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WO2020039401A1 - Traitement comprenant des anticorps se liant à il-1 βeta et ses combinaisons - Google Patents

Traitement comprenant des anticorps se liant à il-1 βeta et ses combinaisons Download PDF

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WO2020039401A1
WO2020039401A1 PCT/IB2019/057121 IB2019057121W WO2020039401A1 WO 2020039401 A1 WO2020039401 A1 WO 2020039401A1 IB 2019057121 W IB2019057121 W IB 2019057121W WO 2020039401 A1 WO2020039401 A1 WO 2020039401A1
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Prior art keywords
anemia
approximately
canakinumab
binding antibody
use according
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Inventor
Shalini CHATURVEDI
Hans Menssen
Thomas Radimerski
Paul Ridker
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Novartis AG
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Novartis AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • C07K16/245—IL-1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/55—Medicinal preparations containing antigens or antibodies characterised by the host/recipient, e.g. newborn with maternal antibodies

Definitions

  • 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.
  • 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.
  • 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.
  • Myeloproliferative neoplasms 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).
  • MF myelofibrosis
  • ET essential thrombocythemia
  • PV polycythemia vera
  • MF Philadelphia chromosome-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).
  • MF developed from PV, ET or as a primary disorder 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.
  • 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.
  • cytokine and growth factor receptors utilize non-receptor tyrosine kinases, the Janus kinases (JAKs), to transmit extracellular ligand binding into an intracellular response.
  • JAKs non-receptor tyrosine kinases
  • 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.
  • 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.
  • JAK2V 617F mutation alters the JAK2 tyrosine kinase making it constitutively active.
  • polycythemia, thrombocythemia and leukocytosis can develop independently from growth factor regulation.
  • the detection of STAT activation suggests dysregulated JAK activity.
  • the malignant cells appear to retain their responsiveness to JAK activating cytokines and/or growth factors; hence, they may benefit from JAK inhibition.
  • JAKs inhibitors including ruxolitinib (approved under the name Jakavi®/JakafiTM) 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.
  • 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.
  • IL- lRa recombinant IL-l receptor antagonist
  • Myelofibrosis is defined by progressive bone marrow (BM) fibrosis and a consecutive reduction of blood cells.
  • BM bone marrow
  • the disruption of the medullary erythropoietic niche is the primary mechanism governing the bone marrow failure and anemia, which typify MF.
  • Hb hemoglobin
  • 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.
  • the present invention relates, in part, to the finding that direct inhibition of inflammation by administration of IL-l b binding antibodies reduces anemia.
  • 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.
  • 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
  • FIG. 1 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 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.
  • composition“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.
  • 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.
  • 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.
  • 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.
  • the term“about” in relation to a numerical value x means, for example, +/- 10%.
  • 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.
  • the term“approximately” means that the indicated time in weeks or months may vary by ⁇ 5 days or ⁇ 10 days.
  • 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.
  • 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.
  • a condition e.g., a specific disease or disorder or clinical symptom thereof such as anemia
  • 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.
  • 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.
  • an“effective amount” refers to an amount sufficient to effect beneficial or desired results.
  • 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.
  • 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.
  • terapéuticaally 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.
  • anemia 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).
  • WHO World Health Organization
  • “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
  • “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)
  • treatment of anemia refers to“stabilizing anemia” or“improving anemia”, for example, in comparison to pre-treatment situation or in comparison to standard of treatment.
  • 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).
  • improving anemia refers to a decrease in severity of anemia or improvement (e.g. increase) of hemoglobin level.
  • 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.
  • 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).
  • CDR complementarity determining regions
  • FR framework regions
  • 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.
  • 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.
  • 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).
  • Fab fragment a monovalent fragment consisting of the VL, VH, CL and CH1 domains
  • 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
  • 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).
  • single chain Fv single chain Fv
  • 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.
  • 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.
  • human antibody 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.
  • 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).
  • 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.
  • KD 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.
  • 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.
  • a subject is“in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
  • the term“patient” is used interchangeably with the term“subject” and refers to a human patient.
  • 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
  • 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.
  • C-reactive protein and“CRP” refers to serum C-reactive protein, which is used as an indicator of the acute phase response to inflammation.
  • 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.
  • 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.
  • 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).
  • a given marker e.g., hsCRP and/or hemoglobin
  • MI myocardial infarction
  • MI acute myocardial infarction
  • STEM ST- elevated MI
  • NSTEMI non-ST-elevated MI
  • 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 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.
  • 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.
  • hsCRP C-reactive protein
  • 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.
  • 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.
  • 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.
  • anemia of inflammation also known as“anemia of chronic inflammation” or“anemia of chronic disease” (ACD)
  • ACD anemia of inflammation
  • CKD chronic kidney disease
  • anemia of cancer anemia associated with cancer having at least a partial inflammatory basis
  • anemia of (e.g. associated with) hematological malignancy anemia of (e.g.
  • ESA erythropoiesis stimulating agent
  • ESA erythropoiesis stimulating agent
  • EPO erythropoietin
  • ESA hyporesponsive anemia e.g., EPO hyporesponsive anemia
  • functional iron- deficiency anemia iron-restricted anemia
  • iron-restricted anemia anemia associated with a decline or loss of kidney function (chronic renal failure)
  • 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).
  • autoimmune disease e.g., rheumatoid arthritis
  • 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 refers to a patient with a hematologic malignancy having anemia.
  • Hematological malignancies or hematologic cancer or blood cancer refers to a cancer that begins in blood-forming tissue, such as the bone marrow, or in the cells of the immune system.
  • hematologic cancer are leukemia, lymphoma, and multiple myeloma.
  • the hematological malignancy is myelofibrosis.
  • 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.
  • 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).
  • NSCLC non-small cell lung cancer
  • RCC renal cell carcinoma
  • breast cancer breast cancer
  • prostate cancer head and neck cancer (
  • 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.
  • RA rheumatoid arthritis
  • IBD inflammatory bowel disease
  • lupus including systemic lupus erythematosus or SLE
  • MS multiple sclerosis
  • CHF congestive heart failure
  • cardiovascular inflammation neoplastic diseases.
  • 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.
  • 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.
  • said IL-1 b binding antibody or functional fragment thereof is an IL-1 b binding antibody.
  • the IL- 1b binding antibody or functional fragment thereof is a neutralizing antibody.
  • 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 I ⁇ - ⁇ b with a dissociation constant of about 500 pM or less. In some embodiments, the I ⁇ - ⁇ b binding antibody or functional fragment thereof binds to human G ⁇ - ⁇ 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.
  • 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 I ⁇ - ⁇ b binding antibody or functional fragment thereof binds to human IL- 1 b with dissociation constant of about 0.3 pM or less.
  • 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.
  • said I ⁇ - ⁇ 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.
  • said I ⁇ - ⁇ b binding antibody is canakinumab.
  • said I ⁇ - ⁇ 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).
  • said I ⁇ - ⁇ b 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 I ⁇ - ⁇ b binding to its signaling receptor.
  • Gevokizumab is disclosed in W02007/002261 which is hereby incorporated by reference in its entirety.
  • said IL-1 b binding antibody is LY-2189102, which is a humanised interleukin-l beta (IL- 1 b) monoclonal antibody.
  • said IL- 1 b binding antibody or a functional fragment thereof is CDP- 484 (Celltech), which is an antibody fragment blocking IL-l b.
  • said IL-1 b binding antibody or a functional fragment thereof is IL-l Affibody (SOBI 006, Z-FC (Swedish Orphan Biovitrum/Affibody)).
  • 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 I ⁇ - ⁇ b binding antibody or functional fragment thereof to a subject in need thereof.
  • a method of treating or preventing anemia of inflammation comprising administering a therapeutically effective dose of an I ⁇ - ⁇ b binding antibody or functional fragment thereof to a subject in need thereof.
  • a method of treating or preventing anemia of cancer comprising administering a therapeutically effective dose of an I ⁇ - ⁇ b binding antibody or functional fragment thereof to a subject in need thereof.
  • a method of treating or preventing anemia of cancer with partial inflammatory basis comprising administering a therapeutically effective dose of an I ⁇ - ⁇ b binding antibody or functional fragment thereof to a subject in need thereof.
  • a method of treating or preventing anemia comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof.
  • a method of treating or preventing anemia of inflammation comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof.
  • a method of treating or preventing anemia of cancer comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof.
  • 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.
  • a method of treating or preventing anemia comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof.
  • a method of treating or preventing anemia of inflammation comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof.
  • a method of treating or preventing anemia of cancer comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof.
  • 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.
  • 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.
  • a method of treating or preventing anemia associated with myelofibrosis comprising administering a therapeutically effective dose of canakinumab to a subject in need thereof.
  • a method of treating or preventing anemia associated with myelofibrosis comprising administering a therapeutically effective dose of gevokizumab to a subject in need thereof.
  • 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.
  • 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.
  • 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.
  • the invention relates to methods for treating anemia associated with an elevated level of hepcidin, comprising administering a therapeutically effective dose of an G ⁇ - ⁇ b binding antibody or functional fragment thereof to a subject in need thereof.
  • 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.
  • 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.
  • said patient has hsCRP level of >2 mg/L before administration of the IL-l b binding antibody or functional fragment thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • said hsCRP level is >5 mg/L before first administration canakinumab and reduced to ⁇ 5 mg/L assessed after administration of canakinumab.
  • 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.
  • 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.
  • 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.
  • said hsCRP level is >5 mg/L before first administration gevokizumab and reduced to ⁇ 5 mg/L assessed after administration of gevokizumab.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • said patient has previously suffered myocardial infarction (MI).
  • MI myocardial infarction
  • hsCRP high sensitivity C-reactive protein
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • cytokine and growth factor receptors utilize non-receptor tyrosine kinases, the Janus kinases (JAKs), to transmit extracellular ligand binding into an intracellular response.
  • JAKs non-receptor tyrosine kinases
  • 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.
  • 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.
  • 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.
  • IC50 half maximal inhibitory concentration
  • the JAKs is a JAK2 inhibitor, suitably pacritinib or a pharmaceutically acceptable salt thereof or fedratinib or a pharmaceutically acceptable salt thereof.
  • the JAKs inhibitor is a JAK2 V617F inhibitor, suitably gandotinib or a pharmaceutically acceptable salt thereof.
  • the JAKs inhibitor is a JAK2 inhibitor, suitably BMS-911543 or a pharmaceutically acceptable salt thereof.
  • the JAKs inhibitor is a JAK1 inhibitor, suitably itacitinib or a pharmaceutically acceptable salt thereof, in particular itacitinib adipate.
  • the JAKs inhibitor is a JAK2/Src inhibitor, suitably NS-018 or a pharmaceutically acceptable salt thereof.
  • 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:
  • ruxolitinib refers to the free form
  • 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®.
  • Ruxolitinib, or pharmaceutically acceptable salt thereof, in particular ruxolitinib phosphate can be in a unit dosage form (e.g. tablet), which is administered orally.
  • 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.
  • 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.
  • 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.
  • 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.
  • “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:
  • each Ri, R 2 , R3, R4, R5, Re, R7, Rs, R9, Rio, R11, R12, R13, Ri4, R15, R1 ⁇ 2 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.
  • a deuterated ruxolitinib is selected from the group consisting of:
  • a deuterated ruxolitinib is
  • 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
  • WO2011/112662 which is incorporated herein by reference.
  • “itacitinib” refers to the free form
  • any reference to“a pharmaceutically acceptable salt thereof’ refers to“a pharmaceutically acceptable acid addition salt thereof’, in particular itacitinib adipate.
  • 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.
  • the pharmaceutical combination is for use in the treatment of myelofibrosis.
  • 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.
  • a pharmaceutical combination comprising a) gevokizumab and (b) ruxobtinib, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical combination comprising a) canakinumab and (b) ruxobtinib, or a pharmaceutically acceptable salt thereof.
  • compositions 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.
  • the pharmaceutical combination is for use in the treatment of myelofibrosis in a subject in need thereof.
  • 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.
  • 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.
  • ruxobtinib 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.
  • ruxobtinib 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Myelofibrosis comprises primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera myelofibrosis (PPV-MF).
  • PMF primary myelofibrosis
  • PET-MF post-essential thrombocythemia myelofibrosis
  • PSV-MF post-polycythemia vera myelofibrosis
  • PMF primary myelofibrosis
  • WHO World Health Organization
  • Primary myelofibrosis encompasses prefibrotic/early primary myelofibrosis (prePMF) and overt primary myelofibrosis (overt PMF).
  • prePMF prefibrotic/early primary myelofibrosis
  • overt PMF overt primary myelofibrosis
  • bone marrow fibrosis 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;
  • grading i.e. grading of fiber density and quality
  • 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.
  • PTT-MF post-essential thrombocythemia myelofibrosis
  • PV polycythemia vera
  • WHO World Health Organization
  • MF post-polycythemia myelofibrosis
  • Table 4 Criteria for diagnosis of post-polycythemia myelofibrosis
  • 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.
  • Immature myeloid cells constitute blasts + promyelocytes + myelocytes +
  • metamyelocytes + nucleated red blood cells In splenectomized patients, ⁇ 5% immature myeloid cells is allowed.
  • 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.
  • PRBC packed red blood cells
  • 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.
  • 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.
  • 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.
  • 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.
  • a JAKs inhibitor suitably ruxolitinib or a pharmaceutically acceptable salt thereof
  • the term “newly diagnosed” refers to diagnosis of the disorder, e.g. myelofibrosis and said patient has not received any treatment.
  • 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.
  • triple-negative myelofibrosis patient refers to a patient who lacks JAK2, CALR and MPL mutations.
  • 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.
  • 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
  • splenomegaly 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 cm 3 ).
  • CT computed tomography
  • treatment of splenomegaly 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.
  • IWG-MRT International Working Group-Myeloproliferative Neoplasms Research and Treatment
  • EPN European Leukemia Net
  • 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.
  • MRI magnetic resonance imaging
  • CT computed tomography
  • 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.
  • hepatomegaly 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 cm 3 ).
  • CT computed tomography
  • treatment of hepatomegaly 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.
  • IWG-MRT International Working Group-Myeloproliferative Neoplasms Research and Treatment
  • EPN European Leukemia Net
  • 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.
  • MRI magnetic resonance imaging
  • CT computed tomography
  • thrombocytopenia refers to a platelet count, in blood specimen laboratory test, lower than normal.
  • severeity of thrombocytopenia refers, for example, to specific grade 1-4 of thrombocytopenia according to CTCAE (version 4.03).
  • treatment of thrombocytopenia 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.
  • stabilizing thrombocytopenia refers, for example, to prevent an increase in the severity of thrombocytopenia, namely the platelet count remains stable.
  • improving thrombocytopenia refers to alleviation of the severity of thrombocytopenia, namely increasing blood platelet count.
  • 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.
  • 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
  • neutrophil count refers to an absolute neutrophil count (ANC), in blood specimen laboratory test, lower than normal value.
  • severeity of neutropenia refers, for example, to specific grade 1 -4 of neutropenia according to CTCAE (version 4.03).
  • treatment of neutropenia 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.
  • stabilizing neutropenia refers, for example, to prevent an increase in the severity of neutropenia.
  • improving neutropenia refers, for example, to a decrease in the severity of neutropenia.
  • 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.
  • 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-
  • the term“severity of anemia”, as used herein, refers, for example, to specific grade 1 -4 of anemia according to CTCAE (version 4.03)].
  • treatment of anemia 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.
  • 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).
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • the disclosure provides a pharmaceutical combination comprising a) the G ⁇ -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.
  • 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.
  • 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.
  • 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.
  • the disclosure provides a pharmaceutical combination comprising a) the G ⁇ -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.
  • treatment of bone marrow fibrosis associated with MF 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.
  • stabilizing bone marrow fibrosis refers, for example, to prevent increase in severity of bone marrow fibrosis.
  • 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.
  • a pharmaceutical combination comprising a) an I ⁇ - ⁇ 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.
  • 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.
  • 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.
  • 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
  • substitutional symptoms associated with myelofibrosis 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).
  • treatment of constitutional symptoms associated with myelofibrosis 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).
  • 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.
  • 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
  • one or more of the constitutional symptoms associated with MF are alleviated (e.g. by eliminating or by reducing intensity, duration or frequency).
  • 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.
  • TSS total symptom score
  • 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.
  • 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.
  • 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
  • sonidegib, vismodegib an anti-fibrotic agent, such as serotonin P or a monoclonal antibody (e.g. fresolimumab, suppressuzumab); 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
  • a dual CYP2C9-CYP3A4 inhibitor e.g. fluconazole
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • said IL- 1 b binding antibody or functional fragment thereof is administered approximately every four weeks (approximately monthly).
  • 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).
  • 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).
  • said IL- 1 b binding antibody or functional fragment thereof is administered approximately every 3 months.
  • a method for treating, preventing or reducing the incidence of anemia comprising administering a therapeutically effective dose of canakinumab approximately every 3 months.
  • a method for treating, preventing or reducing the incidence of anemia comprising administering a therapeutically effective dose of gevokizumab approximately every 3 months.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present disclosure provides the G ⁇ -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.
  • a method of treating anemia of hematological malignancy, leukemia or myelofibrosis comprising administering a therapeutically effective dose of a G ⁇ -1 b binding antibody, wherein the G ⁇ -1 b binding antibody is selected from canakinumab and gevokizumab, to a subject in need thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present disclosure provides the G ⁇ - ⁇ 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.
  • 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).
  • the patient with myelofibrosis and/or anemia of hematological malignancy, leukemia or myelofibrosis receives canakinumab monthly or every three weeks.
  • 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.
  • 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).
  • the dose can be down-titrated, preferably by increasing the dosing interval, preferably by doubling or tripling the dosing interval.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the dose can be down-titrated, preferably by increasing the dosing interval, preferably by doubling or tripling the dosing interval.
  • 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.
  • 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.
  • 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.
  • per treatment 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.
  • the dosing regimens disclosed herein apply equally to gevokizumab and to a functional fragment thereof or to canakinumab and a functional fragment thereof.
  • 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.
  • 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.
  • 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
  • a surfactant e.g., polysorbate 20 or polysorbate 80
  • 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.
  • canakinumab 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.
  • 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.
  • 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 ).
  • 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 :
  • ECG changes indicative of new ischemia (new ST-T changes or new LBBB)
  • 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).
  • 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.
  • 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.
  • 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.
  • 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
  • LDLC low density lipoprotein (LDL) cholesterol
  • HDLC high density lipoprotein (HDL) cholesterol
  • TG triglycerides
  • IL-6 interleukin-6
  • SC subcutaneous
  • q quarterly
  • 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
  • LDLC low density lipoprotein (LDL) cholesterol
  • HDLC high density lipoprotein (HDL) cholesterol
  • TG triglycerides
  • SC subcutaneous
  • q quarterly
  • LDLC low density lipoprotein (LDL) cholesterol
  • HDLC high density lipoprotein (HDL) cholesterol
  • TG triglycerides
  • SC subcutaneous
  • q quarterly
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • ALT alanine aminotransferase
  • AST aspartate transaminase
  • ALP alkaline phosphatase
  • CANTOS was designed to test directly the inflammatory hypothesis of atherothrombosis.
  • hsCRP levels and IL-6 levels were significantly reduced by canakinumab, with no reduction in lipid levels.
  • 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.
  • 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).
  • IL- 1 b 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 (Kieri 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.
  • 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.
  • 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).
  • those with anemia who were excluded from this secondary analysis
  • GFR glomerular filtration rate
  • 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.
  • 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 m 2 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 m 2 (Table 16)
  • canakinumab treatment associated with a significant decrease in incident anemia comparing all doses of canakinumab to placebo.
  • 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.
  • 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.
  • standard clinical practice e.g. placebo control study, for example in analogy to COMFORT-l trial
  • ECG Eastern Cooperative Oncology Group
  • PS performance status
  • 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.
  • PMF primary myelofibrosis
  • WHO World Health Organization
  • PTT-MF post-ET
  • PV-MF post-PV myelofibrosis
  • IWG-MRT International Working Group for Myelofibrosis Research and Treatment
  • Severely impaired renal function defined by: Serum creatinine > 2 mg/dL.
  • Active bacterial including active and latent tuberculosis
  • fimgal including active and latent tuberculosis
  • parasitic including active and latent tuberculosis
  • viral infection that requires therapy.
  • HIV human immunodeficiency virus
  • 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
  • hematopoietic colony-stimulating growth factors e.g. G-CSF, GM-CSF, M- CSF
  • ESA erythropoietin stimulating agents
  • 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.
  • PO 5-25 mg twice a day
  • 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):
  • Spleen volume progression is defined as a spleen volume increase of 25% or more from baseline as determined by MRI/CT
  • TSS total symptom score
  • 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.
  • MRI Magnetic Resonance Imaging
  • CT Computed Tomography
  • MRI of the spleen 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.
  • 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.
  • 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.
  • TSS total symptom score
  • C1D1 baseline symptom worsening 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.
  • 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.
  • 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.
  • LCM lower costal margin
  • an MRI/CT scan is conducted to confirm spleen size progression.
  • MRI/CT scan is conducted to confirm spleen size progression.
  • 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.
  • PFS Progression free survival
  • 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%
  • dCP Deteriorating cytopenia independent from treatment defined for all patients by platelet count ⁇ 35 xlO A 9/L or neutrophil count ⁇ 0.75 x lO A 9/L that lasts for at least 4 weeks.
  • the progression date will be the date of first decrease of platelets ⁇ 35 xlO A 9/L or neutrophils ⁇ 0.75 x lO A 9/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 A 9/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 A 9/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.).
  • 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.
  • MRI/CT will be conducted to confirm spleen size progression.
  • the progression date is the date of MRI/CT assessment confirming spleen volume increase of at least 25% from baseline.
  • 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]
  • WHO World Health Organization
  • 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.
  • ECGs electrocardiograms

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Abstract

La présente invention concerne des anticorps se liant à IL-1ß ou des fragments fonctionnels de ceux-ci pour traiter, prévenir ou réduire l'incidence de l'anémie. L'invention concerne également des combinaisons pharmaceutiques comprenant de tels anticorps se liant à IL-1ß ou des fragments fonctionnels de ceux-ci et au moins un autre agent pharmaceutique, de préférence le ruxolitinib ou un sel pharmaceutiquement acceptable de celui-ci.
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