Compositions and methods for treating rheumatoid arthritis

Abstract

The present invention provides methods for using anti-IL6 receptor antibodies in monotherapy to treat rheumatoid arthritis and to improve the physical function and quality of life of subjects suffering from rheumatoid arthritis. [Solution] Provided is an antibody for use in a method for improving physical function in a subject suffering from rheumatoid arthritis, wherein: the antibody comprises a heavy chain variable region comprising a specific sequence and a light chain variable region comprising a specific sequence; the antibody is administered subcutaneously to the subject at about 150 mg or about 200 mg once every two weeks; the subject is not administered any other disease-modifying antirheumatic drugs (DMARDs) during the course of administration of the antibody; and the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD different from the antibody, but to no avail.

Description

[Technical Field]

[0001] Related Applications This application claims priority to European Patent Application No. 16305253.3, filed March 7, 2016; European Patent Application No. 16170664.3, filed May 20, 2016; and European Patent Application No. 16306111.2, filed September 5, 2016, each of which is incorporated herein by reference in its entirety.

[0002] FIELD OF THE INVENTION The present invention relates to the field of rheumatoid arthritis. More particularly, the present invention relates to a method for treating rheumatoid arthritis by administering an anti-IL6 antibody to a patient receiving anti-IL6 antibody as a monotherapy. The present invention relates to a method for improving physical function in a subject suffering from rheumatoid arthritis, a method for improving health-related quality of life in a subject suffering from rheumatoid arthritis, and a method for treating rheumatoid arthritis in a subject suffering from rheumatoid arthritis, comprising administering to the subject an antibody to the disease. [Background technology]

[0003] background It is estimated that approximately 0.5% to 1% of the adult population in North America and Europe suffers from rheumatoid arthritis (RA). RA affects women twice as often as men, with incidence highest among women over 40 years of age. stomach.

[0004] RA is characterized by persistent synovitis in multiple joints and progressive destruction of cartilage and bone. The hallmark of this disease is symmetric polyarthritis, characteristically involving the small joints of the hands and feet. The inflammatory process can also target other organs, characteristically bone marrow (anemia), eyes (scleritis, episcleritis), lungs (interstitial pneumonia, pleuritis), heart (pericarditis), and skin (nodules, leukocytoclastic vasculitis). Systemic inflammation is manifested by anemia, elevated erythrocyte sedimentation rate, fibrinogen, and C-reactive protein. Laboratory abnormalities such as CRP (chemically reactive protein), as well as clinical symptoms of fatigue, weight loss, and It is characterized by muscle atrophy in the joint area. The presence of polyclonal high-titer rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies provides evidence of immune dysregulation. It has been estimated that 65% to 70% of people with HIV have a progressive disease that leads to joint destruction, disability, and premature death.

[0005] In addition to improving the clinical symptoms of RA patients, there has been growing interest in improving their physical function and health-related quality of life. Indeed, the patient's health status (the existence of the disease and its consequences) In addition to the usual equipment intended to assess the presence or absence of have developed a new instrument to measure a patient's physical function and quality of life, which is a useful parameter for assessing his or her patient's overall response to a particular treatment. Quality of life goes beyond the continuum of impairment / disability and handicap by asking about what the patient's health condition prevents them from doing and also about their emotional response to these limitations. Quality of life also reflects the influence of the personal, social and economic resources that an individual has and the way these interact with their health condition (Non-Patent Document 1). Physical function assessment in RA patients typically involves measuring the upper limbs. It takes into account fine motor activity, locomotor activity of the lower limbs, and activities involving both the upper and lower limbs. These parameters are now widely used by doctors, clinicians, and regulatory agencies to compare different treatment options offered to RA patients. In some cases, two treatments with similar efficacy profiles may have different quality of life or physical function improvement profiles. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] British Journal of Rheumatology 1997;36:884-888 Summary of the Invention [Means for solving the problem]

[0007] Abstract The inventors of the present invention have demonstrated that anti-IL6 receptor antibodies administered both as single agents are effective for the treatment of RA. It has been shown that it can show remarkable efficacy in treating RA and also can significantly improve the physical function and quality of life of subjects suffering from RA.

[0008] Examples of embodiments of the present invention are listed below:

[0009] Embodiment 1 1. A method of improving physical function in a subject suffering from rheumatoid arthritis, comprising administering to the subject an antibody, wherein: - the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2, - the antibody is administered subcutaneously to the subject at 150 mg or 200 mg once every two weeks; - the subject is not receiving any other disease-modifying antirheumatic drugs (DMARDs) during the course of administration of the antibody, and - the subject has previously been treated for rheumatoid arthritis with at least one DMARD other than the antibody, but without success; The above method.

[0010] Embodiment 2 2. The method of embodiment 1, wherein the subject achieves a change from baseline (BL) in the Health Assessment Questionnaire Disability Index (HAQ-DI) of at least 0.22 at least 24 weeks after administration of the antibody.

[0011] Embodiment 3 3. The method of embodiment 1 or 2, wherein the subject achieves a change from baseline (BL) in Health Assessment Questionnaire-Disability Index (HAQ-DI) of at least 0.30 after at least 24 weeks of administration of the antibody.

[0012] Embodiment 4 4. The method of any one of embodiments 1-3, wherein the subject achieves a change from baseline (BL) in Health Assessment Questionnaire-Disability Index (HAQ-DI) of at least 0.40 at least 24 weeks after administration of the antibody.

[0013] Embodiment 5 5. The method of any one of embodiments 1-4, wherein the subject achieves a change from baseline (BL) in Health Assessment Questionnaire-Disability Index (HAQ-DI) of at least 0.50 at least 24 weeks after administration of the antibody.

[0014] EMBODIMENT 6 6. The method of any one of embodiments 1-5, wherein the subject achieves a change from baseline (BL) in Health Assessment Questionnaire-Disability Index (HAQ-DI) of at least 0.60 at least 24 weeks after administration of the antibody.

[0015] EMBODIMENT 7 7. The method of any one of embodiments 1-6, wherein the subject achieves a change from baseline (BL) in Health Assessment Questionnaire-Disability Index (HAQ-DI) of at least 0.61 at least 24 weeks after administration of the antibody.

[0016] EMBODIMENT 8 1. A method of improving health-related quality of life in a subject suffering from rheumatoid arthritis, comprising administering to the subject an antibody, wherein: - the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2, - the antibody is administered subcutaneously to the subject at 150 mg or 200 mg once every two weeks; - the subject is not receiving any other disease-modifying antirheumatic drugs (DMARDs) during the course of administration of the antibody, and - the subject has previously been treated for rheumatoid arthritis with at least one DMARD other than the antibody, but without success; The above method.

[0017] EMBODIMENT 9 9. The method of embodiment 8, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 2.5 at least 24 weeks after administration of the antibody.

[0018] EMBODIMENT 10 10. The method of embodiment 8 or 9, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 3 at least 24 weeks after administration of the antibody.

[0019] EMBODIMENT 11 The method of any one of embodiments 8 to 10, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 4 at least 24 weeks after administration of the antibody.

[0020] EMBODIMENT 12 The method of any one of embodiments 8 to 11, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 5 at least 24 weeks after administration of the antibody.

[0021] EMBODIMENT 13 13. The method of any one of embodiments 8 to 12, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 6 at least 24 weeks after administration of the antibody.

[0022] EMBODIMENT 14 The method of any one of embodiments 8 to 13, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 7 at least 24 weeks after administration of the antibody.

[0023] EMBODIMENT 15 Subjects must achieve a baseline (BL) score of at least 8 on the Short Form-36 Physical Component Summary (SF-36 PCS) at least 24 weeks after administration of the antibody. 15. The method of any one of embodiments 8 to 14, wherein the change from

[0024] EMBODIMENT 16 16. The method of any one of embodiments 8 to 15, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of 8.74 at least 24 weeks after administration of the antibody.

[0025] EMBODIMENT 17 1. A method of treating rheumatoid arthritis in a subject comprising administering to the subject an antibody, wherein: - the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2, - The antibody is administered subcutaneously at 150 mg or 200 mg once every two weeks, - the subject is not receiving any other disease-modifying antirheumatic drugs (DMARDs) during the course of administration of the antibody, and - the subject has previously been treated for rheumatoid arthritis with at least one DMARD other than the antibody, but without success; The above method.

[0026] EMBODIMENT 18 Subjects will have a minimum of 24 weeks post-administration of the antibody and a minimum of 24 weeks post-administration of the antibody. 18. The method of embodiment 17, wherein the patient achieves a 20% improvement in Acute Critical Care Disease Index (ACR20).

[0027] EMBODIMENT 19 19. The method of embodiment 17 or 18, wherein the subject achieves a 50% improvement in the American College of Rheumatology Core Set Disease Index (ACR50) at least 24 weeks after administration of the antibody.

[0028] EMBODIMENT 20 20. The method of any one of embodiments 17-19, wherein the subject achieves a 70% improvement in the American College of Rheumatology Core Set Disease Index (ACR70) at least 24 weeks after administration of the antibody.

[0029] EMBODIMENT 21 The method of any one of embodiments 17 to 20, wherein the subject achieves a change from baseline (BL) in Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR) of at least 2 after at least 24 weeks of administration of the antibody.

[0030] EMBODIMENT 22 The method of any one of embodiments 17 to 21, wherein the subject achieves a change from baseline (BL) in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) of at least 2.5 after at least 24 weeks of administration of the antibody.

[0031] EMBODIMENT 23 23. The method of any one of embodiments 17-22, wherein the subject achieves a change from baseline (BL) in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) of at least 3, at least 3.2, or about 3.28 after at least 24 weeks of administration of the antibody. How to post.

[0032] EMBODIMENT 24 The method of any one of embodiments 17 to 23, wherein the subject achieves a DAS28-ESR score of less than 3.2 at least 24 weeks after administration of the antibody.

[0033] EMBODIMENT 25 The method of any one of embodiments 17 to 23, wherein the subject achieves a DAS28-ESR score of less than 2.6 at least 24 weeks after administration of the antibody.

[0034] EMBODIMENT 26 The method according to any one of embodiments 1 to 25, wherein the subject who has previously been treated for rheumatoid arthritis by administering one or more DMARDs different from the antibody but without success is a subject who previously had an inadequate response to or was intolerant to one or more disease-modifying antirheumatic drugs (DMARDs).

[0035] EMBODIMENT 27 27. The method according to any one of embodiments 1 to 26, wherein the subject who has previously been treated for rheumatoid arthritis by administering at least one DMARD other than the antibody, but without effect, is a subject who has previously been treated for rheumatoid arthritis by administering methotrexate, but without effect.

[0036] EMBODIMENT 28 The method according to any one of embodiments 1 to 27, wherein the subject who has previously been treated for rheumatoid arthritis by administering one or more DMARDs other than the antibody but without success is a subject who previously had an inadequate response to or was intolerant to methotrexate.

[0037] EMBODIMENT 29 The method according to any one of embodiments 1 to 28, wherein the subject suffering from rheumatoid arthritis is a subject suffering from moderate to severe active rheumatoid arthritis.

[0038] EMBODIMENT 30 30. The method of any one of embodiments 1 to 29, wherein the antibody is administered using a pre-filled syringe.

[0039] EMBODIMENT 31 31. The method of any one of embodiments 1 to 30, wherein the antibody is administered using an auto-injector.

[0040] EMBODIMENT 32 32. The method of any one of embodiments 1-31, wherein the antibody is administered in a buffered aqueous solution of about pH 6.0 containing about 21 mM histidine, about 45 mM arginine, about 0.2% (wt / vol) polysorbate 20, and about 5% (wt / vol) sucrose.

[0041] EMBODIMENT 33 33. The method of embodiment 32, wherein the solution comprises at least 130 mg / mL of antibody.

[0042] EMBODIMENT 34 33. The method of embodiment 32, wherein the solution comprises 131.6 mg / mL of antibody.

[0043] EMBODIMENT 35 33. The method of embodiment 32, wherein the solution comprises 175 mg / mL of antibody.

[0044] EMBODIMENT 36 The method according to any one of embodiments 1 to 35, wherein the antibody (comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2) is sarilumab.

[0045] EMBODIMENT 37 1. An antibody for use in a method of improving physical function in a subject suffering from rheumatoid arthritis, comprising: - the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2, - the antibody is administered subcutaneously to the subject at 150 mg or 200 mg once every two weeks; - the subject is not receiving any other disease-modifying antirheumatic drugs (DMARDs) during the course of administration of the antibody, and - the subject has previously been treated for rheumatoid arthritis with at least one DMARD other than the antibody, but without success; The above antibody.

[0046] EMBODIMENT 38 The antibody of embodiment 37, wherein the subject achieves a change from baseline (BL) in Health Assessment Questionnaire-Disability Index (HAQ-DI) of at least 0.22 after at least 24 weeks of administration of the antibody.

[0047] EMBODIMENT 39 The antibody of embodiment 37 or 38, wherein the subject achieves a change from baseline (BL) in Health Assessment Questionnaire-Disability Index (HAQ-DI) of at least 0.30 after at least 24 weeks of administration of the antibody.

[0048] EMBODIMENT 40 The antibody of any one of embodiments 37 to 39, wherein the subject achieves a change from baseline (BL) in the Health Assessment Questionnaire-Disability Index (HAQ-DI) of at least 0.40 at least 24 weeks after administration of the antibody.

[0049] EMBODIMENT 41 The antibody of any one of embodiments 37 to 40, wherein the subject achieves a change from baseline (BL) in the Health Assessment Questionnaire-Disability Index (HAQ-DI) of at least 0.50 at least 24 weeks after administration of the antibody.

[0050] EMBODIMENT 42 The antibody of any one of embodiments 37 to 41, wherein the subject achieves a change from baseline (BL) in the Health Assessment Questionnaire-Disability Index (HAQ-DI) of at least 0.60 at least 24 weeks after administration of the antibody.

[0051] EMBODIMENT 43 The antibody of any one of embodiments 37 to 42, wherein the subject achieves a change from baseline (BL) in the Health Assessment Questionnaire-Disability Index (HAQ-DI) of at least 0.61 at least 24 weeks after administration of the antibody.

[0052] EMBODIMENT 44 1. An antibody for use in a method for improving health-related quality of life in a subject suffering from rheumatoid arthritis, comprising: - the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2, - the antibody is administered subcutaneously to the subject at 150 mg or 200 mg once every two weeks; - the subject is not receiving any other disease-modifying antirheumatic drugs (DMARDs) during the course of administration of the antibody, and - the subject has previously been treated for rheumatoid arthritis with at least one DMARD other than the antibody, but without success; The above antibody.

[0053] EMBODIMENT 45 The antibody for use of embodiment 44, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 2.5 after at least 24 weeks of administration of the antibody.

[0054] EMBODIMENT 46 The antibody for use of embodiment 44 or 45, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 3 at least 24 weeks after administration of the antibody.

[0055] EMBODIMENT 47 The antibody for use according to any one of embodiments 44 to 46, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 4 at least 24 weeks after administration of the antibody.

[0056] EMBODIMENT 48 The antibody for use according to any one of embodiments 44 to 47, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 5 at least 24 weeks after administration of the antibody.

[0057] EMBODIMENT 49 The antibody for use according to any one of embodiments 44 to 48, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 6 at least 24 weeks after administration of the antibody.

[0058] EMBODIMENT 50 The antibody for use according to any one of embodiments 44 to 49, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 7 at least 24 weeks after administration of the antibody.

[0059] EMBODIMENT 51 The antibody for use according to any one of embodiments 44 to 50, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 8 at least 24 weeks after administration of the antibody.

[0060] EMBODIMENT 52 Subjects will demonstrate a change from baseline (BL) of 8.7% on the Short Form-36 Physical Component Summary (SF-36 PCS) at least 24 weeks after administration of the antibody. An antibody for use according to any one of embodiments 44 to 51, which achieves 4.

[0061] EMBODIMENT 53 1. An antibody for use in a method of treating rheumatoid arthritis in a subject, comprising: - the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2, - the antibody is administered subcutaneously to the subject at about 150 mg or about 200 mg once every two weeks; - the subject is not receiving any other disease-modifying antirheumatic drugs (DMARDs) during the course of administration of the antibody, and - the subject has previously been treated for rheumatoid arthritis with at least one DMARD other than the antibody, but without success; The above antibody.

[0062] EMBODIMENT 54 The antibody for use described in embodiment 53, wherein the subject achieves a 20% improvement in the American College of Rheumatology Core Set Disease Index (ACR20) at least 24 weeks after administration of the antibody.

[0063] EMBODIMENT 55 55. The antibody for use of embodiment 53 or 54, wherein the subject achieves a 50% improvement in the American College of Rheumatology Core Set Disease Index (ACR50) at least 24 weeks after administration of the antibody.

[0064] EMBODIMENT 56 56. The antibody for use according to any one of embodiments 53 to 55, wherein the subject achieves a 70% improvement in the American College of Rheumatology Core Set Disease Index (ACR70) at least 24 weeks after administration of the antibody.

[0065] EMBODIMENT 57 The antibody for use described in any one of embodiments 53 to 56, wherein the subject achieves a change from baseline (BL) in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) of at least 2 after at least 24 weeks of administration of the antibody.

[0066] EMBODIMENT 58 The antibody for use described in any one of embodiments 53 to 57, wherein the subject achieves a change from baseline (BL) in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) of at least 2.5 after at least 24 weeks of administration of the antibody.

[0067] EMBODIMENT 59 The antibody for use according to any one of embodiments 53 to 58, wherein the subject achieves a change from baseline (BL) in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) of at least 3, at least 3.2, or about 3.28 after at least 24 weeks of administration of the antibody.

[0068] EMBODIMENT 60 The antibody for use according to any one of embodiments 53 to 59, wherein the subject achieves a DAS28-ESR score of less than 3.2 at least 24 weeks after administration of the antibody.

[0069] EMBODIMENT 61 The antibody for use according to any one of embodiments 53 to 60, wherein the subject achieves a DAS28-ESR score of less than 2.6 at least 24 weeks after administration of the antibody.

[0070] EMBODIMENT 62 62. The antibody for use according to any one of embodiments 37 to 61, wherein the subject who has previously been treated for rheumatoid arthritis by administering one or more DMARDs different from the antibody but without success is a subject who previously had an inadequate response to or was intolerant to one or more disease-modifying antirheumatic drugs (DMARDs).

[0071] 63. An antibody for use according to any one of embodiments 37 to 62, wherein the subject who has previously been treated for rheumatoid arthritis by administering at least one DMARD different from the antibody, but without effect, is a subject who has previously been treated for rheumatoid arthritis by administering methotrexate, but without effect.

[0072] 64th embodiment 64. The antibody for use according to any one of embodiments 37 to 63, wherein the subject who has previously been treated for rheumatoid arthritis by administering one or more DMARDs different from the antibody but without success is a subject who previously had an inadequate response to or was intolerant to methotrexate.

[0073] EMBODIMENT 65 The antibody for use according to any one of embodiments 37 to 64, wherein the subject suffering from rheumatoid arthritis is a subject suffering from moderately active to severely active rheumatoid arthritis.

[0074] 66. The method of claim 66, 66. The antibody for use according to any one of embodiments 37 to 65, wherein the antibody is administered using a pre-filled syringe.

[0075] 67. The method of claim 67, The antibody for use according to any one of embodiments 37 to 66, wherein the antibody is administered using an auto-injector.

[0076] 68. The method of claim 68, 68. The antibody for use according to any one of embodiments 37 to 67, wherein the antibody is administered as a buffered aqueous solution of about pH 6.0 containing about 21 mM histidine, about 45 mM arginine, about 0.2% (wt / vol) polysorbate 20, and about 5% (wt / vol) sucrose.

[0077] 69. The method of claim 69, 69. The antibody for use according to embodiment 68, wherein the solution comprises at least 130 mg / mL of the antibody.

[0078] EMBODIMENT 70 69. The antibody for use according to embodiment 68, wherein the solution comprises 131.6 mg / mL of antibody.

[0079] EMBODIMENT 71 69. The antibody for use according to embodiment 68, wherein the solution comprises 175 mg / mL of the antibody.

[0080] EMBODIMENT 72 An antibody for use according to any one of embodiments 37 to 71, wherein the antibody (comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2) is sarilumab.

[0081] EMBODIMENT 73 73. The antibody for use according to any one of embodiments 37 to 72, wherein the antibody is administered subcutaneously to the subject at 150 mg once every two weeks.

[0082] EMBODIMENT 74 73. The antibody for use according to any one of embodiments 37 to 72, wherein the antibody is administered subcutaneously to the subject at 200 mg once every two weeks.

[0083] EMBODIMENT 75 The antibody for use according to any one of embodiments 1 to 74, wherein the subject is intolerant to one or more DMARDs.

[0084] EMBODIMENT 76 The antibody for use according to embodiment 75, wherein the DMARD is methotrexate.

[0085] EMBODIMENT 77 77. The antibody for use according to any one of claims 1 to 76, wherein the subject has moderate to severe active rheumatoid arthritis and has had an inadequate response to or is intolerant to one or more disease-modifying antirheumatic drugs.

[0086] EMBODIMENT 78 The antibody for use according to embodiment 77, wherein the DMARD is methotrexate.

[0087] EMBODIMENT 79 The antibody for use according to any one of embodiments 1 to 78, wherein the subject is suffering from a decrease in quality of life due to RA.

[0088] EMBODIMENT 80 78. The antibody for use of embodiment 77, wherein the subject scores more severe than average on a scale selected from: change from baseline in European Quality of Life-5 Dimension 3 Level (EQ-5D-3L), change from baseline in Rheumatoid Arthritis Disease Impact (RAID), days missed from work due to arthritis, work productivity reduced by ≥ 50% due to arthritis, percentage of arthritis interfering with work productivity, days missed from housework due to arthritis, days missed from housework productivity reduced by ≥ 50% due to arthritis, days missed from family / social / leisure activities due to arthritis, days using hired outside help due to arthritis, percentage of RA interfering with housework productivity, morning stiffness VAS, individual ACR components - TJC and SJC, individual ACR components - physician global VAS, participant global VAS and pain VAS, and individual ACR component - ESR level.

[0089] EMBODIMENT 81 81. The antibody for use according to any one of embodiments 1 to 80, wherein the antibody is administered subcutaneously to the subject at 150 mg once every two weeks.

[0090] EMBODIMENT 82 The antibody for use according to any one of embodiments 37 to 80, wherein the antibody is administered subcutaneously to the subject at 200 mg once every two weeks.

[0091] 83rd Embodiment A composition comprising an antibody described in any one of embodiments 37 to 82.

[0092] 84th embodiment 1. Use of an antibody for the manufacture of a medicament for improving physical function in a subject suffering from rheumatoid arthritis, comprising: - the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2, - the antibody is administered subcutaneously at 150 mg or approximately 200 mg once every two weeks; - the subject is not receiving any other DMARDs during the course of administration of the antibody, and - the subject has previously been treated for rheumatoid arthritis with at least one DMARD other than the antibody, but without success; Use the above.

[0093] EMBODIMENT 85 1. Use of an antibody for the manufacture of a medicament for improving health-related quality of life in a subject suffering from rheumatoid arthritis, comprising: - the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2, - the antibody is administered subcutaneously at 150 mg or approximately 200 mg once every two weeks; - the subject is not receiving any other DMARDs during the course of administration of the antibody, and - the subject has previously been treated for rheumatoid arthritis with at least one DMARD other than the antibody, but without success; Use the above.

[0094] 86. The method of claim 85, 1. Use of an antibody for the manufacture of a medicament for treating rheumatoid arthritis in a subject, comprising: - the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2, - the antibody is administered subcutaneously at 150 mg or approximately 200 mg once every two weeks; - the subject is not receiving any other DMARDs during the course of administration of the antibody, and The subject has previously been treated for rheumatoid arthritis by administering at least one DMARD other than the antibody, but without success. Use the above.

[0095] Detailed Description The present inventors have shown that an anti-IL6R antibody administered as a monotherapy is effective for treating rheumatoid arthritis. Furthermore, the present inventors have also shown that the antibody administered as a monotherapy is effective for improving the physical function and quality of life of subjects with rheumatoid arthritis.

[0096] According to the present invention, "monotherapy" means that the subject receiving the antibody is not receiving any other DMARD during the course of administration of the antibody.

[0097] The efficacy of antibodies for treating rheumatoid arthritis is typically measured using standard methods in the art, such as DAS-28 and ACR parameters, commonly used by clinicians and rheumatologists. ESR, ACR20, ACR50 and ACR70 parameters are measured using a meter such as the DAS-28 .

[0098] Improvement in physical function in subjects with rheumatoid arthritis is measured in various embodiments using standard methods in the field commonly used by clinicians and rheumatologists, namely, HAQ-DI parameters.

[0099] Improvement in quality of life for subjects with rheumatoid arthritis is measured in various embodiments using standard methods in the field commonly used by clinicians and rheumatologists, such as SF36 parameters, and in some embodiments, SF-36 PCS parameters. It is determined.

[0100] Baseline (also referred to herein as "BL") is defined as the score obtained by a subject before receiving an antibody according to the invention.

[0101] A change from baseline is defined as the difference between the score obtained by the subject at baseline and the score obtained after being administered an antibody in accordance with the invention, e.g., measured at least 24 weeks after the first administration of the antibody, including 24 weeks after the first administration of the antibody.

[0102] DAS28-ESR The DAS28 is a composite score that includes four variables: - Number of tender joints (based on 28 joints: shoulder (n=2), elbow (n=2), wrist (n=2), metacarpophalangeal joint (n=10), thumb interphalangeal joint (n=2), proximal interphalangeal joint (n=8), knee (n=2)) - Number of swollen joints (based on 28 joints: shoulder (n=2), elbow (n=2), wrist (n=2), metacarpophalangeal joint (n=10), thumb interphalangeal joint (n=2), proximal interphalangeal joint (n=8), knee (n=2)) - Patient Global Health Assessment (GH) assessed from the ACR RA Core Set Questionnaire (Patient Global Assessment) on a 100 mm visual analogue scale (VAS) - Markers of inflammation assessed by CRP in mg / L or ESR in mm / h.

[0103] It is a continuous measure that allows measurement of absolute change in disease activity and percentage improvement. DAS28-ESR is calculated using the following formula:

number

[0104] The DAS28-ESR score provides a number that indicates the current disease activity of RA. A DAS28-ESR score greater than 5.1 indicates high disease activity, whereas a DAS28-ESR score less than 3.2 indicates low disease activity. and a DAS28-ESR score of less than 2.6 indicates disease remission. When calculating the 28TJC and 28SJC, individual missing joint scores are imputed as the mean of the joints scored ("replaced" or "fused" joints are considered as swollen or tender counts). The number of tender / swollen joints after imputation was as follows: 28TJC / 28SJC = Total (scored tender / swollen joints) * (number of joints in the complete joint set) / number of tender / swollen joints scored). The number of joints in the complete joint set was defined as (28 - number of joints replaced or fused), and joints were scored (0 - no pain, 1 - painful). This refers to those who have the answer (mi). If a subject responds that he or she is not experiencing pain (i.e., ESR=0), for purposes of calculating the DAS-ESR score, the value ESR=1 is inserted instead for purposes of the DAS28-ESR calculation. should be entered to allow for a complete score. The DAS28-ESR is considered missing if one of the components is missing.

[0105] Visual analog score (VAS) The VAS is a scale that assesses the severity of rheumatoid arthritis in patients. Make a vertical mark through each of the two lines that best indicates the amount of pain caused by the gore. ranging from mild to most severe pain.

[0106] ACR20 To be classified as an ACR20 responder, patients must meet baseline criteria for both TJC and SJC. 20% improvement compared to the original version, and at least one of the five remaining ACR components A 20% improvement in three must be achieved: Physician's Global Assessment of Disease Activity, Patient's Global Assessment of Disease Activity, pain, HAQ-DI, and CRP.

[0107] ACR50 ACR50 was defined as achieving at least a 50% improvement in both TJC and SJC, and at least a 50% improvement in at least three of the five remaining ACR components. It is defined as:

[0108] ACR70 ACR70 is defined as the achievement of at least a 70% improvement in both TJC and SJC, and at least a 70% improvement in at least three of the five remaining ACR components.

[0109] The seven ACR components that assess the signs and symptoms of RA are defined below (AG):

[0110] A) Tender joint count (TJC) A total of 68 joints will be evaluated for tenderness. The 68 joints tested for tenderness are: temporomandibular (n=2), sternoclavicular (n=2), acromio-clavicular (n=2), shoulder (n=2), elbow (n=2), wrist (n=2), metacarpophalangeal joint (n=10), thumb interphalangeal (n=2), distal interphalangeal (n=8), proximal interphalangeal (n=8), hip (n=2), knee (n=2), and talar (n=2). Ankle mortise (n=2), tarsus (n=2), metatarsophalangeal (n=10), hallux interphalangeal (n=2), and proximal / distal interphalangeal of the toes (n=8). Formal counts of joints are performed by trained assessors. Joint tenderness is defined as pain elicited by pressure on the joint exerted by the assessor's thumb and index finger. The assessor classifies each joint as painful (yes / no) and swollen (yes / no). A score of 0 / 1 is given to each joint, with 0 representing no pain and 1 representing pain. Tender joint counts range from 0 to 68, where 0 is considered the best. 68 is considered the worst.

[0111] B) Swollen Joint Count (SJC) The 66 joints examined for swelling are the same as those examined for tenderness, except that the hip joints are not included. Formal counting of the joints is performed by trained assessors, who classify each joint as swollen (yes / no). A score of 0 / 1 is given to each swollen joint, with 0 representing no swelling. The joint swelling score ranges from 0 to 66, where 0 is considered the best. and 66 is considered the worst.

[0112] C) Physician's Global Assessment of Disease Activity The physician's global assessment of the patient's current disease activity was assessed on a fixed 100 mm horizontal VAS, where 0 was considered the best disease activity (no disease activity) and 100 was considered the worst disease activity (maximum disease activity).

[0113] D) Patient's Global Assessment of Disease Activity The patient's global assessment of their current disease activity was assessed on a fixed 100 mm horizontal VAS, where 0 was considered the best disease activity (no disease activity) and 100 was considered the worst disease activity (maximum disease activity).

[0114] E) Patient assessment of pain Patients are asked to indicate the intensity of pain caused by their RA using a 100 mm horizontal VAS, where 0 is considered "no pain" and 100 is considered "the worst pain imaginable."

[0115] F) Patient Assessment of Physical Function - Health Assessment Questionnaire Disability Index (HAQ-DI) The HAQ-DI is a standardized questionnaire developed for use in RA. Using the past week as the time frame, the HAQ-DI focuses on whether the respondent is "able" to perform activities and covers eight categories in 20 items: dressing and grooming, getting up, eating, walking, hygiene, reaching, grasping, and activity, with at least two responses per category. The four responses to the HAQ-DI questions are graded as follows: no difficulty = 0; with some difficulty = 1; with considerable difficulty = 2; and unable to do = 3. To calculate a standard HAQ-DI score (using an aid / device), three steps are taken: be: 1. Eight categories were selected by using the highest subcategory score from each category. The category scores are summed. For example, in the category diet, there are three subcategory items. Patients answer 1, 2, and 0, respectively; the category score is 2. 2. Coordinate the use of aids / devices and / or assistance from another person, if indicated. do. - Adjust the score for a category by incrementing by 0 or 1-2. - If the patient's highest score for that subcategory is a 2, it remains a 2, and if it is a 3, it remains a 3. - Data entered in the "Other specify" column will not be used to adjust the score. stomach. 3. Combined category score by the number of categories answered (must be a minimum of 6) Divide by to obtain a HAQ-DI score of 0–3 (3 = worst functioning). HAQ-DI scores cannot be validly calculated if there is a score below 6 in any of the 8 categories. HAQ-DI scores range between 0 and 3. High HAQ-DI scores have been shown to be a strong predictor of morbidity and mortality in RA. A difference of 0.22 units is considered clinically significant.

[0116] G) Levels of acute phase reactants measured by CRP High-sensitivity CRP is the main evaluation. CRP levels are related to interleukin-6 (IL-6) receptor activity. It is believed that an active dosing regimen has a dramatic lowering effect on CRP levels, as it directly correlates with Therefore, post-dose CRP will be kept confidential by the investigator, sponsor, and patient throughout the study. I kept it hidden.

[0117] ACR components are further described in Table 1.

[0118] [Table 1]

[0119] SF-36 V2 QualityMetric's SF-36v2 (R) The Health Survey is a multipurpose, short-form health survey with 36 questions, which yields scores in eight domains (physical functioning, role functioning, and cognitive functioning). (Physical), bodily pain, general well-being, vitality, social functioning, role functioning (Mental), and mental health (where each domain is scored from 0 to 100, with higher scores indicating better health and well-being), plus two summary measures of physical and mental health: Physical Component Summary (PCS) and Mental Component mental component summary (MCS).

[0120] The scoring process is summarized below: 1. Enter the item response data. 2. Recode the item response values. 3. Determine the health domain scale raw scores. 4. Convert the health domain scale raw scores into a 0–100 score. 5. Convert the health domain scale 0–100 into a norm-based score. 6. Score PCS and MCS scales.

[0121] The following table shows the constructs and summary measures of the SF-36: [Table 2]

[0122] Table: SF-36 V2 measurement model *MCS and PCS are derived from eight scales (Ware, JE. et al. 1994 "SF-36 Physical and Mental Health Summary Scales: A Users' Manual”. Boston: The Health Institute) The abbreviated items are as follows: 3a Vigorous activity, such as running, heavy lifting, or strenuous sports participate in events; 3b Moderate activity, such as moving a table, pushing a vacuum cleaner, bowling, or playing golf Play; 3c Lifting or carrying groceries; 3d Climb several flights of stairs; 3e Go up one flight of stairs; 3f bending, kneeling, or stooping; 3g Walking longer than one mile; 3h Walk a few hundred yards; 3i Walk a hundred yards; 3j Bathing or dressing oneself; 4a reduced the amount of time spent on work or other activities; 4b I didn't do as well as I thought I would; 4c Restricted the type of work or other activity; 4d Difficulty doing work or other activities (e.g., putting in extra effort); 7 Intensity of body pain; 8 Pain that interferes with normal work; 1 Your health is: excellent, very good, good, not very good, poor; 11a think you are more susceptible to illness than other people; 11b Being as healthy as a person; 11c My health seems to be getting worse; 11d Health is excellent; 9a I think it's vibrant; 9e Very cheerful; 9g feeling exhausted; 9i Feeling tired; 6 the extent to which health problems interfere with normal social activities; 10 the frequency of health problems that interfere with social activities; 5a reduced the amount of time spent on work or other activities; 5b I didn't do as well as I thought I would; 5c Having difficulty concentrating at work or other activities; 9b It was quite nerve-wracking; 9c I was so depressed that nothing I did could cheer me up; 9d I felt calm and peaceful; 9f felt discouraged and depressed; and 9h I felt happy.

[0123] PCS and MCS summary scale scores are available for at least 50% of the component scales. Scale scores are calculated if at least 50% of the items are within the corresponding scale. Missing items are imputed to available items.

[0124] General Scoring Information Items and scales are scored on a three-point scale: Step 1. Record the 10 items required for recording. Step 2. Calculate the scale score by summing across the items on the same scale (raw scale). ; and · Step 3. Convert the raw scale scores to a 0–100 scale (transformed scale).

[0125] Item Record All 36 items should be checked for outlying values ​​before assigning a final item value. All outlying values ​​should be recorded as missing data. The table below shows the record of answer choices.

[0126] How to handle missing data Scale scores are based on whether the respondent answered correctly on at least half (or an odd number) of the items in a multi-item scale. For scales with items, add half to the answer in 1). The recommended algorithm is to substitute a person-specific estimate for any missing items if the respondent completed at least 50 percent of the items in the scale. A psychometrically reliable estimate is the mean score across completed items in the same scale for that respondent. For example, if a respondent left one item blank in a five-item mental health scale, the respondent's mean score (across the four mental health items) should be used in place of that single item. When estimating a respondent's mean score, use the respondent's final item value.

[0127] Calculate the raw scale score After item recording, including handling of missing data, a raw score is calculated for each scale, which is the simple algebraic sum of the responses to all items in that scale. If a respondent answers at least 50% of the items in a multi-item scale, a score can be calculated. If a respondent does not answer at least 50% of the items, the score for that scale should be set to missing.

[0128] Scale score conversion The next step involves converting each raw score to a 0 to 100 scale using the following formula: Transformed scale = [(actual raw score - lowest possible raw score) / possible raw score] Core Range] x 100 This transformation converts the lowest and highest possible scores to zero and 100, respectively.

[0129] [Table 3]

[0130] The scores for each of the 36 items were collected in a CRF (case report form). Stem) codes (e.g., those provided by the QualityMetric survey) are used to calculate the eight scales, two summary scale scores, and a standardized summary score.

[0131] PCS and MCS summaries if at least 50% of the component scales are available Calculate the scale score. If at least 50% of the items are available within the corresponding scale, If so, a scale score was calculated. Missing items were imputed using the mean of the available items.

[0132] Changes in SF-36 scores (physical component summary score and mental component summary score, as well as eight domains) from BL will then be analyzed.

[0133] SF-36 V2 Scoring General Scoring Information: Items and scales are scored in three steps (as directed by the QualityMetric survey manual): Step 1. Record the items, then record the 10 items that need to be recorded. Step 2. Calculate the scale score by summing across items on the same scale. (raw scale score); and Step 3. Convert raw scale scores to a 0–100 scale (transformed scale) Step 5: Calculate the Z-score Step 6: Convert Z-scores to norm-based scores for the domain PCS: Calculates an aggregate PCS score using a specific weighted formula and converts this into a norm-based score MCS: Calculates an aggregated MCS score using a specific weighted formula and converts this into a norm-based score

[0134] Item Record: All 36 items should be checked for out-of-range values ​​before assigning a final item value. All out-of-range values ​​should be recorded as missing data.

[0135] How to handle missing data Respondents must answer at least half of the items on a multi-item scale (or an odd number of items on a scale containing an odd number of items). The scale score was calculated when the answer to question 1) was added half.

[0136] If a respondent completes at least 50 percent of the items on a scale, the recommended algorithm substitutes a person-specific estimate for any missing items. A psychometrically reliable estimate is the mean score across completed items on the same scale for that respondent. For example, if a respondent leaves one item on a five-item mental health scale blank, If the item was not included, the average score of the respondent (across all four completed mental health items) was used instead of that single item. When estimating the respondent's mean score, the respondent's final item value is used.

[0137] Calculate the raw scale score After item recoding, including treatment of missing data, a raw score is calculated for each scale, which is the simple algebraic sum of the responses for all items in that scale.

[0138] For multi-item scales, if the respondent answers at least 50% of the items, a score can be calculated. If the respondent does not answer at least 50% of the items, the score for that scale should be set to missing.

[0139] Scale score conversion The next step involves converting each raw score to a scale of 0 to 100 using the following formula: Transformed scale = [(actual raw score - lowest possible raw score) / possible raw score] Core Range] x 100 This transformation converts the lowest and highest possible scores to 0 and 100 respectively.

[0140] antibody The present disclosure includes methods comprising administering an antibody or antigen-binding fragment thereof that specifically binds to hIL-6R. As used herein, the term "hIL-6R" refers to a human cytokine receptor that specifically binds to human interleukin-6 (IL-6). In certain embodiments, the antibody administered to a patient specifically binds to the extracellular domain of hIL-6R.

[0141] The term "antibody" as used herein is intended to refer to an immunoglobulin molecule comprising four polypeptide chains, two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions are often Each VH and VL can be further subdivided into regions of hypervariability called complementarity-determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs). At the carboxy terminus, it is composed of three CDRs and four FRs arranged in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the antibody (or antigen-binding portion thereof) may be identical to human germline sequences or may be naturally or artificially modified. The amino acid sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0142] The term "antibody" as used herein also includes antigen-binding fragments of intact antibody molecules. As used herein, the terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, include naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptides or glycoproteins that specifically bind to an antigen to form a complex. Antigen-binding fragments of antibodies can be obtained, for example, by proteolytic digestion or recombinant genetic manipulation, including the manipulation and expression of DNA encoding antibody variable domains and, optionally, constant domains. Such DNA may be derived from an intact antibody molecule using any suitable standard technique, such as synthetic techniques. Such DNA may be obtained from, for example, commercial sources, DNA libraries (e.g., These antibodies are readily available from sources such as phage antibody libraries, or can be synthesized. DNA can be sequenced and analyzed chemically or using molecular biology techniques, e.g. For example, one or more variable and / or constant domains may be engineered to place them in an appropriate configuration, or to introduce codons, or to introduce codons, to create cysteine ​​residues, to modify, add or delete amino acids, etc.

[0143] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) subunits consisting of amino acid residues that mimic the hypervariable regions of an antibody. small recognition units (e.g., isolated complementarity determining regions (CDRs) such as CDR3 peptides), or constraints Constrained FR3-CDR3-FR4 peptides are also included. Antibodies include: monovalent, bivalent, and bivalent nanobodies; domain-deleted antibodies; chimeric antibodies; CDR-grafted antibodies; diabodies; triabodies; tetrabodies; minibodies; nanobodies (e.g., monovalent nanobodies, bivalent nanobodies, etc.); Small modular immunopharmaceuticals (SMIPs) and other engineered molecules such as shark variable IgNAR domains are also encompassed within the expression "antigen-binding fragment" as used herein.

[0144] Antigen-binding fragments of antibodies typically contain at least one variable domain. The variable domain may be of any size or amino acid composition and generally contains at least one CDR that is contiguous or in-frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, In the present invention, the VH and VL domains may be positioned relative to each other in any suitable configuration. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers. Alternatively, An antigen-binding fragment of an antibody can contain a monomeric VH or VL domain.

[0145] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that may be found in an antigen-binding fragment of an antibody of the invention include: (i) VH-CH1; (ii) VH-CH2; (iii) VH-CH3; (iv) VH-CH1-CH2; (v) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) VL-CH3; (xi) VL-CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be directly linked to each other or may be linked by a complete or partial hinge or linker region. The hinge region may, in various embodiments, consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that create a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, in various embodiments, antigen-binding fragments of antibodies may be non-covalently associated (e.g., via disulfide bonds) with each other and / or with one or more monomeric VH or VL domains. a homodimer of any of the variable and constant domain configurations listed above) The amino acid sequence may comprise a dimer or heterodimer (or other multimer).

[0146] Like intact antibody molecules, antigen-binding fragments can be monospecific or multispecific (e.g., bispecific). Multispecific antigen-binding fragments of antibodies typically contain at least two different variable domains, where each variable domain can specifically bind to a separate antigen or a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can, in various embodiments, be synthesized in the context of an antigen-binding fragment of an anti-IL-6R antibody using routine techniques available in the art. It may be adapted for use in

[0147] The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of the antibody can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0148] As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies featured in the invention may contain human constant regions, e.g., in the CDRs and in some embodiments CDR3. These antibodies may include amino acid residues not encoded by germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, as used herein, the term "human antibody" refers to an antibody in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The term "antibodies" is not intended to include antibodies that are

[0149] As used herein, the term "recombinant human antibody" refers to any human antibody that is produced, expressed, created, or isolated by recombinant means, e.g., antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) transgenic for human immunoglobulin genes (see, e.g., Taylor et al. (1992) Nucl. Acids Res. 20:6287-6295, incorporated herein by reference in its entirety), or antibodies produced, expressed, created, or isolated by any other means, including splicing of human immunoglobulin gene sequences into other DNA sequences. The term "recombinant human antibodies" is intended to include isolated antibodies. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies have been subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis), and therefore, the amino acid sequences of the VH and VL regions of the recombinant antibodies, while derived from and related to human germline VH and VL sequences, may not naturally occur within the human antibody germline repertoire in vivo.

[0150] Human antibodies can exist in two forms related to hinge heterogeneity. In one embodiment, the immunoglobulin molecule comprises a stable four-chain construct of approximately 150-160 kDa, where the dimers are linked by interchain heavy chain disulfide bonds. In another embodiment, the dimers are not linked via interchain disulfide bonds, and an approximately 75-80 kDa molecule composed of covalently coupled light and heavy chains (half antibodies) is formed. These embodiments / forms have been very difficult to separate, even after affinity purification.

[0151] The frequency of the second form in various intact IgG isotypes is related to the hinge region of the antibody. This is due to, but is not limited to, structural differences associated with region isotypes. A single amino acid substitution in the hinge region of a human IgG4 hinge can significantly reduce the occurrence of the second form to the level typically observed using a human IgG1 hinge (Angal et al. (1993) Molecular Immunology 30:105). The present invention provides a method for the detection of one or more amino acid substitutions in the hinge, CH2, or CH3 region. These include antibodies with mutations such as α- and β-glucan-1, ...

[0152] As used herein, an "isolated antibody" refers to an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which it naturally occurs or is naturally produced, is an "isolated antibody." In various embodiments, an isolated antibody also includes an antibody in situ within a recombinant cell. In other embodiments, an isolated antibody is an antibody that has been subjected to at least one purification or isolation step. In various embodiments, an isolated antibody can be substantially free of other cellular material and / or chemicals.

[0153] The term "specifically binds" or the like means that an antibody or an antigen-binding fragment thereof forms a relatively stable complex with an antigen under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, etc. For example, the term "specifically binds to IL-6R" used herein refers to a method for determining whether an antibody specifically binds to an antigen. An antibody that "specifically binds" to IL-6R or a portion thereof is an antibody that specifically binds to IL-6R or a portion thereof as measured by a surface plasmon resonance assay. For example, less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, Less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM However, antibodies that bind to human IL-6R with a KD of less than about 1 nM or less than about 0.5 nM are also included. An isolated antibody that binds heterologously may bind to other antigens, such as IL-6R molecules from other (non-human) species. may have cross-reactivity to

[0154] As used herein, the term "surface plasmon resonance" refers to a method for measuring surface plasmon resonance, e.g., BIAcore TM Biosystems (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ) were used. Refers to an optical phenomenon that allows for the analysis of real-time interactions by detecting changes in protein concentration within a sensor matrix.

[0155] As used herein, the term "KD" is intended to refer to the equilibrium dissociation constant of a particular antibody-antigen interaction.

[0156] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule, known as the paratope. A single antigen can have more than one epitope. Thus, different antibodies may bind to different regions of an antigen and have different biological effects. Epitopes can be either conformational or linear. Conformational epitopes are formed by spatially adjacent amino acids from different segments of a linear polypeptide chain. Linear epitopes are formed by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes can include saccharide, phosphoryl, or sulfonyl moieties on the antigen.

[0157] Anti-IL-6R antibodies useful for the methods featured herein can be used in various embodiments. In such cases, the antibody may have one or more amino acid substitutions, insertions, or substitutions in the framework and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibody is derived. The amino acid sequences disclosed herein may include insertions, and / or deletions. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein to germline sequences available, for example, from public antibody sequence databases. The present invention, in various embodiments, includes methods that involve the use of antibodies and antigen-binding fragments thereof derived from any of the amino acid sequences disclosed herein, wherein one or more framework and / or one or more CDR regions are modified. One or more amino acids within the VH and / or VL domains are mutated to the corresponding residue in the germline sequence from which the antibody was derived, or to the corresponding residue in another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence changes are collectively referred to herein as "germline mutations"). Numerous antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof can be readily constructed. In certain embodiments, all of the framework and / or CDR residues within the VH and / or VL domains are mutated to the corresponding residue in the germline sequence from which the antibody was derived, or to the corresponding residue in another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue (such sequence changes are collectively referred to herein as "germline mutations"). In other embodiments, only specific residues, e.g., only mutated residues found within the first eight amino acids of FR1 or the last eight residues of FR4, or only mutated residues found within CDR1, CDR2, or CDR3, are backmutated to the original germline sequence. In other embodiments, one or more of the framework and / or CDR residues are mutated to a different germline sequence (i.e., the sequence from which the antibody was originally derived). In addition, antibodies may be prepared by mutating any of two or more germline mutations in the framework and / or CDR regions to the corresponding residues in the germline sequence (which differ from the germline sequence). Combinations may be included, for example, where certain individual residues are mutated to the corresponding residue in a particular germline sequence, while certain other residues that differ from the original germline sequence are either maintained or mutated to the corresponding residue in a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonist or agonist biological properties (as the case may be), reduced immunogenicity, etc. Uses of antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present invention.

[0158] The present invention also provides HCVRs disclosed herein with one or more conservative substitutions. The present invention includes methods that involve the use of anti-IL-6R antibodies containing any variant of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein. The present invention also encompasses the use of anti-IL-6R antibodies having HCVR, LCVR, and / or CDR amino acid sequences that contain, for example, 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, or other conservative amino acid substitutions compared to any of the amino acid sequences.

[0159] According to the present invention, the anti-IL-6R antibody or antigen-binding fragment thereof can be used in various embodiments. and a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity determining region (CDR). No. 7,582,298, which is incorporated herein by reference in its entirety. In the context of the method of the present invention, the present invention includes any of the amino acid sequences of the anti-IL-6R antibodies claimed in the present application. The anti-IL-6R antibody or antigen-binding fragment thereof that can be used in the present invention comprises a heavy chain complementarity-determining region (HCDR) of HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain complementarity-determining region (LCVR) of IL-6R comprising the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the anti-IL-6R antibody or its antigen comprises a light chain complementarity determining region (LCDR). The binding fragment comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In yet another embodiment, the anti-IL-6R antibody or The antigen-binding fragment comprises an HCVR comprising SEQ ID NO:1 and an LCVR comprising SEQ ID NO:2.

[0160] In another embodiment, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. According to a specific exemplary embodiment, the methods of the present invention involve the use of the anti-IL-6R antibody designated sarilumab and known in the art, or its biological equivalent. This includes the use of bioequivalents.

[0161] As used herein, the term "bioequivalent" refers to a compound that has similar bioavailability (availability) after administration at the same molar dose and under similar conditions (e.g., the same route of administration). Two pharmaceutical compositions containing an anti-IL-6R antibody are considered bioequivalent if they are pharmaceutically equivalent, and contain the same amount of an active ingredient (e.g., an IL-6R antibody) in the same dosage form for the same route of administration. Bioequivalence means that two compositions have the same or comparable bioavailability and meet the same or comparable standards. Bioequivalence can be determined, for example, by in vivo studies comparing the pharmacokinetic parameters of two compositions. Parameters commonly used in bioequivalence studies include peak plasma concentration (Cmax) and area under the plasma drug concentration-time curve (AUC). Examples include:

[0162] In certain embodiments, the present invention provides a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and SEQ ID NO: The method comprises administering to a subject an antibody comprising a light chain variable region comprising the sequence of SEQ ID NO:2.

[0163] The present disclosure provides pharmaceutical compositions comprising the above antibodies, and methods of using these compositions.

[0164] An antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2 specifically binds to human interleukin-6 receptor (hIL-6R). See International Publication No. WO2007 / 143168 (incorporated herein by reference in its entirety).

[0165] In one embodiment, the antibody comprising a heavy chain variable region comprising the sequence of SEQ ID NO: 1 and a light chain variable region comprising the sequence of SEQ ID NO: 2 is sarilumab.

[0166] DMARD DMARDs are defined by their use to slow disease progression in rheumatoid arthritis It is a drug that is used

[0167] DMARDs have been classified as synthetic (sDMARDs) and biologic (bDMARDs). Synthetic DMARDs include, non-inclusively, methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. Biologic DMARDs include, non-inclusively, adalimumab, golimumab, and fluticasone. These include rifamet, etanercept, abatacept, infliximab, rituximab, and tocilizumab.

[0168] Administration method and formulation The antibody is administered to a subject in various embodiments. In various embodiments, the antibody is administered at about 100 mg, 150 mg, or about 200 mg once every two weeks. "Once every two weeks" has the same meaning as "q2w" or "once every two weeks," i.e., the antibody is administered once in a two-week period. In certain embodiments, the antibody is administered subcutaneously.

[0169] In certain embodiments, the antibody is administered at about 100 mg, 150 mg, or about 200 mg once every two weeks. In this context, "about" refers to an amount within 5% of the stated amount. For example, "about 100 mg" is a range between 95 and 105 mg. According to certain embodiments, the antibody is administered subcutaneously.

[0170] The antibody is, in various embodiments, administered in a formulation that includes carriers, excipients, and other agents suitable for improved transport, delivery, tolerability, etc., and that is suitable for subcutaneous injection.

[0171] Injectable preparations can be prepared by known methods. For example, injectable preparations can be prepared by dissolving, suspending, or emulsifying the above-mentioned antibody or a salt thereof in a sterile aqueous or oily medium conventionally used for injections. Aqueous media for injection include, for example, physiological saline, isotonic solutions containing glucose and other auxiliary agents, and these include alcohol ( The oil medium may be used in combination with a suitable solubilizer such as ethanol, polyhydric alcohols (e.g., propylene glycol, polyethylene glycol), nonionic surfactants (e.g., polysorbate 20 or 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)), etc. Examples of oily vehicles include sesame oil and soybean oil, which may be used in combination with a solubilizer such as benzyl benzoate, benzyl alcohol, etc. The injection preparation thus prepared is filled into a suitable ampule.

[0172] Antibodies are typically described in detail herein and in WO2011 / 085158 (incorporated by reference in its entirety). The formulation is as described in U.S. Pat. No. 6,239,999, incorporated herein by reference.

[0173] In various embodiments, the antibody - approximately 21 mM histidine, - about 45 mM arginine, - approximately 0.2% (weight / volume) polysorbate 20, - approximately 5% (mass / volume) sucrose, and - between about 100 mg / mL and about 200 mg / mL of antibody It is administered as a buffered aqueous solution at about pH 6.0 containing:

[0174] In another embodiment, the antibody - approximately 21 mM histidine, - about 45 mM arginine, - approximately 0.2% (weight / volume) polysorbate 20, - approximately 5% (mass / volume) sucrose, and - at least about 130 mg / mL of antibody It is administered as a buffered aqueous solution at pH 6.0 containing:

[0175] In another embodiment, the antibody - approximately 21 mM histidine, - about 45 mM arginine, - approximately 0.2% (mass / volume) polysorbate 20, - approximately 5% (mass / volume) sucrose, and - Antibody approximately 131.6 mg / mL It is administered as a buffered aqueous solution at about pH 6.0 containing:

[0176] In another embodiment, the antibody - approximately 21 mM histidine, - about 45 mM arginine, - approximately 0.2% (mass / volume) polysorbate 20, - approximately 5% (mass / volume) sucrose; and - Antibody approximately 175 mg / mL It is administered as a buffered aqueous solution at about pH 6.0 containing:

[0177] In other embodiments, the antibody - 21 mM histidine, - 45 mM arginine, - 0.2% (mass / volume) polysorbate 20, - 5% (mass / volume) sucrose, and - Antibodies between 100 mg / mL and 200 mg / mL It is administered as a buffered aqueous solution at pH 6.0 containing:

[0178] In another embodiment, the antibody - 21 mM histidine, - 45 mM arginine, - 0.2% (mass / volume) polysorbate 20, - 5% (mass / volume) sucrose, and - At least 130 mg / mL of antibody It is administered as a buffered aqueous solution at pH 6.0 containing:

[0179] In another embodiment, the antibody - 21 mM histidine, - 45 mM arginine, - 0.2% (mass / volume) polysorbate 20, - 5% (mass / volume) sucrose, and - Antibody 131.6 mg / mL It is administered as a buffered aqueous solution at pH 6.0 containing:

[0180] In another embodiment, the antibody - 21 mM histidine, - 45 mM arginine, - 0.2% (mass / volume) polysorbate 20, 5% (mass / volume) sucrose; and - Antibody 175 mg / mL It is administered as a buffered aqueous solution at pH 6.0 containing:

[0181] Antibodies according to the invention can be administered to a subject using any acceptable device or mechanism. For example, administration can be accomplished using a syringe and needle, or with a reusable pen and / or autoinjector delivery device. The methods of the invention include the use of a number of reusable pen and / or autoinjector delivery devices to administer the antibody (or pharmaceutical formulation comprising the antibody). Examples of such devices include, but are not limited to, the AUTOPEN, to name a few. TM (Owen Mumford, Inc., Woodstock, UK), DISETRONIC TM Pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25 TM Pen, HUMALOG TM Pen, HUMALIN 70 / 30 TM Pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN TM I, II & III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR TM(Novo Nordisk, Copenhagen, Denmark), BD TM Penn (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN TM ,OPTIPEN PRO TM , OPTIPEN STARLET TM , and OPTICLIK TM (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen and / or auto-injector delivery devices that have utility in the subcutaneous delivery of pharmaceutical compositions of the present invention include, but are not limited to, SOLOSTAR, to name a few. TM Pen (sanofi-aventis), FLEXPEN TM (Novo Nordisk), and KWIKPEN TM (Eli Lilly), SURECLICK TM Auto-injector (Amgen, Thousand Oaks, CA), PENLET TM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), HUMIRA TM PEN (Abbott Labs, Abbott Park, IL), DAI (R) Auto-injector (SHL Group) and PUSHCLICK TM technology (SHL Group).

[0182] In one embodiment, the antibody is administered using a pre-filled syringe.

[0183] In another embodiment, the antibody is administered using a pre-filled syringe that includes a safety feature. For example, the safety feature prevents accidental needle sticks. In various embodiments, the antibody is administered using an ERIS TM Prefilled syringes containing safety devices (West Pharmaceutical Services Inc.) were used. See also U.S. Patent Nos. 5,215,534 and 9,248,242, which are incorporated by reference in their entireties.

[0184] In another embodiment, the antibody is administered using an auto-injector. TM The composition and / or antibody are administered using an auto-injector featuring technology (SHL Group). In various embodiments, the auto-injector is a device containing a syringe that allows a dose of the composition and / or antibody to be administered to a subject. See also U.S. Patent Nos. 9,427,531 and 9,566,395, which are incorporated by reference in their entireties.

[0185] Patient population According to the present invention, "subject" means a human subject or a human patient.

[0186] In various embodiments, the antibodies of the invention are administered to subjects who have previously been treated for rheumatoid arthritis with one or more DMARDs other than the antibody, but have not been successful in treating the disease. It is administered.

[0187] In accordance with the present invention, a subject who is considered to have been "treated but without benefit" by his or her physician is, in various embodiments, a subject who has demonstrated intolerance to one or more DMARDs tested by the physician and / or a subject who has demonstrated an inadequate response to one or more DMARDs tested by the physician, typically a subject who has previously Do you still have active rheumatoid arthritis despite receiving one or more DMARDs? or a subject who is deemed by a physician to have active rheumatoid arthritis. "Active rheumatoid arthritis" is typically defined as: - at least 6 swollen joints out of 66 and 8 tender joints out of 68 as counted by a physician in a typical quantitative swollen and tender joint count test; - High-sensitivity C-reactive protein (hs-CRP) ≥ 8 mg / L or ESR ≥ 28 mm / H - DAS28ESR > 5.1 It is defined as follows.

[0188] In one embodiment, the antibody is administered in combination with at least one other DMARD. Subjects who have previously been treated for rheumatoid arthritis without success should be advised to have received a DMARD. In various embodiments, the DMARD is methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. In various embodiments, the DMARD is selected from the group consisting of methotrexate, roroquine, and loracetamide. It is.

[0189] In another embodiment, the patient has previously been administered one or more DMARDs different from the antibody. Subjects who have been treated for rheumatoid arthritis with methotrexate without success are subjects who previously had an inadequate response to or were intolerant to methotrexate.

[0190] According to the present invention, the antibody can be effectively treated by previously administering one or more DMARDs different from the antibody. For subjects who have been treated for rheumatoid arthritis with DMARDs but have not responded, the one or more DMARDs are no longer administered to the subject, and the antibody is administered alone, in various embodiments, as a single agent. The therapeutic agent is administered to a subject.

[0191] In various embodiments, the subject has one or more symptoms from treatment with a DMARD. Intolerance to DMARDs due to a physical reaction, condition, or symptom. These include allergies, pain, nausea, diarrhea, azotemia, stomach bleeding, intestinal bleeding, stomatitis, thrombocytopenia, intestinal perforation, bacterial infection, inflammation of the gums or mouth, and inflammation of the stomach or intestinal lining. Symptoms may include inflammation of the rectum, bacterial sepsis, gastric ulcers, intestinal ulcers, sun-sensitive skin, dizziness, loss of appetite, low energy, and vomiting. In certain embodiments, intolerance may be determined by the subject or by a healthcare professional upon examination of the subject. In various embodiments, the DMARD is methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. In certain embodiments, the DMARD is methotrexate. do.

[0192] In other embodiments, the subject suffers from a decline in quality of life due to RA.In certain embodiments, the subject suffers from a decline in quality of life due to RA and is scored as more severe than average on a scale selected from the following: change from baseline in European Quality of Life-5 Item 3 Level (EQ-5D-3L), change from baseline in Rheumatoid Arthritis Disease Impact (RAID), days of absence from work due to arthritis, work productivity that is reduced by ≥ 50% due to arthritis, the percentage of arthritis that interferes with work productivity, days of absence from housework due to arthritis, days of decrease in housework productivity due to arthritis by ≥ 50%, days of absence from family / social / leisure activities due to arthritis, days of using hired outside help due to arthritis, the percentage of RA that interferes with housework productivity, morning stiffness VAS, individual ACR component-TJC and SJC, individual ACR component-physician global VAS, participant global VAS and pain VAS, and individual ACR component-ESR level. In other embodiments, the subject has a more severe than average HAQ-DI or DAS-28 score prior to the start of treatment.

[0193] In certain embodiments, a subject who scores more severe than average on one or more metrics has a score that is more severe than the baseline value for the metrics listed in one or more of Tables 2, 3, 5, or 8 below. In various embodiments, after receiving treatment, a subject has a score that is more severe than the baseline value for one or more of the metrics listed in one or more of Tables 2, 3, 5, or 8 below. A subject having a baseline value or a score that is more significant than the baseline value in any one or more of the measures listed in one or more of Tables 2, 3, 5, or 8 below after receiving treatment indicates that the subject is an inadequate responder to treatment.

[0194] In certain embodiments, a subject having a metric score that is more severe than the baseline value for a metric listed in one or more of Tables 2, 3, 5, or 8 has a score that is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% more severe than baseline.

[0195] All publications mentioned herein are hereby incorporated by reference in their entirety for all purposes.

[0196] Example A randomized, double-blind, parallel-group study to evaluate the efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy in patients with rheumatoid arthritis (Study number EFC14092, Study title: SARIL-RA-MONARCH) the purpose: Main purpose : Intolerance or inappropriateness of continued treatment with methotrexate (MTX) or inadequate after at least 12 weeks of continued treatment with MTX. Patients with active RA who are determined to be responders will have DAS28-ESR assessed at week 24 To demonstrate that sarilumab monotherapy is superior to adalimumab monotherapy with respect to signs and symptoms. Secondary Objectives : intolerant or deemed an inappropriate candidate for continued treatment with MTX or determined to be an inadequate responder after at least 12 weeks of continued treatment with MTX. In patients with active RA: - Reduction in signs and symptoms of RA at 24 weeks - Measured by patient reported outcomes questionnaire at 24 weeks and improve quality of life To demonstrate that sarilumab monotherapy is superior to adalimumab in To assess the safety and tolerability (including immunogenicity) of sarilumab monotherapy throughout the study.

[0197] Methodology: A randomized, double-blind, double-dummy, parallel-group study with 24 weeks of open-label sarilumab treatment. Randomization was stratified by region.

[0198] Number of patients: Plan: 340 Randomized: 369 Action: 368 Rating: Effectiveness: 369 Safety:368

[0199] Diagnostic and inclusion criteria: Patients with active RA for 3 months or more who are intolerant to continued treatment with MTX or are considered inadequate candidates; or who are determined to be inadequate responders after at least 12 weeks of continued treatment with MTX.

[0200] Study Procedures Investigational product: Sarilumab 200 mg q2w or q2w in prefilled syringes for subcutaneous administration. placebo and adalimumab 40 mg q2w or placebo. Treatment period: 24 weeks of randomized treatment Observation Period: Randomization period up to week 34 (4-week screening, 24-week treatment, and 6-week post-treatment observation if patient does not enter open-label extension)

[0201] Evaluation criteria: Effectiveness : Primary endpoint: Change from baseline in DAS28-ESR at week 24 Secondary endpoints: DAS28-ESR (remission) - 24 weeks ACR50 Response - 24 Weeks ACR70 response - 24 weeks ACR20 response - 24 weeks HAQ-DI - 24 weeks SF-36 Body – 24 weeks FACIT Fatigue - 24 weeks SF-36 Spirit – 24 weeks

[0202] safety : Patient-reported or investigator-noted adverse events, adjudicated cardiovascular events, and standard hematology and blood chemistry, electrocardiogram (ECG), physical examination, and adverse events to sarilumab were assessed. Development of drug antibodies.

[0203] Statistical methods: The efficacy analysis population was the intent-to-treat (ITT) population, which included all randomized controlled trials. The primary efficacy analysis included randomized subjects. For efficacy analyses, subjects were analyzed in the treatment group to which they were randomized, regardless of the treatment they actually received. The primary safety analysis was conducted on all randomized patients exposed to at least one injection of study drug. Subjects were analyzed in the treatment group to which they actually received, regardless of which group they were randomized to. For the primary efficacy, change from baseline in DAS28-ESR at Week 24, Adalimumab Data were collected at or before week 24, including after mab (or matching placebo) dose escalation was used. Data collected after treatment discontinuation were set as missing. No data imputation was performed. The primary efficacy endpoint was assessed using a mixed model for repeated measures (MMRM) with factors for baseline covariates and treatment, region, visit, and visit by treatment interaction.

[0204] The safety summary was descriptive and no hypothesis testing was performed. The summary of treatment-emergent adverse events (TEAEs) was based on MedDRA coding of verbatim terms reported by the investigator. TEAEs were defined as adverse events that were new-onset, worsened, or became severe on or after the day of taking the first dose of investigational medicinal product (IMP) until the end of the study or the start of extension treatment. Clinically significant abnormalities (PCSAs) were also assessed for selected laboratory tests, including vital signs and ECGs, and the incidence of potentially clinically significant abnormalities. values ​​were collected.

[0205] Population characteristics: 369 patients were in the intention-to-treat population. 368 patients were in the safety population. 321 (87%) patients The patients successfully completed the 24-week treatment period, of which 320 patients received long-term sarilumab. It was decided to continue the open-label extension phase to continue treatment. 47 (12.7%) patients Double-blind study treatment was permanently discontinued, of which 17 patients continued for follow-up visits through week 24. Baseline demographic and disease characteristics were generally similar between treatment groups (baseline (See Table 2 for the CRP values.) Patients on sarilumab tended to be younger with longer RA duration and lower baseline CRP compared with adalimumab.

[0206] The mean duration of study treatment was 158 days in the sarilumab group and 158 days in the adalimumab group. The percentage of patients with IMP compliance ≥ 80% was 154 days. The results were 99% and 100%, respectively.

[0207] [Table 4]

[0208] [Table 5]

[0209] [Table 6]

[0210] [Table 7]

[0211] Efficacy Results: Primary endpoint The change from baseline to week 24 in DAS28-ESR (Disease Activity Score 28-Erythrocyte Sedimentation Rate) score showed a significantly greater reduction in the sarilumab group compared with adalimumab (mean difference of -1.077 units, p-value <0.0001, Table 3). This effect was seen as early as week 12. Both planned sensitivity analyses confirmed these data.

[0212] [Table 8]

[0213] Secondary endpoints Table 4 shows the prespecified primary and secondary efficacy endpoints, including quality of life / physical function assessments. Results are shown for the strata specified. Bolded results are statistically significant according to the analytical procedure. The final statistically significant outcome in the study tier was the SF-36 physical score. It was.

[0214] [Table 9]

[0215] As can be seen in Table 4, the number of patients who achieved DAS28-ESR remission (<2.6) at 24 weeks was 1.2%. It was significantly higher in the sarilumab group versus the tumab group (26.6% of patients vs. 7% of patients, p-value <0.0001).

[0216] Furthermore, data were obtained showing that the number of patients who achieved low disease activity (DAS28-ESR <3.2) at 24 weeks was also significantly higher in the sarilumab group compared with the adalimumab group (patients (42.9% of subjects vs. 14.1% of patients, p<0.0001). Furthermore, and as can be seen from Table 4: The number of patients achieving an ACR20 response at 24 weeks was significantly higher in the sarilumab group than in the adalimumab group. significantly higher in patients with HIV (71.7% vs. 58.4% of patients, p < 0.008). The number of patients achieving an ACR50 response at 24 weeks was significantly higher in the sarilumab group than in the adalimumab group. significantly higher in patients with HIV (45.7% of patients vs. 29.7% of patients, p value < 0.002), The number of patients achieving an ACR70 response at 24 weeks was significantly higher in the sarilumab group than in the adalimumab group. significantly higher in patients with glaucoma (23.4% of patients vs. 11.9% of patients, p value < 0.004).

[0217] Regarding physical function assessment (HAQ-DI score), a more detailed analysis is shown in Tables 5, 6, and 7. Tables 4 and 5 show that the LS mean change from baseline in HAQ-DI was 0.43 in the adalimumab group. The mean mean RR of the sarilumab group was 0.61 compared with 0.61 in the sarilumab group (p value < 0.004).

[0218] [Table 10]

[0219] [Table 11]

[0220] Table 6 shows that the number of patients achieving a change from baseline of ≥ 0.3 on HAQ-DI was significantly higher in the sarilumab group versus the adalimumab group (62% vs. 47.6% of patients, p-value < 0.006).

[0221] [Table 12]

[0222] Table 7 shows the number of patients achieving a change from baseline of ≥ 0.22 on the HAQ-DI. The results show that the mean age at onset was significantly higher in the sarilumab group than in the tumab group (67.4% of patients). vs. 54.1%, p-value<0.009).

[0223] Additionally, Table 8 shows the baseline DAS28-CRP (Disease Activity Score 28 - C-reactive protein) score. The change from baseline to week 24 showed a significantly greater decrease in the sarilumab group compared to adalimumab (mean difference -0.884 units, p-value <0.0001).

[0224] [Table 13]

[0225] The number of patients who achieved DAS28-CRP remission (<2.6) at 24 weeks was also significantly higher in the sarilumab group versus the adalimumab group (34.2% of patients vs. 13.5% of patients, p-value <0.0001).

[0226] Table 9 showed that patients in the sarilumab group were also twice as likely to achieve Clinical Disease Activity Index (CDAI) remission (CDAI ≤ 2.8) at 24 weeks compared with adalimumab (P < 0.05).

[0227] [Table 14]

[0228] The CDAI is a composite index constructed to measure clinical remission in RA without laboratory tests and is the numerical sum of four components: SJC (28 joints), tender joint count (28 joints), patient global disease activity (cm), and physician global assessment (cm). The score ranges from 0 to 76. Aletaha, D and Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI): A review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol 2005;23 (Suppl. 39) :S100-S108, which is incorporated by reference in its entirety.

[0229] Additionally, Table 10 shows that the change in CDAI score from baseline to week 24 showed a significantly greater decrease in the sarilumab group compared to adalimumab (mean difference of -3.741 units, p-value <0.002).

[0230] [Table 15]

[0231] [Table 16]

[0232] Analysis population description ITT population. Number of participants analyzed = participants with EQ-5D-3L score assessments at both baseline and 24 weeks, where "n" is the number of participants with data available for the specified category Represents the number of participants.

[0233] [Table 17]

[0234] [Table 18]

[0235] Safety Group Explanation ITT population. Number of participants analyzed = participants with RAID assessment at both baseline and 24 weeks.

[0236] [Table 19]

[0237] [Table 20]

[0238] Analysis population description ITT population. Number of participants analyzed = participants with WPS-RA: individual item assessments at both baseline and week 24.

[0239] [Table 21]

[0240] [Table 22]

[0241] Analysis population description ITT population. Number of participants analyzed = participants with WPS-RA: individual item assessments at both baseline and 24 weeks.

[0242] [Table 23]

[0243] [Table 24]

[0244] Analysis population description ITT population. Number of participants analyzed = participants with WPS-RA: individual item assessments at both baseline and 24 weeks.

[0245] [Table 25]

[0246] [Table 26]

[0247] Analysis population description ITT population. Number of participants analyzed = participants with WPS-RA: individual item assessments at both baseline and 24 weeks.

[0248] [Table 27]

[0249] [Table 28]

[0250] Analysis population description ITT population. Number of participants analyzed = participants with WPS-RA: individual item assessments at both baseline and 24 weeks.

[0251] [Table 29]

[0252] [Table 30]

[0253] Analysis population description ITT population. Number of participants analyzed = participants with WPS-RA: individual item assessments at both baseline and 24 weeks.

[0254] [Table 31]

[0255] [Table 32]

[0256] Analysis population description ITT population. Number of participants analyzed = participants with WPS-RA: individual item assessments at both baseline and 24 weeks.

[0257] [Table 33]

[0258] [Table 34]

[0259] Analysis population description ITT population. Number of participants analyzed = participants with WPS-RA: individual item assessments at both baseline and 24 weeks.

[0260] [Table 35]

[0261] [Table 36]

[0262] Analysis population description ITT population. Number of participants analyzed = participants with morning stiffness VAS assessment at both baseline and 24 weeks.

[0263] [Table 37]

[0264] [Table 38]

[0265] Analysis population description ITT population. Number of participants analyzed = participants with TJC and SJC assessments at both baseline and 24 weeks.

[0266] [Table 39]

[0267] [Table 40]

[0268] Analysis population description Number of participants analyzed = number of participants with individual ACR component assessments at both baseline and specific time points, where "n" is the number of participants available for a particular category. The number of participants with data is indicated.

[0269] [Table 41]

[0270] [Table 42]

[0271] Analysis population description ITT population. Number of participants analyzed = participants with CRP assessments at both baseline and 24 weeks Participant.

[0272] [Table 43]

[0273] [Table 44]

[0274] Analysis population description ITT population. Number of participants analyzed = had both baseline and week 24 ESR assessments participants.

[0275] [Table 45]

Claims

1. 1. A pharmaceutical composition comprising an antibody that specifically binds to interleukin-6 receptor (IL-6R) for use in a method of improving physical function in a subject suffering from rheumatoid arthritis, wherein: the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10, - the antibody is administered subcutaneously to the subject at about 150 mg or about 200 mg once every two weeks; - the subject is not receiving any other disease-modifying antirheumatic drugs (DMARDs) other than the antibody during the course of administration of the antibody, and - the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD different from the antibody without success, The above pharmaceutical composition.

2. 2. The pharmaceutical composition of claim 1, wherein the subject achieves a change from baseline (BL) in Health Assessment Questionnaire Disability Index (HAQ-DI) of at least 0.22, particularly at least 0.30, and more particularly at least 0.60, at least 24 weeks after administration of the antibody.

3. 1. A pharmaceutical composition comprising an antibody that specifically binds to interleukin-6 receptor (IL-6R) for use in a method of improving health-related quality of life in a subject suffering from rheumatoid arthritis, wherein: the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10, - the antibody is administered subcutaneously to the subject at about 150 mg or about 200 mg once every two weeks; - The subject is not receiving any disease-modifying antirheumatic drugs (DMDs) other than the antibody during the course of administration of the antibody. MARD) was not administered, and - the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD different from the antibody without success, The above pharmaceutical composition.

4. 4. The pharmaceutical composition of claim 3, wherein the subject achieves a change from baseline (BL) in Short Form-36 Physical Component Summary (SF-36 PCS) of at least 2.5, particularly at least 3, and more particularly at least 8, at least 24 weeks after administration of the antibody.

5. 1. A pharmaceutical composition comprising an antibody that specifically binds to interleukin-6 receptor (IL-6R) for use in a method of treating rheumatoid arthritis in a subject, wherein: the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10, - the antibody is administered subcutaneously to the subject at about 150 mg or about 200 mg once every two weeks; - the subject is not receiving any other disease-modifying antirheumatic drugs (DMARDs) other than the antibody during the course of administration of the antibody, and - the subject has previously been treated for rheumatoid arthritis by administering at least one DMARD different from the antibody without success, The above pharmaceutical composition.

6. 6. The pharmaceutical composition of claim 5, wherein the subject achieves a 20% improvement in the American College of Rheumatology Core Set Disease Index (ACR20), particularly a 50% improvement in the American College of Rheumatology Core Set Disease Index (ACR50), more particularly a 70% improvement in the American College of Rheumatology Core Set Disease Index (ACR70) at least 24 weeks after administration of the antibody.

7. 7. The pharmaceutical composition of claim 5 or 6, wherein the subject achieves a change from baseline (BL) in Disease Activity Score 28 minus Erythrocyte Sedimentation Rate (DAS28-ESR) of at least 2, particularly at least 2.5, more particularly at least 3, after at least 24 weeks of administration of the antibody, or wherein the subject achieves a DAS28-ESR score of less than 3.2, particularly less than 2.6, after at least 24 weeks of administration of the antibody.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the subject who has previously been treated for rheumatoid arthritis by administering at least one DMARD other than the antibody, but ineffectively, is a subject who has previously been treated for rheumatoid arthritis by administering methotrexate, but ineffectively.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the subject suffering from rheumatoid arthritis is a subject suffering from moderate to severe active rheumatoid arthritis.

10. 10. The pharmaceutical composition of any one of claims 1 to 9, wherein the pharmaceutical composition is in the form of a pre-filled syringe or pen, or is administered using an auto-injector, or wherein the antibody is administered as a buffered aqueous solution containing histidine, arginine, polysorbate 20, and sucrose at about pH 6.

0.

11. 11. The pharmaceutical composition of claim 10, wherein the solution comprises at least about 130 mg / mL of antibody, particularly wherein the solution comprises between 131 mg / mL and 132 mg / mL of antibody, or more particularly wherein the solution comprises 131.6 mg / mL of antibody.

12. 11. The pharmaceutical composition of claim 10, wherein the solution comprises at least about 170 mg / mL of antibody, particularly wherein the solution comprises about 175 mg / mL of antibody.

13. 2. The pharmaceutical composition of claim 1, wherein the subject is intolerant to one or more DMARDs different from the antibody.

14. 2. The pharmaceutical composition of claim 1, wherein the subject has moderate to severe active rheumatoid arthritis and has had an inadequate response to one or more DMARDs other than the antibody.

15. A pharmaceutical composition described in claim 13 or 14, wherein one or more DMARDs different from the antibody include methotrexate.

16. The pharmaceutical composition of claim 1 , wherein the subject is suffering from a decrease in quality of life due to rheumatoid arthritis prior to administration of the antibody.

17. The pharmaceutical composition of any one of claims 1 to 16, wherein the antibody is administered subcutaneously to the subject at about 150 mg once every two weeks.

18. The pharmaceutical composition of any one of claims 1 to 16, wherein the antibody is administered subcutaneously to the subject at about 200 mg once every two weeks.

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