pre-treatment situation or in comparison to best available therapy or to placebo control. The term“stabilizing thrombocytopenia” refers, for example, to prevent an increase in the severity of thrombocytopenia, namely the platelet count remains stable. The term“improving thrombocytopenia” refers to alleviation of the severity of thrombocytopenia, namely increasing blood platelet count. In one embodiment, the disclosure provides a pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of thrombocytopenia associated with myelofibrosis, resulting in stabilizing thrombocytopenia or improving thrombocytopenia from pre treatment baseline to, for example, week 24 or week 48 of treatment.

[0134] The term“neutropenia”, as used herein, refers to an absolute neutrophil count (ANC), in blood specimen laboratory test, lower than normal value. The term“severity of neutropenia”, as used herein, refers, for example, to specific grade 1 -4 of neutropenia according to CTCAE (version 4.03).

[0135] The term“treatment of neutropenia”, as used herein, refers to“stabilizing neutropenia” or “improving neutropenia”, for example, in comparison to the pre-treatment situation or in comparison to best available therapy or to placebo control. The term“stabilizing neutropenia” refers, for example, to prevent an increase in the severity of neutropenia. The term“improving neutropenia” refers, for example, to a decrease in the severity of neutropenia. In one embodiment, the disclosure provides a pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of neutropenia associated with myelofibrosis, resulting in stabilizing neutropenia or improving neutropenia from pre-treatment baseline to, for example, week 24 or week 48 of treatment.

[0136] The term“severity of anemia”, as used herein, refers, for example, to specific grade 1 -4 of anemia according to CTCAE (version 4.03)].

[0137] The term “treatment of anemia”, as used herein, refers to “stabilizing anemia” or “improving anemia”, for example, in comparison to the pre-treatment situation or in comparison to best available therapy or to placebo control. The term“stabilizing anemia” refers, for example, to prevent an increase in the severity of anemia (e.g. preventing that a“transfusion-independent” patient becomes a“transfusion-dependent” patient or preventing anemia grade 2 becomes anemia grade 3). The term“improving anemia” refers to a decrease in the severity of anemia or an improvement in hemoglobin level. Improvement of hemoglobin level is considered to be an increase in hemoglobin levels of at least 1 g/dL or at least 1.5 g/dL or at least 2 g/dL or at least 2.5 g/dL or at least 3 g/dL or at least 3.5 g/dL or at least 4 g/dL or at least 4.5 g/dL or at least 5 g/dL compared to baseline. Preferred is an increase of hemoglobin of at least 1 g/dL. In one embodiment, the disclosure provides a pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of anemia associated with myelofibrosis, resulting in stabilizing anemia or improving anemia from pre-treatment baseline to, for example, week 24 or week 48 of treatment. In one embodiment, the disclosure provides a pharmaceutical combination comprising a) the IL- 1 b binding antibody canakinumab or functional fragment thereof and b) the JAK inhibitor ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of anemia associated with myelofibrosis, resulting in stabilizing anemia or improving anemia from pre-treatment baseline to, for example, week 24 or week 48 of treatment. In one embodiment, the disclosure provides a pharmaceutical combination comprising a) the IL-l b binding antibody canakinumab or functional fragment thereof and b) the JAK inhibitor ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of anemia associated with myelofibrosis, resulting in improving anemia from pre-treatment baseline by increasing hemoglobin levels by at least 1 g/dL, for example, at week 24 or at week 48 of treatment. In another embodiment, the disclosure provides a pharmaceutical combination comprising a) the IL- 1 b binding antibody canakinumab or functional fragment thereof and b) the JAK inhibitor ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of anemia associated with myelofibrosis, resulting in improving anemia from pre-treatment baseline by increasing hemoglobin levels by at least 1.5 g/dL, for example, at week 24 or at week 48 of treatment. In one embodiment, the disclosure provides a pharmaceutical combination comprising a) the Gί-1 b binding antibody canakinumab or functional fragment thereof and b) the JAK inhibitor ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of anemia associated with myelofibrosis, resulting in improving anemia from pre-treatment baseline by increasing hemoglobin levels by at least 2 g/dL, for example, at week 24 or at week 48 of treatment. In one embodiment, the disclosure provides a pharmaceutical combination comprising a) the IL- 1 b binding antibody gevokizumab or functional fragment thereof and b) the JAK inhibitor ruxobtinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of anemia associated with myelofibrosis, resulting in stabilizing anemia or improving anemia from pre-treatment baseline to, for example, week 24 or week 48 of treatment. In one embodiment, the disclosure provides a pharmaceutical combination comprising a) the IL- 1 b binding antibody gevokizumab or functional fragment thereof and b) the JAK inhibitor ruxobtinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of anemia associated with myelofibrosis, resulting in improving anemia from pre-treatment baseline by increasing hemoglobin levels by at least 1 g/dL, for example, at week 24 or at week 48 of treatment. In another embodiment, the disclosure provides a pharmaceutical combination comprising a) the IL-l b binding antibody gevokizumab or functional fragment thereof and b) the JAK inhibitor ruxobtinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of anemia associated with myelofibrosis, resulting in improving anemia from pre-treatment baseline by increasing hemoglobin levels by at least 1.5 g/dL, for example, at week 24 or at week 48 of treatment. In one embodiment, the disclosure provides a pharmaceutical combination comprising a) the Gί-1 b binding antibody gevokizumab or functional fragment thereof and b) the JAK inhibitor ruxobtinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of anemia associated with myelofibrosis, resulting in improving anemia from pre-treatment baseline by increasing hemoglobin levels by at least 2 g/dL, for example, at week 24 or at week 48 of treatment.

[0138] The term“treatment of bone marrow fibrosis associated with MF”, as used herein, means “stabilizing bone marrow fibrosis” or“improving bone marrow fibrosis”, for example, in comparison to the pre-treatment situation or in comparison to best available therapy or to placebo control. The term“stabilizing bone marrow fibrosis” refers, for example, to prevent increase in severity of bone marrow fibrosis. The term“improving bone marrow fibrosis” refers to a decrease in severity of bone marrow fibrosis (e.g. by at least 1 grade), for example, from pre-treatment baseline, according to the 2005 European consensus grading system. In one embodiment, provided is a pharmaceutical combination comprising a) an Iί-ΐ b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of bone marrow fibrosis associated with MF, resulting in stabilizing bone marrow fibrosis or improving bone marrow fibrosis from pre-treatment baseline to, for example, week 24 or week 48 of treatment. In one embodiment, provided is a pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of bone marrow fibrosis associated with MF, resulting in improving bone marrow fibrosis by > 1 grade from pre treatment baseline, for example, at week 24 or at week 48 of treatment. In another embodiment, provided is a pharmaceutical combination comprising a) the IL-l b binding antibody canakinumab or functional fragment thereof and b) the JAK inhibitor ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of bone marrow fibrosis associated with MF, resulting in improving bone marrow fibrosis by > 1 grade from pre-treatment baseline, for example, at week 24 or at week 48 of treatment. In another embodiment, provided is a pharmaceutical combination comprising a) the IL- 1 b binding antibody gevokizumab or functional fragment thereof and b) the JAK inhibitor ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of bone marrow fibrosis associated with MF, resulting in improving bone marrow fibrosis by > 1 grade from pre-treatment baseline, for example, at week 24 or at week 48 of treatment

[0139] The term“constitutional symptoms associated with myelofibrosis”, as used herein, refers to common debilitating chronic myelofibrosis symptoms, such as fever, pruritus (i.e. itching), abdominal pain/discomfort, weight loss, fatigue, inactivity, early satiety, night sweats or bone pain; for example, as described by Mughal et al (Int J Gen Med. 2014 Jan 29;7:89-l0l).

[0140] The term“treatment of constitutional symptoms associated with myelofibrosis”, as used herein, refers to“improvement of constitutional symptoms associated with myelofibrosis”, for example, in comparison to the pre-treatment situation or in comparison to best available therapy or to placebo control, for example, a reduction in total symptom score as measured by the modified myelofibrosis symptom assessment form version 2.0 diary (modified MFSAF v2.0) (Cancer 201 l;l 17:4869-77; NEngl JMed 2012; 366:799-807, the entire contents of which are incorporated herein by reference). In one embodiment, the disclosure provides a pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, particularly for the treatment of constitutional symptoms associated with myelofibrosis, resulting in improvement of constitutional symptoms associated with myelofibrosis from pre-treatment baseline to, for example, week 24 or week 48 of treatment.

[0141] In another embodiment of any method or use described herein, one or more of the constitutional symptoms associated with MF are alleviated (e.g. by eliminating or by reducing intensity, duration or frequency). In one embodiment, the reduction of constitutional symptoms is at least >20%, at least >30%, at least >40% or at least >50% as assessed by the modified MFSAF v4.0 from pre-treatment baseline to, for example, week 24 or week 48. The present disclosure also provides a pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab and b) a JAK inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof, for use in the treatment of myelofibrosis, wherein myelofibrosis symptoms do not worsen, wherein myelofibrosis symptoms worsening is defined as a total symptom score (TSS) increase of 10 or more from baseline assessed by MFSAF version 4.0.

[0142] In another aspect, provided is a pharmaceutical combination comprising a) an K-1 b binding antibody or functional fragment thereof, suitably gevokizumab or canakinumab, b) a JAK inhibitor, suitably ruxolitinib or a pharmaceutically acceptable salt thereof and c) at least one additional further active agent for use in the treatment of myelofibrosis.

[0143] In one embodiment, said further active agent is selected from from the group consisting of an HDAC inhibitor (e.g. panobinostat, givinostat, pracinostat, vorinostat); a DNA methyltransferase inhibitor (e.g. 5-azacytidine, decitabine); an mTOR inhibitor (e.g. rapamycin, everolimus); an AKT inhibitor (e.g. MK-2206); a PI3K inhibitor (e.g. buparlisib, dactolisib); a Hedgehog inhibitor (e.g. glasdegib, saridegib, erismodegib); an SMO inhibitor (e.g. sonidegib, vismodegib); an anti-fibrotic agent, such as simtuzumab, serum amyloid P or a monoclonal antibody (e.g. fresolimumab, simtuzumab); an Aurora-A kinase inhibitor (e.g. dimetylfasudil, alisertib); a TNF-alpha modulator (e.g. danazol); an immunomodulatory agent (e.g. lenalidomide, pomalidomide, thalidomide); a glucocorticoid (e.g. prednisone); a telomerase inhibitor (e.g. imetelstat); an anti-anemics agent (e.g. an erythropoiesis stimulating agent such as sotatercept); a CYP3A4 inhibitor (e.g. ketoconazole, clarithromycin, itraconazole, nefazodone, telithromycin);and a dual CYP2C9-CYP3A4 inhibitor (e.g. fluconazole); or, in each case, a pharmaceutically acceptable salt thereof.

Dosing regimen

[0144] In one embodiment, provided is a method of treating, preventing or reducing the incidence of anemia comprising administering 25-300 mg of an IL-l b-binding antibody or fragment thereof, suitably selected from canakinumab and gevokizumab, to a subject in need thereof.

[0145] In one embodiment, provided is a method of treating, preventing or reducing the incidence of anemia comprising administering 50 mg of an IL- l b-binding antibody or fragment thereof, suitably canakinumab, to a subject in need thereof

[0146] In one embodiment, provided is a method of treating, preventing or reducing the incidence of anemia comprising administering 150 mg of an IL- l b-binding antibody or fragment thereof, suitably canakinumab, to a subject in need thereof

[0147] In one embodiment, provided is a method of treating, preventing or reducing the incidence of anemia comprising administering 200 mg of an IL- l b-binding antibody or fragment thereof, suitably canakinumab, to a subject in need thereof

[0148] In one embodiment, provided is a method of treating, preventing or reducing the incidence of anemia comprising administering 250 mg of an IL- l b-binding antibody or fragment thereof, suitably canakinumab, to a subject in need thereof

[0149] In one embodiment, provided is a method of treating, preventing or reducing the incidence of anemia comprising administering 300 mg of an IL- l b-binding antibody or fragment thereof, suitably canakinumab, to a subject in need thereof

[0150] In one embodiment, provided is a method of treating, preventing or reducing the incidence of anemia comprising administering about 25, 75, 100, 125, 175, 200, 225, 250, 275, 300 mg or any combination thereof of the IL- l b binding antibody or functional fragment thereof, suitably selected from canakinumab and gevokizumab, to a subject in need thereof. In other embodiments of the administration regimens described above, a dose of about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300 mg or any combination thereof of said IL-l p binding antibody or functional fragment thereof can be administered, suitably selected from canakinumab and gevokizumab, to a subject in need thereof. In one embodiment of any method for treating, preventing or reducing the incidence of anemia described herein, said IL- 1 b binding antibody or functional fragment thereof is administered approximately every 2 weeks, approximately every 3 weeks, approximately every four weeks (approximately monthly), approximately every 6 weeks, approximately every 8 weeks (approximately every 2 months), approximately every 12 weeks (approximately every 3 months), approximately every 4 months, approximately every 5 months, or approximately every 6 months. Suitably, said IL- 1 b binding antibody or functional fragment thereof is administered approximately every four weeks (approximately monthly). Accordingly, in one embodiment provided is a method for treating, preventing or reducing the incidence of anemia comprising administering a therapeutically effective dose of canakinumab approximately every four weeks (approximately monthly). In another embodiment, provided is a method for treating, preventing or reducing the incidence of anemia comprising administering a therapeutically effective dose of gevokizumab approximately every four weeks (approximately monthly). Suitably, said IL- 1 b binding antibody or functional fragment thereof is administered approximately every 3 months. Accordingly, in one embodiment provided is a method for treating, preventing or reducing the incidence of anemia comprising administering a therapeutically effective dose of canakinumab approximately every 3 months. In another embodiment, provided is a method for treating, preventing or reducing the incidence of anemia comprising administering a therapeutically effective dose of gevokizumab approximately every 3 months.

[0151] In one embodiment, provided is a method of treating myelofibrosis and/or anemia of hematological malignancy, leukemia or myelofibrosis comprising administering a therapeutically effective dose of an IL-1 b binding antibody. Said IL-1 b binding antibody may be administered in monotherapy or it may be administered in combination with one or more additional therapeutic agent. Preferably, said IL- 1 b binding antibody is administered in combination with a JAKs inhibitor to a patient for treating myelofibrosis and/or anemia of hematological malignancy, leukemia or myelofibrosis. The following embodiments of the dosing regimens disclosed herein are applicable to each and every IL-1 b binding antibody or binding fragment thereof, suitably gevokizumab or canakinumab, related embodiment disclosed herein, including but not limited to monotherapy or in combination with at least one further therapeutic agent for treating myelofibrosis and/or anemia of hematological malignancy, leukemia or myelofibrosis. [0152] The present disclosure provides an IL- 1 b binding antibody or binding fragment thereof, suitably canakinumab or a binding fragment thereof or gevokizumab or a binding fragment thereof, for use in the treatment of myelofibrosis, wherein said IL-l b binding antibody or binding fragment thereof, is administered to a subject in need thereof in combination with ruxolitinib, or a pharmaceutically acceptable salt thereof, wherein ruxolitinib is administered in an amount of from 5 mg twice daily to 25 mg twice daily, such as 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, 20 mg twice daily or 25 mg twice daily, depending on the patient’s blood count according to the prescribing information for Jakavi®/Jakafi® and the judgment of the treating physician.

[0153] In one embodiment the present disclosure provides the IL- 1 b binding antibody canakinumab or binding fragment thereof, for use in the treatment of myelofibrosis, wherein canakinumab or a binding fragment thereof, is administered to a subject in need thereof in combination with ruxolitinib, or a pharmaceutically acceptable salt thereof, wherein ruxolitinib is administered in an amount of from 5 mg twice daily to 25 mg twice daily, such as 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, 20 mg twice daily or 25 mg twice daily, depending on the patient’s blood count according to the prescribing information for Jakavi®/Jakafi® and the judgment of the treating physician.

[0154] In another embodiment the present disclosure provides the Gί-1 b binding antibody gevokizumab or binding fragment thereof, for use in the treatment of myelofibrosis, wherein gevokizumab or a binding fragment thereof, is administered to a subject in need thereof in combination with ruxolitinib, or a pharmaceutically acceptable salt thereof, wherein ruxolitinib is administered in an amount of from 5 mg twice daily to 25 mg twice daily, such as 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, 20 mg twice daily or 25 mg twice daily, depending on the patient’s blood count according to the prescribing information for Jakavi®/Jakafi® and the judgment of the treating physician.

[0155] In one embodiment, provided is a method of treating anemia of hematological malignancy, leukemia or myelofibrosis comprising administering a therapeutically effective dose of a Gί-1 b binding antibody, wherein the Gί-1 b binding antibody is selected from canakinumab and gevokizumab, to a subject in need thereof.

[0156] In one embodiment, the IL-l b binding antibody is canakinumab, comprising administering canakinumab to a patient with anemia of hematological malignancy, leukemia or myelofibrosis at a dose in the range of about 100 mg to about 400 mg (e.g. about 100, 125, 175, 200, 225, 250, 275, 300, 325, 350, 375 or 400 mg or any combination thereof), preferably 200 mg per treatment or 250 mg per treatment. In one embodiment the present disclosure provides a the IL-l b binding antibody canakinumab or binding fragment thereof, for use in the treatment of myelofibrosis, wherein canakinumab or a binding fragment thereof, is administered at a dose in the range of about 100 mg to about 400 mg (e.g. about 100, 125, 175, 200, 225, 250, 275, 300, 325, 350, 375 or 400 mg or any combination thereof), to a subject in need thereof in combination with ruxolitinib, or a pharmaceutically acceptable salt thereof, wherein ruxolitinib is administered in an amount of from 5 mg twice daily to 25 mg twice daily, such as 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, 20 mg twice daily or 25 mg twice daily, depending on the patient’s blood count according to the prescribing information for Jakavi®/Jakafi® and the judgment of the treating physician. In one embodiment the present disclosure provides the IL- l b binding antibody canakinumab or binding fragment thereof, for use in the treatment of myelofibrosis, comprising administering to a subject in need thereof canakinumab or a binding fragment thereof at a dose in the range of about 100 mg to about 400 mg (e.g. about 100, 125, 175, 200, 225, 250, 275, 300, 325, 350, 375 or 400 mg or any combination thereof) per treatment in combination with ruxolitinib, or a pharmaceutically acceptable salt thereof, wherein ruxolitinib is administered in an amount of from 5 mg twice daily to 25 mg twice daily, such as 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, 20 mg twice daily or 25 mg twice daily, depending on the patient’s blood count according to the prescribing information for Jakavi®/Jakafi® and the judgment of the treating physician. In one embodiment the present disclosure provides the Gί-ΐ b binding antibody canakinumab or binding fragment thereof, for use in the treatment of myelofibrosis, comprising administering to a subject in need thereof about 200 mg of canakinumab or a binding fragment thereof per treatment in combination with ruxolitinib, or a pharmaceutically acceptable salt thereof, wherein ruxolitinib is administered in an amount of from 5 mg twice daily to 25 mg twice daily, such as 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, 20 mg twice daily or 25 mg twice daily, depending on the patient’s blood count according to the prescribing information for Jakavi®/Jakafi® and the judgment of the treating physician. In another embodiment the present disclosure provides the IL- 1 b binding antibody canakinumab or binding fragment thereof, for use in the treatment of myelofibrosis, comprising administering to a subject in need thereof about 250 mg of canakinumab or a binding fragment thereof per treatment in combination with ruxolitinib, or a pharmaceutically acceptable salt thereof, wherein ruxolitinib is administered in an amount of from 5 mg twice daily to 25 mg twice daily, such as 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, 20 mg twice daily or 25 mg twice daily, depending on the patient’s blood count according to the prescribing information for Jakavi®/Jakafi® and the judgment of the treating physician. Canakinumab is administered to said patient with myelofibrosis and/or with anemia of hematological malignancy, leukemia or myelofibrosis every 2 weeks, every 3 weeks, every 4 weeks (monthly), every 6 weeks, bimonthly (every 2 months), every 9 weeks or quarterly (every 3 months). In one embodiment, the patient with myelofibrosis and/or anemia of hematological malignancy, leukemia or myelofibrosis receives canakinumab monthly or every three weeks. In one embodiment the preferred dose of canakinumab for a patient with myelofibrosis and/or anemia of hematological malignancy, leukemia or myelofibrosis is 200 mg every 3 weeks. In one embodiment the preferred dose of canakinumab for a patient with myelofibrosis and/or with anemia of hematological malignancy, leukemia or myelofibrosis is 200 mg monthly. In one embodiment the preferred dose of canakinumab for a patient with myelofibrosis and/or anemia of hematological malignancy, leukemia or myelofibrosis is about 250 mg every 3 weeks. In one embodiment the preferred dose of canakinumab for a patient with myelofibrosis and/or anemia of hematological malignancy, leukemia or myelofibrosis is about 250 mg every four weeks (monthly). When safety concern arise, the dose can be down-titrated, preferably by increasing the dosing interval, preferably by doubling or tripling the dosing interval. For example, 200 mg monthly or every 3 weeks regimen can be changed to every 2 month or every 6 weeks, respectively or every 3 month or every 9 weeks, respectively. In an alternative embodiment the patient with myelofibrosis and/or anemia of hematological malignancy, leukemia or myelofibrosis receives canakinumab at a dose of 200 mg every two month or every 6 weeks in the down-titration phase or in the maintenance phase independent from any safety issue or throughout the treatment phase. In an alternative embodiment the patient with myelofibrosis and/or anemia of hematological malignancy, leukemia or myelofibrosis receives canakinumab at a dose of 200 mg every 3 month or every 9 weeks in the down-titration phase or in the maintenance phase independent from any safety issue or throughout the treatment phase.

[0157] In one embodiment, the IL-l b binding antibody is gevokizumab, comprising administering gevokizumab to a patient with anemia of hematological malignancy, leukemia or myelofibrosis at a dose in the range of about 20 mg to about 240 mg per treatment, preferably in the range of 30 mg to 180 mg, preferably in the range of 30 mg to 120 mg, preferably 30 mg to 60 mg, preferably 60 mg to 120 mg per treatment. In one embodiment the present disclosure provides the IL- 1 b binding antibody gevokizumab or binding fragment thereof, for use in the treatment of myelofibrosis, comprising administering to a subject in need thereof gevokizumab or a binding fragment thereof at a dose in the range of about 20 mg to about 240 mg per treatment in combination with ruxolitinib, or a pharmaceutically acceptable salt thereof, wherein ruxolitinib is administered in an amount of from 5 mg twice daily to 25 mg twice daily, such as 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, 20 mg twice daily or 25 mg twice daily, depending on the patient’s blood count according to the prescribing information for Jakavi®/Jakafi® and the judgment of the treating physician. In one embodiment said patient receives 30 mg to 120 mg gevokizumab per treatment. In one embodiment patient receives 30 mg to 60 mg gevokizumab per treatment. In one embodiment patient receives 30 mg, 60 mg, 90 mg, 120 mg or 180 mg gevokizumab per treatment. In one embodiment the patient with anemia of hematological malignancy, leukemia or myelofibrosis receives each treatment every 2 weeks, every 3 weeks, monthly (every 4 weeks), every 6 weeks, bimonthly (every 2 months), every 9 weeks or quarterly (every 3 months). In one embodiment the patient receives each treatment of gevokizumab every 3 weeks. In one embodiment the patient receives each treatment of gevokizumab every 4 weeks.

[0158] When safety concerns arise, the dose can be down-titrated, preferably by increasing the dosing interval, preferably by doubling or tripling the dosing interval. For example, 60 mg monthly or every 3 weeks regimen can be doubled to every 2 months or every 6 weeks, respectively or tripled to every 3 months or every 9 weeks, respectively. In an alternative embodiment the patient with anemia of hematological malignancy, leukemia or myelofibrosis receives gevokizumab at a dose of 30 mg to 120 mg every 2 months or every 6 weeks in the down-titration phase or in the maintenance phase independent from any safety issue or throughout the treatment phase. In an alternative embodiment the patient with anemia of hematological malignancy, leukemia or myelofibrosis receives gevokizumab at a dose of 30 mg to 120 mg every 3 months or every 9 weeks in the down-titration phase or in the maintenance phase independent from any safety issue or throughout the treatment phase.

[0159] The term“per treatment”, as used in this application and particularly in this context, should be understood as the total amount of drug received per hospital visit or per self administration or per administration helped by a health care giver. Normally and preferably the total amount of drug received per treatment is administered to a patient within one day, preferably within half a day, preferably within 4 hours, preferably within 2 hours.

[0160] The dosing regimens disclosed herein apply equally to gevokizumab and to a functional fragment thereof or to canakinumab and a functional fragment thereof.

[0161] In embodiments of any method or use disclosed herein, canakinumab or gevokizumab can be administered parenterally, e.g., subcutaneously or intravenously. Canakinumab can be administered in a reconstituted formulation comprising canakinumab at a concentration of 50-200 mg/ml, 50-300 mM sucrose, 10-50 mM histidine, and 0.01-0.1% surfactant and wherein the pH of the formulation is 5.5-7.0. Canakinumab can be administered in a reconstituted formulation comprising canakinumab at a concentration of 50-200 mg/ml, 270 mM sucrose, 30 mM histidine and 0.06% polysorbate 20 or 80, wherein the pH of the formulation is 6.5.

[0162] In embodiments of any method or use disclosed herein, canakinumab can also be administered in a liquid formulation comprising canakinumab at a concentration of 50-200 mg/ml, a buffer system selected from the group consisting of citrate, histidine and sodium succinate, a stabilizer selected from the group consisting of sucrose, mannitol, sorbitol, arginine hydrochloride, and a surfactant, e.g., polysorbate 20 or polysorbate 80, and wherein the pH of the formulation is 5.5-7.0. Canakinumab can also be administered in a liquid formulation comprising canakinumab at a concentration of 50-200 mg/ml, 50-300 mM mannitol, 10-50 mM histidine and 0.01-0.1% surfactant, and wherein the pH of the formulation is 5.5-7.0. Canakinumab can also be administered in a liquid formulation comprising canakinumab at a concentration of 50-200 mg/ml, 270 mM mannitol, 20 mM histidine and 0.04% polysorbate 20 or 80, wherein the pH of the formulation is 6.5.

[0163] When administered subcutaneously according to any method or use disclosed herein, canakinumab can be administered to the patient in a liquid form contained in a prefilled syringe, autoinjector or as a lyophilized form for reconstitution.

[0164] It is to be understood that each embodiment may be combined with one or more other embodiments described herein to the extent that such a combination is consistent with the description of the embodiments. It is further to be understood that the embodiments provided above are understood to include all embodiments, including such embodiments as result from combinations of embodiments. [0165] Other features, objects, and advantages of the disclosure will be apparent from the description and drawings, and from the claims.

EXAMPLES

[0166] The following Examples illustrate the disclosure described above; they are not, however, intended to limit the scope of the disclosure in any way. Other variants of the disclosure will be readily apparent to one of ordinary skill in the art and are encompassed by the appended claims.

A randomized, double-blind, placebo-controlled, event-driven trial of quarterly subcutaneous canakinumab in the prevention of recurrent cardiovascular events among stable post-myocardial infarction patients with elevated hsCRP.

[0167] This study was designed as a multi-center, randomized, parallel group, placebo-controlled, double-blind, event-driven trial to provide definitive evidence on the effects of canakinumab on cardiovascular adverse events in patients with recent MI and elevated inflammatory burden as evidenced by elevated hsCRP. This study design was the most robust clinical trial design to test the hypothesis that anti-inflammatory treatment with canakinumab reduce major adverse cardiovascular events.

Rationale of study design

[0168] Trial Population. Patients were eligible for enrollment if they had a prior history of myocardial infarction and had blood levels of hsCRP of 2 mg/L or greater despite use of aggressive secondary prevention strategies. The trial excluded from enrollment those with a history of chronic or recurrent infection, prior malignancy other than basal cell skin carcinoma, suspected or known immunocompromised state, a history of or high risk for tuberculosis or HIV-related disease, or ongoing use of other systemic anti-inflammatory treatments.

[0169] Inclusion criteria

Patients eligible for inclusion in the study had to fulfill all of the following criteria:

1. Written informed consent obtained before any assessment performed.

2. Male, or Female of non-child-bearing potential

3. Age > 18 years at Visit 1. 4. Documented spontaneous MI (diagnosed according to the universal MI criteria with or without evidence of ST segment elevation) at least 30 days before randomization (Duewell P etal, Nature. 2010;464(7293): 1357-61).

• Diagnosis of the qualifying MI should be based on medical history of clinical symptoms consistent with myocardial ischemia associated with elevation of cardiac biomarkers above the 99th percentile of the upper reference limit (preferably troponin) OR development of new pathological Q waves regardless of symptoms. For details, refer to the Universal Definition of MI (Duewell P etal, Nature. 2010;464(7293):1357-61 ).

a. Acute MI (hospitalization records): requires documentation of a rise and/or fall of cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit (URL) or above criteria diagnostic for MI and evidence of myocardial ischemia as demonstrated by at least one of the following :

i. Symptoms of ischemia

ii. ECG changes indicative of new ischemia (new ST-T changes or new LBBB)

iii. Development of pathologic Q waves

iv. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

b. Prior MI (no hospital records for acute event available): requires documentation of any one of the following:

i. Development of pathological Q waves, with or without symptoms

ii. Imaging evidence of a region of loss of viable myocardium that is thinned and fails to contract, in the absence of a non-ischemic cause

iii. Pathologic findings of a healed or healing MI

• Patients with MI resulting from PCI or CABG were not eligible

5. Have an hsCRP >2 mg/L (collected less than 60 days prior to Visit 2 and performed at the central laboratory, which is a minimum of 28 days after qualifying MI or after any PCI performed separately from qualifying MI) on stable (at least 4 weeks) long term (cardiovascular) medications (standard of care).

[0170] Randomization. Patients were initially randomized to canakinumab 150 mg, canakinumab 300 mg, or placebo in a 1 :l :l ratio. After the enrollment of 741 participants, a 50 mg dose was added at regulatory request, with the randomization ratio adjusted accordingly; we sought to achieve a final randomization ratio of 1.5: 1 : 1 : 1. All study-drug doses and placebo were administered subcutaneously once every three months; for the 300 mg dose, the regimen was 300 mg every two weeks for the first two doses, then once every three months. Randomization was performed with the use of a centralized computer system, with stratification by time since index myocardial infarction and by trial part (before versus after inclusion of the 50 mg dose).

[0171] End Points. The primary efficacy end point was time to first occurrence of nonfatal myocardial infarction, any nonfatal stroke, or cardiovascular death. The trial had two key secondary efficacy end points. The first key secondary end point included the components of the primary end point as well as hospitalization for unstable angina requiring urgent revascularization. The two other pre-specified secondary end points were all-cause mortality and the composite of nonfatal myocardial infarction, any nonfatal stroke, or all-cause mortality. All components of these end points were adjudicated by an end point adjudication committee, with members masked to study-drug assignment.

[0172] Statistical Analysis. Distributions of percent change from baseline in hsCRP and lipid levels were compared between placebo and each canakinumab group at intervals up to 48 months. Similar comparisons were made for IL-6 up to 12 months. Log-rank tests and Cox proportional- hazards models, stratified by time since index myocardial infarction and trial part, were used to analyze the pre-specified primary and key secondary cardiovascular outcomes that occurred during trial follow-up according to the intention-to-treat principle. Formal evaluation of significance for individual doses, adjusted for multiplicity, followed a closed testing procedure. Based on the closed testing procedure, and using the pre-specified allocation of alpha error, the two-sided P value thresholds for statistical significance for the primary end point were 0.01058 for the test of the 300 mg dose of canakinumab versus placebo and 0.02115 for the tests of the other two doses versus placebo. The closed testing procedure also specified that formal significance testing for the key secondary end points would be performed for any given dose only if the significance threshold for the primary end point for that dose had been met.

While the primary analysis strategy was based on pair-wise comparisons of individual dose groups to the placebo group, comparisons were also made between incidence rates on placebo and incidence rates across ascending canakinumab doses (using scores of 0, 1, 3, and 6 proportional to doses in a trend analysis) and for the combined active canakinumab treatment groups versus placebo. In addition, on-treatment analyses were performed with follow-up for each patient censored 119 days after the last study injection received. The significance thresholds for these tests were not adjusted for multiplicity. Similar analyses were used for adverse events. All P values are two-sided and all confidence intervals computed at the 95% level.

[0173] Patients. Trial enrollment began in April 2011 and was completed in March 2014; the last trial visit was in June 2017. Of 17,482 post- infarction patients who underwent screening in the central laboratory, 10,061 (57.6%) were correctly randomized and received at least one dose of trial medication (Figure 1). The most common reasons for exclusion were hsCRP less than 2 mg/L (46% of excluded subjects), active tuberculosis or tuberculosis risk factors (25.4%), and exclusionary concomitant disorders (9.9%).

The mean age of randomized participants was 61 years, 26% were women, and 40% had diabetes (Table 6). Most participants had undergone prior revascularization procedures (67% percutaneous coronary interventions, 14% coronary bypass surgery). At baseline, anti-thrombotic therapy was taken by 95%, lipid-lowering therapy by 93%, anti-ischemia agents by 91%, and inhibitors of the renin-angiotensin system by 79%. The median hsCRP at entry was 4.2 mg/L and the median LDL cholesterol was 82 mg/dL.

Table 6: Characteristics of trial participants

SC=subcutaneously; SD=standard deviation; STEMI=ST elevation myocardial infarction;

PCI=percutaneous coronary intervention; CABG=coronary bypass graft surgery; hsCRP=high sensitivity C-reactive protein; IL-6=interleukin 6; HDL=high density lipoprotein cholesterol; LDL=low density lipoprotein cholesterol; eGFR=estimated glomerular filtration rate* P-value <0.05 in comparison of canakinumab to placebo.

** Beta-blocking agents, nitrates, or calcium channel blocking agents † Median (IQR) values are presented for all measured plasma variables and body mass index

[0174] Effects on inflammatory biomarkers and lipid levels. Compared to placebo, at 48 months, hsCRP was reduced by 26%, 37%, and 41% in the canakinumab 50 mg, 150 mg, and 300 mg groups, respectively (all P-values <0.001 in comparisons of the median percent change on canakinumab to the median percent change on placebo) (Tables 7-11). Similar effects were observed for IL-6 (measured up to 12 months). By contrast, canakinumab use resulted in no reduction in LDL cholesterol or HDL cholesterol, and a 4 to 5% median increase in triglycerides. Table 7. Effects of 3-month treatment with canakinumab on hsCRP, IL-6, and lipid levels. P- values reflect change from baseline.

LDLC = low density lipoprotein (LDL) cholesterol, HDLC = high density lipoprotein (HDL) cholesterol, TG = triglycerides, IL-6 = interleukin-6, SC=subcutaneous, q=quarterly

Table 8. Effects of 12-month treatment with canakinumab on hsCRP, IL-6, and lipid levels. P- values reflect change from baseline.

LDLC = low density lipoprotein (LDL) cholesterol, HDLC = high density lipoprotein (HDL) cholesterol, TG = triglycerides, IL-6 = interleukin-6, SC=subcutaneous, q=quarterly Table 9. Effects of 24-month treatment with canakinumab on hsCRP and lipid levels. P-values reflect change from baseline.

LDLC = low density lipoprotein (LDL) cholesterol, HDLC = high density lipoprotein (HDL) cholesterol, TG = triglycerides, SC=subcutaneous, q=quarterly

Table 10. Effects of 36-month treatment with canakinumab on hsCRP and lipid levels. P-values reflect change from baseline.

Table 11. Effects of 48-month treatment with canakinumab on hsCRP and lipid levels. P-values reflect change from baseline.

[0175] Follow-up and Effects on Clinical End Points. By the end of follow-up, 18.1% of patients in the placebo group had discontinued study drug, as compared to 18.7% of patients in the combined canakinumab groups. At a median follow-up of 3.7 years, the incidence rates for the primary end point (which included nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) in the placebo, 50 mg, 150 mg, and 300 mg groups were 4.50, 4.11, 3.86, and 3.90 per 100 person-years, respectively (Table 12).

Table 12. Incidence rates (per 100 person years) and hazard ratios for major clinical outcomes and all-cause mortality

P values for trend, P values for the combination of all doses compared to placebo, and P values for all secondary end points other than the key secondary cardiovascular end point have not been adjusted for multiplicity.

* Primary end point = nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. * * Key secondary cardiovascular end point = nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring unplanned revascularization, or cardiovascular death

^# Statistically significant compared to placebo, adjusted for multiplicity and accounting for two efficacy interim analyses, in accordance with the pre-specified closed-testing. The threshold P value for the primary end point for the 150 mg dose was 0.02115. The threshold P value for the key secondary cardiovascular end point for the 150 mg dose was 0.00529.

† Not statistically significant compared to placebo based on the prespecified closed-testing procedure. The threshold P value for the primary end point for the 50 mg dose was 0.02115. The threshold P value for the primary end point for the 300 mg dose was 0.01058.

s Exploratory analyses. [0176] No significant effect was observed for the primary end point in the canakinumab 50 mg dose group compared to placebo (hazard ratio [HR] 0.93, P=0.30). By contrast, a statistically significant effect for the primary end point was observed in the canakinumab 150 mg dose group (HR 0.85, P=0.02075, threshold P value 0.02115). In the canakinumab 300 mg dose group, the hazard ratio was similar but the P value did not meet the prespecified significance threshold (HR 0.86, P=0.03 l4, threshold P value 0.01058). The P value for trend across the active-dose groups compared to placebo was 0.020, and the P value for comparison of all doses combined versus placebo was 0.015 (both results not adjusted for multiple testing).

[0177] For the key secondary cardiovascular end point (which included the components of the primary end point plus hospitalization for unstable angina requiring urgent revascularization), incidence rates in the placebo, 50 mg, 150 mg, and 300 mg groups were 5.13, 4.56, 4.29, and 4.25 per 100 person-years, respectively. For the canakinumab 150 mg dose (for which the P value met the significance threshold for the primary end point), the hazard ratio for the secondary cardiovascular endpoint was 0.83 (P=0.00525, threshold P value 0.00529). According to the closed testing procedure, formal significance testing for the prespecified secondary end point was not performed for the 50 mg and 300 mg doses. The hazard ratios for these doses were 0.90 and 0.83, respectively. The P value for trend across the active-dose groups compared to placebo was 0.003, and the P value for comparison of all doses combined versus placebo was 0.001 (both results not adjusted for multiple testing).

[0178] Analyses of the additional secondary end points, and of the components of the primary and secondary end points, were not adjusted for multiple testing. Nominally significant reductions were seen in myocardial infarction for the 150 mg dose of canakinumab; in hospitalization for unstable angina requiring urgent revascularization for the 150 mg and 300 mg doses; and in any coronary revascularization for all three doses. All-cause mortality was neutral in comparisons of all canakinumab doses to placebo (HR 0.94, 95%CI 0.83-1.06, P=0.3l). In on-treatment analyses for the primary end point, the observed hazard ratios in the placebo, 50 mg, 150 mg, and 300 mg groups were 1.0, 0.90, 0.83, and 0.79 (P-trend across groups=0.003). In comparable analyses for the key secondary cardiovascular end point, the corresponding hazard ratios were 1.0, 0.88, 0.80, and 0.77 (P-trend across groups <0.001).

[0179] Adverse Events and Other Clinical Outcomes. Neutropenia was more common among those allocated to canakinumab and there was a statistically significant increase in fatal events attributed to infection or sepsis when the three canakinumab groups were pooled and compared to placebo (incidence rates 0.31 versus 0.18 per 100 person years, P=0.023) (Table 13). Participants succumbing to infection tended to be older and more likely to have diabetes. Six confirmed cases of tuberculosis occurred in the trial with similar rates in the canakinumab and placebo groups (0.06%); five cases occurred in India and one in Taiwan.

[0180] Thrombocytopenia was more common among those allocated to canakinumab, but no difference in hemorrhage was observed. No increase in injection site reactions was observed. No significant hepatic toxicity was noted (Table 13). There was also a significant reduction in cancer mortality with canakinumab.

Table 13. Incidence rates (per 100-person years), number (N) of serious adverse events, and selected on-treatment safety laboratory data (%, N), stratified by study group.

Data are shown as incidence rates per 100 person-years (with number of patients with event) for adverse events and as percentages of patients with the condition (with number of patients) for hepatic variables to facilitate the comparison of rates between groups.

All adverse event categories are based on standardized Medical Dictionary for Regulatory Activities (MedDRA), version 20.0, queries or classification levels, except those otherwise indicated.

SAE= serious adverse event; ALT=alanine aminotransferase; AST=aspartate transaminase; ALP=alkaline phosphatase

+ Sponsor categorization of adverse events of special interest

+ + Included are malignancies adjudicated by the Cancer Endpoint Adjudication Committee ** Hepatic variable percent of patients with condition (No.)

[0181] CANTOS was designed to test directly the inflammatory hypothesis of atherothrombosis. In this trial, among patients with a prior history of myocardial infarction, hsCRP levels and IL-6 levels were significantly reduced by canakinumab, with no reduction in lipid levels. While the 50 mg dose of canakinumab did not have a statistically significant effect on the primary cardiovascular end point compared to placebo, participants in the 150 mg dose group experienced relative hazard reductions of 15% for the primary end point (from 4.50 to 3.86 events per 100 person-years) and 17% for the key secondary cardiovascular end point (from 5.13 to 4.29 events per 100 person-years). The P values for both of these end points met pre-specified multiplicity- adjusted thresholds for statistical significance. Although the hazard reductions for the 300 mg dose group were similar to those for the 150 mg dose group, the prespecified thresholds for statistical significance were not met for this group. Both a pooled analysis of all canakinumab doses and a trend analysis, however, suggested a beneficial effect of canakinumab on cardiovascular outcomes. Specific targeting of IL- 1 b as a cytokine-based therapy for the secondary prevention of atherosclerotic events rests on several observations. The pro-inflammatory cytokine IL- 1 b plays multiple roles in atherothrombotic plaque development including induction of procoagulant activity, promotion of monocyte and leucocyte adhesion to vascular endothelial cells, and the growth of vascular smooth muscle cells (Dinarello CA et al, Nat Rev Drug Discov. 20l2;l l(8):633-52; Dinarello CA. Blood. 20l l ;l l7(l4):3720-32; Libby P et al, Am J Pathol. 1986;124(2): 179-85). In mice, deficiency of IL- 1 b reduces lesion formation, while in cholesterol- fed pigs, exposure to exogenous IL-1 b increases intimal medial thickening (Kirii H et al, Arterioscler Thromb Vase Biol. 2003;23(4):656-60; Shimokawa H et al, J Clin Invest. l996;97(3):769-76). The Nod-like receptor protein 3 (NLRP3) inflammasome activates IL-l p, a process promoted by cholesterol crystals, neutrophil extracellular traps, local hypoxia, and atheroprone flow (Duewell P e/a/, Nature. 2010;464(7293):1357-61; Rajamaki K e/a/, PLoS One. 20l0;5(7):el l765; Xiao H et al, Circulation. 20l3;l28(6):632-42 ; Folco EJ et al, Circ Res. 2014;115(10):875-83). This activation ofIL-lB stimulates the downstream IL-6 receptor signaling pathway, implicated by Mendelian randomization studies as a potential causal pathway for atherothrombosis (Hingorani AD et al, Lancet. 20l2;379(9822): 1214-24; Sarwar N et al, Lancet. 20l2;379(9822): 1205-13. Most recently, parabiotic mouse studies (Sager HB et al, Circulation. 2015;132(20):1880-90) and studies of clonal hematopoiesis (Fuster JJ et al, Science. 2017;355(6327): 842-7; Jaiswal S et al, N Engl J Med. 20l7;377(2):l 11-21) have implicated IL- 1 b in processes by which bone marrow activation accelerates atherosclerosis. Canakinumab in incident anemia

[0182] Of 10,061 participants randomized, baseline anemia (hemoglobin less than 12 g/dL for women and 13 g/dL for men) was present in 417 women and 899 men, while 4 participants did not have baseline hemoglobin measurements. Thus, 8,741 CANTOS participants were included in this analysis. Blood samples were obtained from all trial participants in the canakinumab and placebo groups at randomization and during the trial (baseline, 3,6,9,12,18, 24, 30, 36, 42, 48, 54, and 60 months after randomization). All samples underwent standard hematology assessments, including hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and platelet count. Follow-up CBCs permitted assessment of incident anemia, defined prospectively as a hemoglobin <13 g/dl for men and <12 g/dl for women arising in individuals with normal hemoglobin upon enrollment in the trial.

[0183] The distributions of baseline clinical characteristics that could contribute to anemia (such as age, renal function, hsCRP, alcohol use, diabetes, and hypertension) were compared between placebo or active treatment groups using Chi-square analysis for categorical variables. For continuous variables, Kruskal-Wallis testing was performed for multiple-group comparisons and Wilcoxon rank-sum testing for two group comparisons between placebo and the active treatment group. On a per-protocol pre-specified basis, univariate and adjusted Cox proportional-hazards models stratified by time since index myocardial infarction and trial part were used to estimate relative hazards for incident anemia in the three canakinumab groups (50 mg, 150 mg and 300 mg), compared with those allocated placebo. P-values for the test of trend were calculated across these groups. Scores of 0, 1, 3 and 6 which were proportional to canakinumab doses were used in the trend analysis. Kaplan-Meier curves were constructed to visually evaluate any differences between groups. To parallel treatment response analyses that were pre-specified in the CANTOS protocol for the trial primary cardiovascular endpoints, similar analyses were performed to address whether the magnitude of anti-inflammatory response achieved by individual participants after a single dose of either placebo or canakinumab related to incident anemia. This analysis divided the canakinumab treated participants into two groups according to whether the hsCRP levels fell below 2 mg/L at three months (robust responders) or above 2 mg/L at three months (less robust responders). This time point corresponds with the trough following the first dose, just before the second dose of canakinumab. Additional subgroup analyses were performed assessing factors associated with anemia and chronic inflammation, including age and kidney function. All analyses were by intention to treat. All p-values are two-sided and all confidence intervals calculated at the 95% level.

[0184] The 8,741 CANTOS participants without anemia at baseline randomly received placebo, or canakinumab at 50 mg, 150 mg, or 300 mg administered subcutaneously every 3 months. The groups had well matched baseline clinical characteristics, including those predisposing to anemia, such as age, kidney function, and underlying inflammation as assessed by baseline hsCRP (Table 1). Compared to those without anemia at baseline, those with anemia (who were excluded from this secondary analysis) were significantly older, more likely to be female, and had a higher burden of co-morbid illness (higher rates of hypertension and type 2 diabetes mellitus), decreased GFR, and higher levels of hsCRP (Table 14).

Table 14. Baseline clinical characteristics of trial participants without baseline anemia and those excluded for baseline anemia

No anemia at baseline Anemia at baseline

(n=8741) (n=1316)

Age, years 61.0 (54.0-67.0) 65.0 (57.0-73.0)^*

Female sex 2168 (24.8) 417 (31.7) ^*

Hemoglobin (g/tlL)

Body-mass index (kg/m²) 29.9 (26.7-33.8) 29.0 (25.4-33.7)^*

Alcohol use (> one drink per day) 364 (4.17) 32 (2.43) ^*

Hypertension 6901 (79.0) 1104 (83.9)^*

Type 2 Diabetes mellitus 3351 (38.3) 676 (51.4)^*

hsCRP (mg/L) 4.05 (2.75-6.60) 5.68 (3.25-10.7)^*

Estimated GFR (mL/min per 1.73 m²) 79.0 (66.0-94.0) 70.0 (53.0-87.0)^*

Continuous data are reported as median (IQR), dichotomous data are reported as n(%). Significant between-group differences at baseline are noted. hsCRP= high-sensitivity C-reactive protein.

GFR=glomerular filtration rate.

^*P<0.05 for the comparison of participants with anemia at baseline versus those without anemia at baseline.

[0185] Baseline levels of hsCRP associated with incident anemia. Specifically, among those with hsCRP levels in the lowest (<3.l mg/L), middle, and highest (>5.45 mg/L) tertiles, incidence rates of anemia were 5.63, 6.55, and 7.91 per 100 person-years, respectively (P -trend across tertiles <0.0001).

[0186] Compared to placebo, participants allocated to any dose of canakinumab had a statistically significant reduction in incident anemia (hemoglobin <13 g/dL in men, <12 g/dL in women) throughout (Figure 2) as compared to placebo (HR=0.84, 95% Cl 0.77-0.93, pO.OOOl). The reduction was irrespective of dose: For the 50 mg group (N=l907) the hazard ratio compared to placebo for incident anemia was 0.83 (95% Cl 0.73-0.94, P=0.004). For the 150 mg group (N=l987) the hazard ratio compared to placebo for incident anemia was 0.84 (95% Cl 0.74-0.95, P=0.006). For the 300 mg group (N=l94l) the hazard ratio compared to placebo for incident anemia was 0.85 (95% Cl 0.75-0.96, P=0.008). The incidence rates for anemia per 100 person- years was 7.49 in the placebo group, 6.17 in the 50 mg group, 6.33 in the 150 mg group, 6.34 in the 300 mg group and 6.28 in all active doses of canakinumab (r=0.014 for trend across active dose groups compared to placebo). Analysis of combined canakinumab doses compared with placebo demonstrated a pronounced decrease in rates of incident anemia in those patients who achieved on-treatment hsCRP levels less than 2 mg/L after the first dose of canakinumab (HR=0.78, 95% Cl 0.70-0.87, p<0.000l). In contrast, individuals with an on-treatment hsCRP > 2 mg/L, had similar rates of incident anemia as the placebo group (HR 1.01, 95% Cl 0.91-1.13, p=0.82). Specifically, among those with hsCRP < 2 mg/L three months after initiating canakinumab, HRs for anemia, compared to placebo were 0.67 (95% Cl 0.56-0.81, p<0.000l) for the 50 mg group, 0.78 (95% Cl 0.67-0.91, p=0.002) for the 150 mg group, 0.76 (95% Cl 0.65- 0.88, pO.OOOl) for the 300 mg group. In contrast, participants who had hsCRP > 2 mg/L at three months had HRs for anemia, compared to placebo of 0.97 (95% Cl 0.84-1.13, p=0.699) for the 50 mg group, 0.89 (95% Cl 0.76-1.05, p=0T7l) for the 150 mg group, and 1.05 (95% Cl 0.88-1.25, p=0.570) for the 300 mg group. Notably, the effects of canakinumab on reduction in incident anemia was greater in patients older than 65 years of age (HR=0.78, 95% Cl 0.68-0.89, p<0.000l) than patients younger than 65 years of age (HR=0.88, 95% Cl 0.78-1.00, p=0.056) (Figure 3 and Figure 4). Specifically, among participants 65 years or older, the HRs for anemia associated with canakinumab as compared to placebo were 0.80 (95% Cl 0.66-0.96, r=0.017) for the 50 mg group, 0.73 (95% Cl 0.61-0.88, p=0.00l) for the 150 mg group, and 0.80 (95% Cl 0.67-0.96, r=0.018) for the 300 mg group (Table 15). Table 15. Risk of incident anemia stratified by high-sensitivity CRP at three months.

Incidence rates are per 100 person-years (with numbers ^' participants with event) p-values for trend and p-values for the combination of all doses are compared to placebo. Cl represents confidence interval, hsCRP represents high-sensitivity C-reactive protein.

[0187] As also anticipated, participants with an eGFR less than 60 ml/min per 1.73 m² had a higher incidence of anemia compared to participants with an eGFR greater than or equal to 60 mL/min per 1.73 m². Incidence rates for anemia were 14.55 and 11.24 per 100 person-years for placebo and all doses of canakinumab, respectively in participants with an eGFR less than 60 mL/min per 1.73 m² and 6.43 and 5.47 per 100 person-years for placebo and all doses of canakinumab for participants with an eGFR greater than or equal to 60 mL/min per 1.73 m² (Table 16) For participants with an eGFR less than 60 mL/min per 1.73 m² and for those with an eGFR greater than or equal to 60 mL/min per 1.73 m², canakinumab treatment associated with a significant decrease in incident anemia comparing all doses of canakinumab to placebo. HRs for anemia for all groups of canakinumab, compared to placebo, were 0.78 (95% Cl 0.65-0.94, p=0.009) for participants with an eGFR less than 60 mL/min per 1.73 m² and 0.85 (95% Cl 0.77-0.95, p=0.005) (Table 16).

Table 16. Risk of incident anemia stratified by baseline eGFR^a

^a Incidence rates are per 100 person-years (with numbers of participants with event) p-values for trend and p-values for the combination of all doses are compared to placebo. Cl represents confidence interval.

[0188] These data have practical implications for the use of an IL- 1 b-binding antibody such as canakinumab as an adjunctive therapy for the treatment of anemia, such as anemia of inflammation.

A randomized, open-label open platform study evaluating safety and efficacy of ruxolitinib and an IL-Ib inhibitor, e.g. gevokizumab, combination in myelofibrosis patients

[0189] Clinical testing of the IL- 1 b inhibitor in combination with ruxolitinib, is conducted, for example, according to standard clinical practice (e.g. placebo control study, for example in analogy to COMFORT-l trial) in patients with myelofibrosis, in particular with primary myelofibrosis.

[0190] Inclusion criteria

Subjects eligible for inclusion in this study must meet all of the following criteria:

1. Male or female subjects are at least 18 years of age at the time of signing the informed consent form (ICF)

2. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2.

3. Subjects have diagnosis of primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria, or diagnosis of post-ET (PET-MF) or post-PV myelofibrosis (PPV-MF) according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) 2007 criteria.

4. Palpable spleen of at least 5 cm from the left costal margin (LCM) to the point of greatest splenic protrusion or enlarged spleen volume of at least 450 cm3 per MRI or CT scan at baseline (a MRI/CT scan up to 8 weeks prior to first dose of study treatment can be accepted).

5. Have been treated with ruxolitinib for at least 24 weeks prior to first dose of study treatment.

6. Are stable (no dose adjustments) on the prescribed ruxolitinib dose (between 5 and 25 mg BID) for > 8 weeks prior to first dose of study treatment. 7. Hemoglobin < 10 g/dL.

8. Absolute neutrophil count (ANC) > l000/pL.

9. Platelet counts > 50 000/pL

10. Subjects must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted

[0191] Exclusion criteria

1. Peripheral blood blasts count of > 10%.

2. Inadequate liver function defined by any of these: Direct bilirubin > 2.5 x upper limit of normal (ULN); Alanine aminotransferase (ALT) > 2.5 x ULN; Aspartate aminotransferase (AST) > 2.5 x ULN.

3. Severely impaired renal function defined by: Serum creatinine > 2 mg/dL.

4. Active bacterial (including active and latent tuberculosis), fimgal, parasitic, or viral infection that requires therapy.

5. Known confirmed diagnosis of human immunodeficiency virus (HIV) infection or other immunodeficiency syndromes such as X-linked agammaglobulinemia and common variable immune deficiency.

6. Evidence of active HB V or HCV viral infection (HBsAg in the absence of HBs Ab OR HCV Ab positive with HCV RNA positive). Subjects whose disease is controlled under antiviral therapy should not be excluded.

7. History of progressive multifocal leuko-encephalopathy (PML).

8. History of a second primary malignancy in the past 3 years in need of systemic treatment.

9. History or current diagnosis of uncontrolled or significant cardiac disease including any of the following:

Myocardial infarction within the last 6 months

Uncontrolled congestive heart failure

Unstable angina pectoris within the last 6 months

10. History or current diagnosis of ECG abnormalities indicating significant risk of cardiac disease such as:

Resting QTcF > 470 msec at pretreatment (baseline) for both male and female or impossibility to determine QTc Concomitant clinically significant cardiac arrhythmias (e.g ventricular tachycardia), and clinically significant second or third degree AV block without a pacemaker

History of familial long QT syndrome or know family history of Torsades de Pointe

11. History of drug-induced pneumonitis or current pneumonitis.

12. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M- CSF) < 2 weeks prior to start of study drug treatment and use of erythropoietin stimulating agents (ESA) < 3 months prior to first dose of study treatment.

13. Splenic irradiation within 6 months prior to the first dose of study drug.

14. Received blood platelet transfusion within 28 days prior to first dose of study treatment.

15. Subjects with known TP53 mutation or deletion of TP53.

[0192] Dosing

Ruxolitinib as a single agent has been tolerated up to doses of 25 mg BID (Verstovsek et al (2010) N. Engl. J. Med. p. 1117-27). In different clinical studies 15 mg BID and 20 mg BID was established as the most effective and safest starting dose, followed by individualized dose titration. In patients with moderate thrombocytopenia, data show the feasibility of starting with 5 mg BID and then escalating to 10 mg and occasionally to 15 mg BID, without causing severe thrombocytopenia (Cervantes (2014) Blood p. 2635-42.). Ruxolitinib is administered orally (PO) at 5-25 mg twice a day (BID) every day in a 28-day treatment cycle with or without food at the stable dose at the time of study entry.

[0193] Response rate for the composite primary efficacy endpoint

The primary efficacy endpoint is the response rate (RR) of the composite of the following, assessed at the end of cycle 6 (around 24 weeks):

Improvement in anemia of > 1.5 g/dL, and

No spleen volume progression, and

No symptoms worsening

The composite criteria are defined as follows:

• Anemia improvement requires an increase of hemoglobin from baseline of at least 1.5 g/dL • Spleen volume progression is defined as a spleen volume increase of 25% or more from baseline as determined by MRI/CT

• Symptoms worsening is defined as a total symptom score (TSS) increase of 10 or more from baseline assessed by MFSAF version 4.0

The following assessments are utilized to determine the 3 components for the response rate (RR):

• Improvement in Anemia

Anemia improvement requires an increase of hemoglobin from baseline of at least 1.5 g/dL as measured at the end of Cycle 6 (week 24). The increase in hemoglobin should be confirmed at least 2 weeks later. Anemia improvement requires the absence of any PRBC transfusion in the 12 weeks prior to achieving an increase of 1.5 g/dL.

Laboratory Hb assessments taken at the end of Cycle 6 (week 24) in comparison to cycle 1 day 1 (C1D1, i.e. baseline) are used to determine those subjects that achieved an improvement of > 1.5 g/dL.

• Spleen volume progression

Evaluation of spleen volume is performed by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT) scan. MRI of the spleen (or CT if MRI is contraindicated) is performed as regular assessment at screening, at the end of Cycle 6 (week 24), the end of Cycle 12 (week 48), and at EOT (if not performed in the past 12 weeks). Volumetric spleen size progression is defined as a spleen volume increase of at least 25% from baseline, as per IWG-MRT revised criteria (Tefferi et al (2013) Blood p. 1395-8). MRI is performed with a body coil because the objective is to measure organ volume, not to find very small lesions. MRIs are performed and assessed by local radiologists who are instructed to provide a quantitative and a qualitative assessment of spleen volume (as enlarged, smaller, larger, etc.). Spleen volume is obtained by outlining the circumference of the organ and determining the volume using the validated technique of least squares. The MRI does determine spleen length below the costal margin, as there are no validated approaches for determining this measurement. The site radiologist provides the read-out and the results from the local evaluations are used for the endpoints analyses. MRI is the preferred method for obtaining spleen volume data. However, CT scans may be performed at the visits where MRI would be conducted if the subject is not a candidate for MRI (because of the presence of metal clips in the body, or because of claustrophobia, for example), or if MRI is unavailable to the study site.

Generally, the same method (MRI or CT) should be consistently used for all visits for a given subject unless a new contraindication to the use of MRI (eg, pacemaker insertion) occurs.

• Total symptom score (TSS) worsening

Symptom worsening occurs when the total symptom score (TSS) assessed by MFSAF v4.0 increases 10 or more scores from baseline (C1D1) at the end of Cycle 6. The TSS absolute increase of 10 or more from baseline is considered as a clinical meaningful symptom worsening based on the COMFORT -I trial data using a combination of distribution- and anchor- based approaches (Dueck et al, EHA Library, May 18, 2017; 181107; El 331). An absolute score change, rather than a percentage change, is the criterion as the latter would either require not enough change in magnitude for a lower baseline or too much change in magnitude for a higher baseline.

[0194] Secondary efficacy endpoints

The following assessments are performed as secondary efficacy endpoints:

• Hb measurement to assess proportion of subjects who achieved improvement in Hb level of > 1.5 g/dL or > 2.0 g/dL

• Evaluation of a change in spleen length by palpation and spleen volume by MRECT

• Changes in MFSAF v4.0 and EORTC QLQ-C30

• Estimation of time to PFS events

• Evaluation of the effect on bone marrow fibrosis

Proportion of subjects achieving improvement of Hb level

The improvement in anemia based on an increase of hemoglobin from baseline of at least > 1.5 g/dL or > 2.0 g/dL is assessed at the end of Cycle 6 (week 24) and at the end of Cycle 12 (week 48). The increase in hemoglobin should be confirmed at least 2 weeks later. Anemia improvement requires the absence of any PRBC transfusion in the 12 weeks prior to achieving an increase of 1.5 g/dL or 2.0 g/dL.

Laboratory Hb assessments taken at the end of Cycle 6 (week 24) and at the end of Cycle 12 (week 48) are compared to baseline (C1D1) to determine the proportion of those subjects that have achieved an improvement of > 1.5 g/dL or > 2.0 g/dL from baseline.

Changes in spleen length and spleen volume

Evaluation of spleen size changes for secondary endpoint is assessed by performing manual palpation and MRI/CT imaging as outlined below.

Spleen length measurements are conducted by manual palpation at regular intervals during the study in order to evaluate changes in spleen length in each treatment arm. Manual palpation is performed on days 1 and 15 of cycles 1 to 3, and day 1 of subsequent cycles. The edge of the spleen shall be determined by palpation, and measured in centimeters, from the lower costal margin (LCM) to the point of greatest splenic protrusion. In case of spleen length increase that meets any of the criteria for progressive spleen size as described below are met, an MRI/CT scan is conducted to confirm spleen size progression.

• A > 100% increase in palpable distance, below LCM, for baseline splenomegaly of 5-10 cm, or

• A 50% increase in palpable distance, below LCM, for baseline splenomegaly of > 10 cm, as per IWG-MRT revised criteria (Tefferi et al (2013) Blood p. 1395-8.).

In case any of the criteria for progressive spleen size as described above are met, MRI/CT scan is conducted to confirm spleen size progression.

Change in MFSAF v4.0 and EORTC QLQ-C30

The changes in symptoms of myelofibrosis in each treatment arm using MFSAF v4.0 and EORTC QLQ-C30 patient reported outcomes (PROs) from baseline are evaluated.

MFSAF v4.0 is a harmonized, consensus-based PRO questionnaire recently developed for use in MF trials by a PRO Consortium Working Goup (Gwaltney et al (2017) Leuk. Res.p. 26-31), which focuses on the 7 core symptoms of MF : fatigue, night sweats, pruritus, abdominal discomfort, pain under the ribs on the left side, early satiety and bone pain. Subjects record symptom severity at its worst for each of the 7 symptoms on an 11 -point numeric rating scale, from 0 (absent) to 10 (worst imaginable). The Total Symptom Score (TSS) is the sum of all the scores for all 7 symptoms.

The EORTC QLQ-C30 PRO is one of the most widely used and validated instruments to measure health-related quality of life (QoL) in subjects with cancer (Aaronson et al (1993) J Natl Cancer Inst. 1993 Mar 3;85(5):365-76.). The core questionnaire, the QLQ-C30 version 3.0, is the current standard.

The EORTC QLQ-C30 includes 5 functional scales (physical, emotional, social, role, cognitive), eight symptom scales (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, and appetite loss), as well as global health/quality-of-life and financial impact. This instrument asks the subject to respond according to the past week recall period, with the exception of the first 5 questions that represent physical functioning and capture the subject’s current status. Raw scores are linearly converted to a 0-100 scale. For functional and global health status/QoL scales, higher scores indicate better QoL and level of functioning; for symptom scales, higher scores indicate greater level of symptoms or difficulties.

Progression Free Survival

Progression free survival (PFS) is defined as the time from randomization until earliest time for one of the following progression events.

• Progressive splenomegaly as assessed by increasing spleen volume (by MRI/CT) of >25% from baseline

• Accelerated phase defined by an increase in circulating peripheral blood blast content of > 10% confirmed after 8 weeks. The progression date is the date of first increase in peripheral blood blast content of > 10%

• Deteriorating cytopenia (dCP) independent from treatment defined for all patients by platelet count < 35 xlO^A9/L or neutrophil count < 0.75 x lO^A9/L that lasts for at least 4 weeks. The progression date will be the date of first decrease of platelets < 35 xlO^A9/L or neutrophils < 0.75 x lO^A9/L confirmed after 4 weeks

• Leukemic transformation defined by an increase in peripheral blood blast content of > 20% associated with an absolute blast count of > lxlO^A9/L that lasts for at least 2 weeks or a bone marrow blast count of > 20%. The progression date will be the date of first increase in peripheral blood blast content of > 20% associated with an absolute blast count of > lxlO^A9/L OR the date of the bone marrow blast count of > 20% as per IWG-MRT revise criteria (Tefferi et al (2013) Blood p. 1395-8.).

• Death from any cause

Progressive splenomegaly:

For the PFS assessment, progressive splenomegaly is defined as an increased spleen volume from baseline of at least 25% as measured by MRI/CT. The spleen length regular assessment done by palpation is used to trigger splenomegaly progression.

In case of spleen length increase that meet any of the criteria for progressive spleen size as described below are met, MRI/CT will be conducted to confirm spleen size progression.

• A > 100% increase in palpable distance, below FCM, for baseline splenomegaly of 5-10 cm, or

• A 50% increase in palpable distance, below FCM, for baseline splenomegaly of > 10 cm.

The progression date is the date of MRI/CT assessment confirming spleen volume increase of at least 25% from baseline.

Change in bone marrow fibrosis and histomorphology

Bone marrow fibrosis should be graded using the grading system as applied by European consensus according to "The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia " (Arber et al (2016) Blood p. 2391 -405, as described hereinabove in [0118]

[0195] Safety and Tolerability:

Safety and tolerability are assessed by monitoring the frequency, duration and severity of adverse events, performing physical exams, and evaluating changes in vital signs, electrocardiograms (ECGs), serum chemistry, hematology and urinalysis results.

Claims

1. A pharmaceutical combination comprising a) an IL- 1 b binding antibody or functional fragment thereof and b) a JAK inhibitor.

2. The pharmaceutical combination according to claim 1, wherein said IL- 1 b binding antibody or functional fragment thereof is an IL-l b binding antibody.

3. The pharmaceutical combination according to claim 1 or 2, wherein said IL- 1 b binding antibody is canakinumab.

4. The pharmaceutical combination according to claim 1 or 2, wherein said K-1 b binding antibody is gevokizumab.

5. The pharmaceutical combination according to any of claims 1-4, wherein said JAK inhibitor is JAK1/JAK2 inhibitor, a JAK2/FLT3 inhibitor, a JAK2^V617F inhibitor, a JAK2 inhibitor, JAK1 inhibitor or a JAK2/Src inhibitor.

6. The pharmaceutical combination according to any of claims 1-5, wherein said JAK inhibitor is ruxobtinib, or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical combination according to any of claims 1 -6 for use in the treatment of anemia associated with hematological malignancy, anemia associated with leukemia or anemia associated with myelofibrosis in a subject in need thereof.

8. The pharmaceutical combination according to any of claims 1 -7 for use in the treatment of myelofibrosis in a subject in need thereof.

9. The pharmaceutical combination for use according to any of claims 7-8, comprising administering ruxobtinib or a pharmaceutically acceptable salt thereof in an amount of from 5 mg twice daily to 25mg twice daily, such as 5 mg twice daily, 10 mg twice daily, 15 mg twice daily, 20 mg twice daily or 25 mg twice daily.

10. The pharmaceutical combination for use according to any of claims 7-9, comprising administering 25-300 mg of canakinumab.

11. The pharmaceutical combination for use according to any of claims 7-10, comprising administering about 250 mg of canakinumab.

12. The pharmaceutical combination for use according to any of claims 7-11, comprising administering about 200 mg of canakinumab.

13. The pharmaceutical combination for use according to any of claims 7-12, wherein canakinumab is administered approximately every 2 weeks, approximately every three weeks, approximately monthly, approximately every four weeks, approximately every 6 weeks, approximately every 8 weeks (approximately every 2 months), or approximately every 12 weeks (approximately every 3 months).

14. The pharmaceutical combination for use according to any of claims 7-13, comprising administering about 200 mg of canakinumab approximately every three weeks.

15. The pharmaceutical combination for use according to any of claims 7-13, comprising administering about 200 mg of canakinumab approximately every four weeks.

16. The pharmaceutical combination for use according to any of claims 7-13, comprising administering about 250 mg of canakinumab approximately every four weeks.

17. The pharmaceutical combination for use according to any of claims 7-9, comprising administering 30-120 mg of gevokizumab.

18. The pharmaceutical combination for use according to any of claims 7-9 and 17, comprising administering 30-60 mg of gevokizumab.

19. The pharmaceutical combination for use according to any of claims 7-9 and 17, comprising administering 60-120 mg of gevokizumab.

20. The pharmaceutical combination for use according to any of claims 7-9 and 17-18, comprising administering 30 mg of gevokizumab.

21. The pharmaceutical combination for use according to any of claims 7-9 and 17-19, comprising administering 60 mg of gevokizumab.

22. The pharmaceutical combination for use according to any of claims 7-9, 17 and 19, comprising administering 90 mg of gevokizumab.

23. The pharmaceutical combination for use according to any of claims 7-9, 17 and 19, comprising administering 120 mg of gevokizumab.

24. The pharmaceutical combination for use according to any of claims 7-9 and 17-23, wherein gevokizumab is administered approximately every 2 weeks, approximately every 3 weeks, approximately monthly, approximately every four weeks, approximately every 6 weeks, approximately every 8 weeks (approximately every 2 months), or approximately every 12 weeks (approximately every 3 months).

25. The pharmaceutical combination for use according to any of claims 7-9 and 17-24, wherein gevokizumab is administered approximately every 3 weeks.

26. The pharmaceutical combination for use according to any of claims 7-9 and 17-24, wherein gevokizumab is administered approximately every 4 weeks (monthly).

27. An IL- 1 b-binding antibody or functional fragment thereof for use in treating, preventing or reducing the incidence of anemia in a subject in need thereof.

28. The IL- 1 b-binding antibody or functional fragment thereof for use according to claim 27, wherein said anemia is anemia of inflammation.

29. The IL- 1 b-binding antibody or functional fragment thereof for use according to claim 27 or 28, wherein said anemia is anemia of cancer.

30. The IL-1 b-binding antibody or functional fragment thereof for use according to any of claims 27-29, wherein said anemia is anemia of cancer having at least a partial inflammatory basis.

31. The IL-1 b-binding antibody or functional fragment thereof for use according to any of claims 27-30, wherein said patient has hsCRP level of >2 mg/L before administration of the IL-1 b binding antibody or functional fragment thereof.

32. The IL-1 b-binding antibody or functional fragment thereof for use according to any of claims 27-31, wherein said patient is over 60 years of age.

33. The IL-1 b-binding antibody or functional fragment thereof for use according to any of claims 27-32, wherein said patient has suffered from a myocardial infarction (MI) before administration of the IL-1 b binding antibody or functional fragment thereof.

34. The IL-1 b-binding antibody or functional fragment thereof for use according to any of claims 27-33, wherein the hsCRP level of said patient has reduced to <5 mg/L, <4 mg/L, <3 mg/L, or <2 mg/L assessed at least approximately 3 months after first administration of the IL-1 b binding antibody or functional fragment thereof.

35. The IL-1 b-binding antibody or functional fragment thereof for use according to any of claims 27-34, wherein said PMb binding antibody or functional fragment thereof is an IL- 1 b binding antibody.

36. The IL-1 b-binding antibody or functional fragment thereof for use according to any of claims 27-35, wherein said PMb binding antibody is canakinumab.

37. Canakinumab for use according to claim 36, comprising administering 25-300 mg of canakinumab.

38. Canakinumab for use according to claim 37, wherein canakinumab is administered every 2 weeks, every 3 weeks, approximately monthly, approximately every four weeks, approximately every 6 weeks, approximately every 8 weeks (approximately every 2 months), approximately every 12 weeks (approximately every 3 months), approximately every 4 months, approximately every 5 months, or approximately every 6 months.

39. Canakinumab for use according to claim 37 or 38, comprising administering canakinumab approximately every 3 months.

40. The IL- 1 b-binding antibody or functional fragment thereof for use according to any of claims 27-35, wherein said IL- 1 b binding antibody is gevokizumab.

41. Gevokizumab for use according to claim 40, comprising administering 30-120 mg of gevokizumab.

42. The IL- 1 b-binding antibody or functional fragment thereof for use according to any of claims 27-41 or the pharmaceutical combination for use according to any of claims 7-26, wherein said IL-1 b binding antibody or functional fragment thereof is administered subcutaneously.

43. The IL-1 b-binding antibody or functional fragment thereof for use according to any of claims 27-41 or the pharmaceutical combination for use according to any of claims 7-26, wherein said IL-1 b binding antibody or functional fragment thereof is administered intravenously.