Use of Kanakinumab

Abstract

Methods are provided for reducing the risk of progression of osteoarthritis ("OA") in a patient and / or for alleviating adverse events associated with OA. The method includes administering an IL-1β inhibitor such as canakinumab.

Description

Technical Field

[0001] The present disclosure generally relates to novel uses and methods for reducing the risk of osteoarthritis and related complications, including administering a therapeutic dose of an IL-1β inhibitor, such as a binding antibody or functional fragment exemplified by canakinumab.

Background Art

[0002] Osteoarthritis ("OA") is one of the most common and chronic health conditions and a major cause of pain and disability in adults. OA is a degenerative, chronic, progressive joint disease associated with painful symptoms. Currently, there is no treatment aimed at preventing the degeneration associated with OA ("DMOAD"). Hip / knee OA affects 240 million people worldwide. Worldwide estimates of OA indicate that 9.6% of men and 18.0% of women over 60 years of age have osteoarthritis of the knee or related symptoms. In addition, the prevalence of OA is steadily increasing and is expected to be the single largest cause of disability in the entire population by 2030. Furthermore, there are serious complications associated with OA. The degenerative nature of this disease causes many complications. For example, in the United States in 2010, 7.2 million people required total hip / knee arthroplasty. Therefore, there is an unmet medical need for treatments to reduce the progression of OA and related adverse events.

Summary of the Invention

Means for Solving the Problems

[0003] Inflammation is involved in all stages of the atherothrombotic process and is associated with hsCRP and IL-6. Patients with elevated inflammatory biomarkers, such as, despite the use of aggressive secondary prevention strategies, have an increased vascular risk. The present disclosure is somewhat related to the finding that direct inhibition of inflammation by administration of an IL-1β antagonist, such as canakinumab, reduces or prevents the risk of disease progression in OA, reduces adverse events ("AE") associated with OA, and reduces the overall need for total joint replacement ("TJR"). Accordingly, the present invention relates to a method of preventing or reducing AE associated with OA. The present invention also relates to a method of reducing the risk that TJR will be necessary in OA patients. Accordingly, the present invention also relates to canakinumab for use in reducing the risk of progression of OA, the risk that TJR will be necessary in OA patients, and / or the risk of AE associated with OA. The present invention further relates to canakinumab for use in the manufacture of a medicament for reducing the risk of OA, the risk that TJR will be necessary in OA patients, and / or the risk of AE associated with OA.

[0004] The present invention also relates to the use of canakinumab for use in the manufacture of a medicament for reducing the risk of OA, the risk that TJR will be necessary in OA patients, and / or the risk of AE associated with OA.

[0005] The present disclosure is illustrated by the numbered embodiments described below:

[0006] 1. To reduce the risk of progression of a patient's osteoarthritis ("OA") and / or OA

[0007]

[0008]

[0009]

[0010] ​​​​​​​​​​A method for reducing adverse events associated therewith, comprising administering an IL-1β antagonist, wherein the patient has a high-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or more or 3 mg / L or more evaluated before the first administration of the IL-1β antagonist, and wherein the patient has a reduced hsCRP level of less than 2.3 mg / L evaluated 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 in a patient and / or reducing adverse events associated with OA, comprising administering an IL-1β antagonist, wherein the patient has a high-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or more evaluated before the first administration of the IL-1β antagonist, and wherein the patient has a reduced hsCRP level of less than 2.3 mg / L evaluated at a predetermined time point after the first administration of the IL-1β antagonist, whereby the administration of the IL-1β antagonist to the patient is continued. 3. A method for reducing the risk of progression of OA in a patient and / or reducing adverse events associated with OA, comprising administering canakinumab, wherein the patient has a high-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or more evaluated before the first administration of canakinumab, and wherein the patient has a reduced hsCRP level of less than 2.3 mg / L evaluated after about 3 months or more after the first administration of canakinumab. 4. A method for reducing the risk of progression of OA in a patient and / or reducing adverse events associated with OA

[0011]

[0012]

[0013] A method for reduction, comprising administering canakinumab, wherein the patient has a high-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or higher evaluated before the first administration of canakinumab, and the patient has a reduced hsCRP level of less than 2.3 mg / L evaluated after about 3 months from the first administration of canakinumab, then the administration of canakinumab to the patient will be continued. Method.

[0014] 5. The method according to any of the above embodiments, wherein the progression of the OA includes arthroplasty.

[0015] 6. The method according to any of the above embodiments, wherein the patient has documented OA and / or symptomatic OA. Method.

[0016] 7. The method according to any of the above embodiments, comprising administering 150 mg to 300 mg of canakinumab. Method.

[0017] 8. The method according to any of the above embodiments, comprising administering 150 mg of canakinumab. Method.

[0018] 9. The method according to any of the above embodiments, comprising administering 150 mg of canakinumab approximately every 3 months. Method.

[0019] 10. The method according to any of the above embodiments, wherein the reduced level of hsCRP evaluated after about 3 months from the first administration of canakinumab, or after a predetermined time point after the first administration of the IL-1β antagonist, is less than 1.5 mg / L. Method. Method.

[0020] 11. After about 3 months from the first administration of canakinumab, or after a predetermined time point after the first administration of the IL-1β antagonist, The reduced level of hsCRP evaluated after a predetermined time point after the first administration is less than 1.0 mg / L The method according to any one of the preceding embodiments.

[0021] 12. About 3 months after the first administration of canakinumab, or after the first The reduced level of hsCRP evaluated after a predetermined time point after the first administration is less than 2.2 mg / L less than, less than 2.1 mg / L, less than 2.0 mg / L, less than 1.9 mg / L, less than 1.8 mg / L less than, less than 1.7 mg / L, less than 1.6 mg / L, less than 1.5 mg / L, less than 1.4 mg / L less than, less than 1.3 mg / L, less than 1.2 mg / L, less than 1.1 mg / L, less than 1.0 mg / L less than, less than 0.9 mg / L, less than 0.8 mg / L, less than 0.7 mg / L, less than 0.6 mg / L less than, or less than 0.5 mg / L, the method according to any one of the preceding embodiments.

[0022] 13. The method according to any one of the preceding embodiments, wherein OA supported by documents is evaluated using X-ray and / or MRI

[0023] 14. The method according to any one of the preceding embodiments, wherein the evidence of OA symptoms is pain and / or dysfunction

[0024] 15. The method according to any one of the preceding embodiments, wherein the patient is not a candidate for surgery

[0025] 16. The method according to any one of the preceding embodiments, wherein the patient does not respond to NSAIDs

[0026] 17. The level of IL-6 at a predetermined time point after the first administration of the IL-1β antagonist or 3 months after the first administration of canakinumab is less than 1.15 mg / L or less than 2 mg / L The method according to any one of the preceding embodiments. ​​​

[0027] 18. The method according to any one of the embodiments, wherein the patient has previously suffered from a CV event.

[0028] 19. The method according to any one of the embodiments, wherein the patient has previously suffered from a myocardial infarction.

[0029] 20. A method for reducing the risk of progression of OA in a patient and / or reducing adverse events associated with OA, comprising administering an IL-1β antagonist, wherein the patient has a high-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or more as evaluated before the first administration of the IL-1β antagonist.

[0030] 21. The method according to embodiment 20, wherein the IL-1β antagonist is canakinumab.

[0031] 22. The method according to embodiment 20 or 21, comprising administering 150 mg to 300 mg of canakinumab.

[0032] 23. The method according to any one of embodiments 20 to 22, comprising administering 150 mg to 300 mg of canakinumab approximately every 3 months.

[0033] 24. The method according to any one of embodiments 20 to 23, wherein OA supported by documentation is evaluated using X-ray and / or MRI.

[0034] 25. The method according to any one of embodiments 20 to 24, wherein the evidence of OA symptoms is pain and / or dysfunction.

[0035] 26. The method according to any one of embodiments 20 to 25, wherein the patient is not a candidate for surgery. ​​​​​​​​​

[0036] 27. The method according to any one of Embodiments 20 to 26, wherein the patient does not respond to NSAIDs.

[0037] 28. The method according to any one of Embodiments 20 to 27, wherein the patient has previously suffered from a CV event.

[0038] 29. The method according to any one of Embodiments 20 to 28, wherein the patient has previously suffered from myocardial infarction.

[0039] 30. The method according to any one of the above embodiments, wherein the total joint replacement can be a total knee replacement or a total hip replacement.

[0040] 31. The method according to any one of the above embodiments, wherein the patient suffers from shoulder OA, hand OA, or spondylosis (degenerative spondylosis).

[0041] 32. The method according to any one of the above embodiments, wherein the total joint replacement can be a total shoulder replacement.

[0042] 33. The method according to any one of Embodiments 1, 2, and 7 to 9, wherein the predetermined time point is between 2 weeks and 6 months.

[0043] 34. The method according to any one of Embodiments 1, 2, and 7 to 9, wherein the predetermined time point is between 4 weeks and 12 weeks.

[0044] Further features and advantages of the present disclosure will become apparent from the following detailed description of the invention.

Brief Description of the Drawings

[0045]

Figure 1

Figure 2

Figure 3

Figure 4

Mode for Carrying Out the Invention

[0046] The present invention provides a method for preventing or reducing the disease progression of OA, including the need for arthroplasty in such patients, by administering an IL-1β antagonist such as canakinumab to OA patients; and / or a method for preventing or reducing AEs related to OA. Furthermore, it provides a method for preventing or reducing the disease progression of OA, including the need for arthroplasty in such patients, by administering an IL-1β antagonist such as canakinumab to OA patients; and / or a method for preventing or reducing AEs related to OA. Furthermore, it provides a method for preventing or reducing the disease progression of OA, including the need for arthroplasty in such patients, by administering an IL-1β antagonist such as canakinumab to OA patients; and / or a method for preventing or reducing AEs related to OA.

[0047] Canakinumab (International Nonproprietary Name (INN) number 8836) is disclosed in International Publication No. 02 / 16436 pamphlet, the entire disclosure content of which is incorporated herein by reference. Canakinumab is disclosed in International Publication No. 02 / 16436 pamphlet, the entire disclosure content of which is incorporated herein by reference. Canakinumab is a fully human monoclonal anti-human IL-1β antibody of the IgG1 / k isotype, developed for the treatment of inflammatory diseases caused by IL-1β. Canakinumab is a fully human monoclonal anti-human IL-1β antibody of the IgG1 / k isotype, developed for the treatment of inflammatory diseases caused by IL-1β. Canakinumab is designed to bind to human IL-1β and thereby block the interaction between the cytokine and its receptor. The antagonistic effect of IL-1β-mediated inflammation using canakinumab in reducing high-sensitivity C-reactive protein (hsCRP) and other inflammatory marker levels has been demonstrated in patients with cryopyrin-associated periodic syndromes (CAPS) and rheumatoid arthritis during the acute-phase response. The antagonistic effect of IL-1β-mediated inflammation using canakinumab in reducing high-sensitivity C-reactive protein (hsCRP) and other inflammatory marker levels has been demonstrated in patients with cryopyrin-associated periodic syndromes (CAPS) and rheumatoid arthritis during the acute-phase response. The antagonistic effect of IL-1β-mediated inflammation using canakinumab in reducing high-sensitivity C-reactive protein (hsCRP) and other inflammatory marker levels has been demonstrated in patients with cryopyrin-associated periodic syndromes (CAPS) and rheumatoid arthritis during the acute-phase response. shown. This evidence is in type 2 diabetes mellitus (T2DM) using canakinumab, and has been reproduced in patients receiving other IL-1β antibody therapies under development, but the reduction in h sCRP levels in T2DM did not lead to an increase in efficacy over standard therapy. Inhibition of IL-1β over a long period of time may have unexpected effects, whether favorable or not, as it thereby inhibits major inflammatory pathways, so large-scale randomized placebo-controlled clinical trials monitoring multiple parameters are necessary.

[0048] The inventors have found that treatment with canakinumab significantly reduces the risk of osteoarthritis, related conditions, and side effects. Inflammatory cytokines are important mediators of metabolic disorders and catabolism promotion in joint tissues involved in OA. IL-1β, TNF, and IL-6 appear to be the major inflammatory and catabolism-promoting cytokines in OA driving the inflammatory cascade, although IL-15, IL-17, IL-18, IL-21, leukemia inhibitory factor (LIF), and chemokines are also involved. IL-1β and TNF are produced by chondrocytes, monocytes, osteoblasts, and synovial tissue. Activation of cells by IL-1β is mediated only by binding to its specific cell surface receptor, IL-1RI. The levels of both IL- 1β and TNF increase in synovial fluid, synovium, subchondral bone, and cartilage. Furthermore, IL-1β and TNF can act independently or in concert with other cytokines to initiate and propagate inflammation. IL-1β upregulates the nociception-promoting mediator (i.e., NGF ), increasing pain. Furthermore, IL-1β and TNF degrade cartilage and TNF increase in synovial fluid, synovium, subchondral bone, and cartilage. Furthermore, IL-1β and TNF can act independently or in concert with other cytokines to initiate and propagate inflammation. IL-1β upregulates the nociception-promoting mediator (i.e., NGF ), increasing pain. Furthermore, IL-1β and TNF degrade cartilage ), increasing pain. Furthermore, IL-1β and TNF degrade cartilage ​​Stimulate the cells to release several proteolytic enzymes: MMP: MMP1 (interstitial collagenase ), MMP3 (stromelysin 1), and MMP13 (collagenase 3).

[0049] In one embodiment, any method of the invention comprises administering canakinumab in an amount of about 50 mg, 150 mg, 175 mg, 20 0 mg, 225 mg, 250 mg, 275 mg, 300 mg, or any combination thereof.

[0050] One embodiment of any method of the invention comprises administering 150 mg of canakinumab or 300 mg of canakinumab. Another embodiment of any method of the invention comprises administering 150 mg of canakinumab. Yet another embodiment comprises administering 225 mg of canakinumab. In other embodiments, 50 mg or 200 mg of canakinumab is administered.

[0051] In one embodiment of any method of the invention, the reduced hsCRP level evaluated about 3 months after the first administration of canakinumab is less than 1.9 mg / L, less than 1.8 mg / L, 1.7 mg / L, less than 1.6 mg / L, less than 1.5 mg / L, less than 1.4 mg / L, 1.3 mg / L, less than 1.2 mg / L, less than 1.1 mg / L, less than 1.0 mg / L, 0.9 mg / L, less than 0.8 mg / L, less than 0.7 mg / L, less than 0.6 mg / L, or 0 mg / L. In one embodiment, the reduced hsCRP level evaluated about 3 months after the first administration of canakinumab is less than 1.0 mg / L. In another embodiment, the reduced hsCRP level evaluated about 3 months after the first administration of canakinumab is 2 mg / L. ​​​​​​​is less than L. In yet another embodiment, the reduced level of hsCRP is below 3 mg / L.

[0052] In a further aspect of any method of the present disclosure, a first dose of 150 mg of canakinumab is administered to an affected patient and responds, i.e., the hsCRP level of the patient decreases. However, if the decrease in the hsCRP level evaluated at least 3 months after the first dose of canakinumab is not less than 2 mg / L, instead of stopping the treatment of the patient, a first dose of canakinumab is administered again. If the hsCRP level evaluated at least 3 months after the administration of the additional initial dose is less than 2 mg / L, the patient will continue treatment and thereafter, a dose of 150 mg or preferably 300 mg of canakinumab is administered approximately every 3 months.

[0053] In another aspect of any method of the present disclosure, after the first dose of canakinumab such as 50 mg, 150 mg, 200 mg, 225 mg, or 300 mg, the levels of related biomarkers such as IL-6 or hsCRP are measured at a predetermined time after the first dose, preferably 3 months later. Thereafter, the biomarker is measured again at a second predetermined time after the first dose, preferably 6 months later. Then, according to the measured level of the biomarker, a second dose of canakinumab such as 50 mg, 150 mg, 200 mg, 225 mg, or 300 mg can be administered to the patient.

[0054] In one embodiment, the method of the present invention further comprises, optionally, administering an additional dose of 300 mg of canakinumab to the patient approximately 2 weeks (+ / - 3 days) after the first dose of canakinumab. ​​​​​​​​​​​​​​

[0055] Canakinumab can be administered subcutaneously or intravenously. Canakinumab is administered in a reconstituted formulation containing canakinumab at a concentration of 50- 200 mg / ml, 50-300 mM sucrose, 10-50 mM histidine, and 0.01-0.1% surfactant, and the pH of this formulation is 5.5-7.0. Canakinumab is administered in a reconstituted formulation containing canakinumab at a concentration of 50-200 mg / ml, 270 mM sucrose, 30 mM histidine, and 0 .06% polysorbate 20 or 80, and the pH of the formulation is 6.5.

[0056] Canakinumab can also be administered in a liquid formulation containing canakinumab at a concentration of 50-300 mg / ml, a buffer system selected from the group consisting of citrate, histidine, and sodium succinate, and a stabilizer selected from the group consisting of sucrose, mannitol, sorbitol, arginine hydrochloride, and surfactant, and the pH of this formulation is 5.5-7.0 . Canakinumab can also be administered in a liquid formulation containing canakinumab at a concentration of 50-300 mg / ml, 50-300 mM mannitol, 10-50 mM histidine, and 0.01-0.1% surfactant, and the pH of this formulation is 5.5-7.0. Can akinumab can also be administered in a liquid formulation containing canakinumab at a concentration of 50-300 mg / ml, 270 mM mannitol, 20 mM histidine, and 0.04% polysorbate 20 or 80, and the pH of this liquid formulation is 6.5. When administered subcutaneously, canakinumab is included in prefilled syringes, autoinjectors with liquid

[0057] ​​​The compound may be administered to the patient in whole or lyophilized form for reconstitution.

[0058] In another embodiment of any of the methods of the invention, a biologic other than hsCRP, such as IL-6, may be used. Markers can be used to determine response to canakinumab.

[0059] Another embodiment of the present invention is a method for the treatment of cancer by any of the uses or methods described herein. Including the use of numab.

[0060] General: All patents, published patent applications, publications, references, and other materials mentioned herein are hereby incorporated by reference in their entirety. , which is incorporated herein by reference in its entirety.

[0061] As used herein, the term "comprising" means "in "comprising" and "consisting of", e.g., X A composition "comprising" may consist solely of X or may contain any additional , for example X+Y.

[0062] As used herein, the term "canakinumab" refers to a compound, e.g., canakinumab, or a standard of care agent. The term "administer" is used to refer to the delivery of the compound by any delivery route. do.

[0063] As used herein, the term "about" in reference to a numerical value x means, for example, + / - 10%. It means.

[0064] As used herein, the term "substantially" does not exclude "completely." For example, a composition that is "substantially free" of Y may be completely free of Y. Thus, the term "substantially" may be excluded from the definitions of the present disclosure.

[0065] As used herein, the term "three months" in one embodiment includes the period extended up to one week before and one week after three months (three months ± one week). In other embodiments the term "about three months" includes 90 days + / - 15 days or 90 days + / - 10 days.

[0066] As used herein, the term "biomarker" generally refers to a molecule, i.e., a gene (or the nucleic acid encoding said gene), a protein, the expression of which in a biological sample from a patient can be detected by methods standard in the art and which predicts or indicates the state of the patient from whom it was obtained. According to the present invention, exemplary biomarkers include, but are not limited to, hsCRP and IL-6.

[0067] As used herein, the term "assay" is used to refer to the act of detection, identification, screening, or determination, any of which can be performed by conventional means. For example, by using an ELISA assay, Northern blot, imaging, etc., a sample can be assayed for the presence of a specific marker to detect whether the marker is present in the sample.

[0068] As used herein, the terms "C-reactive protein" and "CRP" refer to serum C-reactive protein used as an indicator of the acute phase response to inflammation. As used herein, the term "hsCRP" refers to CRP in blood measured by a high-sensitivity CRP test. Refers to the level of P. The level of CRP or hsCRP in plasma can be expressed at any concentration, e.g., m g / dl, mg / L, nmol / L. The level of CRP or hsCRP can be measured by various well-known methods, e.g., radial immunodiffusion, electroimmunoassay, immunoturbidimetry, ELI SA, turbidimetry, fluorescence polarization immunoassay, and laser nephelometry. In the CRP test, a standard CRP test or a high-sensitivity CRP (hsCRP) test (i.e., a high-sensitivity test that can measure low levels of CRP in a sample using laser nephelometry) can be utilized. Kits for detecting the level of CRP or hsCRP are available for purchase from various companies, e.g., Calbiotech, Cayman Chemical, Ro che Diagnostics Corporation, Abazyme, DADE Behring, Abnova Corporation, Aniara Corpo ration, Bio-Quant Inc., Siemens Healthcare Diagnostics, etc. The terms "patient" and "subject" as used herein are used interchangeably. Other features, objects, and advantages of the present invention will become apparent from the description, drawings, and claims.

[0069] The terms "osteoarthritis" and "degenerative joint disease" as used herein are used interchangeably and encompass a wide range of conditions such as spinal OA, related spinal degenerative diseases, and OA of the upper and lower extremities. Non-limiting examples are included in the following table:

[0070] will become apparent.

[0071] The terms "osteoarthritis" and "degenerative joint disease" as used herein are used interchangeably and include a wide range of conditions such as spinal OA, related spinal degenerative diseases, and OA of the upper and lower extremities. Non-limiting examples are included in the following table:

[0072] ​​

Table 1

[0073] As used herein, canakinumab is defined by the INN number 8836 and has the following sequence: having:

Chemical Structure

[0074] As used herein, an antibody refers to an antibody having the natural biological form of an antibody. Such an antibody is a glycoprotein and is composed of four polypeptides (two identical heavy chains and two identical light chains) that bind together to form a "Y"-shaped molecule. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region is composed of three or four constant domains (CH1, CH2, CH3, and CH4 depending on the antibody class or isotype). Each light chain is composed of a light chain variable region (VL) and a light chain constant region having one domain CL. The proteolytic enzyme papain cleaves the "Y"-shape into three separate molecules (two are so-called "Fab" fragments (Fab = antigen-binding fragment) and one is so-called "Fc" fragment (Fc = crystallizable fragment)). The Fab fragment is composed of the entire light chain and a part of the heavy chain. The VL and VH regions are located at the tips of the "Y"-shaped antibody molecule. Each of VL and VH has three complementarity-determining regions (CDRs). Thus, such an antibody is a glycoprotein and is composed of four polypeptides (two identical heavy chains and two identical light chains) that bind together to form a "Y"-shaped molecule. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region is composed of three or four constant domains (CH1, CH2, CH3, and CH4 depending on the antibody class or isotype). Each light chain is composed of a light chain variable region (VL) and a light chain constant region having one domain CL. The proteolytic enzyme papain cleaves the "Y"-shape into three separate molecules (two are so-called "Fab" fragments (Fab = antigen-binding fragment) and one is so-called "Fc" fragment (Fc = crystallizable fragment)). The Fab fragment is composed of the entire light chain and a part of the heavy chain. The VL and VH regions are located at the tips of the "Y"-shaped antibody molecule. Each of VL and VH has three complementarity-determining regions (CDRs). Thus, such an antibody is a glycoprotein and is composed of four polypeptides (two identical heavy chains and two identical light chains) that bind together to form a "Y"-shaped molecule. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region is composed of three or four constant domains (CH1, CH2, CH3, and CH4 depending on the antibody class or isotype). Each light chain is composed of a light chain variable region (VL) and a light chain constant region having one domain CL. The proteolytic enzyme papain cleaves the "Y"-shape into three separate molecules (two are so-called "Fab" fragments (Fab = antigen-binding fragment) and one is so-called "Fc" fragment (Fc = crystallizable fragment)). The Fab fragment is composed of the entire light chain and a part of the heavy chain. The VL and VH regions are located at the tips of the "Y"-shaped antibody molecule. Each of VL and VH has three complementarity-determining regions (CDRs). Thus, such an antibody is a glycoprotein and is composed of four polypeptides (two identical heavy chains and two identical light chains) that bind together to form a "Y"-shaped molecule. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region is composed of three or four constant domains (CH1, CH2, CH3, and CH4 depending on the antibody class or isotype). Each light chain is composed of a light chain variable region (VL) and a light chain constant region having one domain CL. The proteolytic enzyme papain cleaves the "Y"-shape into three separate molecules (two are so-called "Fab" fragments (Fab = antigen-binding fragment) and one is so-called "Fc" fragment (Fc = crystallizable fragment)). The Fab fragment is composed of the entire light chain and a part of the heavy chain. The VL and VH regions are located at the tips of the "Y"-shaped antibody molecule. Each of VL and VH has three complementarity-determining regions (CDRs). Thus, such an antibody is a glycoprotein and is composed of four polypeptides (two identical heavy chains and two identical light chains) that bind together to form a "Y"-shaped molecule. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region is composed of three or four constant domains (CH1, CH2, CH3, and CH4 depending on the antibody class or isotype). Each light chain is composed of a light chain variable region (VL) and a light chain constant region having one domain CL. The proteolytic enzyme papain cleaves the "Y"-shape into three separate molecules (two are so-called "Fab" fragments (Fab = antigen-binding fragment) and one is so-called "Fc" fragment (Fc = crystallizable fragment)). The Fab fragment is composed of the entire light chain and a part of the heavy chain. The VL and VH regions are located at the tips of the "Y"-shaped antibody molecule. Each of VL and VH has three complementarity-determining regions (CDRs). Thus, such an antibody is a glycoprotein and is composed of four polypeptides (two identical heavy chains and two identical light chains) that bind together to form a "Y"-shaped molecule. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region is composed of three or four constant domains (CH1, CH2, CH3, and CH4 depending on the antibody class or isotype). Each light chain is composed of a light chain variable region (VL) and a light chain constant region having one domain CL. The proteolytic enzyme papain cleaves the "Y"-shape into three separate molecules (two are so-called "Fab" fragments (Fab = antigen-binding fragment) and one is so-called "Fc" fragment (Fc = crystallizable fragment)). The Fab fragment is composed of the entire light chain and a part of the heavy chain. The VL and VH regions are located at the tips of the "Y"-shaped antibody molecule. Each of VL and VH has three complementarity-determining regions (CDRs). Thus, such an antibody is a glycoprotein and is composed of four polypeptides (two identical heavy chains and two identical light chains) that bind together to form a "Y"-shaped molecule. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region is composed of three or four constant domains (CH1, CH2, CH3, and CH4 depending on the antibody class or isotype). Each light chain is composed of a light chain variable region (VL) and a light chain constant region having one domain CL. The proteolytic enzyme papain cleaves the "Y"-shape into three separate molecules (two are so-called "Fab" fragments (Fab = antigen-binding fragment) and one is so-called "Fc" fragment (Fc = crystallizable fragment)). The Fab fragment is composed of the entire light chain and a part of the heavy chain. The VL and VH regions are located at the tips of the "Y"-shaped antibody molecule. Each of VL and VH has three complementarity-determining regions (CDRs). Thus, such an antibody is a glycoprotein and is composed of four polypeptides (two identical heavy chains and two identical light chains) that bind together to form a "Y"-shaped molecule. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region is composed of three or four constant domains (CH1, CH2, CH3, and CH4 depending on the antibody class or isotype). Each light chain is composed of a light chain variable region (VL) and a light chain constant region having one domain CL. The proteolytic enzyme papain cleaves the "Y"-shape into three separate molecules (two are so-called "Fab" fragments (Fab = antigen-binding fragment) and one is so-called "Fc" fragment (Fc = crystallizable fragment)). The Fab fragment is composed of the entire light chain and a part of the heavy chain. The VL and VH regions are located at the tips of the "Y"-shaped antibody molecule. Each of VL and VH has three complementarity-determining regions (CDRs). Thus, such an antibody is a glycoprotein and is composed of four polypeptides (two identical heavy chains and two identical light chains) that bind together to form a "Y"-shaped molecule. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region is composed of three or four constant domains (CH1, CH2, CH3, and CH4 depending on the antibody class or isotype). Each light chain is composed of a light chain variable region (VL) and a light chain constant region having one domain CL. The proteolytic enzyme papain cleaves the "Y"-shape into three separate molecules (two are so-called "Fab" fragments (Fab = antigen-binding fragment) and one is so-called "Fc" fragment (Fc = crystallizable fragment)). The Fab fragment is composed of the entire light chain and a part of the heavy chain. The VL and VH regions are located at the tips of the "Y"-shaped antibody molecule. Each of VL and VH has three complementarity-determining regions (CDRs). Thus, such an antibody is a glycoprotein and is composed of four polypeptides (two identical heavy chains and two identical light chains) that bind together to form a "Y"-shaped molecule. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region is composed of three or four constant domains (CH1, CH2, CH3, and CH4 depending on the antibody class or isotype). Each light chain is composed of a light chain variable region (VL) and a light chain constant region having one domain CL. The proteolytic enzyme papain cleaves the "Y"-shape into three separate molecules (two are so-called "Fab" fragments (Fab = antigen-binding fragment) and one is so-called "Fc" fragment (Fc = crystallizable fragment)). The Fab fragment is composed of the entire light chain and a part of the heavy chain. The VL and VH regions are located at the tips of the "Y"-shaped antibody molecule. Each of VL and VH has three complementarity-determining regions (CDRs). Thus, such an antibody is a glycoprotein and is composed of four polypeptides (two identical heavy chains and two identical light chains) that bind together to form a "Y"-shaped molecule. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region is composed of three or four constant domains (CH1, CH2, CH3, and CH4 depending on the antibody class or isotype). Each light chain is composed of a light chain variable region (VL) and a light chain constant region having one domain CL. The proteolytic enzyme papain cleaves the "Y"-shape into three separate molecules (two are so-called "Fab" fragments (Fab = antigen-binding fragment) and one is so-called "Fc" fragment (Fc = crystallizable fragment)). The Fab fragment is composed of the entire light chain and a part of the heavy chain. The VL and VH regions are located at the tips of the "Y"-shaped antibody molecule. Each of VL and VH has three complementarity-determining regions (CDRs). Thus, such an antibody is a glycoprotein and is composed of four polypeptides (two identical heavy chains and two identical light chains) that bind together to form a "Y"-shaped molecule. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region is composed of three or four constant domains (CH1, CH2, CH3, and CH4 depending on the antibody class or isotype). Each light chain is composed of a light chain variable region (VL) and a light chain constant region having one domain CL. The proteolytic enzyme papain cleaves the "Y"-shape into three separate molecules (two are so-called "Fab" fragments (Fab = antigen-binding fragment) and one is so-called "Fc" fragment (Fc = crystallizable fragment)). The Fab fragment is composed of the entire light chain and a part of the heavy chain. The VL and VH regions are located at the tips of the "Y"-shaped antibody molecule. Each of VL and VH has three complementarity-determining regions (CDRs).

[0075] An "IL-1β binding antibody" specifically binds to IL-1β, and as a result, inhibits or modulates the binding of IL-1β to its receptor, and further as a result, inhibits IL-1β function An "IL-1β binding antibody" specifically binds to IL-1β, and as a result, inhibits or modulates the binding of IL-1β to its receptor, and further as a result, inhibits IL-1β function Means any antibody that can be made. Preferably, the IL-1β binding antibody does not bind to IL-1 α.

[0076] Preferably, the IL-1β binding antibody comprises: (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): (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 (3) An antibody comprising the six CDRs described in either (1) or (2), wherein one or more of the CDR sequences, preferably at most two CDRs, preferably only one CDR, has one amino acid different from the corresponding sequence described in either (1) or (2).

[0077] Preferably, the IL-1β binding antibody comprises: (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 a VH having the amino acid sequence specified in SEQ ID NO: 8; (2) A VL having the amino acid sequence specified in SEQ ID NO: 4, and an amino acid sequence VYG MN (SEQ ID NO: 5), IIWYDGDNQYYADSVKG (SEQ ID NO: 6), and DLR An antibody comprising three VH CDRs having TGP (SEQ ID NO: 7); (3) 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 an antibody comprising a VH having the amino acid sequence specified in SEQ ID NO: 16; An antibody comprising a VL having the amino acid specified in SEQ ID NO: 12, and three VH CDRs having the amino acid sequences TSGM (4) GVG (SEQ ID NO: 13), HIWWDGDESYNPSLK (SEQ ID NO: 14), and NR YDPPWFVD (SEQ ID NO: 15); An antibody comprising three VH CDRs having the amino acid sequences specified in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15; (5) An antibody comprising three VL CDRs and a VH sequence as described in (1) or (3), wherein one or more of the VL CDR sequences, preferably at most two of the CDRs, preferably only one of the CDRs, differ by one amino acid from the corresponding sequences described in (1) or (3) respectively, and the VH sequence is at least 90% identical to the corresponding sequences described in (1) or (3) respectively; and An antibody comprising a VL sequence as described in (2) or (4) and three VH CDRs, wherein the VL sequence is at least 90% identical to the corresponding sequences described in (2) or (4) respectively, and one or more of the VH CDR sequences, preferably at most two of the CDRs, preferably only one of the CDRs, differ by one amino acid from the corresponding sequences described in (2) or (4) respectively; Preferably, the IL-1β binding antibody comprises: (1) A VL having the amino acid sequence specified in SEQ ID NO: 4, and a VH having the amino acid sequence specified in SEQ ID NO: 8 respectively; An antibody comprising a VL having the amino acid sequence specified in SEQ ID NO: 12, and three VH CDRs having the amino acid sequences specified in SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15; wherein the VL sequence is at least 90% identical to the corresponding sequences described in (2) or (4) respectively, and one or more of the VH CDR sequences, preferably at most two of the CDRs, preferably only one of the CDRs, differ by one amino acid from the corresponding sequences described in (2) or (4) respectively; Preferably, the IL-1β binding antibody comprises: (1) A VL having the amino acid sequence specified in SEQ ID NO: 4, and a VH having the amino acid sequence specified in SEQ ID NO: 8 respectively;

[0078] Preferably, the IL-1β binding antibody comprises the following: (1) A VL having the amino acid sequence specified in SEQ ID NO: 4, and a VH having the amino acid sequence specified in SEQ ID NO: 8 an antibody comprising a VH having the amino acid sequence; (2) a VL having the amino acids specified in SEQ ID NO: 12, and a VH having the amino acid sequence specified in SEQ ID NO: 16; an antibody comprising a VH having the amino acid sequence; and (3) an antibody according to either (1) or (2) above, wherein the constant region of the heavy chain, the constant region of the light chain, or both are changed to a different isotype compared to canakinumab or gevokizumab. Preferably, the IL-1β binding antibody comprises canakinumab (SEQ ID NOs: 17 and 18). The IL-1β binding antibody defined above has CDR sequences that are substantially identical or identical to the CDR sequences of canakinumab. Accordingly, the IL-1β binding antibody binds to the same epitope on IL-1β and has a binding affinity similar to that of canakinumab or gevokizumab. Clinically appropriate dosages and dosing regimens established for canakinumab as being therapeutically effective in the treatment of OA will be applicable to other IL-1β binding antibodies.

[0079] Preferably, the IL-1β binding antibody comprises canakinumab (SEQ ID NOs: 17 and 18).

[0080] The IL-1β binding antibody defined above has CDR sequences that are substantially identical or identical to the CDR sequences of canakinumab. Accordingly, the IL-1β binding antibody binds to the same epitope on IL-1β and has a binding affinity similar to that of canakinumab or gevokizumab. Clinically appropriate dosages and dosing regimens established for canakinumab as being therapeutically effective in the treatment of OA will be applicable to other IL-1β binding antibodies. The IL-1β binding antibody defined above has CDR sequences that are substantially identical or identical to the CDR sequences of canakinumab. Accordingly, the IL-1β binding antibody binds to the same epitope on IL-1β and has a binding affinity similar to that of canakinumab or gevokizumab. Clinically appropriate dosages and dosing regimens established for canakinumab as being therapeutically effective in the treatment of OA will be applicable to other IL-1β binding antibodies. The IL-1β binding antibody defined above has CDR sequences that are substantially identical or identical to the CDR sequences of canakinumab. Accordingly, the IL-1β binding antibody binds to the same epitope on IL-1β and has a binding affinity similar to that of canakinumab or gevokizumab. Clinically appropriate dosages and dosing regimens established for canakinumab as being therapeutically effective in the treatment of OA will be applicable to other IL-1β binding antibodies. The IL-1β binding antibody defined above has CDR sequences that are substantially identical or identical to the CDR sequences of canakinumab. Accordingly, the IL-1β binding antibody binds to the same epitope on IL-1β and has a binding affinity similar to that of canakinumab or gevokizumab. Clinically appropriate dosages and dosing regimens established for canakinumab as being therapeutically effective in the treatment of OA will be applicable to other IL-1β binding antibodies. The IL-1β binding antibody defined above has CDR sequences that are substantially identical or identical to the CDR sequences of canakinumab. Accordingly, the IL-1β binding antibody binds to the same epitope on IL-1β and has a binding affinity similar to that of canakinumab or gevokizumab. Clinically appropriate dosages and dosing regimens established for canakinumab as being therapeutically effective in the treatment of OA will be applicable to other IL-1β binding antibodies.

[0081] In addition to, or instead of, the IL-1β antibody refers to an antibody that can specifically bind to IL-1β with an affinity in a range similar to that of canakinumab. The Kd of canakinumab in WO 2007 / 050607 pamphlet is referred to as 30.5 pM. Accordingly, a similar range of affinity refers to between about 0.05 pM and 300 pM, preferably between 0.1 pM and 100 pM. Such an affinity does not prevent IL-1β from binding to the receptor but prevents activation of the receptor. Preferably, the IL-1β antibody is in a range similar to that of canakinumab, preferably In addition to, or instead of, the IL-1β antibody refers to an antibody that can specifically bind to IL-1β with an affinity in a range similar to that of canakinumab. The Kd of canakinumab in WO 2007 / 050607 pamphlet is referred to as 30.5 pM. Accordingly, a similar range of affinity refers to between about 0.05 pM and 300 pM, preferably between 0.1 pM and 100 pM. Such an affinity does not prevent IL-1β from binding to the receptor but prevents activation of the receptor. Preferably, the IL-1β antibody is in a range similar to that of canakinumab, preferably In addition to, or instead of, the IL-1β antibody refers to an antibody that can specifically bind to IL-1β with an affinity in a range similar to that of canakinumab. The Kd of canakinumab in WO 2007 / 050607 pamphlet is referred to as 30.5 pM. Accordingly, a similar range of affinity refers to between about 0.05 pM and 300 pM, preferably between 0.1 pM and 100 pM. Such an affinity does not prevent IL-1β from binding to the receptor but prevents activation of the receptor. Preferably, the IL-1β antibody is in a range similar to that of canakinumab, preferably In addition to, or instead of, the IL-1β antibody refers to an antibody that can specifically bind to IL-1β with an affinity in a range similar to that of canakinumab. The Kd of canakinumab in WO 2007 / 050607 pamphlet is referred to as 30.5 pM. Accordingly, a similar range of affinity refers to between about 0.05 pM and 300 pM, preferably between 0.1 pM and 100 pM. Such an affinity does not prevent IL-1β from binding to the receptor but prevents activation of the receptor. Preferably, the IL-1β antibody is in a range similar to that of canakinumab, preferably In addition to, or instead of, the IL-1β antibody refers to an antibody that can specifically bind to IL-1β with an affinity in a range similar to that of canakinumab. The Kd of canakinumab in WO 2007 / 050607 pamphlet is referred to as 30.5 pM. Accordingly, a similar range of affinity refers to between about 0.05 pM and 300 pM, preferably between 0.1 pM and 100 pM. Such an affinity does not prevent IL-1β from binding to the receptor but prevents activation of the receptor. Preferably, the IL-1β antibody is in a range similar to that of canakinumab, preferably In addition to, or instead of, the IL-1β antibody refers to an antibody that can specifically bind to IL-1β with an affinity in a range similar to that of canakinumab. The Kd of canakinumab in WO 2007 / 050607 pamphlet is referred to as 30.5 pM. Accordingly, a similar range of affinity refers to between about 0.05 pM and 300 pM, preferably between 0.1 pM and 100 pM. Such an affinity does not prevent IL-1β from binding to the receptor but prevents activation of the receptor. Preferably, the IL-1β antibody is in a range similar to that of canakinumab, preferably Or a binding affinity in the range of 1 pM to 300 pM, preferably in the range of 10 pM to 100 pM and preferably, said antibody directly inhibits binding.

[0082] As used herein, the term "functional fragment" of an antibody as used herein 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 included within the term "functional fragment" of an antibody include single-chain Fv ( scFv), a Fab fragment which is a monovalent fragment consisting of V L , V H , CL, and CH1 domains; a bivalent fragment containing two Fab fragments linked by disulfide bridges in the hinge region ; an F(ab)2 fragment which is a bivalent fragment containing two Fab fragments linked by disulfide bridges in the hinge region; an Fd fragment consisting of V and CH1 domains; a V of a single arm of an antibody H and an Fv fragment consisting of V , V L and V H domains; a dAb fragment consisting of V H domains (Ward et al., 1989); and isolated complementarity-determining regions (CDRs); and one or more CDRs disposed on a peptide scaffold that is smaller, larger, or foldable differently than a typical antibody and is included. The term "functional fragment" may also refer to one of the following:

[0083] · Bispecific single-chain Fv dimers (International Application PCT / US92 / 09965) · "Diabodies" or "triabodies", multivalent or multimeric specificity fragments constructed by gene fusion (Tomlinson I & Hollinger P (2000) M ethods Enzymol. 326:461-79; W094113804; Hol et al., 1993; Hollinger et al., 1994; W093111614; Liger P et al.,(1993)Proc.Natl.Acad.Sci. USA,90:6444-48) ·scFv genetically fused to the same or different antibodies (Coloma MJ & Mo rrison SL(1997)Nature Biotechnology,15(2 ):159-163) ·scFv, diabody, or domain antibody fused to the Fc region ·scFv fused to the same or different antibodies ·Fv, scFv, or diabody molecules can be stabilized by incorporating disulfide cross-links that link the VH and VL domains (Reiter, Y. et al,(1996)Nature Biotech,14,1239-1245) 。 。 ·Miniantibodies containing scFv bound to the CH3 domain can also be produced (Hu, S. et al,(1996)Cancer Res.,56,3055-3061) 。 ·Another example of a binding fragment is a Fab' that differs from a Fab fragment by having several residues added to the carboxyl terminus of the heavy chain CH 1 domain containing one or more cysteines from the antibody hinge region, and a Fab'-SH which is a Fab' fragment in which the cysteine residue(s) of the constant domain have free thiol groups. 。 。

[0084] Typically, and preferably, the functional fragment of the IL-1β binding antibody is a part or fragment of the "IL-1β binding antibody" as defined above.

[0085] Other features, objects, and advantages of the present invention will become apparent from the description and drawings, as well as from the claims. 。

[0086] The following examples illustrate the above invention; however, they are not intended to limit the scope of the present invention in any way.

Example

[0087] Example 1: CANTOS Trial The data generated from the CANTOS trial are disclosed in WO 2013 / 049278 pamphlet, the entire contents of which are incorporated herein by reference. CANTOS is a randomized, double-blind, placebo-controlled, event-driven trial designed to evaluate whether quarterly subcutaneous canakinumab administration can prevent recurrent cardiovascular events in stable post-myocardial infarction patients with elevated hsCRP. Ten thousand and sixty-one enrolled patients with myocardial infarction and inflammatory atherosclerotic disease had high-sensitivity C-reactive protein (hsCRP) of 2 mg / L or higher. Three increasing doses of canakinumab (50 mg, 150 mg, 300 mg administered subcutaneously every three months) were compared with placebo.

[0088] The following are the details of the CANTOS trial, identified as NTC01327846, the contents of which are incorporated herein by reference in their entirety.

[0089] A randomized, double-blind, placebo-controlled, event-driven trial of quarterly subcutaneous canakinumab for the prevention of recurrent cardiovascular events in stable post-myocardial infarction patients with elevated hsCRP.

[0090] This study provides clear evidence regarding the effect of canakinumab on cardiovascular adverse events in patients with recent MI and high inflammatory burden demonstrated by elevated hsCRP. ​​​​​​​Therefore, it was designed as a multi-facility randomized parallel group placebo-controlled double-blind event-driven trial. This study design was the most robust clinical trial design for verifying the hypothesis that anti-inflammatory treatment with canakinumab reduces major adverse cardiovascular events.

[0091] Theoretical basis of the study design Study population. Patients were eligible for enrollment if they had a history of myocardial infarction and had a blood hsCRP concentration of 2 mg / L or higher despite the use of aggressive secondary prevention strategies. In this trial, patients with a history of chronic or recurrent infection, past malignancies other than basal cell skin cancer, suspected or known immunodeficiency states, a history of tuberculosis or HIV-related diseases or a high risk thereof, or those receiving anti-inflammatory treatment for other systemic diseases were excluded from enrollment.

[0092] Criteria for trial subjects Patients suitable for inclusion in the study had to meet all of the following criteria: 1. Obtained informed consent before any evaluations were performed 2. Male, or female with no possibility of childbirth 3. 18 years of age or older at the first visit 4. A documented spontaneous MI at least 30 days prior to randomization (diagnosed according to universal MI criteria regardless of the presence or absence of evidence of ST segment elevation) · The diagnosis of MI should be consistent with a clinical history of myocardial ischemia associated with an elevation of cardiac biomarkers (preferably troponin) above the upper limit of the reference (URL) 99th percentile, or based on the development of new pathological Q waves regardless of symptoms. For details, refer to the universal definition of MI. a. Acute MI (hospital admission record): at least Evidence of an increase and / or decrease in a cardiac biomarker (preferably troponin) having the above criteria diagnosis for at least one value or MI, and by at least one of the following Evidence of myocardial ischemia is required: i. Symptoms of ischemia ii. Changes in the ECG indicating new ischemia (new ST-T changes or new LBBB) iii. Development of pathological Q waves iv. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormalities b. Past MI (no hospital records of acute event): Any of the following evidence is required is: i. Development of pathological Q waves with or without symptoms ii. Imaging evidence of areas of loss of thin, non-contracting viable myocardium in the absence of non-ischemic causes iii. Pathological findings of healed or healing MI · Patients with MI due to PCI or CABG were excluded 5. Having hsCRP of 2 mg / L or more on a stable (at least 4 weeks) long-term (cardiovascular) drug (standard treatment) (collected before 60 days of the second visit, performed in a central laboratory, which is at least 28 days after MI certification or after any PCI performed separately from MI certification).

[0093] Randomization. Patients were randomized to canakinumab 150 mg, canakinumab 300 mg, or placebo in a 1:1:1 ratio. After the enrollment of 741 participants, a 50 mg dose was added in response to the requirements of the regulatory authority, and the randomization ratio was adjusted accordingly; the inventors attempted to achieve a final randomization ratio of 1.5:1:1:1. All doses of the study drug and placebo were administered subcutaneously once every 3 months; for the 300 mg dose, the regimen was 300 mg every 2 weeks for the first 2 doses and then once every 3 months. Random and placebo were administered subcutaneously once every 3 months; for the 300 mg dose, the regimen was 300 mg every 2 weeks for the first 2 doses and then once every 3 months. Random Stratification was performed using a centralized computer system with time from index myocardial infarction and by test part (before and after including a dose of 50 mg).

[0094] Evaluation items. The primary efficacy evaluation item was the time to the first occurrence of non-fatal myocardial infarction, any non-fatal stroke, or cardiovascular death. This trial had two important secondary efficacy evaluation items. The first important secondary evaluation item included the components of the primary evaluation item and hospitalization for unstable angina requiring urgent revascularization. The other two pre-specified secondary evaluation items were all-cause death and the composite of non-fatal myocardial infarction, non-fatal stroke, or all-cause death. All components of these evaluation items were adjudicated by an evaluation item adjudication committee, and the members were blinded to the allocation of the test drug.

[0095] Statistical analysis. The distribution of the rate of change from baseline of hsCRP and lipid levels was compared between placebo and each canakinumab group at intervals of up to 48 months. For IL-6, a similar comparison was made for up to 12 months. Log-rank tests and Cox proportional hazards models stratified by time from index myocardial infarction and test part were used to analyze pre-specified primary and important secondary cardiovascular outcomes that occurred during the follow-up of the trial according to the intention-to-treat principle. Formal evaluation of significance for individually dose-adjusted multiplicity was performed according to a closed procedure. Based on the closed procedure, using the pre-specified α-error allocation, the threshold for the two-sided P-value for statistical significance of the primary evaluation item was canakinumab at a dose of 300 mg. ​​​​​​​In the test with the placebo, it was 0.01058, and in the tests with the other two doses and the placebo, it was 0. 02115. In the closed procedure, the formal significance test for important secondary evaluation items was only conducted at any given dose if the significance threshold for the primary evaluation item at that dose was met as specified.

[0096] The main analysis strategy was based on pairwise comparisons between individual dose groups and the placebo group, but also included a comparison of the incidence rate in the placebo and the incidence rate in all canakinumab with increasing doses (using scores of 0, 1, 3, 6 proportional to the dose in the trend analysis), and a comparison of the combined effective canakinumab treatment group with the placebo. Additionally, a on-treatment analysis was performed to follow each patient until 11 9 days after the last study injection. The significance thresholds for these tests were not adjusted for multiplicity. A similar analysis was used for adverse events. All P - values were two - sided, and all confidence intervals were calculated at the 95% level of confidence.

[0097] Patients. The trial registration started in April 2011 and was completed in March 2014; the last study visit was in June 2017. Of the 17,482 post - infarction patients screened at the central laboratory, 10,061 (57.6%) were correctly randomized and received at least one dose of the study drug. The most common reasons for exclusion were hsCRP less than 2 mg / L (46% of the excluded subjects), active tuberculosis or tuberculosis risk factors (25.4%), and concomitant diseases to be excluded (9.9%).

[0098] The mean age of the randomized participants was 61 years, 26% were female, and 40% had diabetes mellitus. Most participants had previously undergone revascularization (67% had percutaneous coronary intervention ​​​​Intervention, 14% had coronary artery bypass grafting). At baseline, antithrombotic therapy was 95 %, lipid-lowering therapy was 93%, anti-ischemic agents were 91%, and renin-angiotensin system inhibitors were 79%. The median hsCRP at entry was 4.2 mg / L, and the median LDL cholesterol was 82 mg / dL.

[0099] Effect on inflammatory biomarkers and lipid levels. Compared with placebo, at 48 months, hsCRP decreased by 26%, 37%, and 41% in the canakinumab groups of 50 mg, 150 mg, and 300 mg, respectively (all P values < 0.001 in the comparison of the median increase / decrease rate with canakinumab and the median increase / decrease rate with placebo). A similar effect was also observed for IL-6 (measured up to 12 months). In contrast, with the use of canakinumab, LDL cholesterol or HDL cholesterol did not decrease, and the median triglyceride increased by 4 - 5%.

[0100] Effect on follow-up and clinical evaluation items: By the end of the follow-up, 18.1% of the patients in the placebo group discontinued the study drug, compared with 18.7% of the patients in the combined canakinumab group. At the median follow-up period of 3.7 years, the incidence of the primary evaluation (including non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death) in the placebo group, 50 mg group, 150 mg group, and 300 mg group was 4.50, 4.11, 3.86, and 3.9 per 100 person-years, respectively. No significant effect was observed for the primary evaluation items in the canakinumab 50 mg dose group compared with placebo (hazard ratio [HR] 0.93, P = 0.30). In contrast, in the canakinumab 150 mg dose group, a statistically significant effect on the primary evaluation items was observed ta (HR 0.85, P = 0.02075, threshold P value 0.02115). Canakinumab 3 In the 00 mg dose group, the hazard ratio was similar, but the P value did not meet the pre-specified significance threshold value (HR 0.86, P = 0.0314, threshold P value 0.01058). The P value for the overall trend of the effective dose groups compared to placebo was 0.020, and the P value for the comparison of all combined doses with placebo was 0.015 (both results were not adjusted in multiple tests). Furthermore, a subgroup of patients who showed a significant decrease in hsCRP levels after treatment with canakinumab 3 months later had a statistically significant reduction in the risk of MACE compared to the entire treatment population. Canakinumab at 150 mg and 300 mg respectively was administered, and responder patients with hsCRP levels reduced to less than 1.8 mg / L showed a reduction in the relative risk of MACE of 24% and 22% respectively, based on estimates from 500 bootstrap samples based on a causal inference analysis assuming an exponential survival distribution Canakinumab at 150 mg and 300 mg respectively was administered, and responder patients with hsCRP levels reduced to less than 1.5 mg / L showed a reduction in the relative risk of MACE of 26% and 27% respectively, based on estimates from 500 bootstrap samples based on a causal inference analysis assuming an exponential survival distribution For important secondary cardiovascular evaluation items (including hospitalization for unstable angina requiring urgent revascularization in addition to the primary evaluation item), the incidence rates in the placebo group, 50 mg group, 150 mg group, and 3 00 mg group were 5.13, 4.56, 4.29, and 4.25 per 100 person-years respectively (Table 2). The dose of canakinumab 150 mg (P value for the primary evaluation item was significant for the primary evaluation item) showed a significant reduction in the risk of MACE compared to the placebo group, but the difference was not statistically significant for the secondary evaluation items

[0101] For important secondary cardiovascular evaluation items (including hospitalization for unstable angina requiring urgent revascularization in addition to the primary evaluation item), the incidence rates in the placebo group, 50 mg group, 150 mg group, and 3 00 mg group were 5.13, 4.56, 4.29, and 4.25 per 100 person-years respectively (Table 2). The dose of canakinumab 150 mg (P value for the primary evaluation item was significant for the primary evaluation item) showed a significant reduction in the risk of MACE compared to the placebo group, but the difference was not statistically significant for the secondary evaluation items In those who met the secondary cardiovascular evaluation criteria (i.e., met the secondary threshold), the hazard ratio of the secondary cardiovascular evaluation items was 0.83 (P = 0.00525, threshold P-value 0.00529) (Figure 2D). According to the closed procedure, the formal significance test for the pre-specified secondary evaluation items was not performed at doses of 50 mg and 300 mg. The hazard ratios for these doses were 0.90 and 0.83, respectively. The P-value for the overall trend of the active dose groups compared with placebo was 0.003, and the P-value for the comparison of all combined doses with placebo was 0.001 (both results were not adjusted in multiple trials). For the additional analysis of secondary evaluation items and the analysis of the components of the primary and secondary evaluation items, no adjustment was made in multiple trials. A nominally significant decrease was seen in myocardial infarction with canakinumab at a dose of 150 mg; hospitalizations for unstable angina requiring urgent revascularization were seen at doses of 150 mg and 300 mg; and all coronary artery revascularization procedures were seen at all three doses. In the comparison of all doses of canakinumab with placebo, the all-cause mortality rate was neutral (HR 0.94, 95% CI 0.83 - 1.06, P = 0.31). In the analysis during treatment of the primary evaluation items, the hazard ratios observed in the placebo group, 50 mg group, 150 mg group, and 300 mg group were 1.0, 0.90, 0.83, and 0.79, respectively (P-trend for the overall group = 0.003). In the comparative analysis of important secondary cardiovascular evaluation items, the corresponding hazard ratios were 1.0, 0.88, 0.80, and 0.77, respectively (P-trend for the overall group < 0.001).

[0102] Adverse events and other clinical outcomes. Neutropenia occurred among those assigned canakinumab. In the comparison of all doses of canakinumab with placebo, the all-cause mortality rate was neutral (HR 0.94, 95% CI 0.83 - 1.06, P = 0.31). In the analysis during treatment of the primary evaluation items, the hazard ratios observed in the placebo group, 50 mg group, 150 mg group, and 300 mg group were 1.0, 0.90, 0.83, and 0.79, respectively (P-trend for the overall group = 0.003). In the comparative analysis of important secondary cardiovascular evaluation items, the corresponding hazard ratios were 1.0, 0.88, 0.80, and 0.77, respectively (P-trend for the overall group < 0.001). In the comparison of all doses of canakinumab with placebo, the all-cause mortality rate was neutral (HR 0.94, 95% CI 0.83 - 1.06, P = 0.31). In the analysis during treatment of the primary evaluation items, the hazard ratios observed in the placebo group, 50 mg group, 150 mg group, and 300 mg group were 1.0, 0.90, 0.83, and 0.79, respectively (P-trend for the overall group = 0.003). In the comparative analysis of important secondary cardiovascular evaluation items, the corresponding hazard ratios were 1.0, 0.88, 0.80, and 0.77, respectively (P-trend for the overall group < 0.001). .94, 95% CI 0.83 - 1.06, P = 0.31). In the analysis during treatment of the primary evaluation items, the hazard ratios observed in the placebo group, 50 mg group, 150 mg group, and 300 mg group were 1.0, 0.90, 0.83, and 0.79, respectively (P-trend for the overall group = 0.003). In the comparative analysis of important secondary cardiovascular evaluation items, the corresponding hazard ratios were 1.0, 0.88, 0.80, and 0.77, respectively (P-trend for the overall group < 0.001). = 0.003). In the comparative analysis of important secondary cardiovascular evaluation items, the corresponding hazard ratios were 1.0, 0.88, 0.80, and 0.77, respectively (P-trend for the overall group < 0.001). = 0.003). In the comparative analysis of important secondary cardiovascular evaluation items, the corresponding hazard ratios were 1.0, 0.88, 0.80, and 0.77, respectively (P-trend for the overall group < 0.001). 1.0, 0.88, 0.80, and 0.77, respectively (P-trend for the overall group < 0.001). 01).

[0103] Adverse events and other clinical outcomes. Neutropenia occurred among those assigned canakinumab. More generally, when pooling three canakinumab groups and comparing with placebo, there was a statistically significant increase in fatal events due to infection or sepsis (incidence rate per 100 person - years 0.31 vs. 0.18, P = 0.023). Participants who developed infections were older and had a tendency to be more prone to diabetes. In this trial, the incidence of tuberculosis was confirmed in 6 cases at the same rate in both the canakinumab group and the placebo group (0.06%); 5 cases occurred in India and 1 case occurred in Taiwan. Thrombocytopenia was more common among patients assigned canakinumab, but no bleeding differences were observed. No increase in injection - site reactions was observed. Consistent with the known effects of IL - 1β inhibition, canakinumab resulted in a significant

[0104] decrease in reports of arthritis, gout, and osteoarthritis (explained in more detail in Example 2). Also, canakinumab significantly reduced the mortality rate due to cancer. CANTOS was designed to directly test the inflammatory hypothesis of atherothrombosis. In this trial, among patients with a history of myocardial infarction, canakinumab significantly reduced hsCRP levels and IL - 6 levels, and lipid levels were not reduced. The 50 - mg dose of canakinumab had no statistically significant effect on the primary cardiovascular assessment compared with placebo, but participants in the 150 - mg dose group experienced a 15% relative hazard

[0105] reduction in the primary assessment (4.50 - 3.86 events per 100 person - years) and a 17% reduction in an important secondary cardiovascular assessment (5.13 - 4.29 events per 100 person - years). The P - values for both of these assessments met the pre - specified statistical significance multiplicity - adjustment threshold. The 300 - mg dose of canakinumab had no statistically significant effect on the primary cardiovascular assessment compared with placebo, but participants in the 150 - mg dose group experienced a 15% relative hazard reduction in the primary assessment (4.50 - 3.86 events per 100 person - years) and a 17% reduction in an important secondary cardiovascular assessment (5.13 - 4.29 events per 100 person - years). The P - values for both of these assessments met the pre - specified statistical significance multiplicity - adjustment threshold. The 300 - mg dose The reduction in the hazard of the group was similar to that of the 150 mg dose group, but the pre-specified threshold of statistical significance was not met in this group. However, both the meta-analysis and trend analysis of all canakinumab doses suggest a beneficial effect of canakinumab on cardiovascular outcomes. The specific targeting of IL-1β as a cytokine-based therapy for the secondary prevention of atherosclerotic events is based on several observations. The pro-inflammatory cytokine IL-1β plays multiple roles in the development of atherothrombotic plaques, including the induction of procoagulant activity, the promotion of monocyte and leukocyte adhesion to vascular endothelial cells, and the growth of vascular smooth muscle cells. In mice, deficiency of IL-1β reduces lesion formation, while in cholesterol-fed pigs, exposure to exogenous IL-1β increases intimal hyperplasia . The Nod-like receptor protein 3 (NLRP3) inflammasome activates IL-1β, which is a process promoted by cholesterol crystals, neutrophil extracellular traps, local hypoxia, and atherosclerotic flow. This activation of IL-1β stimulates the downstream IL- 6 receptor signaling pathway, which is suggested by Mendelian randomization studies as a potential causal pathway for atherothrombosis. More recently, studies in congenic mice and clonal hematopoiesis have confirmed the involvement of IL-1β in the process by which bone marrow activation accelerates atherosclerosis. Furthermore, the expression of specific inflammasome gene modules that affect IL-1β is associated with an increased all-cause mortality and atherosclerosis in the elderly. . The activation of IL-1β in this way is a process promoted by cholesterol crystals, neutrophil extracellular traps, local hypoxia, and atherosclerotic flow. This activation of IL-1β stimulates the downstream IL- 6 receptor signaling pathway, which is suggested by Mendelian randomization studies as a potential causal pathway for atherothrombosis. More recently, studies in congenic mice and clonal hematopoiesis have confirmed the involvement of IL-1β in the process by which bone marrow activation accelerates atherosclerosis. Furthermore, the expression of specific inflammasome gene modules that affect IL-1β is associated with an increased all-cause mortality and atherosclerosis in the elderly. In CANTOS, patients generally had well-controlled LDL cholesterol levels. The expression of specific inflammasome gene modules that affect IL-1β is associated with an increased all-cause mortality and atherosclerosis in the elderly.

[0106] Patients in CANTOS generally had well-controlled LDL cholesterol levels. ​However, the event rate of placebo was high, and the cumulative incidence rate exceeded 20% in 5 years. Therefore, according to the data of the present inventors, patients who received statin treatment with residual inflammatory risk evaluated to have a baseline hsCRP exceeding 2 mg / L have at least the same, if not higher, future event rate than patients who received statin treatment with residual risk due to LDL cholesterol. These two patient groups may be different and individual treatment approaches may be required. Despite the fact that cholesterol levels did not decrease, the magnitude of the effect of canakinumab (administered every 3 months) on cardiovascular events was comparable to the magnitude of the effect associated with monoclonal antibodies targeting PCSK9 (administered every 2 - 4 weeks). However, the inhibition of IL-1β is a narrow - scope intervention corresponding to only one of many potential anti - inflammatory pathways that may serve as targets for atherosclerotic plaque formation inhibition. The present inventors observed a statistically significant increase in fatal infections and sepsis due to canakinumab, as well as a decrease in platelet count without an increase in bleeding. In contrast, there was a significant decrease in cancer mortality among patients assigned to canakinumab, which is consistent with experimental data associating IL - 1 with the progression and invasion of certain tumors, particularly lung cancer. There was no significant difference in all - cause mortality between treatment groups. No significant hepatotoxicity was observed. The beneficial effects of canakinumab observed in arthritis, gout, and osteoarthritis are consistent with the well - described effects of the IL - 1 and IL - 6 pathways in these disorders. In conclusion, in CANTOS, patients with a history of myocardial infarction and hsCRP levels of 2 mg / L or higher were randomized to receive one of three doses of canakinumab or placebo. According to the data of the present inventors, patients who received statin treatment with residual inflammatory risk evaluated to have a baseline hsCRP exceeding 2 mg / L have at least the same, if not higher, future event rate than patients who received statin treatment with residual risk due to LDL cholesterol. These two patient groups may be different and individual treatment approaches may be required. Despite the fact that cholesterol levels did not decrease, the magnitude of the effect of canakinumab (administered every 3 months) on cardiovascular events was comparable to the magnitude of the effect associated with monoclonal antibodies targeting PCSK9 (administered every 2 - 4 weeks). However, the inhibition of IL-1β is a narrow - scope intervention corresponding to only one of many potential anti - inflammatory pathways that may serve as targets for atherosclerotic plaque formation inhibition. The present inventors observed a statistically significant increase in fatal infections and sepsis due to canakinumab, as well as a decrease in platelet count without an increase in bleeding. In contrast, there was a significant decrease in cancer mortality among patients assigned to canakinumab, which is consistent with experimental data associating IL - 1 with the progression and invasion of certain tumors, particularly lung cancer. There was no significant difference in all - cause mortality between treatment groups. No significant hepatotoxicity was observed. The beneficial effects of canakinumab observed in arthritis, gout, and osteoarthritis are consistent with the well - described effects of the IL - 1 and IL - 6 pathways in these disorders. In conclusion, in CANTOS, patients with a history of myocardial infarction and hsCRP levels of 2 mg / L or higher were randomized to receive one of three doses of canakinumab or placebo. However, the event rate of placebo was high, and the cumulative incidence rate exceeded 20% in 5 years. Therefore, according to the data of the present inventors, patients who received statin treatment with residual inflammatory risk evaluated to have a baseline hsCRP exceeding 2 mg / L have at least the same, if not higher, future event rate than patients who received statin treatment with residual risk due to LDL cholesterol. These two patient groups may be different and individual treatment approaches may be required. Despite the fact that cholesterol levels did not decrease, the magnitude of the effect of canakinumab (administered every 3 months) on cardiovascular events was comparable to the magnitude of the effect associated with monoclonal antibodies targeting PCSK9 (administered every 2 - 4 weeks). However, the inhibition of IL-1β is a narrow - scope intervention corresponding to only one of many potential anti - inflammatory pathways that may serve as targets for atherosclerotic plaque formation inhibition. have at least the same, if not higher, future event rate than patients who received statin treatment with residual risk due to LDL cholesterol. These two patient groups may be different and individual treatment approaches may be required. Despite the fact that cholesterol levels did not decrease, the magnitude of the effect of canakinumab (administered every 3 months) on cardiovascular events was comparable to the magnitude of the effect associated with monoclonal antibodies targeting PCSK9 (administered every 2 - 4 weeks). However, the inhibition of IL-1β is a narrow - scope intervention corresponding to only one of many potential anti - inflammatory pathways that may serve as targets for atherosclerotic plaque formation inhibition. The present inventors observed a statistically significant increase in fatal infections and sepsis due to canakinumab, as well as a decrease in platelet count without an increase in bleeding. In contrast, there was a significant decrease in cancer mortality among patients assigned to canakinumab, which is consistent with experimental data associating IL - 1 with the progression and invasion of certain tumors, particularly lung cancer. There was no significant difference in all - cause mortality between treatment groups. No significant hepatotoxicity was observed. The beneficial effects of canakinumab observed in arthritis, gout, and osteoarthritis are consistent with the well - described effects of the IL - 1 and IL - 6 pathways in these disorders. In conclusion, in CANTOS, patients with a history of myocardial infarction and hsCRP levels of 2 mg / L or higher were randomized to receive one of three doses of canakinumab or placebo. It was randomized. 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 while maintaining the acceptable level of side effects.

[0107] Example 2: Canakinumab ((Ilaris®)) prevents hip and knee arthroplasty (THR / TKR) in OA patients: Results of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANT OS) trial Background / Purpose: In OA, there is no treatment method to prevent the progression of the disease (DMOAD). Canakinumab, a monoclonal antibody targeting interleukin-1β, reduced the incidence of inflammation and cardiovascular events in the CANTOS trial. The CANTOS trial randomized a total of 10,061 men and women with a history of myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg / L or higher to one of three doses (50 mg, 150 mg, or 300 mg ) of placebo or canakinumab administered subcutaneously once every three months. The median follow-up period was 3.7 years.

[0108] Methods: A post hoc analysis of CANTOS data designed to address the impact of canakinumab on the incidence of OA-related adverse events (AEs) and serious adverse events (particularly SAEs, as well as total knee arthroplasty (TKR) and total hip arthroplasty (THR)) in all patients and patients with a history of OA. The relationship between OA-related events and the on-treatment concentrations of hsCRP and IL-6 was also examined. A clinical database was searched using the high-level osteoarthritis (OAP). ​​​​​​​​​ Survival time analysis was performed on the incidence rate of the first occurrence of related AEs. The drug treatment group was compared with the placebo by the two-sided log-rank test. Next, the drug treatment groups were pooled and the time until OA-related AEs, SA Es, and TKR / THR occurred was analyzed by Cox proportional hazards regression .

[0109] The following table shows the analysis:

[0110]

Table 2

[0111] As shown above, a total of 1,569 patients (15.6%) had a history of OAP (total of the canakinumab group N = 1073 and the placebo group N = 496). A total of 259 (16 .5%) of OA-related AEs, 82 (5.2%) of SAEs, and 67 (4.3%) of THR / TKR occurred in OAP patients. In the entire population, there were 52 THR and 47 TKR present, corresponding to 0.98% of the entire CANTOS population. hsCRP and IL-6 decreased in a dose-responsive manner with 300 m g of canakinumab and decreased by 46% compared to the placebo at 3 months. Table 3 shows the results of the reduction of OA and degenerative effects.

[0112]

Table 3

[0113] Conclusion: Treatment with canakinumab reduces the risk of worsening of OA (AEs and SAEs) ("RRR") and significantly reduces the risk of THR and TK R in patients with known existing OA and in the entire CANTOS population, providing evidence of the DMOAD effect of canakinumab in this population. administered. Canakinumab demonstrated a reduction in OA-related AEs and SAEs compared to placebo, regardless of OA history. In the overall population, during the double-blind period (median follow-up of 3.7 years), canakinumab reduced the risk of OA-related AEs by 23% compared to placebo [95% CI; 9% - 35%], p = 0.002. The time to the first OA-related AE due to treatment is shown in Figure 1 below, which demonstrates a significant reduction in AEs over time for both 50 mg and 150 mg of canakinumab compared to placebo (p-values were 0.0033 and 0.0016, respectively). For 300 mg of canakinumab, the p-value was 0.068 8. The results are clear: · There were a total of 123 OA-related SAEs in the database.

[0114] · Classification into total hip / knee arthroplasty (THR / TKR) was determined between two TMEs, and two uncertain cases were determined as one replacement and the other as "other" surgery. · There were 52 THR and 47 TKR, which corresponded to 0.98% of the total CANTOS population. · The results illustrated in Figures 1 and 2 are impressive. As seen in Figure 1, the time to the first OA-related AE in patients is clearly dose-dependent. The time to the first OA increases with the three measured doses of canakinumab at 50 mg, 150 mg, and 300 mg. As shown in the table above, in all patients and patients with a history of OA, a 45% significant relative risk reduction was seen in the pooled canakinumab group and placebo in the time to hip or knee replacement. Figure 2 shows the time to hip or knee replacement in OA patients

[0115] The results illustrated in Figures 1 and 2 are impressive. As seen in Figure 1, the time to the first OA-related AE in patients is clearly dose-dependent. The time to the first OA is clearly dose-dependent up to the first OA-related AE in patients. The time to the first OA increases with the three measured doses of canakinumab at 50 mg, 150 mg, and 300 mg. As shown in the table above, in all patients and patients with a history of OA, a 45% significant relative risk reduction was seen in the pooled canakinumab group and placebo in the time to hip or knee replacement. Figure 2 shows the time to hip or knee replacement in OA patients up to hip or knee replacement in OA patients shows the average time. Canakinumab clearly shows a significant improvement compared to placebo. Therefore, canakinumab is very effective in reducing the risk of knee and hip arthroplasty.

[0116] Example 3: OA-related AE as a function of hsCRP level Figure 3 shows a graph presentation of the risk of OA-related AE in groups classified by hsCRP concentration. In this table, a total of 259 (16.5%) OA-related AEs occurred in patients with a history of OA. Patients were classified based on hsCRP levels of less than 1 mg, or 1 mg or more and less than 2 mg, or 2 mg or more at 3 months, and levels correlated with OA-related AE over the study period. From the graph, it is clear that patients with lower hsCRP levels at both cut-offs of 1 mg / L and 2 mg / L had a higher response rate compared to placebo patients with similar levels of hsCRP, or regardless of comparing with placebo patients at any level (unclassified). )

[0117] Example 4: Total joint replacement in OA patients as a function of hsCRP level Figure 4 shows a graph presentation of the total number of joint replacements in patients with a history of OA as a function of hsCRP level. In this table, a total of 67 (4.3%) THR / TKRs occurred in patients with a history of OA. Patients were classified based on hsCRP levels of less than 1 mg, or 1 mg or more and less than 2 mg, or 2 mg or more at 3 months, and levels correlated with hip / knee replacement (TKR) over the study period. The table clearly shows that patients with lower hsCRP levels at both cut-offs of 1 mg / L and 2 mg / L had a higher response rate. %) ​​​​​​​​​​

[0118] Example 5: OA Phase III Confirmation Test a. Purpose The purpose of this test is to demonstrate that canakinumab reduces the structural progression of OA in patients with a high inflammatory burden (hsCRP level of 2 mg / L or higher). This test, using the results of CANTOS, is used to support the registration of canakinumab for the treatment of osteoarthritis in patients with hsCRP of 2 mg / L or higher at the start of treatment. of osteoarthritis in patients with hsCRP of 2 mg / L or higher at the start of treatment. of osteoarthritis in patients with hsCRP of 2 mg / L or higher at the start of treatment. b. Patient Population Adult patients diagnosed with osteoarthritis who meet the following criteria: · Major Selection Criteria 1. Age 40 years or older 2. Weight over 35 or 40 kg and body mass index (BMI) less than 40 kg / m 2 not met. 3. Diagnosed with knee osteoarthritis based on the clinical and radiological criteria of the American College of Rheumatology. 4. High-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or higher 5. History of knee pain for at least 6 months and on most days (more than 50%) in the previous month. 6. Symptom severity defined by pain of 40 mm or more and 90 mm or less on the VAS (100 mm). 7. Need for knee OA treatment with symptomatic therapy as warranted - systemic non-steroidal anti-inflammatory drugs (NSAIDs) and / or other analgesics, documented as needed 8. WPI less than 8 · Important Exclusion Criteria 1. Severe clinical knee malalignment by the investigator. 2. An artificial knee has already been implanted (less than 1 year) or is poorly tolerated (opposite side). 2. An artificial knee has already been implanted (less than 1 year) or is poorly tolerated (opposite side). 3. A knee prosthesis (either side) already foreseen during the study period 4. A hip prosthesis (either recently implanted (less than 1 year) or anticipated during the study period) side). 5. Previous osteotomy of the lower limb (on either side). 6. Planned targeted knee surgery within 12 months prior to screening or during the study Surgery. 7. Arthroscopy of the target knee joint within 6 months prior to screening or planned during the study inspection. 8. Any other medical condition affecting the knee. 9. Having an MRI of the knee due to incompatibility with the scanner or knee coil Contraindications to MRI, including inability to 10. c. Dosage regimen The dosing schedule for canakinumab was 150 mg subcutaneously every 3 months. This dosing regimen is selected based on the pharmacokinetic (PK) and pharmacodynamic (PD) properties of canakinumab. Safety, biomarker and efficacy data observed in the CANTOS trial and the completion The selection will be based on safety data from completed and ongoing canakinumab trials. d. Sample size Patients will be randomized in a 1:1 ratio to one of two treatment arms: Canakinumab 150mg administered subcutaneously once every 3 months Matching dose of placebo administered subcutaneously every 3 months e. Treatment period The trial will run for 52 / 104 weeks f. Primary endpoint This Phase III study appears to demonstrate that canakinumab reduces structural progression of OA. The primary endpoint of the study was quantitative MRI of the knee joint at 52 weeks. Thus, the change from the base line of the cartilage thickness of the evaluated central medial tibiofemoral compartment (cMTFC:central medial tibiofemoral compartment). is a change from the base line of the cartilage thickness of the evaluated central medial tibiofemoral compartment (cMTFC). g. Secondary evaluation items 1. The percentage of those with progressive OA structure based on the cartilage thickness of the central medial tibiofemoral compartment (cMTFC) evaluated by quantitative MRI of the target knee joint at week 152. 2. The change from the baseline of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC:W estern Ontario and McMaster Universities Osteoarthritis Index) scales the scores of pain, function, and stiffness at week 24 and week 52. 3. The change from the baseline of the pain of the target knee joint measured by a 100-mm visual analog scale (VAS) at week 24 and week 52. 4. The change from the baseline of the global patient assessment of disease activity (PGA) measured by a 100-mm visual analog scale (VAS) at week 24 and week 52. 5. The percentage of OMERACT-OARSI responders at week 52. Based on the OMERACT-OARSI Initiative: Response criteria for OA clinical trials A series of Osteoarthritis Research Society International (OARSI) meetings reexamined Pham et al.2 004. Responders are defined as patients having an improvement of 50% or more in pain or function and an absolute change of 20 or more according to WOMAC and PGA, or having at least 2 of the following 3 improvements: 20% or more improvement in pain and an absolute change of 10 or more or having at least 2 of the following 3 improvements: 20% or more improvement in pain and an absolute change of 10 or more More than 20% function and an absolute change of 10 or more Overall assessment of more than 20% of patients and an absolute change of 10 or more. Change from baseline in cartilage thickness of the total tibiofemoral compartment ( tTFC) of the target knee joint by quantitative MRI at week 6.52 Change from baseline in the bone area of the medial femoral condyle surface of the target knee joint by quantitative MRI at week 7.52 Change from baseline Change from baseline in the bone area of the medial femoral condyle surface of the target knee joint by quantitative MRI at week 8.52 Change from baseline. Change from baseline in the joint space width (JSW) of the target knee joint measured by X-ray at week 9.52 Change from baseline. Change from baseline in SF36-PCS at weeks 10.24 and 52 Change from baseline in SF36-MCS at weeks 11.24 and 52 12. Change in synovitis by MOAKS 13. Pain: Consumption of analgesics over time throughout the study.

[0119] Although various specific embodiments are illustrated and described below, it should be understood that various changes can be made without departing from the spirit and scope of the present disclosure. The present invention may include the following aspects. [1] A method for reducing the risk of progression of osteoarthritis ("OA") in a patient and / or for reducing adverse events associated with OA, comprising administering an IL-1β antagonist, wherein the patient has a high-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or more as evaluated before the first administration of the IL-1β antagonist, and wherein the patient has a reduced hsCRP level of less than 2.3 mg / L as evaluated 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 in a patient and / or for reducing adverse events associated with OA, comprising administering an IL-1β antagonist, wherein the patient has a high-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or more as evaluated before the first administration of the IL-1β antagonist, and wherein the patient has a reduced hsCRP level of less than 2.3 mg / L as evaluated at a predetermined time point after the first administration of the IL-1β antagonist, whereby the administration of the IL-1β antagonist to the patient will be continued. [3] A method for reducing the risk of progression of OA in a patient and / or for reducing adverse events associated with OA, comprising administering canakinumab, wherein the patient has a high-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or more as evaluated before the first administration of canakinumab, and wherein the patient has a reduced hsCRP level of less than 2.3 mg / L as evaluated about 3 months or more after the first administration of canakinumab. [4] A method for reducing the risk of progression of OA in a patient and / or for reducing adverse events, comprising administering canakinumab, wherein the patient has a high-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or more as evaluated before the first administration of canakinumab, and wherein the patient has a reduced hsCRP level of less than 2.3 mg / L as evaluated about 3 months or more after the first administration of canakinumab, whereby the administration of canakinumab to the patient will be continued. [5] The method according to any one of [1] to [4], wherein the progression of the OA includes arthroplasty. [6] The method according to any one of [1] to [5], wherein the patient has documented OA and / or symptomatic OA. [7] The method according to any one of [1] to [6], comprising administering 150 mg to 300 mg of canakinumab. [8] The method according to any one of [1] to [7], comprising administering 150 mg of canakinumab. [9] The method according to any one of [1] to [8], comprising administering 150 mg of canakinumab approximately every three months.

[10] The method according to any one of [1] to [9], wherein the reduced level of hsCRP evaluated approximately 3 months after the first administration of canakinumab, or after a predetermined time point after the first administration of the IL-1β antagonist, is less than 1.5 mg / L.

[11] The method according to any one of [1] to

[10] , wherein the reduced level of hsCRP evaluated approximately 3 months after the first administration of canakinumab, or after a predetermined time point after the first administration of the IL-1β antagonist, is less than 1.0 mg / L.

[12] The method according to any one of [1] to

[11] , wherein the reduced level of hsCRP evaluated approximately 3 months after the first administration of canakinumab, or after a predetermined time point after the first administration of the IL-1β antagonist, is less than 2.2 mg / L, less than 2.1 mg / L, less than 2.0 mg / L, less than 1.9 mg / L, less than 1.8 mg / L, less than 1.7 mg / L, less than 1.6 mg / L, less than 1.5 mg / L, less than 1.4 mg / L, less than 1.3 mg / L, less than 1.2 mg / L, less than 1.1 mg / L, less than 1.0 mg / L, less than 0.9 mg / L, less than 0.8 mg / L, less than 0.7 mg / L, less than 0.6 mg / L, or less than 0.5 mg / L.

[13] The method according to any one of [1] to

[12] , wherein OA supported by the document is evaluated using X-ray and / or MRI.

[14] The method according to any one of [1] to

[13] , wherein the evidence of OA symptoms is pain and / or dysfunction.

[15] The method according to any one of [1] to

[14] , wherein the patient is not a candidate for surgery.

[16] The method according to any one of [1] to

[15] , wherein the patient does not respond to NSAIDs.

[17] The method according to any one of [1] to

[16] , wherein the level of IL-6 is less than 1.15 mg / L or less than 2 mg / L after a predetermined time point after the first administration of the IL-1β antagonist or 3 months after the first administration of canakinumab.

[18] The method according to any one of [1] to

[17] , wherein the patient has previously suffered from a CV event.

[19] The method according to any one of [1] to

[18] , wherein the patient has previously suffered from a myocardial infarction.

[20] A method for reducing the risk of progression of OA in a patient and / or alleviating adverse events associated with OA, comprising administering an IL-1β antagonist, wherein the patient has a high-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or higher evaluated before the first administration of the IL-1β antagonist.

[21] The method according to

[20] , wherein the IL-1β antagonist is canakinumab.

[22] The method according to

[20] or

[21] , comprising administering 150 mg to 300 mg of canakinumab.

[23] The method according to any one of

[20] to

[22] , comprising administering 150 mg to 300 mg of canakinumab approximately every 3 months.

[24] The method according to any one of

[20] to

[23] , wherein OA documented is evaluated using X-ray and / or MRI.

[25] The method according to any one of

[20] to

[24] , wherein the evidence of OA symptoms is pain and / or dysfunction.

[26] The method according to any one of

[20] to

[25] , wherein the patient is not a candidate for surgery.

[27] The method according to any one of

[20] to

[26] , wherein the patient does not respond to NSAIDs.

[28] The method according to any one of

[20] to

[27] , wherein the patient has a history of having suffered from a CV event.

[29] The method according to any one of

[20] to

[28] , wherein the patient has a history of having suffered from a myocardial infarction.

[30] The method according to any one of [1] to

[29] , wherein the total joint replacement may be a total knee arthroplasty or a total hip arthroplasty.

[31] The method according to any one of [1] to

[30] , wherein the patient suffers from shoulder OA, hand OA, or spondylosis (degenerative spondylosis).

[32] The method according to any one of [1] to

[31] , wherein the total joint replacement may be a total shoulder arthroplasty.

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

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

Claims

A pharmaceutical composition comprising canakinumab for use in a method for reducing the risk of total joint replacement in patients with osteoarthritis (OA), said use comprising administering said canakinumab to said patient, (i) said patient having a high-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or more as evaluated before the first administration of canakinumab, and said patient having a reduced hsCRP level of less than 2 mg / L as evaluated at a time point about 3 months or more after the first administration of canakinumab, or (ii) if said patient has a high-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or more as evaluated before the first administration of canakinumab, and said patient has a reduced hsCRP level of less than 2 mg / L as evaluated at a time point about 3 months or more after the first administration of canakinumab, then the administration of canakinumab to said patient will be continued. A pharmaceutical composition. The pharmaceutical composition according to claim 1, wherein said method comprises administering 150 mg to 300 mg of canakinumab. The pharmaceutical composition according to claim 2, wherein said method comprises administering 150 mg of canakinumab. The pharmaceutical composition according to claim 2, wherein said method comprises administering 150 mg of canakinumab approximately every 3 months.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the reduced level of hsCRP evaluated about 3 months after the first administration of canakinumab is less than 1.5 mg / L, or the reduced level of hsCRP evaluated about 3 months after the first administration of canakinumab is less than 1.0 mg / L.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the level of IL-6 after a predetermined time point after the first administration of canakinumab or 3 months after the first administration of canakinumab is less than 1.15 mg / L.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein said patient has (i) previously suffered from a CV event and / or (ii) previously suffered from a myocardial infarction. A pharmaceutical composition comprising canakinumab for use in a method for reducing the risk of total joint replacement in a patient having OA, the method comprising administering canakinumab to the patient, wherein the patient has a high-sensitivity C-reactive protein (hsCRP) level of 2 mg / L or higher as evaluated prior to the first administration of canakinumab. The pharmaceutical composition according to claim 8, wherein the method comprises administering 150 mg to 300 mg of canakinumab. The pharmaceutical composition according to claim 9, wherein the method comprises administering 150 mg to 300 mg of canakinumab approximately every 3 months.

11. The pharmaceutical composition according to any one of claims 8 to 10, wherein the patient has previously suffered from a CV event or has previously suffered from a myocardial infarction.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the total joint replacement is a total knee replacement or a total hip replacement, or the total joint replacement is a total shoulder replacement.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the patient suffers from shoulder OA, hand OA, or spondylosis (also known as osteoarthritis of the spine).

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