Use of kanabernoulli monoclonal antibody

Abstract

Use of an IL-1 [beta] inhibitor, such as kanabernoulli monoclonal antibody, in the treatment and / or prevention of osteoarthritis and associated complications thereof.

Description

[0001] This application is a divisional application of PCT application PCT / IB2018 / 056455, filed on August 24, 2018, with the invention name “Use of Canakinumab”. The date on which the PCT application entered the Chinese national phase is December 4, 2020, and the application number is 201880094285.6. Technical Field

[0002] The present disclosure relates to novel uses and methods for reducing the risk of osteoarthritis and its related complications, which uses and methods generally comprise administering a therapeutic amount of an IL-1β inhibitor, such as a binding antibody or a functional fragment exemplified by canakinumab. Background Art

[0003] Osteoarthritis ("OA") is one of the most common chronic conditions and a leading cause of pain and disability in adults. It is a degenerative, chronic, progressive, painful joint disease. Currently, there is no treatment for OA-associated degeneration (DMOAD). Hip / knee OA affects 240 million people worldwide. Worldwide, OA is estimated to affect 9.6% of men and 18.0% of women over the age of 60 years old or have symptoms related to it. Furthermore, the prevalence of OA is steadily increasing and is expected to become the single largest cause of disability in the general population by 2030. Moreover, there are serious complications that occur with OA. The degenerative nature of the disease leads to many complications. For example, in 2010, 7.2 million people in the United States required total hip / knee replacement surgery. Therefore, there is an unmet medical need for treatments to reduce the progression of OA and its associated adverse events. Summary of the invention

[0004] Inflammation is involved in all stages of the atherothrombotic process, and patients with elevated inflammatory biomarkers such as hsCRP and IL-6 have increased vascular risk despite aggressive secondary prevention strategies. This disclosure relates in part to the finding that direct inhibition of inflammation by administration of IL-1β antagonists such as canakinumab reduces the risk of OA or prevents disease progression of OA, reduces OA-related adverse events (AEs), and reduces the overall need for total joint replacement (TJR).

[0005] Accordingly, the present invention relates to methods of preventing or reducing AEs associated with OA.

[0006] The present invention also relates to methods of reducing the risk of an OA patient requiring a TJR.

[0007] Therefore, the present invention also relates to canakinumab for use in reducing the risk of OA progression, the risk of patients with OA requiring TJR, and / or the risk of AEs associated with OA.

[0008] The present invention further relates to the use of canakinumab for the manufacture of a medicament for reducing the risk of OA, the risk of a patient with OA requiring a TJR, and / or the risk of AEs associated with OA.

[0009] The present invention also relates to the use of canakinumab for the manufacture of a medicament for reducing the risk of OA, the risk of a patient with OA requiring a TJR, and / or the risk of AEs associated with OA.

[0010] The present disclosure is illustrated by the numbered examples listed below:

[0011] 1. A method for reducing the risk of progression of osteoarthritis ("OA") and / or reducing adverse events associated with OA in a patient, the method comprising administering an IL-1β antagonist, wherein the patient has a high sensitivity C-reactive protein (hsCRP) level of ≥2 mg / L or greater than or equal to 3 mg / L as assessed prior to the first administration of the IL-1β antagonist, and wherein the patient has a reduced hsCRP level of <2.3 mg / L as assessed at a predetermined time point after the first administration of the IL-1β antagonist.

[0012] 2. A method for reducing the risk of progression of OA and / or reducing adverse events associated with OA in a patient, the method comprising administering an IL-1β antagonist, wherein the patient is assessed to have a high sensitivity C-reactive protein (hsCRP) level of ≥2 mg / L prior to the first administration of the IL-1β antagonist, and wherein if the patient is assessed to have a reduced hsCRP level of <2.3 mg / L at a predetermined time point after the first administration of the IL-1β antagonist, the patient will continue to receive the IL-1β antagonist.

[0013] 3. A method for reducing the risk of progression of OA and / or reducing adverse events associated with OA in a patient, the method comprising administering canakinumab, wherein the patient is assessed to have a high-sensitivity C-reactive protein (hsCRP) level ≥2 mg / L prior to the first administration of canakinumab, and wherein the patient is assessed to have a reduced hsCRP level of <2.3 mg / L about 3 months or more after the first administration of canakinumab.

[0014] 4. A method for reducing the risk of progression of OA and / or reducing adverse events in a patient, the method comprising administering canakinumab, wherein the patient is assessed to have a high-sensitivity C-reactive protein (hsCRP) level ≥2 mg / L prior to the first dose of canakinumab, and wherein if the patient is assessed to have a reduced hsCRP level of <2.3 mg / L about 3 months or more after the first administration of canakinumab, the patient will continue to receive canakinumab.

[0015] 5. The method of any of the preceding embodiments, wherein the progression of OA comprises joint replacement.

[0016] 6. The method of any preceding embodiment, wherein the patient has documented and / or symptomatic OA.

[0017] 7. The method of any preceding embodiment, comprising administering 150 mg to 300 mg of canakinumab.

[0018] 8. The method of any preceding embodiment, comprising administering 150 mg of canakinumab.

[0019] 9. The method of any preceding embodiment, comprising administering 150 mg of canakinumab approximately every 3 months.

[0020] 10. The method of any one of the preceding embodiments, wherein the reduced hsCRP level assessed at about 3 months after the first administration of canakinumab or at a predetermined time point after the first administration of the IL-1β antagonist is <1.5 mg / L.

[0021] 11. The method of any one of the preceding embodiments, wherein the reduced hsCRP level assessed at about 3 months after the first administration of canakinumab or at a predetermined time point after the first administration of the IL-1β antagonist is <1.0 mg / L.

[0022] 12. The method of any of the preceding embodiments, wherein the reduced hsCRP level assessed at a predetermined time point about 3 months after the first administration of canakinumab or after the first administration of an IL-1β antagonist is <2.2, <2.1, <2.0, <1.9, <1.8, <1.7, <1.6, <1.5, <1.4, <1.3, <1.2, <1.1, <1.0, <0.9, <0.8, <0.7, <0.6 or <0.5 mg / L.

[0023] 13. The method of any preceding embodiment, wherein the documented OA has been assessed using X-ray and / or MRI.

[0024] 14. The method of any preceding embodiment, wherein the symptomatic evidence of OA is pain and / or impaired function.

[0025] 15. A method according to any of the preceding embodiments, wherein the patient is not eligible for surgery.

[0026] 16. The method according to any one of the preceding embodiments, wherein the patient is unresponsive to NSAIDs.

[0027] 17. The method of any one of the preceding embodiments, wherein the level of IL-6 is below 1.15 mg / L or below 2 mg / L at a predetermined time point after the first administration of the IL-1β antagonist or after 3 months after the first administration of canakinumab.

[0028] 18. The method according to any one of the preceding embodiments, wherein the patient has previously experienced a CV event.

[0029] 19. The method of any one of the preceding embodiments, wherein the patient has previously experienced a myocardial infarction.

[0030] 20. A method for reducing the risk of progression of OA and / or reducing adverse events associated with OA in a patient, the method comprising administering an IL-1β antagonist, wherein the patient is assessed to have a high sensitivity C-reactive protein (hsCRP) level of ≥2 mg / L prior to the first administration of the IL-1β antagonist.

[0031] 21. The method of embodiment 20, wherein the IL-1β antagonist is canakinumab.

[0032] 22. The method of embodiment 20 or 21, comprising administering 150 mg to 300 mg of canakinumab.

[0033] 23. The method of any one of embodiments 20-22, comprising administering 150 mg to 300 mg of canakinumab approximately every 3 months.

[0034] 24. The method of any one of embodiments 20-23, wherein the documented OA has been assessed using X-ray and / or MRI.

[0035] 25. The method of any one of embodiments 20-24, wherein the symptom evidence of OA is pain and / or impaired function.

[0036] 26. A method according to any one of embodiments 20-25, wherein the patient is not eligible for surgery.

[0037] 27. The method of any one of embodiments 20-26, wherein the patient is non-responsive to NSAIDs.

[0038] 28. The method of any one of embodiments 20-27, wherein the patient has previously experienced a CV event.

[0039] 29. The method of any one of embodiments 20-28, wherein the patient has previously experienced a myocardial infarction.

[0040] 30. The method according to any one of the preceding embodiments, wherein the total joint replacement can be a total knee replacement or a total hip replacement.

[0041] 31. The method of any one of the preceding embodiments, wherein the patient suffers from shoulder OA, hand OA, or spondyloarthropathies (degenerative spondyloarthropathies).

[0042] 32. The method of any of the preceding embodiments, wherein the total joint replacement may be a total shoulder replacement.

[0043] 33. The method of any one of embodiments 1, 2, and 7-9, wherein the predetermined time point is 2 weeks to up to 6 months.

[0044] 34. The method of any one of embodiments 1-2 and 7-9, wherein the predetermined time point is 4 weeks to 12 weeks.

[0045] Further features and advantages of the present disclosure will become apparent from the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 is a graphical representation showing the time to OA-related adverse events in the medical history of patients with OA as a function of administration of various levels of canakinumab versus placebo.

[0047] Figure 2 is a graphical representation of the time to hip or knee replacement in patients with OA following administration of canakinumab versus placebo.

[0048] Figure 3 is a graphic representation of the risk of OA-related adverse events in each group stratified by hsCRP concentration.

[0049] Figure 4 is a graphic representation of the risk of total joint replacement (TJR) in patients with a history of OA in groups stratified by hsCRP concentration. DETAILED DESCRIPTION

[0050] The present invention provides methods for preventing or reducing disease progression of OA (including the need for joint replacement in OA patients); and / or preventing or reducing AEs associated with OA by administering an IL-1β antagonist, such as canakinumab, to such patients.

[0051] Canakinumab (International Nonproprietary Name (INN) No. 8836) is disclosed in WO 02 / 16436, which is hereby incorporated by reference in its entirety. Canakinumab is a fully human monoclonal anti-human IL-1β antibody of the IgG1 / k isotype and is being developed for the treatment of IL-1β-driven inflammatory diseases. It is designed to bind to human IL-1β, thereby blocking the interaction of this cytokine with its receptor. Antagonizing IL-1β-mediated inflammation with canakinumab has been shown to improve acute phase responses in patients with cryptopyrin-associated periodic syndrome (CAPS) and rheumatoid arthritis in reducing levels of high-sensitivity C-reactive protein (hsCRP) and other inflammatory markers. This evidence has also been demonstrated in patients with type 2 diabetes mellitus (T2DM) using canakinumab and other IL-1β antibody therapies under development, although the reduction in hsCRP levels in T2DM did not translate into greater efficacy than standard therapy. IL-1β inhibition over a longer period of time, thereby inhibiting major inflammatory pathways, will have unpredictable effects that may or may not be beneficial, and large, randomized, placebo-controlled clinical trials monitoring multiple parameters are needed.

[0052] The inventors have now found that treatment with canakinumab significantly reduces the risk of osteoarthritis, related conditions and side effects. Proinflammatory cytokines are important mediators of metabolic disorders and enhanced catabolism in joint tissues involved in OA. Although IL-15, IL-17, IL-18, IL-21, leukemia inhibitory factor (LIF) and chemokines are also involved, IL-1β, TNF and IL-6 appear to be the main proinflammatory and pro-catalytic cytokines driving the inflammatory cascade in OA. IL-1β and TNF are produced by chondrocytes, monocytes, osteoblasts and synovial tissue. IL-1β activation of cells is mediated only by binding to its specific cell surface receptor IL-1RI. The levels of IL-1β and TNF in synovial fluid, synovium, subchondral bone and cartilage are all increased. In addition, IL-1β and TNF can act independently or in concert with other cytokines to induce and propagate inflammation. IL-1β upregulates pro-nociceptive mediators (i.e., NGF), leading to increased pain. In addition, IL-1β and TNF stimulate chondrocytes to release several proteolytic enzymes: MMPs: MMP1 (interstitial collagenase), MMP3 (matrilysin 1), and MMP13 (collagenase 3).

[0053] In one embodiment, any of the methods of the invention comprise administering about 50, 150, 175, 200, 225, 250, 275, 300 mg, or any combination thereof, of canakinumab.

[0054] One embodiment of any of the methods of the invention comprises administering 150 mg of canakinumab or 300 mg of canakinumab. Another embodiment of any of the methods of the invention comprises administering 150 mg of canakinumab. Yet another embodiment comprises administering 225 mg of canakinumab. In other embodiments, 50 or 200 mg of canakinumab is administered.

[0055] In one embodiment of any of the methods of the invention, the reduced hsCRP level assessed approximately 3 months after the first administration of canakinumab is <1.9, <1.8, <1.7, <1.6, <1.5, <1.4, <1.3, <1.2, <1.1, <1.0, <0.9, <0.8, <0.7, <0.6, or <0.5 mg / L. In one embodiment, the reduced hsCRP level assessed approximately 3 months after the first administration of canakinumab is <1.0 mg / L. In another embodiment, the reduced hsCRP level assessed approximately 3 months after the first administration of canakinumab is <2 mg / L. In yet another embodiment, the reduced hsCRP level is less than or equal to 3 mg / L.

[0056] In another aspect of any of the methods disclosed herein, an initial dose of 150 mg of canakinumab is administered to an already ill patient and results in a response, i.e., a decrease in the patient's hsCRP level. However, the reduced hsCRP level assessed at least three months after the first administration of canakinumab is not less than 2 mg / L, and treatment of the patient is not stopped, but further initial doses of canakinumab are administered. If the hsCRP level assessed at least 3 months after the further initial dose is less than 2 mg / L, the patient will continue treatment and receive subsequent doses of 150 mg or preferably 300 mg canakinumab approximately every 3 months.

[0057] In another aspect of any method disclosed herein, after an initial dose of canakinumab (e.g., 50 mg, 150 mg, 200 mg, 225 mg, or 300 mg), a predetermined time point (preferably 3 months from the initial dose) is followed by measuring the level of a relevant biomarker (e.g., IL-6 or hsCRP). Thereafter, the biomarker is measured again after a second predetermined time point (preferably 6 months from the initial dose). A second dose (e.g., 50 mg, 150 mg, 200 mg, 225 mg, or 300 mg) of canakinumab may then be administered to the patient in response to the measured biomarker levels.

[0058] In one embodiment, the methods of the present invention optionally further comprise administering to the patient an additional dose of 300 mg of canakinumab approximately two weeks (+ / - 3 days) after the first administration of canakinumab.

[0059] Canakinumab can be administered subcutaneously or intravenously. Canakinumab can be administered as 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 as 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.

[0060] Canakinumab can also be administered in the form of a liquid formulation comprising canakinumab at a concentration of 50-300 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, and wherein the pH of the formulation is 5.5-7.0. Canakinumab can also be administered in the form of a liquid formulation comprising canakinumab at a concentration of 50-300 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 as a liquid formulation comprising canakinumab at a concentration of 50-300 mg / ml, 270 mM mannitol, 20 mM histidine, and 0.04% polysorbate 20 or 80, wherein the pH of the formulation is 6.5.

[0061] When administered subcutaneously, canakinumab can be administered to the patient in liquid form prefilled in a syringe, autoinjector, or in lyophilized form for reconstitution.

[0062] In other embodiments of any of the methods according to the invention, biomarkers other than hsCRP, such as IL-6, may be used to determine the response to canakinumab.

[0063] Other embodiments of the invention include the use of canakinumab according to any of the uses or methods described herein.

[0064] Summary:

[0065] All patents, published patent applications, publications, references, and other materials mentioned herein are incorporated by reference in their entirety.

[0066] As used herein, the term "comprising" encompasses "including" as well as "consisting", for example, a composition "comprising" X may consist of X only, or may include something else, such as X+Y.

[0067] As used herein, the term "administering" with respect to a compound, such as canakinumab or a standard of care agent, is used to refer to delivery of the compound by any route of delivery.

[0068] As used herein, the term "about" in relation to a numerical value x means, for example, + / - 10%.

[0069] As used herein, the word "substantially" does not exclude "completely", for example, a composition "substantially free of" Y may be completely free of Y. If necessary, the word "substantially" may be omitted from the definitions of the present disclosure.

[0070] As used herein, in one embodiment, the term "3 months" includes a period of one week before and one week after 3 months (3 months + / - 1 week). In another embodiment, the term "about 3 months" includes a period of 90 days + / - 15 days or 90 days + / - 10 days.

[0071] As used herein, the term "biomarker" generally refers to a molecule (i.e., a gene (or nucleic acid encoding the gene), a protein) whose expression in a biological sample from a patient can be detected by standard methods in the art, and which is predictive or indicative of the condition of the patient obtained therefrom. According to the present invention, exemplary biomarkers include, but are not limited to, hsCRP and IL-6.

[0072] As used herein, the term "determination" is used to refer to the act of detecting, identifying, screening or determining, which can be performed by any conventional means. For example, the presence of a specific marker in a sample can be determined by detecting the presence of the marker in the sample using ELISA assays, Northern blotting, imaging, etc.

[0073] As used herein, the term "C-reactive protein" and "CRP" refer to serum C-reactive protein, which is used as an indicator of acute phase response of inflammation. As used herein, the term "hsCRP" refers to the CRP level in the blood measured by a high-sensitivity CRP test. The CRP or hsCRP levels in plasma can be given at any concentration, such as mg / dl, mg / L, nmol / L. CRP or hsCRP levels can be measured by a variety of known methods, such as radial immune diffusion, electroimmunoassay, immunoturbidimetry, ELISA, turbidimetry, fluorescence polarization immunoassay and laser turbidimetry. CRP test can be tested using standard CRP test or high-sensitivity CRP (hsCRP) test (i.e., a high-sensitivity test that can measure low levels of CRP in a sample, such as using laser turbidimetry). Kits for detecting CRP or hsCRP levels can be purchased from various companies, such as Calbiotech, Cayman Chemical, Roche Diagnostics Corporation, Abazyme, DADE Behring, Abnova Corporation, Aniara Corporation, Bio-Quant Inc., Siemens Healthcare Diagnostics, etc.

[0074] As used herein, the terms "patient" or "subject" are used interchangeably herein.

[0075] Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0076] As used herein, the terms "osteoarthritis" and "osteoarthrosis" are used interchangeably and encompass a variety of conditions, such as spinal OA, related spinal degenerative diseases, and upper and lower extremity OA. Non-limiting examples are included in the following table:

[0077] Table 1: Non-limiting list of OA types

[0078]

[0079]

[0080]

[0081] As used herein, canakinumab is defined under INN number 8836 and has the following sequence:

[0082] Light chain

[0083]

[0084] Heavy Chain:

[0085]

[0086] As used herein, an antibody refers to an antibody having the natural biological form of an antibody. This antibody is a glycoprotein composed of four polypeptides (two identical heavy chains and two identical light chains) connected to form a "Y" shaped molecule. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region consists of three or four constant domains (CH1, CH2, CH3 and CH4, depending on the antibody species or isotype). Each light chain consists of a light chain variable region (VL) and a light chain constant region CL with one domain. Papain (a proteolytic enzyme) splits the "Y" shape into three independent molecules, two of which are called "Fab" fragments (Fab = fragment antigen binding) and the other is called "Fc" fragment (Fc = crystallizable fragment). The Fab fragment consists of the entire light chain and part of the heavy chain. The VL and VH regions are located at the ends of the "Y" shaped antibody molecule. VL and VH each have three complementary determining regions (CDRs).

[0087] "IL-1β binding antibody" refers to any antibody that can specifically bind to IL-1β and thereby inhibit or modulate the binding of IL-1β to its receptor and thereby inhibit the function of IL-1β. Preferably, the IL-1β binding antibody does not bind to IL-1α.

[0088] Preferably, the IL-1β binding antibody comprises:

[0089] (1) an antibody comprising three VL CDRs having the amino acid sequences RASQSIGSSLH (SEQ ID NO: 1), ASQSFS (SEQ ID NO: 2), and HQSSSLP (SEQ ID NO: 3) and three VH CDRs having the amino acid sequences VYGMN (SEQ ID NO: 5), IIWYDGDNQYYADSVKG (SEQ ID NO: 6), and DLRTGP (SEQ ID NO: 7);

[0090] (2) an antibody comprising three VL CDRs having the amino acid sequences RASQDISNYLS (SEQ ID NO: 9), YTSKLHS (SEQ ID NO: 10), and LQGKMLPWT (SEQ ID NO: 11) and three VH CDRs having the amino acid sequences TSGMGVG (SEQ ID NO: 13), HIWWDGDESYNPSLK (SEQ ID NO: 14), and NRYDPPWFVD (SEQ ID NO: 15); and

[0091] (3) An antibody comprising the six CDRs described in (1) or (2), wherein one or more CDR sequences, preferably at most two CDRs, and preferably only one CDR, differ from the corresponding sequences described in (1) or (2) by one amino acid, respectively.

[0092] Preferably, the IL-1β binding antibody comprises:

[0093] (1) an antibody comprising three VL CDRs having the amino acid sequences RASQSIGSSLH (SEQ ID NO: 1), ASQSFS (SEQ ID NO: 2) and HQSSSLP (SEQ ID NO: 3) and comprising a VH having the amino acid sequence shown in SEQ ID NO: 8;

[0094] (2) an antibody comprising a VL having the amino acid sequence shown in SEQ ID NO: 4 and comprising three VH CDRs having the amino acid sequences VYGMN (SEQ ID NO: 5), IIWYDGDNQYYADSVKG (SEQ ID NO: 6), and DLRTGP (SEQ ID NO: 7);

[0095] (3) an antibody comprising three VL CDRs having the amino acid sequences RASQDISNYLS (SEQ ID NO: 9), YTSKLHS (SEQ ID NO: 10), and LQGKMLPWT (SEQ ID NO: 11) and comprising a VH having the amino acids set forth in SEQ ID NO: 16;

[0096] (4) an antibody comprising a VL having the amino acids shown in SEQ ID NO: 12 and comprising three VH CDRs having the amino acid sequences TSGMGVG (SEQ ID NO: 13), HIWWDGDESYNPSLK (SEQ ID NO: 14), and NRYDPPWFVD (SEQ ID NO: 15);

[0097] (5) An antibody comprising the three VL CDR and VH sequences described in (1) or (3), wherein one or more VL CDR sequences, preferably at most two CDRs, preferably only one CDR, differ from the corresponding sequences described in (1) or (3) by one amino acid, respectively, and wherein the VH sequence is at least 90% identical to the corresponding sequences described in (1) or (3), respectively; and

[0098] (6) An antibody comprising a VL sequence and three VH CDRs as described in (2) or (4), wherein the VL sequence is at least 90% identical to the corresponding sequence described in (2) or (4), respectively, and wherein one or more VH CDR sequences, preferably at most two CDRs, preferably only one CDR, differ from the corresponding sequence described in (2) or (4) by one amino acid, respectively.

[0099] Preferably, the IL-1β binding antibody comprises:

[0100] (1) an antibody comprising a VL having an amino acid sequence as shown in SEQ ID NO: 4 and a VH having an amino acid sequence as shown in SEQ ID NO: 8;

[0101] (2) an antibody comprising a VL having the amino acids shown in SEQ ID NO: 12 and comprising a VH having the amino acid sequence shown in SEQ ID NO: 16; and

[0102] (3) The antibody described in (1) or (2), wherein the constant region of the heavy chain, the constant region of the light chain, or both has been changed to a different isotype compared to canakinumab or gevogelizumab.

[0103] Preferably, the IL-1β binding antibody comprises canakinumab (SEQ ID NOs: 17 and 18).

[0104] The IL-1β binding antibody as defined above has a CDR sequence that is substantially identical or identical to that of canakinumab. Thus, it binds to the same epitope on IL-1β and has a similar binding affinity as canakinumab or gevorgizumab. Clinically relevant doses and dosing regimens that have been established for canakinumab that have therapeutic effects in treating OA will be applicable to other IL-1β binding antibodies.

[0105] Additionally or alternatively, an IL-1β antibody refers to an antibody that can specifically bind to IL-1β with an affinity similar to that of canakinumab. The Kd reference for canakinumab in WO 2007 / 050607 is 30.5 pM. Therefore, an affinity in a similar range refers to about 0.05 pM to 300 pM, preferably 0.1 pM to 100 pM. It will not prevent IL-1β from binding to the receptor, but will prevent receptor activation. Preferably, the IL-1β antibody has a binding affinity in a similar range to canakinumab, preferably in the range of 1 pM to 300 pM, preferably in the range of 10 pM to 100 pM, wherein preferably, the antibody directly inhibits binding.

[0106] As used herein, the term "functional fragment" of an antibody refers to a portion or fragment of an antibody that retains the ability to specifically bind to an antigen (e.g., IL-1β). Examples of binding fragments encompassed within the term "functional fragment" of an antibody include single-chain Fv (scFv), Fab fragments, which are composed of V L 、V H A monovalent fragment consisting of the V, CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge at the hinge region; and a Fd fragment, which consists of the V H and CH1 domains; Fv fragment, which consists of the V L and V H domain composition; dAb fragment (Ward et al., 1989), which consists of V H domain composition; and isolated complementarity determining regions (CDRs); and one or more CDRs arranged on a peptide scaffold that may be smaller, larger, or folded differently than a typical antibody.

[0107] The term "functional fragment" may also refer to one of the following:

[0108] Bispecific single-chain Fv dimer (PCT / US 92 / 09965)

[0109] "Diabodies" or "triabodies" constructed by gene fusion, multivalent or multispecific fragments (Tomlinson I & Hollinger P (2000) Methods Enzymol [Enzyme Methods]. 326: 461-79; WO 94113804; Holliger P et al., (1993) Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences of the United States of America], 90: 6444-48)

[0110] Genetic fusion of scFv to the same or different antibodies (Coloma MJ and Morrison SL (1997) Nature Biotechnology, 15(2):159-163)

[0111] scFv, diabodies or domain antibodies fused to Fc region

[0112] scFv fused to the same or different antibody

[0113] • Fv, scFv or diabody molecules can be stabilized by incorporating disulfide bridges linking the VH and VL domains (Reiter, Y. et al., (1996) Nature Biotech, 14, 1239-1245).

[0114] • Small antibodies comprising a scFv linked to a CH3 domain can also be prepared (Hu, S. et al., (1996) Cancer Res., 56, 3055-3061).

[0115] Other examples of binding fragments are Fab' (which differs from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region), and Fab'-SH (which is a Fab' fragment in which one or more cysteine ​​residues of the constant domains bear a free thiol group).

[0116] Typically and preferably, a functional fragment of an IL-1 β binding antibody is a part or fragment of an "IL-1 β binding antibody" as defined above.

[0117] This application also provides the following embodiments 1-34.

[0118] 1. A method for reducing the risk of progression of osteoarthritis ("OA") and / or reducing adverse events associated with OA in a patient, the method comprising administering an IL-1β antagonist, wherein the patient has a high sensitivity C-reactive protein (hsCRP) level of ≥2 mg / L as assessed prior to the first administration of the IL-1β antagonist, and wherein the patient has a reduced hsCRP level of <2.3 mg / L as assessed at a predetermined time point after the first administration of the IL-1β antagonist.

[0119] 2. A method for reducing the risk of progression of OA and / or reducing adverse events associated with OA in a patient, the method comprising administering an IL-1β antagonist, wherein the patient is assessed to have a high sensitivity C-reactive protein (hsCRP) level of ≥2 mg / L prior to the first administration of the IL-1β antagonist, and wherein if the patient is assessed to have a reduced hsCRP level of <2.3 mg / L at a predetermined time point after the first administration of the IL-1β antagonist, the patient will continue to receive the IL-1β antagonist.

[0120] 3. A method for reducing the risk of progression of OA and / or reducing adverse events associated with OA in a patient, the method comprising administering canakinumab, wherein the patient is assessed to have a high-sensitivity C-reactive protein (hsCRP) level ≥2 mg / L prior to the first administration of canakinumab, and wherein the patient is assessed to have a reduced hsCRP level of <2.3 mg / L about 3 months or more after the first administration of canakinumab.

[0121] 4. A method for reducing the risk of progression of OA and / or reducing adverse events in a patient, the method comprising administering canakinumab, wherein the patient is assessed to have a high-sensitivity C-reactive protein (hsCRP) level ≥2 mg / L prior to the first dose of canakinumab, and wherein if the patient is assessed to have a reduced hsCRP level of <2.3 mg / L about 3 months or more after the first administration of canakinumab, the patient will continue to receive canakinumab.

[0122] 5. The method according to any of the preceding embodiments, wherein the progression of OA comprises joint replacement.

[0123] 6. The method according to any one of the preceding embodiments, wherein the patient suffers from documented and / or symptomatic OA.

[0124] 7. The method according to any one of the preceding embodiments, comprising administering 150 mg to 300 mg of canakinumab.

[0125] 8. The method according to any one of the preceding embodiments, comprising administering 150 mg of canakinumab.

[0126] 9. The method according to any one of the preceding embodiments, comprising administering 150 mg of canakinumab approximately every 3 months.

[0127] 10. The method according to any of the preceding embodiments, wherein the reduced hsCRP level assessed at about 3 months after the first administration of canakinumab or at a predetermined time point after the first administration of the IL-1β antagonist is <1.5 mg / L.

[0128] 11. The method according to any of the preceding embodiments, wherein the reduced hsCRP level assessed at about 3 months after the first administration of canakinumab or at a predetermined time point after the first administration of the IL-1β antagonist is <1.0 mg / L.

[0129] 12. A method according to any of the preceding embodiments, wherein the reduced hsCRP level assessed at a predetermined time point about 3 months after the first administration of canakinumab or after the first administration of an IL-1β antagonist is <2.2, <2.1, <2.0, <1.9, <1.8, <1.7, <1.6, <1.5, <1.4, <1.3, <1.2, <1.1, <1.0, <0.9, <0.8, <0.7, <0.6 or <0.5 mg / L.

[0130] 13. The method according to any one of the preceding embodiments, wherein the documented OA has been assessed using X-ray and / or MRI.

[0131] 14. The method according to any one of the preceding embodiments, wherein the symptomatic evidence of OA is pain and / or impaired function.

[0132] 15. A method according to any of the preceding embodiments, wherein the patient is not eligible for surgery.

[0133] 16. The method according to any one of the preceding embodiments, wherein the patient is unresponsive to NSAIDs.

[0134] 17. The method according to any of the preceding embodiments, wherein the level of IL-6 is below 1.15 mg / L or below 2 mg / L at a predetermined time point after the first administration of the IL-1β antagonist or after 3 months after the first administration of canakinumab.

[0135] 18. The method according to any one of the preceding embodiments, wherein the patient has previously experienced a CV event.

[0136] 19. The method according to any one of the preceding embodiments, wherein the patient has previously experienced a myocardial infarction.

[0137] 20. A method for reducing the risk of progression of OA and / or reducing adverse events associated with OA in a patient, the method comprising administering an IL-1β antagonist, wherein the patient is assessed to have a high sensitivity C-reactive protein (hsCRP) level of ≥2 mg / L prior to the first administration of the IL-1β antagonist.

[0138] 21. The method of embodiment 20, wherein the IL-1β antagonist is canakinumab.

[0139] 22. The method of embodiment 20 or 21, comprising administering 150 mg to 300 mg of canakinumab.

[0140] 23. The method of any one of embodiments 20-22, comprising administering 150 mg to 300 mg of canakinumab approximately every 3 months.

[0141] 24. The method of any one of embodiments 20-23, wherein the documented OA has been assessed using X-ray and / or MRI.

[0142] 25. The method of any one of embodiments 20-24, wherein the symptomatic evidence of OA is pain and / or impaired function.

[0143] 26. A method according to any one of embodiments 20-25, wherein the patient is not eligible for surgery.

[0144] 27. The method of any one of embodiments 20-26, wherein the patient is unresponsive to NSAIDs.

[0145] 28. A method according to any one of embodiments 20-27, wherein the patient has previously experienced a CV event.

[0146] 29. A method according to any one of embodiments 20-28, wherein the patient has previously experienced a myocardial infarction.

[0147] 30. The method according to any one of the preceding embodiments, wherein the total joint replacement can be a total knee replacement or a total hip replacement.

[0148] 31. The method according to any one of the preceding embodiments, wherein the patient suffers from shoulder OA, hand OA, or spondyloarthropathies (degenerative spondyloarthropathies).

[0149] 32. The method according to any one of the preceding embodiments, wherein the total joint replacement can be a total shoulder replacement.

[0150] 33. The method of any one of embodiments 1, 2, and 7-9, wherein the predetermined time point is 2 weeks to up to 6 months.

[0151] 34. The method of any one of embodiments 1, 2, and 7-9, wherein the predetermined time point is 4 to 12 weeks.

[0152] Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

[0153] The following examples illustrate the above invention; however, these examples are not intended to limit the scope of the invention in any way.

[0154] Example 1: CANTOS trial

[0155] Data generated from the CANTOS trial are disclosed in WO 2013 / 049278, the entire contents of which are hereby incorporated by reference. CANTOS is a randomized, double-blind, placebo-controlled, event-driven trial designed to evaluate whether quarterly subcutaneous administration of canakinumab can prevent recurrence of cardiovascular events in stable post-myocardial infarction patients with elevated hsCRP. The 10,061 patients with myocardial infarction and inflammatory atherosclerosis recruited had high-sensitivity C-reactive protein (hsCRP) ≥ 2 mg / L. Three ascending doses of canakinumab (50 mg, 150 mg, and 300 mg administered subcutaneously every 3 months) were compared with placebo.

[0156] The following details the setup and results of the CANTOS trial, which is identified as NTC01327846, the contents of which are hereby incorporated by reference in their entirety.

[0157] A randomized, double-blind, placebo-controlled, event-driven trial of quarterly subcutaneous canakinumab to prevent recurrent cardiovascular events in stable post-myocardial infarction patients with elevated hsCRP.

[0158] This study was designed as a multicenter, randomized, parallel-group, placebo-controlled, double-blind, event-driven trial to provide definitive evidence on the effects of canakinumab on adverse cardiovascular events in patients with recent MI and elevated inflammatory burden as evidenced by elevated hsCRP. This study design is the most powerful clinical trial design to test the hypothesis that anti-inflammatory treatment with canakinumab reduces major adverse cardiovascular events.

[0159] Rationale for the study design

[0160] Trial population. Patients were eligible if they had a history of previous myocardial infarction and had a blood hsCRP level ≥2 mg / L despite the use of an aggressive secondary prevention strategy. The trial excluded from recruitment patients with a history of chronic or recurrent infection, previous malignancy other than basal cell skin cancer, suspected or known immunocompromise, a history of or high risk for tuberculosis or HIV-related disease, or ongoing use of other systemic anti-inflammatory treatments.

[0161] Inclusion criteria

[0162] Patients eligible for inclusion in this study must meet all of the following criteria:

[0163] 1. Provide written informed consent before any assessment is performed.

[0164] 2. Male or female with non-child-bearing potential

[0165] 3. Aged ≥ 18 years at the first visit.

[0166] 4. Spontaneous MI (diagnosed according to universal MI criteria, with or without evidence of ST-segment elevation) documented at least 30 days prior to randomization.

[0167] A diagnosis of MI is based on a history of clinical symptoms consistent with myocardial ischemia, accompanied by an elevation of a cardiac biomarker (preferably troponin) above the 99th percentile of the upper reference limit or the presence of new pathological Q waves (regardless of symptoms). See the Common Definition of MI for details.

[0168] a. Acute MI (hospital record): requires documentation of an increase and / or decrease in cardiac biomarkers (preferably troponin) with at least one value above the 99th percentile of the upper reference limit (URL) or above the MI diagnostic criteria, with evidence of myocardial ischemia demonstrated by at least one of the following:

[0169] i. Symptoms of ischemia

[0170] ii. ECG changes suggestive of new ischemia (new ST-T changes or new LBBB)

[0171] iii. The appearance of pathological Q waves

[0172] iv. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormalities

[0173] b. Previous MI (no acute event hospital records available): Requires documentation of any of the following:

[0174] i. The presence of pathological Q waves, with or without symptoms

[0175] ii. Radiographic evidence of loss of viable myocardial areas that are thin and noncontractile in the absence of a nonischemic cause

[0176] iii. Pathological findings of healed or healing MI

[0177] Patients with MI due to PCI or CABG are not eligible

[0178] 5. Have hsCRP ≥ 2 mg / L (collected within 60 days prior to the second follow-up visit and performed in a central laboratory, which is at least 28 days after a qualifying MI or any PCI performed separately from a qualifying MI) and are stable (at least 4 weeks) on long-term (cardiovascular) medication (standard of care).

[0179] Randomization. Patients were initially randomized in a 1:1:1 ratio to canakinumab 150 mg, canakinumab 300 mg, or placebo. After 741 participants were enrolled, the 50-mg dose group was added in response to regulatory requirements, and the randomization ratio was adjusted accordingly; we aimed to achieve a final randomization ratio of 1.5:1:1:1. All study drug doses and placebo were administered subcutaneously every 3 months; for the 300-mg dose, the treatment regimen was 300 mg every 2 weeks for the first two doses and then every 3 months. Randomization was performed with the use of a central computer system, with stratification by time since the index myocardial infarction and by trial part (before vs. after enrollment of the 50-mg dose).

[0180] Endpoints. The primary efficacy endpoint was time to first nonfatal myocardial infarction, to any nonfatal stroke, or to cardiovascular death. The trial had two key secondary efficacy endpoints. The first key secondary endpoint included components of the primary endpoint plus hospitalization for unstable angina requiring urgent revascularization. The other two prespecified secondary endpoints were all-cause mortality and a composite of nonfatal myocardial infarction, any nonfatal stroke, or all-cause mortality. All components of these endpoints were reviewed by an Endpoint Review Committee, whose members were masked to study drug assignment.

[0181] Statistical Analysis. The distribution of percentage changes from baseline in hsCRP and lipid levels was compared between the placebo group and each canakinumab group at intervals up to 48 months. Similar comparisons were made for IL-6 at up to 12 months. Prespecified primary and key secondary cardiovascular outcomes were analyzed at trial follow-up according to the intention-to-treat principle with the use of log-rank tests and Cox proportional hazards models, stratified by time since index myocardial infarction and trial part. Formal assessment of significance for individual doses (adjusted for multiplicity) followed a closed testing procedure. Based on the closed testing procedure, and using prespecified alpha configuration errors, the two-sided P value thresholds for statistical significance were 0.01058 for the primary endpoint of the 300-mg dose of canakinumab versus placebo and 0.02115 for the primary endpoint of the other two doses versus placebo. The closed testing procedure also specified that formal significance testing for key secondary endpoints was performed for any given dose only if the primary endpoint for that dose reached the significance threshold.

[0182] Although the primary analysis strategy was based on pairwise comparisons of individual dose groups with placebo, the incidence in the placebo group was compared with the incidence of ascending doses of canakinumab (using dose-proportional trend analysis with scores of 0, 1, 3, and 6), as well as the combined active canakinumab treatment group with placebo. In addition, treatment analyses and follow-up were performed for each censored patient up to 119 days after the last study injection. The significance thresholds for these tests were not adjusted for multiplicity. Similar analyses were used for adverse events. All P values ​​were two-sided, and all confidence intervals were calculated at the 95% level.

[0183] Patients. Trial recruitment began in April 2011 and was completed in March 2014; the last trial follow-up was in June 2017. Of 17 482 post-infarction patients screened at the central laboratory, 10 061 (57.6%) were appropriately randomized and received at least one dose of the trial drug. The most common reasons for exclusion were hsCRP less than 2 mg / L (46% of excluded subjects), active tuberculosis or tuberculosis risk factors (25.4%), and exclusive comorbid disorders (9.9%).

[0184] The mean age of randomized participants was 61 years, 26% were women, and 40% had diabetes. Most participants had undergone a prior revascularization procedure (percutaneous coronary intervention 67%, coronary artery bypass graft surgery 14%). At baseline, 95% were taking antithrombotic therapy, 93% were taking lipid-lowering therapy, 91% were taking antiischemic medications, and 79% were taking renin-angiotensin system inhibitors. At entry, the median hsCRP was 4.2 mg / L, and the median LDL cholesterol was 82 mg / dL.

[0185] Effects on inflammatory biomarkers and lipid levels. At 48 months, hsCRP was reduced by 26%, 37%, and 41% in the canakinumab 50 mg, 150 mg, and 300 mg groups, respectively, compared with placebo (p values ​​< 0.001 for both comparisons of median percentage change with canakinumab and median percentage change with placebo). Similar effects were observed for IL-6 (measured up to 12 months). In contrast, use of canakinumab did not reduce LDL cholesterol or HDL cholesterol, and the median increase in triglycerides was 4% to 5%.

[0186] Clinical endpoint follow-up and effects: At the end of follow-up, 18.1% of patients in the placebo group discontinued the study drug, compared with 18.7% of patients in the combined canakinumab group. At a median follow-up of 3.7 years, the incidence of the primary endpoint (including non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death) was 4.50, 4.11, 3.86, and 3.90 per 100 person-years in the placebo, 50 mg, 150 mg, and 300 mg groups, respectively. No significant effect was observed on the primary endpoint in the canakinumab 50 mg dose group compared with placebo (hazard ratio [HR] 0.93, P = 0.30). In contrast, a statistically significant effect on the primary endpoint was observed in the canakinumab 150 mg dose group (HR 0.85, P = 0.02075, threshold P value 0.02115). In the canakinumab 300 mg dose group, the hazard ratio was similar, but the P value did not reach the pre-specified significance threshold (HR 0.86, P = 0.0314, threshold P value 0.01058). The trend P value was 0.020 for the active dose group compared with the placebo group, and the P value for the full-dose combination group compared with the placebo group was 0.015 (neither result was adjusted for multiple testing). In addition, compared with the overall treatment population, the subgroup of patients with a greater reduction in hsCRP levels after 3 months of treatment with canakinumab showed a statistically significant greater risk reduction in MACE. Based on a causal inference analysis assuming an exponential survival distribution, based on 500 bootstrap samples evaluated, patients who received 150 mg and 300 mg of canakinumab, respectively, and responded with a reduction in hsCRP levels to <1.8 mg / L, showed a relative risk reduction of 24% and 22%, respectively, for MACE. Based on causal inference analysis assuming an exponential survival distribution, patients who responded with a reduction in hsCRP levels to <1.5 mg / L showed a 26% and 27% relative risk reduction in MACE, respectively, for patients who received 150 mg and 300 mg of canakinumab, respectively.

[0187] For the key secondary cardiovascular end point (which included components of the primary end point and hospitalization for unstable angina requiring urgent revascularization), the incidence rates were 5.13, 4.56, 4.29, and 4.25 per 100 person-years in the placebo, 50-mg, 150-mg, and 300-mg groups, respectively (Table 2). For the 150-mg dose of canakinumab, which met the significance threshold for the primary end point, the hazard ratio for the secondary cardiovascular end point was 0.83 (P = 0.00525, with a threshold P value of 0.00529). No formal significance testing for the prespecified secondary end points was performed for the 50-mg and 300-mg doses, according to closed-test procedures. The hazard ratios for these doses were 0.90 and 0.83, respectively. The P value for trend was 0.003 for the active dose group compared with the placebo group and 0.001 for all combined dose groups compared with the placebo group (neither result was adjusted for multiple testing).

[0188] No adjustments were made for multiple testing for the analyses of additional secondary endpoints and for the combination of primary and secondary endpoints. Nominally, canakinumab resulted in significantly fewer myocardial infarctions at the 150 mg dose; hospitalizations for unstable angina requiring urgent revascularization at doses of 150 mg and 300 mg; and coronary revascularization at all three doses. All-cause mortality was neutral in the comparison of all canakinumab doses with placebo (HR 0.94, 95% CI 0.83-1.06, P=0.31). In the on-treatment analysis of the primary endpoint, hazard ratios of 1.0, 0.90, 0.83, and 0.79 were observed for the placebo, 50 mg, 150 mg, and 300 mg groups, respectively (P trend = 0.003 between groups). In the comparative analysis of the key secondary cardiovascular endpoints, the corresponding hazard ratios were 1.0, 0.88, 0.80, and 0.77 (P trend < 0.001 between groups).

[0189] Adverse Events and Other Clinical Outcomes. Neutropenia was more common in patients receiving canakinumab, and fatal events due to infection or sepsis were statistically significantly increased when the three canakinumab groups were combined and compared with placebo (incidence rate, 0.31 vs. 0.18 per 100 person-years, P = 0.023). Participants who died from infection tended to be older and were more likely to have diabetes. Six confirmed cases of tuberculosis occurred in the trial, with similar incidences in the canakinumab and placebo groups (0.06%); five occurred in India and one in Taiwan, China.

[0190] Thrombocytopenia was more common in patients taking canakinumab, but no differences were observed in bleeding. No increase in injection site reactions was observed. Consistent with the known effects of IL-1β inhibition, canakinumab resulted in a significant reduction in reports of arthritis, gout, and osteoarthritis (discussed in detail in Example 2). Canakinumab also significantly reduced cancer mortality.

[0191] CANTOS was designed to directly test the inflammatory hypothesis of atherothrombosis. In this trial, canakinumab significantly reduced hsCRP and IL-6 levels but not lipid levels in patients with a history of myocardial infarction. Although the 50-mg dose of canakinumab did not have a statistically significant effect on the primary cardiovascular end point, participants in the 150-mg dose group had a relative risk reduction 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) compared with placebo. The P values ​​for both end points met the prespecified thresholds for statistical significance after multiplicity adjustment. Although the risk reduction in the 300-mg dose group was similar to that in the 150-mg dose group, this group did not meet the prespecified threshold for statistical significance. However, pooled analyses of all canakinumab doses and trend analyses showed a beneficial effect of canakinumab on cardiovascular outcomes. The specificity of IL-1β as a cytokine-based therapy for secondary prevention of atherosclerotic events relies on multiple observations. The proinflammatory cytokine IL-1β plays multiple roles in atherosclerotic plaque formation, including induction of procoagulant activity, promotion of monocyte and leukocyte adhesion to vascular endothelial cells, and growth of vascular smooth muscle cells. In mice, IL-1β deficiency reduces lesion formation, whereas in cholesterol-fed pigs, exposure to exogenous IL-1β results in medial intimal thickening. The Nod-like receptor protein 3 (NLRP3) inflammasome activates IL-1β, a process that is promoted by cholesterol crystals, neutrophil extracellular blockade, local hypoxia, and atherogenic flow. This activation of IL-1β stimulates downstream IL-6 receptor signaling pathways, which have been implicated as potential causal pathways for atherothrombosis by Mendelian randomization studies. Recently, studies in inter-ecological mice and clonal hematopoiesis have implicated IL-1β in the process of bone marrow activation that accelerates atherosclerosis. Furthermore, expression of a specific inflammasome gene module affecting IL-1β was associated with all-cause mortality and increased atherosclerosis in the elderly.

[0192] Although LDL cholesterol levels were generally well controlled in the patients in CANTOS, the placebo event rate was high, with a cumulative rate of more than 20% over 5 years. Thus, our data confirm that statin-treated patients with residual inflammatory risk, as measured by baseline hsCRP greater than 2 mg / L, have future event rates that are at least as high, if not higher, than statin-treated patients with residual risk due to LDL cholesterol. These two patient groups may differ and may require personalized treatment approaches. Despite the fact that no reduction in cholesterol levels occurred, the magnitude of the effect of canakinumab (given every 3 months) on cardiovascular events is comparable to that associated with monoclonal antibodies targeting PCSK9 (given every 2 to 4 weeks). However, inhibition of IL-1β is a narrowly defined intervention that represents only one of many potential anti-inflammatory pathways that could be targeted for atherosclerosis protection. We observed a statistically significant increase in fatal infections and sepsis and a decrease in platelet counts with canakinumab, without an increase in bleeding. In contrast, cancer mortality was significantly reduced in patients treated with canakinumab, a finding consistent with experimental data linking IL-1 to the progression and aggressiveness of certain tumors, particularly lung cancer. There was no significant difference in all-cause mortality between treatment groups. No significant hepatotoxicity was found. The beneficial effects of canakinumab on arthritis, gout, and osteoarthritis are consistent with the well-characterized role of the IL-1 and IL-6 pathways in these disorders. In summary, in CANTOS, patients with a history of myocardial infarction and an hsCRP level greater than or equal to 2 mg / L were randomized to one of three doses of canakinumab or placebo. Canakinumab significantly reduced hsCRP levels without reducing LDL cholesterol, HDL cholesterol, and triglycerides, and a dose of 150 mg significantly reduced the incidence of recurrent cardiovascular events with an acceptable level of side effects.

[0193] Example 2: Canakinumab Preventing hip and knee replacement (THR / TKR) in patients with OA: results from the Canakinumab Anti-Inflammatory Thrombotic Outcomes Study (CANTOS) study

[0194] Background / Purpose:

[0195] In OA, there are no therapies that can prevent disease progression (DMOAD). In the CANTOS study, canakinumab, a monoclonal antibody targeting interleukin-1β, reduced the incidence of inflammatory and cardiovascular events. A total of 10,061 men and women with a history of myocardial infarction and a high-sensitivity C-reactive protein level ≥2 mg / L were included in the CANTOS study and randomized to placebo or one of three doses (50 mg, 150 mg, or 300 mg) of canakinumab (administered subcutaneously every 3 months). The median follow-up was 3.7 years.

[0196] method:

[0197] Post hoc analyses of CANTOS data were conducted to address the effect of canakinumab on the incidence of OA-related adverse events (AEs) and serious adverse events (SAEs), as well as total knee replacement (TKR) and total hip replacement (THR) in all patients as well as those with a history of OA. The relationship between OA-related events and therapeutic concentrations of hsCRP and IL-6 was also investigated. Clinical databases were searched using the high-level term osteoarthropathy (OAP). Time-to-event analysis was performed for the first occurrence of an OAP-related AE. Drug treatment groups were compared with placebo by two-sided log-rank tests. Second, drug treatment groups were combined and time to OA-related AEs, SAEs, and TKR / THR were analyzed by Cox proportional hazards regression.

[0198] The analysis is shown in the following table:

[0199] Table 2: Distribution of all patients and subgroups of patients with history of osteoarthritis / no osteoarthritis / osteoarthritis / spinal osteoarthritis by treatment group (percentages represent percentages of the total treatment group (FAS dataset))

[0200]

[0201] CAN = canakinumab

[0202] As shown above, a total of 1569 (15.6%) patients had a history of OAP (N=1073 in the combined canakinumab group and N=496 in the placebo group). A total of 259 (16.5%) OA-related AEs, 82 (5.2%) SAEs, and 67 (4.3%) THR / TKRs occurred in OAP patients. In the total population, there were 52 THRs and 47 TKRs, equivalent to 0.98% of the total CANTOS population. 300 mg of canakinumab reduced hsCRP and IL-6 in a dose-responsive manner, resulting in a 46% reduction in hsCRP and IL-6 compared to the placebo group at 3 months. Table 3 lists the results of OA reduction and degenerative effects:

[0203] Table 3: Results of OA reduction and degenerative effects

[0204]

[0205]

[0206] in conclusion:

[0207] Treatment with canakinumab reduced the risk of worsening OA (AEs and SAEs) (“RRR”) and significantly reduced the risk of THR and TKR in patients with known pre-existing OA and in the entire CANTOS population, providing evidence for the DMOAD effect of canakinumab in this population. Canakinumab reduced OAP-related AEs and SAEs compared with placebo, regardless of the presence or absence of a history of OA. In the overall population during the double-blind period (median follow-up of 3.7 years), canakinumab reduced the risk of OAP-related AEs by 23% [95% CI; 9%-35%] compared with the placebo group, p=0.002. Figure 1 The time to first OAP-related AE by treatment is shown, which shows that 50 mg and 150 mg of canakinumab resulted in a significant reduction in AEs over time compared to the placebo group (p values ​​were 0.0033 and 0.0016, respectively). For the 300 mg canakinumab group, the p value was 0.0688.

[0208] The results are clear:

[0209] ■There were 123 OA-related SAEs in the database

[0210] ■ Total hip / knee replacement (THR / TKR) classification was determined between 2 TMEs, with 2 indeterminate cases determined as: one replacement and the other as “other” surgery

[0211] ■There were 52 THRs and 47 TKRs, equivalent to 0.98% of the total CANTOS population

[0212] Figure 1 and Figure 2 The results shown show surprising results. Figure 1 As shown in the table above, there was a clear dose-dependent time to first OA-related AE in patients. The time to first OA increased at the three doses of canakinumab tested: 50, 150, and 300 mg. As shown in the table above, the combined canakinumab and placebo groups had a significant 45% relative risk reduction in the development of hip or knee replacement in all patients and those with a history of OA. Figure 2The mean time to hip or knee replacement in patients with OA is shown. Canakinumab showed a significant improvement relative to placebo. Therefore, canakinumab is highly effective in reducing the risk of knee and hip replacements.

[0213] Example 3: OA-related AEs as a function of hsCRP levels

[0214] Figure 3 Figure 2 is a graphical representation of the risk of OA-related AEs in each group stratified by hsCRP concentration. For this table, a total of 259 (16.5%) OA-related AEs occurred in patients with a history of OA. Throughout the study period, patients were stratified based on hsCRP levels <1 mg or ≥1 mg and <2 mg or ≥2 mg at 3 months and their levels were correlated with OA-related AEs. It can be clearly seen from the figure that patients with lower hsCRP levels of 1 mg / L and 2 mg / L had higher responder rates, both when compared to patients with similar hsCRP levels in the placebo group and when compared to patients with any hsCRP level (no stratification).

[0215] Example 4: Total joint replacement as a function of hsCRP levels in patients with OA

[0216] Figure 4 The relationship between the total number of joint replacements and hsCRP levels in patients with a history of OA is shown. For this table, a total of 67 (4.3%) THR / TKR occurred in patients with a history of OA. Patients were stratified based on hsCRP levels <1mg or ≥1mg and <2mg or ≥2mg at 3 months throughout the study period and their levels were correlated with hip / knee replacement (TJR). The table clearly shows that patients with lower hsCRP levels of both 1mg / L and 2mg / L had higher response rates.

[0217] Example 5: Confirmatory OA Phase III Study

[0218] a. Goal

[0219] The goal of this study is to demonstrate that canakinumab can reduce structural progression of OA in patients with a high inflammatory burden (hsCRP levels ≥ 2 mg / L). Results from this study and CANTOS will be used to support registration of canakinumab for the treatment of patients with OA who have hsCRP ≥ 2 mg / L at the start of treatment.

[0220] b. Patient population

[0221] Adult patients diagnosed with osteoarthritis who meet the following criteria:

[0222] Key inclusion criteria

[0223] 1. Age ≥ 40 years old

[0224] 2. Weight > 35 or 40 kg, body mass index (BMI) < 40 kg / m 2 .

[0225] 3. Diagnosis of knee osteoarthritis based on the clinical and radiological criteria of the American College of Rheumatology.

[0226] 4. High sensitivity C-reactive protein (hsCRP) level ≥ 2 mg / L

[0227] 5. Knee pain has a history of at least 6 months and occupies most of the time (>50%) in the previous month.

[0228] 6. Symptom severity was defined by pain ≥40 mm and ≤90 mm on the VAS (100 mm).

[0229] 7. Symptomatic treatment of target knee OA with systemic nonsteroidal anti-inflammatory drugs (NSAIDs) and / or other analgesics for documented need for symptoms

[0230] 8.WPI<8

[0231] Key exclusion criteria

[0232] 1. Severe clinical knee dislocation as considered by the investigator.

[0233] 2. The knee prosthesis has been implanted (<1 year) or is poorly tolerated (contralateral side).

[0234] 3. Foresee implantation of knee prosthesis (either side) during the study period

[0235] 4. Recent implantation of hip prosthesis (<1 year) or anticipated implantation of hip prosthesis (either side) during the study period.

[0236] 5. Previous osteotomy of lower limb (either side).

[0237] 6. Surgery on the target knee joint within 12 months before the screening visit or planned during the study period.

[0238] 7. Arthroscopy of the target knee joint within 6 months before the screening visit or planned during the study period.

[0239] 8. Other pathologies affecting the knee joint.

[0240] 9. Any contraindications to MRI, including inability to perform knee MRI due to inability to fit into the scanner or knee coil. 10.

[0242] c. Dosage regimen

[0243] A dosing schedule of 150 mg sc of canakinumab every 3 months was selected based on the pharmacokinetic (PK) and pharmacodynamic (PD) properties of canakinumab, the safety, biomarker, and efficacy data observed in the CANTOS study, and safety data from completed and ongoing studies of canakinumab.

[0244] d. Sample size

[0245] Patients were randomized in a 1:1 ratio to one of the following two treatment groups:

[0246] Canakinumab 150 mg scq for 3 months

[0247] · Matched placebo scq 3 months

[0248] e. Duration of treatment

[0249] The study duration was 52 / 104 weeks

[0250] f. Primary endpoint

[0251] This phase III study was designed to demonstrate that canakinumab can reduce the structural progression of OA. The primary endpoint of the study was the change from baseline in cartilage thickness at week 52, assessed by quantitative MRI of the target knee central medial tibiofemoral compartment (cMTFC).

[0252] g. Secondary endpoints

[0253] 1. The proportion of OA structural progression was based on cartilage thickness assessed by quantitative MRI of the central medial tibiofemoral compartment (cMTFC) of the target knee at week 52.

[0254] 2. Change from baseline in the Western Universities and McMaster Universities Osteoarthritis Index (WOMAC) subscales for pain, function, and stiffness at Week 24 and Week 52.

[0255] 3. Change from baseline in pain in the target knee was measured at Weeks 24 and 52 using a 100-mm visual analog scale (VAS).

[0256] 4. At weeks 24 and 52, the change from baseline in the patient's global assessment of disease activity (PGA) was measured using a 100-mm visual analogue scale (VAS).

[0257] 5. Proportion of OMERACT-OARSI responders at Week 52.

[0258] Based on the OMERACT-OARSI protocol: Osteoarthritis Research Society International set of responder criteria for OA clinical trials revisited Pham et al., 2004. Responders were defined as patients with ≥50% improvement in pain or function and ≥20 absolute change or improvement in at least two of the following three items according to WOMAC and PGA:

[0259] Pain improvement ≥ 20% and absolute change ≥ 10

[0260] Functional improvement ≥ 20% and absolute change ≥ 10

[0261] Patient global assessment ≥20% and absolute change ≥10.

[0262] 6. Changes from baseline in cartilage thickness of the targeted central tibiofemoral compartment (tTFC) of the knee were assessed by quantitative MRI at week 52.

[0263] 7. At week 52, quantitative MRI was used to assess the change in bone area of ​​the medial femoral condyle surface of the target knee from baseline.

[0264] 8. At week 52, quantitative MRI was used to assess the change in bone area of ​​the medial femoral condyle surface of the target knee from baseline.

[0265] 9. Change from baseline in target knee joint space width (JSW) measured by X-ray at Week 52.

[0266] 10. Changes from baseline in SF36-PCS at Week 24 and Week 52.

[0267] 11. Change from baseline in SF36-MCS at Week 24 and Week 52.

[0268] 12. Changes of synovitis in MOAKS

[0269] 13. Pain: Analgesics were used throughout the study.

[0270] Although various specific embodiments have been illustrated and described below, it should be appreciated that various changes can be made without departing from the spirit and scope of the present disclosure.

Claims

1. A method for reducing the risk of progression of osteoarthritis ("OA") and / or reducing adverse events associated with OA in a patient, the method comprising administering an IL-1β antagonist, wherein the patient has a high sensitivity C-reactive protein (hsCRP) level of ≥2 mg / L as assessed prior to the first administration of the IL-1β antagonist, and wherein the patient has a reduced hsCRP level of <2.3 mg / L as assessed at a predetermined time point after the first administration of the IL-1β antagonist.

2. A method for reducing the risk of progression of OA and / or reducing adverse events associated with OA in a patient, the method comprising administering an IL-1β antagonist, wherein the patient is assessed to have a high sensitivity C-reactive protein (hsCRP) level of ≥2 mg / L prior to the first administration of the IL-1β antagonist, and wherein if the patient is assessed to have a reduced hsCRP level of <2.3 mg / L at a predetermined time point after the first administration of the IL-1β antagonist, the patient will continue to receive the IL-1β antagonist.

3. A method for reducing the risk of progression of OA and / or reducing adverse events associated with OA in a patient, the method comprising administering canakinumab, wherein the patient is assessed to have a high-sensitivity C-reactive protein (hsCRP) level ≥2 mg / L prior to the first administration of canakinumab, and wherein the patient is assessed to have a reduced hsCRP level of <2.3 mg / L about 3 months or more after the first administration of canakinumab.

4. A method for reducing the risk of progression of OA and / or reducing adverse events in a patient, the method comprising administering canakinumab, wherein the patient is assessed to have a high-sensitivity C-reactive protein (hsCRP) level ≥2 mg / L prior to the first dose of canakinumab, and wherein if the patient is assessed to have a reduced hsCRP level of <2.3 mg / L about 3 months or more after the first administration of canakinumab, the patient will continue to receive canakinumab.

5. The method of any of the preceding claims, wherein the progression of OA comprises joint replacement.

6. The method according to any one of the preceding claims, wherein the patient has documented and / or symptomatic OA.

7. The method according to any one of the preceding claims, comprising administering 150 mg to 300 mg of canakinumab.

8. The method according to any one of the preceding claims, comprising administering 150 mg of canakinumab.

9. The method of any one of the preceding claims, comprising administering 150 mg of canakinumab approximately every 3 months.

10. The method of any of the preceding claims, wherein the reduced hsCRP level is <1.5 mg / L assessed at about 3 months after the first administration of canakinumab or at a predetermined time point after the first administration of the IL-1β antagonist.

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