Compositions and methods for treating polymyalgia rheumatic by administering IL-6R antagonist

Abstract

The present disclosure relates to the use of an anti-IL6 receptor antibody or antigen-binding fragment thereof for the treatment of polymyalgia rheumatic (PMR).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to the following U.S. Provisional Patent Applications: 63 / 327,850, filed April 6, 2022; 63 / 350,761, filed June 9, 2022; 63 / 389,317, filed July 14, 2022; 63 / 424,035, filed November 9, 2022; 63 / 424,627, filed November 11, 2022; 63 / 445,329, filed February 14, 2023; 63 / 445,331, filed February 14, 2023; and 63 / 447,796, filed February 23, 2023. The entire disclosure of each of these applications is hereby incorporated by reference in its entirety. Technical Field

[0002] The present disclosure relates to the field of therapeutic treatment of polymyalgia rheumatica (PMR). More specifically, the present disclosure relates to the use of interleukin-6 receptor (IL-6R) antagonists, such as anti-IL-6R antibodies, for treating polymyalgia rheumatica. Background Art

[0003] Polymyalgia rheumatica (PMR) is a chronic inflammatory disease of unknown etiology characterized by pain and morning stiffness in the shoulders, neck, and pelvic girdle, and is often associated with low-grade fever, fatigue, weakness, and weight loss. The debilitating effects of the disease can significantly affect the quality of life of PMR patients. It typically affects individuals over 50 years of age, with prevalence varying with age and population (Gonzalez, G. et al., 2009 Arthritis Rheum. 61(10):1454-61). In 2008, the number of PMR cases in the United States was estimated to be 711,000 (Lawrence, RC et al., 2008 Arthritis Rheum. 58(1):26-35). The prevalence is higher in women than in men, and increases sharply with age. According to the only population-based PMR study in the United States, the prevalence ranges from 21 per 100,000 people aged 50-54 years to 4,070 per 100,000 people aged ≥90 years (Lawrence et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States, Part II. Arthritis Rheum. 2008;58(1):26-35). In Europe, higher rates have been noted in northern European populations compared to southern European populations. Among patients ≥50 years of age, the annual incidence is 50 / 100,000 in Sweden and 68 / 100,000 in Denmark, compared to 13 / 100,000 in Italy and 14-19 / 100,000 in Spain (Gonzalez, G. et al., 2009 Arthritis Rheum. 61(10):1454-61).

[0004] Although the cause is unclear, both genetic and environmental factors are thought to be involved. Studies have shown that inflammation of the joints and the bursae surrounding these joints contribute to the pain and stiffness symptoms associated with PMR. Although there is no definitive test, there are guidelines for the clinical diagnosis of PMR (Dasgupta, B. et al. 2010 Rheumatology. 49(1):186-90).

[0005] Although PMR is typically treated with low-dose corticosteroids (CS), some patients are steroid-dependent in the absence of recurrent symptoms, or are unable to gradually reduce the amount of prednisone or equivalent to less than 10 mg / day, and therefore are at risk of complications from long-term steroid therapy. In the 2015 American College of Rheumatology / European League against Rheumatism (ACR / EULAR) guidelines, the recommended minimum effective starting dose is within the range of 12.5-25 mg of prednisone (or equivalent) per day (Dejaco, C. et al. 2017 Rheumatology. [Rheumatology] 56(4): 506-15). The average duration of treatment is approximately 2 to 3 years. For most patients, a slowly tapering CS will quickly alleviate symptoms. However, in one report, nearly half of PMR patients treated with CS did not respond adequately based on laboratory and clinical markers of disease activity (Dasgupta, B. et al. 2010 Rheumatology. 49(1):186-90). In another report, only 30% of patients with a baseline prednisone dose >10 mg / day were in remission at year 1 (Caporali, R. et al. 2004 Ann Intern Med. 141(7):493-500).

[0006] Current treatment options for PMR include long-term oral corticosteroid therapy. A disadvantage of long-term oral corticosteroid therapy is the potential for comorbidities. (Chatzigeorgiou C et al. Comorbidity in polymyalgiarheumatica. Reumatismo. Rheumatol. 2018 Mar 27;70(1):35-43). There remains a need for effective treatments for PMR that have fewer adverse side effects. Summary of the Invention

[0007] In one aspect, a method for treating polymyalgia rheumatica (PMR) in a subject in need thereof is provided, the method comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to an IL-6 receptor.

[0008] In certain exemplary embodiments, the subject has PMR that is refractory to steroids or refractory to steroid tapering. In certain exemplary embodiments, the subject has had an inadequate response to steroids or is unable to tolerate steroid tapering.

[0009] In certain exemplary embodiments, the steroid comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone. In certain exemplary embodiments, the subject was previously treated with prednisone at a dose of ≥7.5 mg / day, and / or ≤25 mg / day, or ≤20 mg / day.

[0010] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered in combination with another therapeutic agent. In certain exemplary embodiments, the therapeutic agent comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0011] In certain exemplary embodiments, prednisone is administered at a dose of about 15 mg / day. In certain exemplary embodiments, the dose of prednisone is discontinued or optionally tapered to <2.5 or 2.0 mg prednisone / day.

[0012] In certain exemplary embodiments, discontinuation of prednisone begins between about 10 weeks and about 20 weeks after administration of the first dose of the antibody. In certain exemplary embodiments, discontinuation of prednisone begins about 14 weeks after administration of the first dose of the antibody.

[0013] In certain exemplary embodiments, the subject was previously treated with a disease-modifying antirheumatic drug (cDMARD).

[0014] In certain exemplary embodiments, the subject is concomitantly treated with a cDMARD.

[0015] In certain exemplary embodiments, the cDMARD is selected from the group consisting of methotrexate, azathioprine, and leflunomide. In certain exemplary embodiments, the cDMARD is methotrexate.

[0016] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg.

[0017] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered in an initial dose of about 200 mg and one or more secondary doses of about 200 mg administered every other week (q2w).

[0018] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) sequence of SEQ ID NOs: 3, 4, and 5, and a light chain complementarity determining region (LCDR) sequence of SEQ ID NOs: 6, 7, and 8.

[0019] In certain exemplary embodiments, the antibody is sarrellumab.

[0020] In one aspect, a method for treating polymyalgia rheumatica (PMR) in a subject in need thereof is provided, comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to an IL-6 receptor, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) sequence of SEQ ID NOs: 3, 4, and 5, and a light chain complementarity determining region (LCDR) sequence of SEQ ID NOs: 6, 7, and 8.

[0021] In certain exemplary embodiments, the subject has PMR that is refractory to steroids or refractory to steroid tapering. In certain exemplary embodiments, the steroid comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0022] In certain exemplary embodiments, the subject was previously treated with a dose of ≥7.5 mg / day of prednisone.

[0023] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered in combination with another therapeutic agent.

[0024] In certain exemplary embodiments, the therapeutic agent comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone. In certain exemplary embodiments, prednisone is administered at a dose of about 15 mg / day. In certain exemplary embodiments, the dose of prednisone is gradually tapered.

[0025] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg.

[0026] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered in an initial dose of about 200 mg and one or more secondary doses of about 200 mg administered every other week (q2w).

[0027] In certain exemplary embodiments, the subject is at least 50 years old.

[0028] In certain exemplary embodiments, the subject suffers from bilateral shoulder pain.

[0029] In certain exemplary embodiments, the subject has a C-reactive protein (CRP) level >10 mg / L and / or an erythrocyte sedimentation rate (ESR) >30 mm / hr.

[0030] In certain exemplary embodiments, the subject suffers from morning stiffness.

[0031] In certain exemplary embodiments, the subject has no joint involvement other than the shoulder joint.

[0032] In certain exemplary embodiments, the subject suffers from hip pain or limited range of motion.

[0033] In certain exemplary embodiments, the subject is seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP).

[0034] In certain exemplary embodiments, the subject does not have a disorder selected from the group consisting of giant cell arteritis, rheumatoid arthritis, inflammatory arthritis, connective tissue disease, rhabdomyolysis, neuromuscular disease, and active fibromyalgia. In certain exemplary embodiments, the connective tissue disease is selected from the group consisting of systemic lupus erythematosus, systemic sclerosis, vasculitis, myositis, mixed connective tissue disease, and ankylosing spondylitis.

[0035] In certain exemplary embodiments, the subject has subdeltoid bursitis and / or biceps tenosynovitis and / or posterior or axillary glenohumeral synovitis in at least one shoulder, and synovitis and / or trochanteric bursitis in at least one hip.

[0036] In certain exemplary embodiments, after administration of the antibody or antigen-binding fragment thereof, at least one symptom of polymyalgia rheumatica in the subject is improved. In certain exemplary embodiments, the symptom is selected from the group consisting of: shoulder pain associated with inflammatory stiffness; hip pain associated with inflammatory stiffness; elevated C-reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR).

[0037] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an improvement in at least one patient-reported outcome measure or clinician-reported outcome measure selected from the group consisting of the Functional Assessment of Chronic Illness Therapy Fatigue Inventory (FACIT-Fatigue), EuroQol Five Dimensions Three Levels Questionnaire (EQ-5D-3L) and Short Form-36v2 (SF-36v2), Health Assessment Questionnaire Disability Index (HAQ-DI), and Physician's Global Assessment of Disease Activity-Visual Analog Scale (MD-VAS).

[0038] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduction in the glucocorticoid toxicity index (GTI) score.

[0039] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduction in a PMR activity score (PMR-AS). In certain exemplary embodiments, the reduction in PMR-AS is at least 3 points. In certain exemplary embodiments, the reduction in PMR-AS is at least 5 points.

[0040] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increased time to first PMR flare. In certain exemplary embodiments, the symptoms of a PMR flare are selected from the group consisting of shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0041] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered for at least 12 weeks. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered for at least 52 weeks.

[0042] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in remission of PMR in the subject.

[0043] In certain exemplary embodiments, the subject does not have a disease flare-up in relief. In certain exemplary embodiments, the symptoms of PMR flare-up are selected from the group consisting of: shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness. In certain exemplary embodiments, the relief is achieved at week 12 after starting treatment with the antibody or its antigen-binding fragment. In certain exemplary embodiments, the relief is sustained at week 52 after starting treatment with the antibody or its antigen-binding fragment. In certain exemplary embodiments, the relief is achieved at week 12 after starting treatment with the antibody or its antigen-binding fragment and continues to week 52. In still other exemplary embodiments, the relief (e.g., no disease flare-up) is achieved at week 16 after starting treatment with the antibody or its antigen-binding fragment and continues to week 52, or the relief is achieved at week 24 after starting treatment with the antibody or its antigen-binding fragment and continues to week 52.

[0044] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.

[0045] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10.

[0046] In certain exemplary embodiments, the antibody is sarrellumab.

[0047] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0048] In certain exemplary embodiments, the antibody is administered using a pre-filled syringe containing about 175 mg / mL sarrelumab.

[0049] In another aspect, a method for treating polymyalgia rheumatica (PMR) in a subject in need thereof is provided, comprising administering to the subject a single initial dose of an antibody or antigen-binding fragment thereof that specifically binds to IL-6 receptor, followed by one or more secondary doses of the antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) sequence of SEQ ID NOs: 3, 4, and 5, and a light chain complementarity determining region (LCDR) sequence of SEQ ID NOs: 6, 7, and 8.

[0050] In certain exemplary embodiments, the subject has PMR that is refractory to steroids or refractory to steroid tapering. In certain exemplary embodiments, the steroid comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0051] In certain exemplary embodiments, the subject was previously treated with a dose of ≥7.5 mg / day of prednisone.

[0052] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered in combination with another therapeutic agent. In certain exemplary embodiments, the therapeutic agent comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone. In certain exemplary embodiments, prednisone is administered at a dose of about 15 mg / day. In certain exemplary embodiments, the dose of prednisone is gradually tapered.

[0053] In certain exemplary embodiments, the initial dose and the second dose of the antibody or antigen-binding fragment thereof are each about 200 mg.

[0054] In certain exemplary embodiments, the second dose is administered every other week (q2w).

[0055] In certain exemplary embodiments, the subject is at least 50 years old.

[0056] In certain exemplary embodiments, the subject suffers from bilateral shoulder pain.

[0057] In certain exemplary embodiments, the subject has a C-reactive protein (CRP) level >10 mg / L and / or an erythrocyte sedimentation rate (ESR) >30 mm / hr.

[0058] In certain exemplary embodiments, the subject suffers from morning stiffness.

[0059] In certain exemplary embodiments, the subject has no joint involvement other than the shoulder joint.

[0060] In certain exemplary embodiments, the subject suffers from hip pain or limited range of motion.

[0061] In certain exemplary embodiments, the subject is seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP).

[0062] In certain exemplary embodiments, the subject has subdeltoid bursitis and / or biceps tenosynovitis and / or posterior or axillary glenohumeral synovitis in at least one shoulder, and synovitis and / or trochanteric bursitis in at least one hip.

[0063] In certain exemplary embodiments, after administration of the antibody or antigen-binding fragment thereof, at least one symptom of polymyalgia rheumatica in the subject is improved. In certain exemplary embodiments, the symptom is selected from the group consisting of: shoulder pain associated with inflammatory stiffness; hip pain associated with inflammatory stiffness; elevated C-reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR).

[0064] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an improvement in at least one patient-reported outcome measure or clinician-reported outcome measure selected from the group consisting of the Functional Assessment of Chronic Illness Therapy Fatigue Inventory (FACIT-Fatigue), EuroQol Five Dimensions Three Levels Questionnaire (EQ-5D-3L) and Short Form-36v2 (SF-36v2), Health Assessment Questionnaire Disability Index (HAQ-DI), and Physician's Global Assessment of Disease Activity-Visual Analog Scale (MD-VAS).

[0065] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduction in the glucocorticoid toxicity index (GTI) score.

[0066] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduction in a PMR activity score (PMR-AS). In certain exemplary embodiments, the reduction in PMR-AS is at least 3 points. In certain exemplary embodiments, the reduction in PMR-AS is at least 5 points.

[0067] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increased time to first PMR flare. In certain exemplary embodiments, the symptoms of a PMR flare are selected from the group consisting of shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0068] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered for at least 12 weeks. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered for at least 52 weeks.

[0069] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in remission of PMR in the subject.

[0070] In certain exemplary embodiments, the subject is free of disease flares during remission. In certain exemplary embodiments, the symptoms of a PMR flare are selected from the group consisting of shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness. In certain exemplary embodiments, the remission is achieved 12 weeks after initiation of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, the remission is sustained 16 weeks after initiation of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, the remission is sustained 24 weeks after initiation of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, the remission is sustained 52 weeks after initiation of treatment with the antibody or antigen-binding fragment thereof.

[0071] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.

[0072] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10.

[0073] In certain exemplary embodiments, the antibody is sarrellumab.

[0074] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0075] In certain exemplary embodiments, the antibody is administered using a pre-filled syringe containing about 175 mg / mL sarrelumab.

[0076] In another aspect, a method of reducing or eliminating dependence of a subject with polymyalgia rheumatica (PMR) on background therapy comprising corticosteroids for treating PMR is provided, the method comprising: (a) selecting a patient with PMR that is partially controlled or uncontrolled with background therapy comprising corticosteroids; (b) administering to the patient a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to an IL-6 receptor at a defined dose at a defined frequency during an initial treatment period, while maintaining the subject's background PMR therapy during the initial treatment period; and (c) gradually reducing or eliminating the dose of corticosteroids administered to the subject over the course of subsequent treatment periods, while continuing to administer the antibody or antigen-binding fragment thereof to the subject at the defined frequency and dose used during the initial treatment period.

[0077] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) sequence of SEQ ID NOs: 3, 4, and 5, and a light chain complementarity determining region (LCDR) sequence of SEQ ID NOs: 6, 7, and 8.

[0078] In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0079] In certain exemplary embodiments, the initial dose of prednisone is about 15 mg / day.

[0080] In certain exemplary embodiments, the subsequent treatment period is at least 14 weeks.

[0081] In certain exemplary embodiments, the subsequent treatment period is at least 52 weeks.

[0082] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg.

[0083] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered every other week (q2w).

[0084] In certain exemplary embodiments, the subject is at least 50 years old.

[0085] In certain exemplary embodiments, the subject suffers from bilateral shoulder pain.

[0086] In certain exemplary embodiments, the subject has a C-reactive protein (CRP) level >10 mg / L and / or an erythrocyte sedimentation rate (ESR) >30 mm / hr.

[0087] In certain exemplary embodiments, the subject suffers from morning stiffness.

[0088] In certain exemplary embodiments, the subject has no joint involvement other than the shoulder joint.

[0089] In certain exemplary embodiments, the subject suffers from hip pain or limited range of motion.

[0090] In certain exemplary embodiments, the subject is seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP).

[0091] In certain exemplary embodiments, the subject has subdeltoid bursitis and / or biceps tenosynovitis and / or posterior or axillary glenohumeral synovitis in at least one shoulder, and synovitis and / or trochanteric bursitis in at least one hip.

[0092] In certain exemplary embodiments, after administration of the antibody or antigen-binding fragment thereof, at least one symptom of polymyalgia rheumatica in the subject is improved. In certain exemplary embodiments, the symptom is selected from the group consisting of: shoulder pain associated with inflammatory stiffness; hip pain associated with inflammatory stiffness; elevated C-reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR).

[0093] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an improvement in at least one patient-reported outcome measure or clinician-reported outcome measure selected from the group consisting of the Functional Assessment of Chronic Illness Therapy Fatigue Inventory (FACIT-Fatigue), EuroQol Five Dimensions Three Levels Questionnaire (EQ-5D-3L) and Short Form-36v2 (SF-36v2), Health Assessment Questionnaire Disability Index (HAQ-DI), and Physician's Global Assessment of Disease Activity-Visual Analog Scale (MD-VAS).

[0094] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduction in the glucocorticoid toxicity index (GTI) score.

[0095] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in a reduction in a PMR activity score (PMR-AS). In certain exemplary embodiments, the reduction in PMR-AS is at least 3 points. In certain exemplary embodiments, the reduction in PMR-AS is at least 5 points.

[0096] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in an increased time to first PMR flare. In certain exemplary embodiments, the symptoms of a PMR flare are selected from the group consisting of shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0097] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered for at least 12 weeks. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered for at least 52 weeks.

[0098] In certain exemplary embodiments, treatment with the antibody or antigen-binding fragment thereof results in remission of PMR in the subject.

[0099] In certain exemplary embodiments, the subject does not have a disease outbreak in the relief. In certain exemplary embodiments, the symptoms of PMR outbreak are selected from the group consisting of: shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness. In certain exemplary embodiments, at the 12th week after starting treatment with the antibody or its antigen-binding fragment, the relief is achieved. In certain exemplary embodiments, at the 52nd week after starting treatment with the antibody or its antigen-binding fragment, the relief is sustained. In certain exemplary embodiments, at the 12th week after starting treatment with the antibody or its antigen-binding fragment, the relief (e.g., no disease outbreak) is achieved and continues to the 52nd week. In still other exemplary embodiments, at the 16th week after starting treatment with the antibody or its antigen-binding fragment, the relief (e.g., no disease outbreak) is achieved and continues to the 52nd week, or at the 24th week after starting treatment with the antibody or its antigen-binding fragment, the relief is achieved and continues to the 52nd week.

[0100] In certain exemplary embodiments, subjects treated with the antibody achieve increased resolution of PMR signs and symptoms or GC-free resolution of PMR signs and symptoms. In certain exemplary embodiments, resolution of PMR signs and symptoms is achieved 4 weeks after initiation of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, GC-free resolution of PMR signs and symptoms is maintained from 16 weeks to 52 weeks after initiation of treatment with the antibody or antigen-binding fragment thereof. In certain exemplary embodiments, the signs and symptoms may include morning stiffness and / or pain in the neck, shoulder, and / or hip girdle; limited range of motion in the shoulder and / or hip girdle; systemic symptoms such as fatigue, weight loss, and low-grade fever; and other features consistent with PMR as determined by the clinician-investigator.

[0101] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.

[0102] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10.

[0103] In certain exemplary embodiments, the antibody is sarrellumab.

[0104] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0105] In certain exemplary embodiments, the antibody is administered using a pre-filled syringe containing about 175 mg / mL sarrelumab.

[0106] In another aspect, a method for treating polymyalgia rheumatica (PMR) in a subject in need thereof is provided, comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to an IL-6 receptor, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) sequence of SEQ ID NOs: 3, 4, and 5, and a light chain complementarity determining region (LCDR) sequence of SEQ ID NOs: 6, 7, and 8, and wherein the subject has had an inadequate response to steroids.

[0107] In certain exemplary embodiments, the steroid comprises a corticosteroid, such as prednisone.

[0108] In certain exemplary embodiments, the subject is an adult.

[0109] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.

[0110] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10.

[0111] In certain exemplary embodiments, the antibody is sarrellumab.

[0112] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0113] In certain exemplary embodiments, the antibody is administered using a pre-filled syringe containing about 175 mg / mL sarrelumab.

[0114] In another aspect, a method for treating polymyalgia rheumatica (PMR) in a subject in need thereof is provided, comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to an IL-6 receptor, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) sequence of SEQ ID NOs: 3, 4, and 5, and a light chain complementarity determining region (LCDR) sequence of SEQ ID NOs: 6, 7, and 8, and wherein the subject is intolerant to a steroid taper.

[0115] In certain exemplary embodiments, the steroid comprises a corticosteroid, such as prednisone.

[0116] In certain exemplary embodiments, the subject is an adult.

[0117] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.

[0118] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10.

[0119] In certain exemplary embodiments, the antibody is sarrellumab.

[0120] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0121] In certain exemplary embodiments, the antibody is administered using a pre-filled syringe containing about 175 mg / mL sarrelumab.

[0122] In another aspect, a method for treating polymyalgia rheumatica (PMR) in a subject in need thereof is provided, comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to an IL-6 receptor, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) sequence of SEQ ID NOs: 3, 4, and 5, and a light chain complementarity determining region (LCDR) sequence of SEQ ID NOs: 6, 7, and 8, and wherein the subject has had an inadequate response to steroids, or wherein the subject is intolerant to a gradual reduction in steroid dosage.

[0123] In certain exemplary embodiments, the steroid comprises a corticosteroid, such as prednisone.

[0124] In certain exemplary embodiments, the subject is an adult.

[0125] In another aspect, a method for treating polymyalgia rheumatica (PMR) in an adult subject in need thereof is provided, comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to an IL-6 receptor, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) sequence of SEQ ID NOs: 3, 4, and 5, and a light chain complementarity determining region (LCDR) sequence of SEQ ID NOs: 6, 7, and 8, and wherein the subject has had an inadequate response to corticosteroids, or wherein the subject is unable to tolerate a gradual reduction in the dose of a corticosteroid.

[0126] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.

[0127] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10.

[0128] In certain exemplary embodiments, the antibody is sarrellumab.

[0129] In another aspect, a method for treating polymyalgia rheumatica (PMR) in an adult subject in need thereof is provided, the method comprising administering an effective amount of sarrellumab, wherein the patient has had an inadequate response to corticosteroids, or wherein the patient cannot tolerate a corticosteroid taper.

[0130] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0131] In certain exemplary embodiments, the antibody is administered using a pre-filled syringe containing about 175 mg / mL sarrelumab.

[0132] In another aspect, a method for treating polymyalgia rheumatica (PMR) in a subject in need thereof is provided, comprising administering to the subject a single initial dose of an antibody or antigen-binding fragment thereof that specifically binds to IL-6 receptor, followed by one or more secondary doses of the antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4, and 5, and light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7, and 8, and wherein the subject has had an inadequate response to steroids.

[0133] In certain exemplary embodiments, the steroid comprises a corticosteroid, such as prednisone.

[0134] In certain exemplary embodiments, the subject is an adult.

[0135] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.

[0136] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10.

[0137] In certain exemplary embodiments, the antibody is sarrellumab.

[0138] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0139] In certain exemplary embodiments, the antibody is administered using a pre-filled syringe containing about 175 mg / mL sarrelumab.

[0140] In another aspect, a method for treating polymyalgia rheumatica (PMR) in a subject in need thereof is provided, comprising administering to the subject a single initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an IL-6 receptor, followed by one or more secondary doses of the antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4, and 5, and light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7, and 8, and wherein the subject is intolerant to a steroid taper.

[0141] In certain exemplary embodiments, the steroid comprises a corticosteroid, such as prednisone.

[0142] In certain exemplary embodiments, the subject is an adult.

[0143] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.

[0144] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10.

[0145] In certain exemplary embodiments, the antibody is sarrellumab.

[0146] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0147] In certain exemplary embodiments, the antibody is administered using a pre-filled syringe containing about 175 mg / mL sarrelumab.

[0148] In another aspect, a method for treating polymyalgia rheumatica (PMR) in a subject in need thereof is provided, the method comprising administering to the subject a single initial dose of an antibody or antigen-binding fragment thereof that specifically binds to an IL-6 receptor, followed by one or more secondary doses of the antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4, and 5, and light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7, and 8, and wherein the subject has had an inadequate response to steroids, or wherein the subject is unable to tolerate a gradual taper of the steroid.

[0149] In certain exemplary embodiments, the steroid comprises a corticosteroid, such as prednisone.

[0150] In certain exemplary embodiments, the subject is an adult.

[0151] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.

[0152] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10.

[0153] In certain exemplary embodiments, the antibody is sarrellumab.

[0154] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0155] In certain exemplary embodiments, the antibody is administered using a pre-filled syringe containing about 175 mg / mL sarrelumab.

[0156] In another aspect, a method for treating polymyalgia rheumatica (PMR) in a subject in need thereof is provided, comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to an IL-6 receptor, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementary determining region (HCDR) sequence of SEQ ID NOs: 3, 4, and 5 and a light chain complementary determining region (LCDR) sequence of SEQ ID NOs: 6, 7, and 8, or wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementary determining region (HCDR) sequence of SEQ ID NOs: 17, 18, and 19 and a light chain complementary determining region (LCDR) sequence of SEQ ID NOs: 14, 15, and 16.

[0157] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2.

[0158] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:9 and a light chain comprising SEQ ID NO:10.

[0159] In certain exemplary embodiments, the antibody is sarrellumab.

[0160] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) and / or a light chain complementarity determining region (LCDR) of a HCVR comprising the amino acid sequence of SEQ ID NO: 13, and a light chain complementarity determining region (LCDR) of a LCVR comprising the amino acid sequence of SEQ ID NO: 12.

[0161] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0162] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is tocilizumab.

[0163] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is administered subcutaneously or intravenously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen delivery device, or an automatic injector.

[0164] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered in combination with another therapeutic agent. In certain exemplary embodiments, the therapeutic agent comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises a glucocorticoid. In certain exemplary embodiments, the glucocorticoid is prednisone or an equivalent.

[0165] In certain exemplary embodiments, the dosage of glucocorticoid is gradually reduced. In certain exemplary embodiments, the experimenter can reduce total glucocorticoid exposure. In certain exemplary embodiments, the experimenter can realize the minimum glucocorticoid dosage that is less than or equal to 2.5mg prednisone every day or equivalent. In certain exemplary embodiments, the experimenter can realize the minimum glucocorticoid dosage that is less than or equal to 2.0mg prednisone every day or equivalent.

[0166] In certain exemplary embodiments, use of the antibody or antigen-binding fragment thereof results in a greater reduction in glucocorticoid exposure compared to use of conventional immunomodulatory (cIM) therapy.

[0167] In certain exemplary embodiments, the subject is able to discontinue glucocorticoid therapy. In certain exemplary embodiments, discontinuation of glucocorticoid therapy is defined as an interval of glucocorticoid use greater than 60 days.

[0168] In certain exemplary embodiments, the time to non-persistence is longer for a subject taking the antibody or antigen-binding fragment thereof compared to a subject taking conventional immunomodulatory (cIM) therapy.

[0169] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is a second-line therapy. In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is a third-line therapy.

[0170] In certain exemplary embodiments, the method comprises administering to the subject a single initial dose of an antibody or antigen-binding fragment thereof that specifically binds to IL-6 receptor, followed by one or more secondary doses of the antibody or antigen-binding fragment thereof.

[0171] In another aspect, a method for reducing or eliminating dependence of a subject with polymyalgia rheumatica (PMR) on background therapy comprising glucocorticoids for treating PMR is provided, the method comprising (a) selecting a patient with PMR that is partially controlled or uncontrolled with background therapy comprising glucocorticoids; and (b) administering to the patient a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to an IL-6 receptor at a defined dose and at a defined frequency during an initial treatment period, while maintaining the subject's background PMR therapy during the initial treatment period, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementary determining region (HCDR) sequence of SEQ ID NOs: 3, 4, and 5 and a light chain complementary determining region (LCDR) sequence of SEQ ID NOs: 6, 7, and 8, or wherein the antibody or antigen-binding fragment thereof comprises a heavy chain complementary determining region (HCDR) sequence of SEQ ID NOs: 17, 18, and 19 and a light chain complementary determining region (LCDR) sequence of SEQ ID NOs: 18, 19, and 20. NO:14, 15 and 16 light chain complementary determining region (LCDR) sequence; and (c) gradually reducing or eliminating the dosage of the glucocorticoid administered to the subject during the subsequent treatment period, while continuing to administer the antibody or its antigen-binding fragment to the subject at the defined frequency and dosage used during the initial treatment period.

[0172] In certain exemplary embodiments, the glucocorticoid comprises prednisone or an equivalent.

[0173] In certain exemplary embodiments, after administration of the antibody or antigen-binding fragment thereof, at least one symptom of polymyalgia rheumatica in the subject is improved. In certain exemplary embodiments, the symptom is selected from the group consisting of: shoulder pain associated with inflammatory stiffness; hip pain associated with inflammatory stiffness; elevated C-reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR). BRIEF DESCRIPTION OF THE DRAWINGS

[0174] The foregoing and other features and advantages of the present disclosure will be more fully understood from the following detailed description of illustrative embodiments, taken in conjunction with the accompanying drawings. The file of this patent contains at least one drawing / photograph executed in color. Copies of this patent with one or more color drawings / photographs will be provided by the Patent Office upon request and payment of the necessary fee.

[0175] Figure 1 A schematic diagram depicts an overview of the study design for Example 1. This study was a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of sarrelumab in patients with polymyalgia rheumatica. The study included two groups of patients with active PMR. Participants in Group 1 received sarrelumab 200 mg every 2 weeks with a 14-week corticosteroid taper. Participants in Group 2 received sarrelumab-matched placebo every 2 weeks with a 52-week corticosteroid taper. All patients received either sarrelumab 200 mg or placebo for 52 weeks.

[0176] Figure 2A-2B Depicted is a questionnaire assessing the Euroqol-5 Dimensions 3 Levels version (EQ-5D-3L), a general PRO instrument for measuring health status.

[0177] Figure 3A-3C The Short Form 36v2 (SF-36v2) questionnaire is described, which is a short-form, generic, 36-item PRO instrument that assesses eight multi-item dimensions of health: physical functioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, energy / vitality, bodily pain, and overall health perception.

[0178] Figure 4 Depicted is the Physician's Global Assessment of Disease Activity-Visual Analog Scale [MD-VAS] questionnaire, which was used to rate patients' disease activity on an anchored 100-mm horizontal VAS, where 0 was considered inactive and 100 was considered most active.

[0179] Figure 5A forest plot depicts the subgroup analysis of the proportion of patients achieving sustained remission at week 52. Subgroup analyses were performed to assess the consistency of the treatment effect. Subgroup analyses of the primary endpoint showed a numerical trend favoring sarrellumab 200 mg every 2 weeks with a 14-week taper compared with placebo with a 52-week taper, except for participants with a baseline weight of less than 60 kg; however, the sample size in this subgroup was very small.

[0180] Figure 6 A Kaplan-Meier plot of the time to first PMR flare after clinical remission in the ITT population up to 52 weeks is presented. Participants in the sarrellumab 200 mg q2w group followed by a 14-week taper were less likely to experience a PMR flare after achieving clinical remission than those in the placebo group followed by a 52-week taper (16.7% vs. 29.3%), with a hazard ratio of 0.56 (95% CI: 0.35 to 0.90; p=0.0153).

[0181] Figure 7 Depicted are the mean changes in PMR activity scores from baseline over time for the ITT population. The greatest reductions in PMR activity were observed from baseline to Week 12 in both the sarilumab 200 mg q2w + 14-week taper group and the placebo + 52-week taper group, with reductions in the sarilumab 200 mg q2w + 14-week taper group sustained through Week 52.

[0182] Figure 8 The SF-36 least squares mean (LSM) physical summary score (PCS) and mental summary score (MCS) are graphically depicted. The LSM difference in PCS in the sarrelumab 200 mg q2w + 14 week taper group compared to the placebo + 52 week taper group was statistically significant (4.784, 95% CI: 0.865, 8.703; p = 0.0172). The LSM difference in MCS score in the sarrelumab 200 mg q2w + 14 week taper group compared to the placebo + 52 week taper group was statistically significant (4.748, 95% CI: 0.484, 9.013; p = 0.0295).

[0183] Figure 9 The statistical significance of the improvement from baseline for sarrelumab compared to placebo in different SF-36 domains is graphically depicted. The SF-36 domains include physical functioning (PF), role physical (RP), bodily pain (BP), global health (GH), vitality (VT), social functioning (SF), role emotional (RE), and mental health (MH). Figure 9As shown, 5 of the 8 domains of the SF-36 showed that sarrelumab resulted in statistically significantly greater improvements compared with placebo (MH, RP, BP, SF, and VT).

[0184] Figure 10 The percentages of patients who reported an improvement greater than or equal to the minimal clinically important difference (MCID) at week 52 for various SF-36 measures (including PCS, MCS, PF, RP, BP, GH, VT, SF, RE, and MH) when treated with sarrellumab and placebo are graphically depicted. The MCID (improvement from baseline) for PCS and MCS was 2.5. The MCID for individual SF-36 domains was 5.0. These results indicate that more patients receiving sarrellumab reported statistically significant improvements greater than or equal to the MCID for PCS (P=0.0161) and five of the eight SF-36 domain scores.

[0185] Figure 11 The percentages of patients who reported scores greater than or equal to the normative values ​​at baseline and week 52 for various SF-36 measures (including PCS, MCS, PF, RP, BP, GH, VT, SF, RE, and MH) in patients treated with sarrellumab and placebo are graphically depicted. The thresholds were as follows: PCS and MCS ≥ 50.0; PF ≥ 66.0, RP ≥ 69.2, BP ≥ 66.4, GH ≥ 66.1, VT ≥ 58.8, SF ≥ 82.1, RE 81.9, and MH ≥ 77.8. These results indicate that numerically more patients receiving sarrellumab reported scores greater than or equal to the normative values ​​for the SF-36 MCS and four SF-36 domain scores.

[0186] Figure 12 The percentage of patients who reported an improvement greater than or equal to the MCID for FACIT-F scores at week 52 in patients treated with sarrellumab and placebo is graphically depicted. The MCID for FACIT-F is an improvement greater than or equal to 4.0. These results indicate that treatment with sarrellumab resulted in numerically greater improvements in FACIT-F scores (higher scores represent better function or less fatigue) compared to treatment with placebo.

[0187] Figure 13 The percentages of patients treated with sarrellumab and placebo who reported FACIT-F scores greater than or equal to the criterion value at baseline and week 52 are graphically depicted. The criterion value threshold was greater than or equal to 43.5. These results demonstrate that treatment with sarrellumab resulted in numerically greater improvements in FACIT-F scores than treatment with placebo.

[0188] Figure 14 The percentage of patients who reported an improvement greater than or equal to the MCID for HAQ-DI scores at week 52 in patients treated with sarrellumab and placebo is graphically depicted. The MCID for HAQ-DI is an improvement greater than or equal to 0.22. These results indicate that treatment with sarrellumab resulted in a numerically greater improvement in HAQ-DI scores (lower HAQ-DI scores represent improvement) compared to treatment with placebo.

[0189] Figure 15 The percentages of patients treated with sarrellumab and placebo who reported HAQ-DI scores greater than or equal to the criterion value at baseline and week 52 are graphically depicted. The threshold for the criterion value was less than or equal to 0.25. These results demonstrate that treatment with sarrellumab resulted in numerically greater improvements in HAQ-DI scores (lower HAQ-DI scores represent improvement) compared with treatment with placebo.

[0190] Figure 16 Depicted graphically are the LSM changes from baseline in Patient Global Assessment of Disease Activity (PtGA) scores at Week 52 in patients treated with sarrellumab and placebo. These results demonstrate that treatment with sarrellumab resulted in numerically greater improvements in PtGA scores compared with treatment with placebo (higher scores representing higher levels of disease activity or worse overall health).

[0191] Figure 17 The percentages of patients who reported an improvement greater than the MCID in PtGA score at week 52 with sarelumab and placebo are graphically depicted. The MCID is an improvement greater than or equal to 10.0. These results indicate that treatment with sarelumab resulted in a numerically greater improvement in PtGA score than treatment with placebo.

[0192] Figure 18 Depicted graphically are the LSM changes from baseline in pain visual analog scale (VAS) scores at Week 52 in patients treated with sarilumab and placebo. These results demonstrate that treatment with sarilumab resulted in numerically greater improvements in pain VAS scores compared to treatment with placebo (higher scores represent greater pain intensity).

[0193] Figure 19The LSM changes from baseline in the EQ-5D index utility score and EQ VAS score at week 52 are graphically depicted in patients treated with sarelumab and placebo. These results demonstrate that sarelumab treatment resulted in a statistically greater improvement from baseline in the EQ-5D index utility score, with an LSM difference of 0.13 compared to placebo (P=0.0336). These results also demonstrate that sarelumab treatment resulted in a numerically greater improvement from baseline in the EQ VAS score (higher scores indicate better health).

[0194] Figure 20 The proportion of patients free of any signs and symptoms of PMR at each follow-up visit is graphically depicted for patients treated with sarelumab (200 mg Q2W + 14-week GC taper) and placebo (52 weeks of GC treatment). The proportion of patients free of PMR signs and symptoms increased at Week 2 with sarelumab compared to placebo and continued to increase over time until Week 52. At each follow-up visit after baseline, a higher proportion of patients in the sarelumab-treated group were free of any signs and symptoms of PMR compared to the placebo-treated group.

[0195] Figure 21 The proportion of patients free of any signs and symptoms of PMR at each follow-up visit (excluding patients receiving rescue therapy) was graphically depicted for patients treated with sarrelumab (200 mg Q2W + 14 weeks of GC tapering) and placebo (52 weeks of GC treatment). The proportion of patients free of PMR signs and symptoms at Week 2 increased with sarrelumab compared to placebo and continued to increase over time until Week 52. At each follow-up visit after baseline, a higher proportion of patients in the sarrelumab group were free of any signs and symptoms of PMR. In addition, compared to those in the Figure 20 Compared with Figure 21 A greater difference between the two treatment groups was observed in the 2 studies because patients receiving rescue therapy were excluded from the Figure 21 Beyond the analysis.

[0196] Figure 22 The cumulative proportion of patients who received rescue therapy with sarrelumab (200 mg Q2W + 14-week GC taper) and placebo (52 weeks of GC treatment) is graphically depicted. These results demonstrate that at every time point from baseline through Week 52, the cumulative proportion of patients requiring rescue therapy was higher in the placebo-treated group.

[0197] Figure 23 Depicted graphically are the percentages of patients achieving sustained remission at Week 52 among patients treated with sarrellumab and placebo, as assessed from Weeks 12 to 52, Weeks 16 to 52, and Weeks 24 to 52.

[0198] Figures 24A-24B Depicted graphically are the percentages of patients achieving disease remission (A) or absence of flares (B) at Week 52 among patients treated with sarrellumab and placebo, as assessed from Weeks 12 to 52, Weeks 16 to 52, and Weeks 24 to 52.

[0199] Figures 25A-25B Graphically depicted are the percentages of patients who achieved sustained normalization of CRP (A) or maintenance of steroid taper (B) at Week 52 among patients treated with sarrelumab and placebo, as assessed from Weeks 12 to 52, Weeks 16 to 52, and Weeks 24 to 52.

[0200] Figure 26 The percentages of patients who achieved GC-free resolution of PMR signs and symptoms by follow-up (no rescue therapy by follow-up) among patients treated with sarrelumab or placebo are graphically depicted.

[0201] Figure 27 The percentages of patients who achieved freedom from signs and symptoms of PMR at follow-up among patients treated with sarrellumab or placebo are depicted graphically.

[0202] Figure 28 The time to first flare after achieving clinical remission compared with the comparator group is graphically depicted.

[0203] Figure 29 The time to non-persistence (discontinuation or switching of IL-6 inhibitor or conventional immunomodulatory drug therapy) was graphically depicted with IL-6 inhibitors (IL-6Ri) compared to conventional immunomodulatory drug therapy (cIM). These results showed that the time to discontinuation was significantly longer in IL-6Ri patients compared to cIM patients (p=0.029).

[0204] Figure 30 Time to and persistence on index PMR therapy, which was either IL-6Ri (sarelumab or tocilizumab) or CIM therapy, is depicted graphically, with survival curves showing persistence after propensity score matching in the second-line cohort. CIM, conventional immunomodulator; IL-6Ri, interleukin-6 receptor inhibitor; PS, propensity score; 2L, second-line.

[0205] Figure 31 Figure 3. Graphical depiction of time and non-switch therapy showing survival curves for the second-line cohort after PS matching for switch therapy. CIM, conventional immunomodulator; IL-6Ri, interleukin-6 receptor inhibitor; PS, propensity score; 2L, second-line. DETAILED DESCRIPTION

[0206] Before describing the present disclosure, it should be understood that the present disclosure is not limited to the specific methods and experimental conditions described, as such methods and conditions may vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the present disclosure will be limited only by the appended claims.

[0207] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0208] As used herein, when used to refer to a specific recited value, the term "about" means that the value may vary from the recited value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0209] As used herein, the terms "treat," "treating," and the like mean to alleviate the symptoms, temporarily or permanently eliminate the cause of the symptoms, or prevent or slow the appearance of symptoms of the referenced disorder or condition.

[0210] As used herein, the term "PMR flare" refers to an increase in PMR symptoms. The symptoms of PMR may be selected from the group consisting of shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0211] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, typical methods and materials are now described. All publications mentioned herein are incorporated by reference in their entirety.

[0212] The present disclosure provides methods and compositions for treating polymyalgia rheumatica (PMR).

[0213] Polymyalgia rheumatica is a chronic inflammatory disorder that occurs almost exclusively in people over the age of 50. (Guggino et al. Pathogenesis of Polymyalgia Rheumatica. Reumatismo. 2018 70(1):10-17 and Chatzigeorgiou C et al. Comorbidity in polymyalgiarheumatica. Reumatismo. 2018 Mar 27;70(1):35-43, incorporated herein by reference in their entirety). Polymyalgia rheumatica presents with pain and stiffness in the shoulders and possibly the hips, elevated (although occasionally normal) inflammatory markers, and a characteristically dramatic response to corticosteroids. Classification criteria for diagnosing polymyalgia rheumatica are described by the European League Against Rheumatism and the American College of Rheumatology (Dasgupta B et al. 2012 provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism / American College of Rheumatology collaborative initiative. Annals of the Rheumatic Diseases 2012;71:484-492, incorporated herein by reference in its entirety). Classification criteria include patients 50 years of age or older presenting with bilateral shoulder pain that is not better explained by an alternative diagnosis and elevated C-reactive protein (CRP) levels and / or an elevated erythrocyte sedimentation rate (ESR). Additional criteria include morning stiffness lasting longer than 45 minutes and the onset of new symptoms involving the hip (e.g., pain, tenderness, and limited motion). Additional classification criteria may include the absence of peripheral synovitis, the absence of positive rheumatoid arthritis (RA) serology (rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA) or both), and the absence of peripheral joint pain. Additional classification criteria may include abnormal musculoskeletal ultrasound findings in bilateral shoulders (subacromial bursitis / biceps tenosynovitis / glenohumeral effusion) or abnormalities in one shoulder and hip (hip effusion, trochanteric bursitis).

[0214] The classification criteria for the diagnosis of polymyalgia rheumatica are described herein. Also referring to the European League Against Rheumatism and the American College of Rheumatology (Dasgupta B et al. 2012provisional classification criteria for polymyalgiarheumatica:a European League Against Rheumatism / American College of Rheumatology collaborative initiative. [temporary classification criteria for polymyalgia rheumatica: European League Against Rheumatism / American College of Rheumatology collaborative initiative] Annals of the Rheumatic Diseases [Annals of the Rheumatic Diseases] 2012; 71:484-492, incorporated herein by reference in its entirety). Classification criteria can include patients aged 50 or above with bilateral shoulder pain (which cannot be better explained by alternative diagnoses) and elevated C-reactive protein (CRP) levels and / or elevated erythrocyte sedimentation rate (ESR). Additional criteria can include morning stiffness present for more than 45 minutes, and the occurrence of new symptoms (such as pain, tenderness, and limited activity) relating to the hip. (The American College of Rheumatology criteria for rheumatic diseases, including polymyalgia rheumatica, can be found at www.rheumatology.org / Practice-Quality / Clinical-Support / Criteria / ACR-Endorse d-Criteria, incorporated herein in its entirety).

[0215] IL-6 interacts directly with the IL-6Rα subunit, and the IL-6 / IL-6Rα pair forms a high-affinity complex with the glycoprotein 130 (gp130) subunit and initiates intracellular signaling via the Janus kinase (JAK)-signaling and activator of transcription (STAT) (JAK / STAT) and Ras / Raf / mitogen-activated protein kinase (MAPK) pathways. IL-6Rα also exists in a soluble form that participates in trans-signaling and enables IL-6 to affect cells that do not express IL-6Rα, including synovial cells.

[0216] Sarirumab (SAR153191), also known as REGN88, is a recombinant IgG1κ monoclonal antibody directed against the fully human sequence of the α subunit of the IL-6 receptor complex (IL-6Rα). Sarirumab blocks the binding of IL-6 and interrupts the cytokine-mediated signaling cascade. Sarirumab is also known by the trade name

[0217] Tocilizumab (TCZ) is a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody that binds to membrane-bound and soluble IL-6 receptors, thereby inhibiting IL-6 signaling. To improve PMR-related patient-reported outcome (PRO) and clinician-reported outcome (ClinRO) measures method

[0218] Methods are provided for improving one or more PMR-related patient-reported outcome (PRO) measures in a subject in need thereof, wherein the methods comprise administering to the subject a pharmaceutical composition comprising an IL-6R antagonist. Methods are provided for improving one or more PMR-related clinically reported outcome (ClinRO) measures in a subject in need thereof, wherein the methods comprise administering to the subject a pharmaceutical composition comprising an IL-6R antagonist.

[0219] Examples of PMR-related PRO measures include: (1) the Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-Fatigue), (2) the EuroQol five-dimensional three-level questionnaire (EQ-5D-3L), (3) the Short Form-36v2 (SF-36v2), (4) the Health Assessment Questionnaire Disability Index (HAQ-DI), (5) the patient's global assessment of disease activity (PtGA), and (6) the pain visual analogue scale (pain-VAS).

[0220] "Improvement in a PMR-related PRO measure" means an increase relative to baseline in one or more of the FACIT-Fatigue score, EQ-5D-3L score, or SF-36v2 score; and / or a decrease relative to baseline in one or more of the HAQ-DI score, PtGA score, or Pain-VAS score. As used herein, the term "baseline" with respect to a PMR-related PRO measure refers to the value of the PRO measure for the patient before or at the time of administration of a pharmaceutical composition comprising an IL-6R antagonist.

[0221] Examples of PMR-related ClinRO measures include the Physician's Global Assessment of Disease Activity - Visual Analog Scale (MD-VAS).

[0222] "Improvement in a PMR-associated ClinRO measure" means a decrease in the MD-VAS score relative to baseline. As used herein, the term "baseline" with respect to a PMR-associated ClinRO measure means the value of the patient's ClinRO measure before or at the time of administration of a pharmaceutical composition comprising an IL-6R antagonist.

[0223] To determine whether a PMR-associated parameter has "improved," the parameter is quantified at baseline and at time points after administration of a pharmaceutical composition as described herein. For example, a PMR-associated parameter can be measured at day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, or week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, week 32, week 40, week 52, or longer after initial treatment with the pharmaceutical composition. The difference between the value of the parameter at a particular time point after the start of treatment and the value of the parameter at baseline is used to determine whether the PMR-related parameter has "improved" (e.g., increased or decreased, as the case may be, depending on the specific parameter being measured).

[0224] As used herein, the terms "acquire" or "acquiring" refer to obtaining possession of a physical entity or value (e.g., a numerical value) by "directly acquiring" or "indirectly acquiring" the physical entity or value (e.g., a PMR-related parameter). "Directly acquiring" means performing a process (e.g., performing a synthesis or analytical method) to obtain the physical entity or value. "Indirectly acquiring" means receiving the physical entity or value from another party or source (e.g., a third-party laboratory that directly acquires the physical entity or value). Directly acquiring a physical entity includes performing a process that involves a physical change in a physical substance (e.g., a starting material). Exemplary changes include: manufacturing a physical entity from two or more starting materials, shearing or fragmenting a substance, isolating or purifying a substance, combining two or more separated entities into a mixture, and performing a chemical reaction that involves breaking or forming covalent or non-covalent bonds. Directly acquiring a value includes performing a process that involves a physical change in a sample or another substance; for example, performing an analytical process (sometimes referred to herein as a "physical analysis") that involves a physical change in a substance (e.g., a sample, an analyte, or a reagent).

[0225] Indirectly acquired information can be provided in the form of a report, for example, in paper or electronic form, such as from an online database or an application ("App"). The report or information can be provided by, for example, a healthcare institution (such as a hospital or clinic); or a healthcare provider (such as a doctor or nurse). Chronic Disease Therapy Functional Assessment Fatigue Scale

[0226] According to certain embodiments, administration of an IL-6R antagonist to a patient results in an increase in the Functional Assessment of Chronic Illness Therapy Fatigue Inventory (FACIT-Fatigue) score relative to baseline. FACIT-Fatigue is a common 13-item PRO tool that measures fatigue. The patient's score for each item is rated on a 0 to 4 scale (0 = not at all, 1 = a little, 2 = a little, 3 = quite a bit, 4 = very much). The scores are summarized to give a total score between 0 and 52. The recall period is the last 7 days.

[0227] Provided are treatments that result in an increase in FACIT-Fatigue score relative to baseline. For example, administering an IL-6R antagonist to a subject in need thereof results in an increase in FACIT-Fatigue score relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. EuroQol-5 Dimensions 3 Levels Version (EQ-5D-3L)

[0228] According to certain embodiments, administration of an IL-6R antagonist to a patient results in an increase in EQ-5D-3L relative to baseline. EQ-5D-3L is a universal PRO tool that measures health status (EuroQol Group, EuroQol-a new facility for the measurement of health-related quality of life, Health Policy 1990; 16(3): 199-208). EQ-5D has two components: a "today" health utility index score derived from 5 items (involving mobility, self-care, daily activities, pain / discomfort, and anxiety / depression), and a current ("at this moment") overall health status score derived from a single 0-100 visual analog scale (VAS). The EQ-5D index utility score for death is assigned to 0, and perfect health is assigned to 1. The VAS is anchored to "best imaginable health" and "worst imaginable health."

[0229] Provided are treatments that result in an increase in EQ VAS score relative to baseline. For example, administering an IL-6R antagonist to a subject in need thereof results in an increase in EQ VAS score relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 , 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points.

[0230] Provided are treatment methods that result in an increase in EQ-5D Index utility score relative to baseline. For example, administering an IL-6R antagonist to a subject in need thereof results in an increase in EQ-5D Index utility score relative to baseline of about 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, or 0.95 points. Simple Form 36v2 (SF-36v2)

[0231] According to certain embodiments, administration of an IL-6R antagonist to a patient results in an increase relative to baseline on the Short Form 36 v2 (SF-36 v2). The Short Form 36 v2 (SF-36 v2) is a short-form, generic, 36-item PRO instrument that assesses eight multi-item dimensions of health: physical functioning (PF; 10 items), social functioning (SF; 2 items), role limitations due to physical problems (RP; 4 items), role limitations due to emotional problems (RE; 3 items), mental health (MH; 5 items), energy / vitality (VT; 4 items), bodily pain (BP; 2 items), and global health perception (GH; 5 items) (Ware et al. The MOS 36-Item Short-Form Health Survey (SF-36): I. Conceptual Framework and Item Selection, Medical Care 1992; 30(6): 473-483). For each dimension, item scores are coded, summed, and converted to a scale ranging from 0 (worst possible health state measured by the questionnaire) to 100 (best possible health state). Two standardized summary scores can also be calculated from the SF-36v2: the physical component summary (PCS) and the mental component summary (MCS) (scales of 0–100) (see Maruish ME (2011) User's manual for the SF-36v2 Health Survey (3rd ed.) Lincoln, RI: QualityMetrics, Inc.).

[0232] Provided are treatments that result in an increase in SF-36v2 score relative to baseline. For example, administering an IL-6R antagonist to a subject in need thereof results in an increase in SF-36v2 score relative to baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points. Health Assessment Questionnaire Disability Index (HAQ-DI)

[0233] The HAQ-DI was developed to assess functional status in adults with arthritis but is now commonly used in many rheumatic conditions (see Wolfe F “A brief clinical health assessment instrument: CLINHAQ,” Arthritis Rheum. 1989;32(Suppl):S9 and Wolfe F. “Data collection and utilization: a methodology for clinical practice and clinical research,” Rheumatoid arthritis: pathogenesis, assessment, outcome and treatment, New York: Marcel Dekker, 1994:463-514). It contains 25 items: 20 4-point Likert-scale questions assessing eight physical dimensions of activities of daily living (dressing and grooming, getting up, eating, walking, washing, reaching, grasping, and chores and housework), 13 additional questions assessing the use of assistive devices, and 8 additional questions assessing help received from another person. The recall phase is for the most recent week. To calculate the HAQ-DI score, there are three steps: summing the eight category scores by using the highest subcategory score in each category; adjusting for the use of assistive devices and / or help from another person when indicated; and dividing the summed category scores by the number of categories answered (which must be at least 6) to obtain an HAQ-DI score of 0-3 (3 = worst function). In addition, the HAQ-DI has two additional questions measured on a 0-100 scale: How much pain did you have in the past week? Please rate your performance on a scale of 0 to 100 (0 representing "excellent" health and 100 representing "very poor" health). These questions (measuring pain and global assessment separately) were scored independently.

[0234] Provided are treatments that result in a decrease in HAQ-DI score relative to baseline. For example, administering an IL-6R antagonist to a subject in need thereof results in a decrease in HAQ-DI score relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 6, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points. Patient global assessment of disease activity (PtGA)

[0235] The PtGA is a single question scored from 0 to 100 that focuses on overall health or disease activity from the patient's perspective. Higher scores represent greater levels of disease activity or worse overall health.

[0236] Provided are treatments that result in a decrease in PtGA score relative to baseline. For example, administering an IL-6R antagonist to a subject in need thereof results in a decrease in PtGA score relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 , 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points. Visual Analog Scale (VAS) for pain

[0237] The pain VAS is a unidimensional patient-reported measure of pain intensity (see Delgado et al. "Validation of digital visual analog scale pain scoring with a traditional paper-based visual analog scale in adults," Journal of the American Academy of Orthopaedic Surgeons, March;2(3). Pain VAS scores range from 0 to 100, with higher scores indicating greater pain intensity.

[0238] Provided are treatments that result in a decrease in pain VAS score relative to baseline. For example, administering an IL-6R antagonist to a subject in need thereof results in a decrease in pain VAS score relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 6, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points. Physician's global assessment of disease activity-visual analog scale [MD-VAS]

[0239] In the MD-VAS, physicians rate a patient's disease activity on an anchored 100-mm horizontal VAS, where 0 is considered inactive and 100 is considered most active (see Huskisson et al. "Vertical or Horizontal Visual Analogue Scales" Ann Rheum Dis. 1979 Dec;38(6):560).

[0240] Provided are treatments that result in a decrease in MD-VAS score relative to baseline. For example, administering an IL-6R antagonist to a subject in need thereof results in a decrease in HAQ-DI score relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 6, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points.

[0241] The methods described herein may further improve one or more other PMR-related outcomes, including but not limited to the PMR activity score (PMR-AS), glucocorticoid toxicity index (GTI), cumulative corticosteroid dose, and time to PMR flare. PMR activity score (PMR-AS)

[0242] PMR-AS was calculated as the sum of CRP (mg / dL), visual analogue scale (VAS) for pain (0 to 10), VAS for physician assessment (0 to 10), duration of morning stiffness (MST [min] x 0.1), and ability to lift the upper limb (EUL [3-0]).

[0243] Provided are treatments that result in a decrease in PMR-AS score relative to baseline. For example, administering an IL-6R antagonist to a subject in need thereof results in a decrease in PMR-AS score relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 6, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points. Glucocorticoid toxicity index

[0244] The Glucocorticoid Toxicity Index (GTI) is a composite scale designed to assess glucocorticoid-related morbidity. The GTI Cumulative Worsening Score (CWS) reflects cumulative glucocorticoid toxicity, whether permanent or temporary. The GTI-CWS can only increase or remain unchanged over time. Lower scores indicate lower glucocorticoid toxicity. The GTI Integrated Improvement Score (AIS) reflects both worsening and improvement in glucocorticoid toxicity. New or worsening toxicity contributes a positive score, while improvement in existing toxicity contributes a negative score. Lower scores indicate lower glucocorticoid toxicity.

[0245] Provided are treatments that result in a decrease in GTI-CWS or GTI-AIS score relative to baseline. For example, administering an IL-6R antagonist to a subject in need thereof results in a decrease in GTI-CWS or GTI-AIS score relative to baseline by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85 , 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points. Cumulative corticosteroid dose

[0246] Cumulative corticosteroid dosage is the amount of corticosteroids taken over a period of time (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75 97, 98, 99, or 100 weeks).

[0247] Provided are methods of treating a subject in need thereof with an IL-6R antagonist that results in a reduction in the cumulative corticosteroid dose over a period of time compared to treatment without the IL-6R antagonist. For example, administering an IL-6R antagonist to a subject in need thereof results in a reduction in the cumulative corticosteroid dose by about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or 3000 mg. Time to PMR outbreak

[0248] Provided are methods of treating a patient that increases the amount of time until a patient experiences a PMR flare. For example, administering an IL-6R antagonist to a patient in need thereof increases the amount of time until the patient experiences a PMR flare by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 weeks. Methods of application and formulations

[0249] The methods described herein comprise administering to a subject a therapeutically effective amount of an anti-IL-6R antibody. As used herein, the phrase "therapeutically effective amount" refers to a dose of a therapeutic agent that results in the treatment of polymyalgia rheumatica. As used herein, "treating" refers to causing a detectable improvement in one or more symptoms associated with polymyalgia rheumatica, or causing a biological effect (e.g., a decrease in the level of a specific biomarker) associated with one or more underlying pathological mechanisms that produce the condition or one or more symptoms. For example, the following symptoms or conditions are associated with polymyalgia rheumatica: bilateral shoulder pain, hip pain or tenderness and limited hip motion, elevated C-reactive protein (CRP) levels, elevated erythrocyte sedimentation rate (ESR), and morning stiffness for more than a few minutes (e.g., 30 or 45 minutes).

[0250] In various embodiments, "improvement" of a PMR-related symptom refers to a decrease in the incidence of PMR symptoms, which may be associated with an improvement in one or more P-related tests, scores, or metrics (as described herein). For example, improvement may be associated with an increase over time relative to baseline in one or more of C-reactive protein (CRP), ESR, IL-6, soluble IL-6R, and / or markers of inflammation and disease activity (as assessed in circulating immune cell types, circulating proteins, and gene expression changes). As used herein, the term "baseline" with respect to a PMR-related parameter means the value of the PMR-related parameter of the patient before or at the time of administration of an antibody described herein.

[0251] At least one test, score or metric described herein can also be used to detect detectable "improvement". In various embodiments, improvement is detected by a reduction in PMR symptoms selected from the group consisting of: morning stiffness, neck pain, shoulder pain, hip girdle pain, limited shoulder range of motion, limited hip girdle range of motion, systemic symptoms (e.g., fatigue, weight loss and low-grade fever), and other features consistent with a PMR outbreak as judged by a clinician-researcher. In various embodiments, improvement is detected using at least one selected from the group consisting of: a patient-reported outcome (PRO) questionnaire, a functional assessment of chronic disease therapy fatigue scale (FACIT-fatigue), EQ-5D-3L, a short form 36v2, HAQ-DI, PMR-AS, ​​and a physician's global assessment of disease activity (e.g., a visual analog scale [MD-VAS]).

[0252] In various embodiments, detectable improvement is defined as sustained remission of the disease. As used herein, "sustained remission" of PMR in a subject is defined as one or more of the following: (i) disease remission, particularly at week 12 after initiation of treatment with a therapeutically effective amount of an anti-IL-6R antibody (i.e., the absence of signs and symptoms of PMR in the subject); (ii) absence of disease flares; (iii) normalization of C-reactive protein, particularly between weeks 12 and 52; or (iv) compliance with a steroid taper regimen, particularly a glucocorticoid taper (e.g., prednisone taper), particularly between weeks 12 and 52.

[0253] In another example, treatment is ineffective when a dose of an anti-IL-6R antibody does not result in a detectable improvement in one or more parameters or symptoms associated with PMR, or does not result in a biological effect related to one or more underlying pathological mechanisms of the condition or one or more symptoms that produce PMR.

[0254] In various embodiments, the IL-6R antibody is administered subcutaneously. In various embodiments, the IL-6R antibody is sarrellumab.

[0255] In various embodiments, the therapeutically effective amount of the anti-IL-6R antibody administered to a subject will vary depending on the age and size (e.g., weight or body surface area) of the subject, as well as the route of administration and other factors known to those of ordinary skill in the art.

[0256] In various embodiments, the dosage is a fixed dose that is independent of the subject's weight or surface area. In various embodiments, the subject is at least 50 years old. In various embodiments, the subject is greater than 50 years old.

[0257] The present disclosure provides methods of using therapeutic compositions comprising an anti-IL-6R antibody or antigen-binding fragment thereof, and optionally one or more additional therapeutic agents. The therapeutic compositions of the present disclosure will be administered with suitable carriers, excipients, and / or other agents incorporated into the formulation to provide improved delivery, transport, tolerability, etc. Many suitable formulations can be found in formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. These formulations include, for example, powders, pastes, ointments, jelly, waxes, oils, lipids, vesicles containing lipids (cationic or anionic), such as ), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsion carbowax (polyethylene glycol with different molecular weights), semisolid gels and semisolid mixtures containing carbowax.

[0258] Various delivery systems are known and can be used to administer the pharmaceutical compositions provided herein, e.g., encapsulation in liposomes, microparticles, microcapsules, receptor-mediated endocytosis. Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered by any convenient route, e.g., by infusion or bolus injection, absorbed through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can be administered with other bioactive agents. Administration can be systemic or local. The IL-6R antibody can be administered subcutaneously.

[0259] The pharmaceutical composition can also be delivered in a vesicle (e.g., liposome). In certain embodiments, the pharmaceutical composition can be delivered in a controlled release system, e.g., using a pump or polymeric material. In certain embodiments, the controlled release system can be placed close to the target of the composition, thus requiring only a fraction of the systemic dose.

[0260] Injectable preparations can include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injections, local injections, drip infusions, etc. These injectable preparations can be prepared by publicly known methods. For example, the above-mentioned antibodies or their salts can be dissolved, suspended or emulsified in a sterile aqueous medium or oily medium conventionally used for injection to prepare injectable preparations. As aqueous media for injection, for example, there are physiological saline, isotonic solutions containing glucose and other adjuvants, which can be used in combination with the following: appropriate solubilizers, such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol); nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc. As oily media, for example, sesame oil, soybean oil, etc. are used, which can be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared can be filled in a suitable ampoule.

[0261] The antibodies are generally formulated as described herein and in International Publication No. WO 2011 / 085158, which is incorporated herein by reference in its entirety.

[0262] In various embodiments, the antibody is administered as an aqueous buffer solution at about pH 6.0 containing - about 21 mM histidine, - about 45 mM arginine, - about 0.2% (w / v) polysorbate 20, - about 5% (w / v) sucrose, and - between about 100 mg / mL and about 200 mg / mL of the antibody.

[0263] In another embodiment, the antibody is administered as an aqueous buffer solution at about pH 6.0 containing - about 21 mM histidine, - about 45 mM arginine, - about 0.2% (w / v) polysorbate 20, - about 5% (w / v) sucrose, and - at least about 130 mg / mL of the antibody.

[0264] In another embodiment, the antibody is administered as an aqueous buffer solution at about pH 6.0 containing - about 21 mM histidine, - about 45 mM arginine, - about 0.2% (w / v) polysorbate 20, - about 5% (w / v) sucrose, and - About 131.6 mg / mL of the antibody.

[0265] In another embodiment, the antibody is administered as an aqueous buffer solution at about pH 6.0 containing - about 21 mM histidine, - about 45 mM arginine, - about 0.2% (w / v) polysorbate 20, - about 5% (w / v) sucrose; and - About 175 mg / mL of the antibody.

[0266] In other embodiments, the antibody is administered as an aqueous buffer solution at pH 6.0 containing -21 mM histidine, -45mM arginine, -0.2% (w / v) polysorbate 20, -5% (w / v) sucrose, and - Between 100 mg / mL and 200 mg / mL of the antibody.

[0267] In another embodiment, the antibody is administered as an aqueous buffer solution at pH 6.0 containing -21 mM histidine, -45mM arginine, -0.2% (w / v) polysorbate 20, -5% (w / v) sucrose, and - At least 130 mg / mL of the antibody.

[0268] In another embodiment, the antibody is administered as an aqueous buffer solution at pH 6.0 containing -21 mM histidine, -45mM arginine, -0.2% (w / v) polysorbate 20, -5% (w / v) sucrose, and -131.6 mg / mL of the antibody.

[0269] In another embodiment, the antibody is administered as an aqueous buffer solution at pH 6.0 containing -21 mM histidine, -45mM arginine, -0.2% (w / v) polysorbate 20, -5% (w / v) sucrose; and -175 mg / mL of the antibody.

[0270] In various embodiments, the antibody is administered in a stable pharmaceutical formulation comprising: (i) histidine at a concentration of 25 mM to 100 mM; (ii) arginine at a concentration of 25 mM to 50 mM; (iii) sucrose in an amount of 3% to 10% w / v; and (iv) polysorbate 20 in an amount of 0.1% to 0.2%, wherein the formulation has a pH of about 5.8, about 6.0, or about 6.2, and at least 90% of the native form of the antibody is recovered after storage at 45° C. for 1 month as determined by size exclusion chromatography. In various embodiments, about 200 mg of the antibody (e.g., sarrelumab) is administered to the subject. In various embodiments, about 150 mg of the antibody (e.g., sarrelumab) is administered to the subject.

[0271] In various embodiments, the antibody is administered in a stable pharmaceutical formulation comprising: (i) histidine at a concentration of about 10 mM to about 25 mM; (ii) arginine at a concentration of about 25 mM to about 50 mM; (iii) sucrose in an amount of about 5% to about 10% w / v; and (iv) polysorbate in an amount of about 0.1% to about 0.2% w / v, wherein the formulation has a pH of about 5.8, about 6.0, or about 6.2, and at least 90% of the native form of the antibody is recovered after storage at 45° C. for 1 month as determined by size exclusion chromatography. In various embodiments, about 200 mg of the antibody (e.g., sarelumab) is administered to the subject. In various embodiments, about 150 mg of the antibody (e.g., sarelumab) is administered to the subject.

[0272] Advantageously, the pharmaceutical composition for oral or parenteral use is prepared into a unit dosage form suitable for matching the dosage of the active ingredient. Such unit dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0273] In various embodiments, the anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) can be administered to a patient using any acceptable device or mechanism. For example, the administration can be accomplished using a syringe and needle or using a reusable pen and / or auto-injector delivery device. The methods of the present disclosure include administering an anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) using a variety of reusable pen and / or auto-injector delivery devices. Examples of such devices include, but are not limited to (Owen Mumford, Inc., Woodstock, UK), Pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG 75 / 25 strokes, Pen, 70 / 30 pen (Eli Lilly and Co., Indianapolis, IN), I, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN (Novo Nordisk, Copenhagen, Denmark), Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN OPTIPEN as well as (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen and / or autoinjector delivery devices for subcutaneous delivery of the pharmaceutical compositions of the present disclosure include, but are not limited to Pen (Sanofi-Aventis), (Sanofi) and (Eli Lilly), Autoinjector (Amgen, Thousand Oaks, CA), (Haselmeier, Stuttgart, Germany), (Dey, LP) and Pen (AbbVie Inc., North Chicago, IL, Abbott Park, IL), to name a few.

[0274] In various embodiments, the antibody is administered with a pre-filled syringe. In various embodiments, the antibody is administered with a pre-filled syringe containing a safety system. For example, the safety system prevents accidental needle stick injuries. In various embodiments, the antibody is administered with a pre-filled syringe containing the ERIS safety system (West Pharmaceutical Services Inc).

[0275] In various embodiments, the antibody is administered with an automatic injector. In various embodiments, the antibody is administered with an automatic injector. The compositions and / or antibodies are administered using an autoinjector with ANTIBIOL® technology (SHL Group). In various embodiments, the autoinjector is a device comprising a syringe that allows for administration of a dose of the composition and / or antibody to a subject.

[0276] Also contemplated herein is the use of a microinfusion set to deliver an anti-IL-6R antibody (or a pharmaceutical formulation comprising the antibody) to a patient. As used herein, the term "microinfusion set" refers to a subcutaneous delivery device designed to slowly administer a large volume (e.g., up to about 2.5 mL or more) of a therapeutic formulation over an extended period of time (e.g., about 10, 15, 20, 25, 30, or more minutes). Microinfusion sets are particularly suitable for delivering large doses of therapeutic proteins contained in high concentrations (e.g., about 100, 125, 150, 175, 200 mg / mL or more) and / or viscous solutions.

[0277] In various embodiments, an inadequate response to a prior treatment refers to a subject's pain not being well controlled after receiving the prior treatment at the maximum tolerated typical dose. In one embodiment, an inadequate response to a prior treatment refers to a subject having moderate or high disease activity and poor prognostic features despite the prior treatment. In various embodiments, an inadequate response to a prior treatment refers to a subject having pain symptoms (e.g., any of the symptoms listed herein) that have not improved or have worsened despite the prior treatment. dose

[0278] The amount of an IL-6R antagonist (e.g., an anti-IL-6R antibody) administered to a subject according to the methods described herein is generally a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" means an amount of an IL-6R antagonist that results in an improvement in one or more PMR-related PRO measures or ClinRO measures (as defined elsewhere herein). A "therapeutically effective amount" also includes an amount of an IL-6R antagonist that inhibits, prevents, alleviates, or delays the progression of PMR in a subject. In some embodiments, a therapeutically effective amount of an anti-IL-6R antibody reduces the dose of a corticosteroid (e.g., prednisone) administered to a subject. In the case of an anti-IL-6R antibody, a therapeutically effective amount can be from about 0.05 mg to about 700 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 5.0 mg, about 7.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 30 0mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 5 In some embodiments, the dosage of the anti-IL-6R antibody is about 10 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, or about 700 mg. In some embodiments, 200 mg of the anti-IL-6R antibody is administered. In some embodiments, 150 mg of the anti-IL-6R antibody is administered. In some embodiments, 300 mg of the anti-IL-6R antibody is administered.

[0279] The amount of IL-6R antagonist contained in an individual dose can be expressed in milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). For example, the IL-6R antagonist can be administered to a patient at a dose of about 0.0001 to about 10 mg / kg of subject body weight. For example, the IL-6R antagonist can be administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, or 6 mg / kg.

[0280] In certain embodiments, the initial dose is about the same as the loading dose. In certain embodiments, the initial dose is about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2.0 times, about 2.5 times, about 3.0 times, or more, the loading dose.

[0281] In certain embodiments, two or more (e.g., 2, 3, 4, or 5 or more) doses are administered at the beginning of a treatment regimen as an "initial dose" or "loading dose," followed by less frequent subsequent doses (e.g., "maintenance doses"). In one embodiment, the maintenance dose may be lower than the loading or initial dose.

[0282] In certain exemplary embodiments, the IL-6R antagonist is administered at a dose of about 150 mg or about 200 mg. In a particular exemplary embodiment, the IL-6R antagonist is administered at an initial dose of about 200 mg and one or more secondary or maintenance doses of about 200 mg, with the secondary doses administered every other week (q2w).

[0283] In certain exemplary embodiments, the subject is an adult and the IL-6R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In exemplary embodiments, the subject is an adult and the IL-6R antagonist is administered at an initial dose of about 600 mg and one or more secondary or maintenance doses of about 300 mg, and the second dose is administered every other week (q2w). In other exemplary embodiments, the subject is an adult and the IL-6R antagonist is administered at an initial dose of about 400 mg and one or more secondary or maintenance doses of about 200 mg, and the second dose is administered every other week (q2w). In certain embodiments, the subject is an adult, the initial dose comprises about 300 mg of the IL-6R antagonist, and the one or more subsequent doses comprise about 300 mg of the IL-6R antagonist administered every other week.

[0284] In certain exemplary embodiments, the IL-6R antagonist is administered using a prefilled device at a concentration of 150 mg / mL. In some embodiments, a 150 mg / mL IL-6R antagonist solution in a prefilled device is used to deliver approximately 300 mg of the IL-6R antagonist in a 2 mL injection. In certain exemplary embodiments, the IL-6R antagonist is administered using a prefilled device at a concentration of 175 mg / mL. In some embodiments, a 175 mg / mL IL-6R antagonist solution in a prefilled device is used to deliver approximately 200 mg of the IL-6R antagonist in a 1.14 mL injection. In certain exemplary embodiments, the IL-6R antagonist is administered using a prefilled device at a concentration of 131 mg / mL. In some embodiments, a 131 mg / mL IL-6R antagonist solution in a prefilled device is used to deliver approximately 150 mg of the IL-6R antagonist in a 1.14 mL injection. Combination therapy

[0285] Certain embodiments of the methods described herein comprise administering to a subject one or more additional therapeutic agents in combination with an IL-6R antagonist. As used herein, the phrase "in combination with" means administering the additional therapeutic agent before, after, or simultaneously with the pharmaceutical composition comprising the IL-6R antagonist. In some embodiments, the term "in combination with" includes administering the IL-6R antagonist and the second therapeutic agent sequentially or concomitantly. Methods of treating PMR or related conditions or complications are provided, comprising administering an IL-6R antagonist in combination with a second therapeutic agent to achieve additive or synergistic activity.

[0286] For example, when administered "before" a pharmaceutical composition comprising an IL-6R antagonist, the additional therapeutic agent can be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the pharmaceutical composition comprising an IL-6R antagonist. When administered "after" a pharmaceutical composition comprising an IL-6R antagonist, the additional therapeutic agent can be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of the pharmaceutical composition comprising an IL-6R antagonist. Administration "concurrently" with a pharmaceutical composition comprising an IL-6R antagonist means that the additional therapeutic agent is administered to the subject within less than 5 minutes of (before, after, or simultaneously with) administration of the pharmaceutical composition comprising the IL-6R antagonist, in a separate dosage form, or as a single combined dosage formulation comprising both the additional therapeutic agent and the IL-6R antagonist.

[0287] In an exemplary embodiment, the additional therapeutic agent administered in combination with the IL-6R antagonist is a background therapy. In some embodiments, the background therapy comprises a steroid. In an exemplary embodiment, the background therapy is a corticosteroid. Corticosteroids are steroid hormones produced in the adrenal cortex of vertebrates, as well as synthetic analogs of these hormones. Corticosteroids include prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortolone pivalate, prednisolone, and methylprednisolone. In some embodiments, the corticosteroid is prednisone. According to other embodiments, the corticosteroid can also be selected from triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-valerate, halometasone, alclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasone-17-propionate, flucortolone hexanoate, flucortolone pivalate, fluprednidene acetate, hydrocortisone-17-butyrate, hydrocortisone-17-acetopropionate, hydrocortisone-17-butypropionate, ciclesonide and prednicarbate.

[0288] In certain embodiments, the method results in a reduced need for background therapy. Reducing the dose of background therapy may also be referred to as "tapering." For example, in certain embodiments, the method results in a reduced dose and / or reduced frequency of background therapy. In an exemplary embodiment, the method results in a reduced dose and / or reduced frequency of corticosteroid background therapy.

[0289] In certain embodiments, the method results in discontinuation of background therapy. In an exemplary embodiment, the method results in discontinuation of corticosteroid background therapy.

[0290] In certain embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in a subject who has had an inadequate response to background therapy (particularly to steroids such as corticosteroids). In exemplary embodiments, the method results in the treatment of PMR (or one or more symptoms of PMR) with a reduced or no need for background therapy with corticosteroids.

[0291] In certain embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in a subject who cannot tolerate a tapering of background therapy (particularly a tapering of steroids such as a corticosteroid). In an exemplary embodiment, the method results in the treatment of PMR (or one or more symptoms of PMR) with a reduced need or no need for background therapy with corticosteroids.

[0292] In certain embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in a subject who has had an insufficient response to background therapy (particularly to steroids such as corticosteroids) and / or who cannot tolerate a gradual reduction in background therapy (particularly a gradual reduction in steroids such as corticosteroids). In an exemplary embodiment, the method results in the treatment of PMR (or one or more symptoms of PMR) with or without a reduced need for corticosteroid background therapy. In certain embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in an adult subject who has had an insufficient response to corticosteroids or who cannot tolerate a gradual reduction in corticosteroids.

[0293] In certain embodiments, the corticosteroid background therapy can be used with about 7.5mg / days to about 80mg / days.In certain embodiments, the corticosteroid background therapy can be used with 15mg / days to 20mg / days, about 20mg / days to about 50mg / days and about 35mg / days to about 80mg / days.In certain embodiments, the corticosteroid background therapy can be used with the dosage of about 7.5mg / days, about 10mg / days, about 12.5mg / days, about 15mg / days, about 20mg / days, about 25mg / days, about 30mg / days, about 35mg / days, about 40mg / days, about 45mg / days, about 50mg / days, about 55mg / days, about 60mg / days, about 65mg / days, about 70mg / days, about 75mg / days or about 80mg / days.In an exemplary embodiment, the corticosteroid background therapy is used with the dosage of about 15mg / days.

[0294] In some embodiments, the dose of background therapy is gradually reduced with treatment with an IL-6R antagonist. Patients with polymyalgia rheumatica who attempt to gradually reduce the daily dose of corticosteroid therapy to a lower dose of corticosteroid may experience at least one flare, e.g., reducing the dose so that the patient no longer experiences shoulder pain, hip girdle pain, or both, and morning inflammatory stiffness that persists for more than a certain time (e.g., 45 minutes). As described herein, treatment with an IL-6R antibody or antibody fragment can reduce flare attacks because the daily dose of the subject's corticosteroid therapy is gradually reduced or decreased over time.

[0295] The additional therapeutic agent can be, for example, another IL-6R antagonist, an IL-6R antagonist, a steroid, etc. In an exemplary embodiment, the additional therapeutic agent is a corticosteroid. In another exemplary embodiment, the additional therapeutic agent is prednisone.

[0296] In some embodiments, the additional therapeutic agent administered in combination with an IL-6R antagonist is a vaccine. In certain exemplary embodiments, the vaccine is a viral vaccine or a bacterial vaccine. In certain exemplary embodiments, the vaccine is a live (e.g., attenuated) viral vaccine or a live (e.g., attenuated) bacterial vaccine.

[0297] Suitable vaccines include, but are not limited to, adenovirus, anthrax (e.g., AVA vaccine (BioThrax)), cholera (e.g., Vaxchora), diphtheria (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), hepatitis A (e.g., HepA (Havrix, Vaqta), HepA-HepB (Twinrix)), hepatitis B (e.g., HepB (Engerix-B, Recombivax)), HB, Heplisav-B), DTaP-HepB-IPV (Pediarix), HepA-HepB (Twinrix)), Haemophilus influenzae type b (Hib) (e.g., Hib (ActHIB, PedvaxHIB, Hiberix), DTaP-IPV / Hib (Pentacel)), human papillomavirus (HPV) (e.g., HPV9 (Gardasil 9)), influenza (flu) (e.g., IIV (also known as IIV3, IIV4, RIV3, RIV4, and ccIIV4) (Afluria, Fluad, Flublok, Flucelvax, FluLaval, Fluarix, Fluvirin, Fluzone, Fluzone High-Dose, Fluzone Intradermal), LAIV (FluMist)), Japanese encephalitis (e.g., JE (Ixiaro)), measles (e.g., MMR (MMR II), MMRV (ProQuad)), meningococcal (e.g., MenACWY (Menactra, Menveo), MenB (Bexsero, Trumenba)), mumps (e.g., MMR (MMR II), MMRV (ProQuad)), pertussis (e.g., DTaP (Daptacel, Infanrix), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), pneumococcal (e.g., PCV13 (Prevnar13), PPSV23 (Pneumovax23)), polio (e.g.,Polio (Ipol), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), rabies (e.g., Rabies (Imovax Rabies, RabAvert)), rotavirus (e.g., RV1 (Rotarix), RV5 (RotaTeq)), rubella (e.g., MMR (MMR II), MMRV (ProQuad)), herpes zoster (e.g., ZVL (Zostavax), RZV (Shingrix)), smallpox (e.g., Vaccinia (ACAM2000)), tetanus (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), tuberculosis, typhoid fever (e.g., Typhoid Oral (Vivotif), Typhoid polysaccharide (Typhim Vi)), varicella (e.g., VAR (Varivax), MMRV (ProQuad)), yellow fever (e.g., YF (YF-Vax)), etc. Suitable vaccines are also listed in the Centers for Disease Control Vaccine List (cdc.gov / vaccines / vpd / vaccines-list.html), which is incorporated herein in its entirety for all purposes. In some embodiments, the vaccine is tetanus, diphtheria, pertussis, and / or seasonal trivalent / quadrivalent influenza vaccine.

[0298] In some embodiments, the vaccine is an inactivated vaccine, a recombinant vaccine, a conjugate vaccine, a subunit vaccine, a polysaccharide vaccine, or a toxoid vaccine. In some embodiments, the vaccine is a yellow fever vaccine. In some embodiments, a subject treated with the vaccine is concurrently treated with an IL-6R antagonist for PMR.

[0299] In certain embodiments, treatment with the IL-6R antagonist is stopped or terminated prior to treatment with the vaccine. In certain embodiments, treatment with the IL-6R antagonist is stopped or terminated prior to treatment with the vaccine. 1 / 2, about 2, about 2 1 / 2, about 3, about 3 1 / 2, about 4, about 4 1 / 2, about 5, about 5 1 / 2, about 6, about 6 1 / 2, about 7, about 7 1 / 2, about 8, about 8 1In some embodiments, the IL-6R antagonist is stopped for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75 about 54, about 55, about 56, about 57, about 58, about 59, or about 60 days after treatment with the IL-6R antagonist is stopped.

[0300] In certain embodiments, treatment with an IL-6R antagonist is resumed after treatment with the vaccine. In certain embodiments, about 1 to about 14 weeks (e.g., about 1, about 1 1 / 2, about 2, about 2 1 / 2, about 3, about 3 1 / 2, about 4, about 4 1 / 2, about 5, about 5 1 / 2, about 6, about 6 1 / 2, about 7, about 7 1 / 2, about 8, about 8 1 / 2, about 9, about 9 1 / 2, about 10, about 10 1 / 2, about 11, about 11 1 / 2, about 12, about 12 1 / 2, about 13, about 13 1 / 2, about 14, about 14 1In some embodiments, at about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83 Treatment with the IL-6R antagonist is resumed on about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, or about 90 days.

[0301] In certain embodiments, the effectiveness of the IL-6R antagonist is not reduced by administration in combination with the vaccine or by subsequent administration of the vaccine.

[0302] In some embodiments, the effectiveness of the vaccine is not reduced by administration in combination with an IL-6R antagonist or by prior and / or subsequent administration of an IL-6R antagonist. In some embodiments, when the vaccine is co-administered with the IL-6R antagonist, the subject develops seroprotective neutralizing titers.

[0303] In certain exemplary embodiments, a vaccine described herein is administered to a subject, wherein at least one dose of an IL-6R antagonist is administered to the subject before, during, or after administration of the vaccine. Administration regimen

[0304] According to certain embodiments, multiple doses of an IL-6R antagonist can be administered to a subject over a defined time course. Such methods include sequentially administering multiple doses of an IL-6R antagonist to a subject. As used herein, "sequential administration" means administering each dose of an IL-6R antagonist to a subject at different time points, e.g., on different days separated by predetermined intervals (e.g., hours, days, weeks, or months). Methods are provided that include sequentially administering to a patient a single initial dose of an IL-6R antagonist, followed by one or more second doses of an IL-6R antagonist, and optionally followed by one or more third doses of an IL-6R antagonist.

[0305] Methods are provided comprising administering to a subject a pharmaceutical composition comprising an IL-6R antagonist at a dosing frequency of about four times a week, twice a week, once a week (q1w), once every two weeks (every two weeks is used interchangeably with every other week, every two weeks, or q2w), once every three weeks (every three weeks or q3w), once every four weeks (monthly or q4w), once every five weeks (q5w), once every six weeks (q6w), once every seven weeks (q7w), once every eight weeks (q8w), once every nine weeks (q9w), once every ten weeks (q10w), once every eleven weeks (q11w), once every twelve weeks (q12w), or less frequently, as long as a therapeutic response is achieved.

[0306] In certain embodiments involving administration of a pharmaceutical composition comprising an anti-IL-6R antibody, a weekly dose of about 150 mg or about 200 mg may be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-6R antibody, a biweekly dose of about 150 mg or about 200 mg may be used (biweekly and every other week, biweekly, or q2w are interchangeable). In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-6R antibody, a three-week dose of about 150 mg or about 200 mg may be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-6R antibody, a four-week dose of about 150 mg or about 200 mg (monthly dose) may be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-6R antibody, a five-week dose of about 150 mg or about 200 mg may be used. In other embodiments involving administration of a pharmaceutical composition comprising an anti-IL-6R antibody, a six-week dose of about 150 mg or about 200 mg may be used. In certain exemplary embodiments, the route of administration is subcutaneous.

[0307] The term "week" or "weeks" refers to a period of (n x 7 days) ± 3 days, for example (n x 7 days) ± 2 days, (n x 7 days) ± 1 day, or (n x 7 days), where "n" indicates the number of weeks, for example, 1, 2, 3, 4, 5, 6, 8, 12 weeks or more.

[0308] The terms "initial dose," "secondary dose," and "tertiary dose" refer to the temporal order in which the IL-6R antagonist is administered. Thus, the "initial dose" is the dose administered at the beginning of a treatment regimen (also referred to as a "baseline dose" or "loading dose"); the "secondary dose" is the dose administered after the initial dose; and the "tertiary dose" is the dose administered after the second dose. The initial, second, and third doses can all contain the same amount of IL-6R antagonist, but can differ from one another in terms of the frequency of administration. However, in certain embodiments, the amount of IL-6R antagonist contained in the initial, second, and / or third doses varies from one another during treatment (e.g., adjusted up or down as appropriate). In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of a treatment regimen as "loading doses," followed by subsequent doses (e.g., "maintenance doses") administered less frequently. In one embodiment, the maintenance dose can be lower than the loading dose. In one embodiment, the second dose / maintenance dose can be equal to the initial dose / loading dose. For example, one or more initial doses / loading doses of 150 mg or 200 mg of the IL-6R antagonist can be administered, followed by a second dose / maintenance dose of about 150 mg or about 200 mg, respectively. In one embodiment, the loading dose can be split, such as two or more doses administered at different time points, e.g., two loading doses, with the second loading dose administered two weeks after the first loading dose.

[0309] In some embodiments, the initial dose comprises 200 mg of the antibody or antigen-binding fragment thereof, and the one or more secondary doses comprise 200 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used interchangeably with every two weeks, once every two weeks, or q2w).

[0310] In an exemplary embodiment, 1 to 14 weeks (e.g., 1, 1 1 / 2, 2, 2 1 / 2, 3, 3 1 / 2, 4, 4 1 / 2, 5, 5 1 / 2, 6, 6 1 / 2, 7, 7 1 / 2, 8, 8 1 / 2, 9, 9 1 / 2, 10, 10 1 / 2, 11, 11 1 / 2, 12, 12 1 / 2, 13, 13 1 / 2, 14, 14 1The phrase "immediately preceding dose" means that in a multiple administration sequence, the patient is administered the dose of the IL-6R antagonist prior to the immediately following dose in the sequence, with no intervening doses.

[0311] The method can include administering any number of second and / or third doses of an IL-6R antagonist to the patient. For example, in certain embodiments, only a single second dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) second doses are administered to the patient. Similarly, in certain embodiments, only a single third dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) third doses are administered to the patient.

[0312] In embodiments involving multiple second doses, each second dose can be administered at the same frequency as the other second doses. For example, each second dose can be administered to the patient 1 to 2 weeks after the previous dose. Similarly, in embodiments involving multiple third doses, each third dose can be administered at the same frequency as the other third doses. For example, each third dose can be administered to the patient 2 to 4 weeks after the previous dose. Alternatively, the frequency of administering the second and / or third doses to the patient can vary over the course of the treatment regimen. The physician can also adjust the frequency of administration during the course of treatment based on the needs of the individual patient after clinical examination.

[0313] Provided are methods comprising sequentially administering an IL-6R antagonist and a second therapeutic agent to a patient to treat PMR or a related condition. In some embodiments, the method comprises administering one or more doses of an IL-6R antagonist, followed by one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) doses of a second therapeutic agent. For example, one or more doses of about 150 mg to about 200 mg of an IL-6R antagonist may be administered, followed by one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) doses of a second therapeutic agent (e.g., a corticosteroid) to treat, alleviate, reduce, or improve one or more PMR symptoms. In some embodiments, administration of one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) doses of an IL-6R antagonist results in improvement in one or more PMR-related parameters, followed by administration of a second therapeutic agent to prevent recurrence of at least one PMR symptom. Alternative embodiments involve concomitant administration of the IL-6R antagonist and the second therapeutic agent. For example, one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) doses of an IL-6R antagonist are administered, and a second therapeutic agent is administered in separate doses at a similar or different frequency relative to the IL-6R antagonist. In some embodiments, the second therapeutic agent is administered before, after, or simultaneously with the IL-6R antagonist.

[0314] In certain embodiments, the IL-6R antagonist is administered every other week for 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 ​​weeks, or longer. In specific embodiments, the IL-6R antagonist is administered for at least 14 weeks. In an exemplary embodiment, the IL-6R antagonist is administered for at least 52 weeks. Treatment population

[0315] The methods provided herein comprise administering a therapeutic composition comprising an IL-6R antagonist to a subject in need thereof. The expression "subject in need thereof" refers to a human or non-human animal that exhibits one or more symptoms or signs of PMR, or has been diagnosed with PMR.

[0316] In related embodiments, a "subject in need thereof" can be a subject who, prior to receiving the IL-6R antagonist, has been prescribed or is currently taking a steroid. In some embodiments, the subject can be a subject who, prior to receiving the IL-6R antagonist, has been prescribed or is currently taking a corticosteroid. In some embodiments, the subject is currently taking prednisone. For example, methods are provided that include administering an IL-6R antagonist to a subject who has been on a regular course of prednisone for eight or more weeks immediately prior to administering the IL-6R antagonist (such prior treatment is referred to herein as "background therapy"). In an exemplary embodiment, the subject has been on a regular course of prednisone at a dose of at least 7.5 mg / day and not more than 20 mg / day.

[0317] In yet other embodiments, the amount of corticosteroid (e.g., the amount of prednisone) is gradually decreased before or after initiation of administration of the IL-6R antagonist.

[0318] In another exemplary embodiment, prior to receiving the IL-6R antagonist, the subject in need thereof is diagnosed with steroid-refractory PMR. In some embodiments, despite treatment with steroids, the subject's PMR symptoms persist. In yet another exemplary embodiment, prior to receiving the IL-6R antagonist, the subject in need thereof is diagnosed with corticosteroid (e.g., prednisone)-refractory PMR. In some embodiments, despite treatment with corticosteroids (e.g., prednisone), the subject's PMR symptoms persist.

[0319] In another exemplary embodiment, prior to receiving the IL-6R antagonist, the subject in need thereof is diagnosed with PMR that is refractory to steroid taper. In some embodiments, upon attempting a steroid taper, the subject experiences a PMR flare. In an exemplary embodiment, the subject is refractory to a corticosteroid (e.g., prednisone) taper, and upon attempting a corticosteroid (e.g., prednisone) taper, the subject experiences a PMR flare.

[0320] In another embodiment, a "subject in need" is a subject whose PMR is not adequately controlled by steroids. In other embodiments, a "subject in need" is a subject whose PMR is not adequately controlled by corticosteroids (e.g., prednisone). In some embodiments, a "subject in need" is a subject for whom steroids are not recommended (i.e., the subject experiences adverse reactions associated with steroids or is undergoing one or more drug treatments that cannot be combined with steroid therapy). In some embodiments, a "subject in need" is a subject for whom corticosteroids (e.g., prednisone) are not recommended (i.e., the subject experiences adverse reactions associated with corticosteroids (e.g., prednisone) or is undergoing one or more drug treatments that cannot be combined with corticosteroids (e.g., prednisone).

[0321] In another exemplary embodiment, a "subject in need thereof" is a subject for whom steroids are medically not recommended (i.e., the subject has a history of allergies, adverse reactions, or other medical history in which steroid administration is not recommended). In an exemplary embodiment, the subject is a subject for whom corticosteroids (e.g., prednisone) are medically not recommended (i.e., the subject has a history of allergies, adverse reactions, or other medical history in which corticosteroids (e.g., prednisone) are not recommended).

[0322] In further exemplary embodiments, a "subject in need thereof" is a subject who has previously had an inadequate response to one or more steroids. In exemplary embodiments, the subject is a subject who has previously had an inadequate response to a corticosteroid (eg, prednisone).

[0323] In further exemplary embodiments, a "subject in need thereof" is a subject who is intolerant to a steroid taper. In exemplary embodiments, the subject is a subject who is intolerant to a corticosteroid taper (eg, a prednisone taper).

[0324] In another exemplary embodiment, a "subject in need thereof" is a subject who has had an inadequate response to steroids and / or is unable to tolerate a gradual reduction in steroid dosage. In an exemplary embodiment, the subject is a subject who has had an inadequate response to a corticosteroid (e.g., prednisone) and / or is unable to tolerate a gradual reduction in corticosteroid dosage (e.g., prednisone tapering).

[0325] In some embodiments, a "subject in need thereof" is at least 50 years old. In an exemplary embodiment, the subject is greater than 50 years old. In other exemplary embodiments, the subject suffers from bilateral shoulder pain. In still other exemplary embodiments, the subject has a C-reactive protein (CRP) level>10 mg / L and / or an erythrocyte sedimentation rate (ESR)>30 mm / hr. In some exemplary embodiments, the subject suffers from morning stiffness. In other exemplary embodiments, the subject does not have joint involvement other than the shoulder joint. In still other exemplary embodiments, the subject suffers from hip pain or limited range of motion. In some exemplary embodiments, the subject is seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP). In other exemplary embodiments, the subject suffers from subdeltoid bursitis and / or biceps tenosynovitis and / or posterior or axillary glenohumeral synovitis in at least one shoulder, and synovitis and / or trochanteric bursitis in at least one hip. Methods for evaluating pharmacodynamic PMR-related parameters

[0326] Methods for assessing one or more pharmacodynamic PMR-related parameters resulting from administration of a pharmaceutical composition comprising an IL-6R antagonist to a subject in need thereof are provided. A reduction in the incidence of PMR symptoms or an improvement in a PMR-related PRO or ClinRO measure can be associated with an improvement in one or more pharmacodynamic PMR-related parameters; however, such an association may not be observed in all cases.

[0327] Examples of "pharmacodynamic PMR-related parameters" include, for example, the following: (a) biomarker expression levels and (b) serum protein and RNA analysis. "Improvement of a pharmacodynamic PMR-related parameter" means, for example, a decrease in one or more of IL-6, IL6R, and C-reactive protein (CRP) levels relative to baseline, or a decrease in erythrocyte sedimentation rate (ESR). As used herein, the term "baseline" with respect to a pharmacodynamic PMR-related parameter means the value of the pharmacodynamic PMR-related parameter of the patient before or at the time of administration of the pharmaceutical composition described herein.

[0328] To assess a pharmacodynamic PMR-related parameter, the parameter is quantified at baseline and at time points after administration of the pharmaceutical composition. For example, a pharmacodynamic PMR-related parameter can be measured at about day 1, about day 2, about day 3, about day 4, about day 5, about day 6, about day 7, about day 8, about day 9, about day 10, about day 11, about day 12, about day 14, or about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 11, about week 12, about week 13, about week 14, about week 15, about week 16, about week 17, about week 18, about week 19, about week 20, about week 21, about week 22, about week 23, about week 24, or longer after initiation of treatment with the pharmaceutical composition. The difference between the parameter value at a specific time point after treatment initiation and the parameter value at baseline is used to determine whether the pharmacodynamic PMR-related parameter has changed, such as "improved" (e.g., increased or decreased, as appropriate, depending on the specific parameter measured).

[0329] In certain embodiments, administration of an IL-6R antagonist to a patient results in a change in the expression of a particular biomarker, such as a decrease or increase. PMR-associated biomarkers include, but are not limited to, total IL-6, IL6R, and C-reactive protein (CRP). For example, administration of an IL-6R antagonist to a PMR patient can result in a decrease in the levels of IL-6, IL6R, or C-reactive protein (CRP). A decrease can be detected at about week 1, about week 2, about week 3, about week 4, about week 5, or longer after administration of the IL-6R antagonist. Biomarker expression can be determined by methods known in the art. For example, protein levels can be measured by ELISA (enzyme-linked immunosorbent assay). RNA levels can be measured by reverse transcription-coupled polymerase chain reaction (RT-PCR).

[0330] Biomarker expression (as discussed above) can be measured by detecting proteins or RNA in serum. Serum samples can also be used to monitor additional protein or RNA biomarkers associated with response to treatment with IL-6R antagonists or IL-6 signaling. In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), such as RNA levels of biomarkers; and in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis). Interleukin-6 receptor antagonists

[0331] The present disclosure includes methods comprising administering to a subject an antibody or antigen-binding fragment thereof that specifically binds hIL-6R. As used herein, the term "hIL-6R" refers to a human cytokine receptor that specifically binds human interleukin-6 (IL-6). In certain embodiments, the antibody administered to the patient specifically binds to the extracellular domain of hIL-6R.

[0332] As used herein, the term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains, namely 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 V H ) and heavy chain constant region. The heavy chain constant region contains three domains, C H 1. C H 2 and C H 3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or V L ) and the light chain constant region. The light chain constant region contains a domain (C L 1). V H Area and V L The V domains can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). H and V L It is composed of three CDRs and four FRs arranged in the following order from amino terminus to carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the antibody (or its antigen-binding portion) may be identical to human germline sequences, or may be natural or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0333] As used herein, the term "antibody" also includes the antigen binding fragment of a complete antibody molecule. As used herein, the term "antigen binding portion thereof," "antigen binding fragment" of an antibody, etc., include any naturally occurring, enzymatically obtainable, synthetic or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. The antigen binding fragment of an antibody can be derived from a complete antibody molecule using any suitable standard technique (such as proteolytic digestion or the recombinant genetic engineering technology of manipulating and expressing the DNA encoding antibody variable domains and optionally constant domains). This DNA is known and / or easily obtained from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. DNA can be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable domains and / or constant domains into a suitable configuration or to introduce codons, produce cysteine ​​residues, modify, add or delete amino acid, etc.

[0334] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., isolated complementary determining regions (CDRs), such as CDR3 peptides), or constrained FR3-CDR3-FR4 peptides. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies and bivalent nanobodies), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains are also encompassed within the expression "antigen-binding fragment" as used herein.

[0335] The antigen-binding fragment of an antibody will generally contain at least one variable domain. The variable domain can be of any size or amino acid composition and will generally contain at least one CDR adjacent to or in frame with one or more framework sequences. L Domain-associated V H In the antigen-binding fragment of the structural domain, V H domain and V L The domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be a dimer and contain V H -V H 、V H -V L or V L -V L Alternatively, the antigen-binding fragment of the antibody may contain a monomer V Hor V L domain.

[0336] 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 include: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v) V H -C H 1-C H 2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L ;(viii)V L -C H 1; (ix) V L -C H 2;(x)V L -C H 3; (xi) V L -C H 1-C H 2; (xii) V L -C H 1-C H 2-C H 3;(xiii)V L -C H 2-C H 3; and (xiv) V L -C L . In any configuration of variable and constant domains (including any of the exemplary configurations listed above), the variable and constant domains may be directly connected to each other, or may be connected by a complete or partial hinge or linker region. In various embodiments, the hinge region may be composed of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that create a flexible or semi-flexible connection between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, in various embodiments, the antigen-binding fragment of an antibody may comprise the above-listed constant domains to each other and / or to one or more monomeric V H or V LA homodimer or heterodimer (or other multimer) of any variable and constant domain configuration in which the domains are non-covalently associated (e.g., through one or more disulfide bonds).

[0337] In certain embodiments, the antibodies or antibody fragments used in the methods disclosed herein can be monospecific antibodies. In certain embodiments, the antibodies or antibody fragments used in the methods disclosed herein can be multispecific antibodies, which can be specific for different epitopes of a target polypeptide, or can contain antigen binding domains that are specific for epitopes of more than one target polypeptide. An exemplary bispecific antibody format that can be used in the context of certain embodiments involves the use of a first immunoglobulin (Ig) C H 3 domains and the second Ig C H 3 domains, of which the first Ig C H 3 domains and the second IgC H The three domains differ from each other by at least one amino acid, and wherein the at least one amino acid difference reduces binding of the bispecific antibody to Protein A compared to a bispecific antibody lacking the amino acid difference. In one embodiment, the first Ig C H 3 domains bind protein A and the second Ig C H The 3 domain contains a mutation that reduces or eliminates protein A binding, such as the H95R modification (according to IMGT exon numbering; H435R according to EU numbering). H 3 may further comprise a Y96F modification (according to IMGT; Y436F according to EU). In the case of IgG1 antibodies, the second C H Other modifications found in 3 include: D16E, L18M, N44S, K52N, V57M, and V82I (according to IMGT; D356E, L358M, N384S, K392N, V397M, and V422I according to EU); in the case of IgG2 antibodies, N44S, K52N, and V82I (according to IMGT; N384S, K392N, and V422I according to EU); and in the case of IgG4 antibodies, Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (according to IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I according to EU). Variations of the above-described bispecific antibody formats are contemplated within the scope of certain embodiments. In various embodiments, any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be adapted for use in the context of antigen-binding fragments of anti-IL-6R antibodies using routine techniques available in the art.

[0338] The fully human anti-IL-6R antibodies disclosed herein may comprise one or more amino acid substitutions, insertions and / or deletions in the architecture and / or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences. Such mutations can be readily determined by comparing the amino acid sequences disclosed herein with germline sequences available from, for example, public antibody sequence databases. The present disclosure includes antibodies and antigen-binding fragments thereof derived from any amino acid sequence disclosed herein, wherein one or more amino acid mutations within one or more architectures and / or CDR regions are reversed to one or more corresponding germline residues or conservative amino acid substitutions (natural or non-natural) of one or more corresponding germline residues (such sequence changes are referred to herein as "germline reversion mutations"). One of ordinary skill in the art can readily generate many antibodies and antigen-binding fragments comprising one or more individual germline reversion mutations or combinations thereof starting from the heavy and light chain variable region sequences disclosed herein. In certain embodiments, V H and / or V L In some embodiments, all framework residues and / or CDR residues in the domain are reversed to germline sequences. In other embodiments, only some residues are mutated back to germline sequences, for example, only the mutated residues found in the first 8 amino acids of FR1 or in the last 8 amino acids of FR4, or only the mutated residues found in CDR1, CDR2 or CDR3. In addition, the present invention includes antibodies that can contain any combination of two or more germline reversed mutations in the framework and / or CDR district, that is, some of which are reversed to germline sequences while retaining some other residues different from germline sequences. Once obtained, one or more desired properties of the antibodies and Fabs containing one or more germline reversed mutations can be easily tested, such as the binding specificity of improvement, the binding affinity of increase, the antagonism of improvement or enhancement or agonistic biological properties (as the case may be), the immunogenicity of reduction, etc. The antibodies and Fabs obtained in this general manner are encompassed within the present disclosure.

[0339] The constant region of an antibody is important in the ability of the antibody to fix complement and mediate cell-dependent cytotoxicity. Therefore, the isotype of an antibody can be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0340] As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, in various embodiments, the human antibodies characterized in the present disclosure (e.g., in CDRs, and in some embodiments, in CDR3s) include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutations in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species (e.g., a mouse) have been transplanted onto human framework sequences.

[0341] As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, generated, or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells (described further below), antibodies isolated from recombinant combinatorial human antibody libraries (described further below), antibodies isolated from animals (e.g., mice) that are transgenic for human immunoglobulin genes, or antibodies prepared, expressed, generated, or isolated by any other means involving splicing human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when using animals that are transgenic for human Ig sequences, in vivo somatic mutagenesis) and thus the V H and V L The amino acid sequence of the region is as follows, derived from human germline V H and V L When a sequence is present and related to a human antibody, the sequence may not naturally exist in the human antibody germline repertoire in vivo.

[0342] Human antibodies can exist in two forms associated with hinge heterogeneity. In one embodiment, the immunoglobulin molecule comprises a stable four-chain construct of approximately 150-160 kDa, in which the dimer is held together by interchain heavy chain disulfide bonds. In another embodiment, the dimer is not connected via interchain disulfide bonds and forms a molecule of approximately 75-80 kDa, which is composed of covalently coupled light and heavy chains (half antibodies). In certain embodiments, these forms are extremely difficult to separate, even after affinity purification.

[0343] The frequency of the second form in each intact IgG isotype is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the frequency of the second form to levels typically observed with the human IgG1 hinge. In various embodiments, the present disclosure encompasses substitutions in the hinge, C H 2 or C HRegion 3: Antibodies with one or more mutations that may be desirable, for example, in production to improve yield of the desired antibody form.

[0344] As used herein, an "isolated antibody" means 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 the antibody 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 separation step. In various embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0345] The term "specifically binds" or the like means that the antibody or its antigen-binding fragment forms a relatively stable complex with the 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, and the like. For example, as used herein, an antibody that "specifically binds" to IL-6R includes an antibody with the following K: D An antibody, or portion thereof, that binds to IL-6R (e.g., human IL-6R) at a K of 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, less than about 1 nM, or about 0.5 nM (as measured in a surface plasmon resonance assay). In some embodiments, the antibody has a K of about 0.1 nM to about 1000 nM or about 1 nM to about 100 nM. D In some embodiments, the antibody binds to IL-6R (e.g., human IL-6Rα) with a K of about 1 pM to about 100 pM or about 40 pM to about 60 pM. D Binds to IL-6R (e.g., human IL-6Rα). Specific binding can also be characterized by a dissociation constant of at least about 1 x 10 -6 M or less. In other embodiments, the dissociation constant is at least about 1×10 -7 M, 1×10 -8 M or 1×10 -9 M. An isolated antibody that specifically binds human IL-6R may, however, have cross-reactivity to other antigens, such as IL-6R molecules from other (non-human) species.

[0346] As used herein, the term "surface plasmon resonance" refers to an optical phenomenon that allows for the The Biacore system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ) detects changes in protein concentration within a biosensor matrix to analyze real-time interactions.

[0347] As used herein, the term "K D ” is intended to refer to the equilibrium dissociation constant of the antibody-antigen interaction.

[0348] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule, called a paratope. A single antigen can have more than one epitope. Therefore, different antibodies can bind to different regions on the antigen and can have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are produced by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. A linear epitope is an epitope produced by adjacent amino acid residues in a polypeptide chain. In some cases, an epitope may include a sugar, phosphoryl, or sulfonyl moiety on the antigen.

[0349] In various embodiments, the anti-IL-6R antibodies useful in the methods described herein may comprise one or more amino acid substitutions, insertions, and / or deletions in the architecture and / or CDR regions of the heavy and light chain variable domains compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily determined by comparing the amino acid sequences disclosed herein with germline sequences available from, for example, public antibody sequence databases. In various embodiments, the present disclosure includes methods involving the use of antibodies and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acid mutations within one or more architecture and / or CDR regions are mutated to one or more corresponding residues of the germline sequence from which the antibody was derived, or one or more corresponding residues of another human germline sequence, or to conservative amino acid substitutions of the one or more corresponding germline residues (such sequence changes are collectively referred to herein as "germline mutations"). Many antibodies and antigen-binding fragments can be constructed that comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all architecture residues and / or CDR residues within the VH and / or VL domains are backmutated to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues (e.g., mutated residues found only within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or mutated residues found only 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 one or more corresponding residues of a different germline sequence (i.e., a germline sequence different from the germline sequence from which the antibody was originally derived). In addition, the antibody can contain any combination of two or more germline mutations within the framework and / or CDR regions, for example, wherein certain single residues are mutated to the corresponding residues of a germline sequence, while maintaining certain other residues different from the original germline sequence or mutating to the corresponding residues of a different germline sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline mutations can be easily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. The uses of antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present disclosure.

[0350] The present disclosure also includes methods involving the use of anti-IL-6R antibodies comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present disclosure includes the use of anti-IL-6R antibodies having HCVR, LCVR, and / or CDR amino acid sequences having, for example, 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc., conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0351] According to the present disclosure, in various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity determining region (CDR) comprising any of the amino acid sequences of the anti-IL-6R antibodies described in U.S. Patent No. 7,582,298, which is incorporated herein by reference in its entirety. In certain embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) of the HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity determining region (LCDR) of the LCVR comprising the amino acid sequence of SEQ ID NO: 2. According to certain embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof 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 other embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[0352] In another embodiment, the anti-IL-6R antibody or antigen-binding fragment thereof 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. In some embodiments, the extracellular domain of hIL-6R comprises the amino acid sequence of SEQ ID NO: 11. According to certain exemplary embodiments, the methods of the present disclosure comprise the use of an anti-IL-6R antibody referred to and known in the art as sarrelumab, or a bioequivalent thereof.

[0353] The amino acid sequence of SEQ ID NO: 1 is EVQLVESGGGLVQPGRSLRLSCAASRFTFDDY AMH WVRQAPGKGLEWVS GISWNSGRIGYADSVKG RFTISRDNAENSLFLQMNGLRAEDTALYYCAK GRDSFDI WGQGTMVTVSS (CDR sequences highlighted: IMGT numbering in bold; Kabat numbering underlined; Chothia numbering in italics). The amino acid sequence of SEQ ID NO: 2 is (CDR sequences highlighted: IMGT numbering in bold; Kabat numbering underlined; Chothia numbering in italics). The amino acid sequence of SEQ ID NO: 3 is RFTFDDYA (CDR-H1 according to IMGT numbering). The amino acid sequence of SEQ ID NO: 4 is ISWNSGRI (CDR-H2 according to IMGT numbering). The amino acid sequence of SEQ ID NO: 5 is AKGRDSFDI (CDR-H3 according to IMGT numbering). The amino acid sequence of SEQ ID NO: 6 is QGISSW (CDR-L1 according to IMGT numbering). The amino acid sequence of SEQ ID NO: 7 is GAS (CDR-L2 according to IMGT numbering). The amino acid sequence of SEQ ID NO: 8 is QQANSFPYT (CDR-L3 according to IMGT numbering). The amino acid sequence of SEQ ID NO:9 is (CDR sequences highlighted: IMGT numbering in bold; Kabat numbering underlined; Chothia numbering in italics). The amino acid sequence of SEQ ID NO: 10 is (CDR sequences highlighted: IMGT numbering in bold; Kabat numbering underlined; Chothia numbering in italics). The amino acid sequence of SEQ ID NO: 11 is MVAVGCALLAALLAAPGAALAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLAVPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQD.

[0354] According to the present disclosure, in various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity determining region (CDR), wherein the HCVR, LCVR, and / or CDR comprise any of the amino acid sequences of the anti-IL-6R antibodies described in U.S. Patent No. 7,521,052 (incorporated herein by reference in its entirety). The hybridoma cell line producing tocilizumab (TCZ) has been internationally deposited as FERM BP-2998 on July 12, 1989, at the International Patent Biological Depository (AIST Tsukuba Central 6, 1-1, Higashi 1-chome, Tsukuba-shi, Ibaraki Pref.) under the Budapest Treaty. In certain embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain complementarity determining region (HCDR) and / or a light chain complementarity determining region (LCDR) of a HCVR comprising the amino acid sequence of SEQ ID NO: 13, and a light chain complementarity determining region (LCDR) of a LCVR comprising the amino acid sequence of SEQ ID NO: 12. According to certain embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof 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: 17; HCDR2 comprises the amino acid sequence of SEQ ID NO: 18; HCDR3 comprises the amino acid sequence of SEQ ID NO: 19; LCDR1 comprises the amino acid sequence of SEQ ID NO: 14; LCDR2 comprises the amino acid sequence of SEQ ID NO: 15; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 16. In various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0355] In another embodiment, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of the heavy chain of TCZ and a light chain comprising the amino acid sequence of the light chain of TCZ. In some embodiments, the extracellular domain of hIL-6R comprises the amino acid sequence of the extracellular domain of TCZ. According to certain exemplary embodiments, the methods of the present disclosure comprise the use of an anti-IL-6R antibody known in the art as tocilizumab or a bioequivalent thereof.

[0356] The amino acid sequence of SEQ ID NO: 12 is DIQMTQSPSSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC The amino acid sequence of SEQ ID NO: 13 is VQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGS LVTVSSASTKGPSVFPLAPSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG. The amino acid sequence of SEQ ID NO: 14 is RASQDISSYLN. The amino acid sequence of SEQ ID NO: 15 is YTSRLHS. The amino acid sequence of SEQ ID NO: 16 is QQGNTLPYT. The amino acid sequence of SEQ ID NO: 17 is SDHAWS. The amino acid sequence of SEQ ID NO: 18 is YISYSGITTYNPSLK. The amino acid sequence of SEQ ID NO: 19 is SLARTTAMDY.

[0357] As used herein, the term "bioequivalent" refers to a molecule that has similar bioavailability (rate and extent of availability) after administration at the same molar dose and under similar conditions (e.g., the same route of administration), such that one would expect to be substantially equivalent to the comparative molecule in terms of both efficacy and safety. Two pharmaceutical compositions comprising an anti-IL-6R antibody are bioequivalent if they are pharmaceutically equivalent, meaning that they contain the same amount of active ingredient (e.g., IL-6R antibody), are in the same dosage form, are for the same route of administration, and meet the same or comparable criteria. Bioequivalence can be determined, for example, by comparing the pharmacokinetic parameters of the two compositions in an in vivo study. Parameters commonly used in bioequivalence studies include peak plasma concentration (Cmax) and the area under the plasma drug concentration-time curve (AUC).

[0358] In certain embodiments, the disclosure relates to methods comprising administering to a subject 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.

[0359] The present disclosure provides pharmaceutical compositions comprising such antibodies, and methods of using these compositions.

[0360] In various embodiments, 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, and is an antibody that specifically binds to the human interleukin-6 receptor (hIL-6R). See International Publication No. WO 2007 / 143168, which is incorporated herein by reference in its entirety. In one embodiment, the antibody comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 9 and a light chain variable region comprising the sequence of SEQ ID NO: 10. In various embodiments, the antibody is sarrelumab. Sarrelumab is also known under the trade name Example 1. A randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of sarrellumab in patients with polymyalgia rheumatica (NCT03600818, EFC15160, Phase 3) Materials and Methods Number of research centers and countries

[0361] A total of 70 sites enrolled at least one participant, and at least one participant was randomized at 60 of these sites, located in 17 countries (Australia, Argentina, Belgium, Canada, Estonia, France, Germany, Hungary, Israel, Italy, Japan, the Netherlands, Russia, Spain, Switzerland, the United Kingdom, and the United States). principle

[0362] Study EFC15160 was designed as a 52-week, double-blind, placebo-controlled, randomized study to evaluate the efficacy and safety of sarrellumab in patients with active polymyalgia rheumatica (PMR). The 52-week study treatment duration reflected the conventional duration and standard of care therapy required to ensure sustained remission in most PMR patients (thus, the primary endpoint of sustained remission was at Week 52). The ability to rapidly taper CS over 14 weeks (as opposed to conventional tapering schedules of 1 year or more) after initiating therapy while maintaining disease remission provided important clinically meaningful benefits compared to usual care. Target Main objectives

[0363] To evaluate the efficacy of sarilumab in patients with PMR as assessed by the proportion of patients with sustained remission at week 52 with sarilumab in the context of a 14-week corticosteroid (CS) taper compared to placebo in the context of a 52-week CS taper. Secondary Objectives

[0364] To demonstrate the efficacy of sarrellumab (14-week CS taper) compared with placebo (52-week CS taper) in patients with PMR with respect to clinical response over time (e.g., component of sustained remission, disease remission rate, time to first disease flare) and cumulative corticosteroid (including prednisone) exposure.

[0365] To assess the safety (including immunogenicity) and tolerability of sarrellumab in patients with PMR.

[0366] Sarrellumab concentrations were measured in the serum of PMR patients.

[0367] To assess the effect of sarrellumab on reducing glucocorticoid toxicity as measured by the composite glucocorticoid toxicity index (GTI) questionnaire. Exploratory goals

[0368] To assess the effect of sarrellumab on physician assessment of disease activity, as measured by the visual analogue scale (MD-VAS).

[0369] The effects of sarrellumab on various PRO concepts were assessed, including fatigue (as measured by the FACIT-Fatigue scale), health status (as measured by the EQ-5D-3L and SF-36v2), physical function (as measured by the HAQ-DI), pain (as measured by a visual analogue scale [VAS] via the HAQ-DI), and patient assessment of disease activity (as measured by the VAS via the HAQ-DI).

[0370] The effects of ESR / CRP levels on remission status were evaluated.

[0371] To characterize disease activity in a subset of patients with PMR who were treated with steroid taper or sarrellumab using a comprehensive approach evaluating circulating immune cell types.

[0372] Disease activity in patients with PMR while receiving steroid taper or sarrellumab was characterized by evaluating circulating proteins, genetics, and gene expression in patients who consented to this optional portion of the study. Study Design

[0373] This was a multicenter, randomized, double-blind, placebo-controlled, 52-week, Phase 3 study evaluating the efficacy and safety of sarrellumab in patients with active PMR.

[0374] like Figure 1 Patients with active PMR who met the eligibility criteria were randomized in a 1:1 ratio to one of two parallel treatment groups (sarilumab 200 mg or placebo plus a regimen-defined 14-week or 52-week CS taper): Group 1: sarilumab 200 mg every 2 weeks with a 14-week CS taper, Group 2: sarilumab-matched placebo every 2 weeks with a 52-week CS taper. All patients received sarilumab 200 mg or placebo for 52 weeks.

[0375] All patients received prednisone (CS tapering) according to the assigned group schedule. Prior to randomization and the start of study treatment, corticosteroid therapy was optimized to minimize the risk of serious adverse events associated with corticosteroid tapering. For the first 2 weeks after randomization, both groups received an initial dose of 15 mg / day of prednisone, followed by prednisone and / or prednisone-matched placebo to ensure a double-blind CS tapering schedule as defined below.

[0376] Group 1: Patients received tapering dose levels of prednisone (prednisone or a combination of prednisone and placebo to prednisone) from Week 2 to Week 13. Starting from Week 14, patients without flare-ups received prednisone-matched placebo.

[0377] Group 2: From week 2 to week 51, patients received gradually decreasing dose levels of prednisone (prednisone or a combination of prednisone and placebo).

[0378] At each on-site visit, the patient's disease was assessed to determine whether the patient could comply with the protocol-defined prednisone taper schedule. During the initial 12 weeks of prednisone taper, treatment of one flare was allowed if the patient could be successfully treated with a low-dose (≤5 mg / day) prednisone add-on taper regimen (completed before Week 12) and provided all other sustained remission parameters were met.

[0379] For patients who experienced a disease flare during the study and required rescue therapy (such as CS) at the discretion of the investigator, they could continue to receive sarrellumab or matching placebo in a double-blind manner for the entire duration of the 52-week treatment period only if corticosteroids were used as rescue therapy. Treatment with non-biological immunosuppressive drugs (such as alkylating agents, hydroxychloroquine, CsA, MMF, AZA, etc.) was not allowed during the study unless used for the purpose of rescue therapy.

[0380] During the study, corticosteroids were the preferred agent for patients who required rescue therapy at the investigator's discretion. Patients were allowed to continue SC administration of sarrellumab or matching placebo only when CS was used as rescue therapy. If patients remained symptomatic despite CS rescue therapy, other treatment options, including non-biologic immunosuppressive agents, were available (patients must have symptomatic PMR disease), and patients were discontinued from study treatment and considered non-responders.

[0381] The total duration of study participation for each patient was 62 weeks: a screening period of up to 4 weeks, a treatment period of 52 weeks, and a post-treatment follow-up period of 6 weeks. The last follow-up visit for the last patient occurred when the last patient completed the 52-week double-blind treatment period and the 6-week follow-up period (Follow-up 13 / end of study (EOS)). The end of the clinical trial was defined as the last follow-up visit for the last patient. Event times are shown in Table 1 below. Notice any signs or symptoms of a hypersensitivity reaction. cPatient-reported outcomes include EQ-5D-3L, FACIT-Fatigue, SF-36v2, and HAQ-DI. Bone mineral density assessments will be performed using DXA scans at baseline (Visit 2) and Week 52 (Visit 12). Scans can be performed within ±14 days of Visit 2 and -14 days of Visit 12 and need to include the lumbosacral and femoral neck regions. However, if a baseline follow-up DXA scan is available within 12 weeks of baseline, a baseline follow-up DXA scan is not required. eIf there is no available chest imaging (X-ray, CT, MRI) that clearly documents the exclusion of TB within the first 12 weeks of V1, or if it does not meet local guidelines and requirements for active TB screening, a chest X-ray is required during the screening period. In countries where specific approval procedures for X-rays are required by a committee other than the local EC / IRB, a chest MRI may be performed between V1 and V2. fHematology (blood should be drawn before drug administration): hemoglobin, hematocrit, red blood cell (RBC) count and morphology (if RBC count is abnormal), white blood cell (WBC) differential, platelet count, absolute neutrophil count (ANC). g Chemistry (blood should be drawn before drug administration): sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine and creatinine clearance, calcium, phosphate, total protein, albumin, alanine aminotransferase (ALT) (SGPT), aspartate aminotransferase (AST) (SGOT), alkaline phosphatase (ALP), total bilirubin, conjugated bilirubin, unconjugated bilirubin, lactate dehydrogenase (LDH), uric acid. hAntinuclear antibodies (ANA) were collected only at Visit 2 and EOT visits. iLipids (blood should be drawn before drug administration): triglycerides (TG), total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol. Fasting is defined as no food or fluid intake (except water / ice) for six hours or more. jBlood should be drawn before drug administration. Fasting is defined as no food or fluid intake (except water / ice) for six hours or more. k CRP and ESR results will be blinded to both the investigator and the sponsor (except at screening and baseline). ESR kits will be provided by a central laboratory, and testing will be performed locally on site; results will be blinded to investigators and staff directly involved in the management of study patients, with the exception of safety assessors. Urinalysis dipstick: Specific gravity, pH, glucose, blood, protein, nitrites, leukocytes, ketones, urobilinogen, and bilirubin (by dipstick) are performed only at the screening visit. If any parameter on the dipstick is abnormal, the urine sample should be sent to a central laboratory for testing. If positive for protein, microscopic analysis is performed by the central laboratory. mHuman immunodeficiency virus antibodies - if required locally, consent will be collected for the required HIV screening tests provided locally; Hepatitis B: Hep B surface antigen, total Hep B core antibody, Hep B surface antibody, and Hep B viral DNA (if necessary); Hepatitis C: HCV antibodies. nIn women of reproductive potential. o Immune Cell Phenotyping (Whole Blood): Approximately 40 patients from each of the two treatment groups will undergo this whole blood draw and immune cell phenotyping analysis. pBefore any sampling is performed, separate informed consent for future sample use must be obtained. Both serum and plasma will be drawn and samples will be used for future analysis (eg, circulating proteins). qSeparate pharmacogenetic study informed consent for the collection of DNA and RNA samples and for sequencing of these samples must be obtained before any sampling is performed. One DNA (at baseline or any treatment or follow-up visit) and RNA sample is required for sequencing sampling time points at baseline and pre-dose (V3). Additional samples were drawn 4-7 days after dosing at Week 24. Since the follow-up interval exceeds 4 weeks, direct-to-patient (DTP) shipments can be used for temporary delivery of IMP to the patient's home so that only 4 weeks of IMP are provided to the patient at a time to minimize adherence errors. If ultrasound is used in the diagnosis of PMR, ultrasound images need to be submitted to a central data reader to confirm that they meet the ultrasound portion of the PMR diagnostic criteria. For patients taking >15 mg / day (but not exceeding 20 mg / day) of prednisone at Screening and during the Screening Period, the investigator should cautiously taper the prednisone to 15 mg / day prior to randomization to prevent flare-ups upon entry into the study on 15 mg / day of prednisone. If ultrasound is used as a diagnostic tool for PMR, images need to be submitted to a central data reader for confirmation of eligibility. w IMP training. Before the first dose of IMP, instructions were provided regarding the preparation and self-injection of the prefilled syringe and the use of the weekly blister pack of prednisone.

[0382] The study was terminated early because the COVID-19 pandemic significantly delayed recruitment timelines. Approximately 118 patients who met the inclusion criteria were enrolled and randomized in a 1:1 ratio into two parallel groups to receive either sarrellumab 200 mg q2w with a 14-week prednisone taper (Group 1) or sarrellumab-matched placebo with a 52-week prednisone taper (Group 2). As shown in Table 2, 117 of the 118 patients were randomized and received treatment. Table 2: Patient Disposition Research Committee

[0383] If ultrasound is used to diagnose PMR and determine patient eligibility, the ultrasound images are centrally reviewed by a rheumatologist (from a panel of rheumatologists) who specializes in the performance and interpretation of diagnostic ultrasound of the shoulder and hip to confirm the diagnosis. In addition, the same panel of rheumatologists helps identify the sites of PMR that patients wish to diagnose using ultrasound. Inclusion criteria

[0384] Signed written informed consent.

[0385] PMR was diagnosed according to the European League against Rheumatism / American College of Rheumatology (EULAR / ACR) classification criteria (all criteria must be met): a) age ≥50 years at diagnosis, b) bilateral shoulder pain, and elevated acute phase reactants (CRP >10 mg / L and / or ESR >30 mm / hr).

[0386] AND one of the following: - A score of 4 or higher when diagnosed based on the following (without ultrasound): morning stiffness lasting >45 minutes: 2 points; hip pain or limited range of motion: 1 point; rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) seronegativity: 2 points; and no other joint involvement: 1 point; or - A score of 5 or higher when diagnosed based on the following (with ultrasound): morning stiffness lasting >45 minutes: 2 points; hip pain or limited range of motion: 1 point; RF and anti-CCP seronegativity: 2 points; no other joint involvement: 1 point; subdeltoid bursitis and / or bicipital tenosynovitis and / or glenohumeral synovitis (posterior or axillary) in at least one shoulder, and synovitis and / or trochanteric bursitis in at least one hip: 1 point (confirmed with ultrasound); and subdeltoid bursitis, bicipital tenosynovitis, or glenohumeral synovitis in both shoulders: 1 point (confirmed with ultrasound).

[0387] At Screening and during the Screening Period, patients must be taking at least 7.5 mg / day (or equivalent) and no more than 20 mg / day of prednisone.

[0388] At the time of randomization, the patient was willing and able to receive 15 mg / day of prednisone.

[0389] Patients must have a history of treatment with prednisone ≥10 mg / day or equivalent for at least 8 weeks.

[0390] Patients must have had at least one clear PMR flare-up during an attempt to taper prednisone to a dose of ≥7.5 mg / day (or equivalent) within the past 12 weeks prior to screening. A clear symptom of a PMR flare-up was defined as shoulder and / or hip girdle pain associated with inflammatory stiffness.

[0391] Patients must have had an ESR ≥ 30 mm / hr or CRP ≥ 10 mg / L, which is associated with PMR disease activity, within 12 weeks prior to screening. Exclusion criteria

[0392] Patients who met all the above inclusion criteria were screened for the following exclusion criteria:

[0393] Diagnosed with giant cell arteritis (GCA) (e.g., persistent or recurrent localized headaches, temporal artery or scalp tenderness, jaw claudication, limb claudication, blurred or loss of vision, stroke symptoms).

[0394] Concurrent rheumatoid arthritis or other inflammatory arthritis or other connective tissue diseases, such as but not limited to systemic lupus erythematosus, systemic sclerosis, vasculitis, myositis, mixed connective tissue disease, and ankylosing spondylitis.

[0395] The diagnosis was concurrent rhabdomyolysis or neuromuscular disease.

[0396] A diagnosis of concurrent active fibromyalgia was made.

[0397] Inadequate treatment of hypothyroidism.

[0398] Organ transplant recipients.

[0399] Any prior (within the time period defined below) or concomitant use of immunosuppressive therapy, including but not limited to the following: Janus kinase (JAK) inhibitors (e.g., tocitinib) within 4 weeks of baseline; cytodepleting agents (e.g., anti-CD20) without evidence of B-cell recovery to baseline levels; anakinra within 1 week of baseline; abatacept within 8 weeks of baseline; tumor necrosis factor (TNF) inhibitors within 2-8 weeks (etanercept within 2 weeks, infliximab, certolizumab pegol, golimumab, or adalimumab within 8 weeks) or at least 5 half-lives after baseline, whichever is longer; alkylating agents, including cyclophosphamide (CYC) within 6 months of baseline; and cyclosporine (CsA), azathioprine (AZA), or mycophenolate mofetil (MMF) or leflunomide within 4 weeks of baseline.

[0400] Treatment failure, including inadequate response or intolerance to or contraindication to a biologic IL-6 antagonist (previous IL-6 antagonist treatment discontinued at least 3 months prior to baseline for reasons unrelated to treatment failure was not excluded).

[0401] Unstable methotrexate (MTX) dose within 3 months of baseline and / or MTX dose >15 mg / week.

[0402] Concurrent use of systemic CS for conditions other than PMR.

[0403] Participation in any clinical investigational study evaluating an investigational drug or therapy within 5 half-lives or 60 days of the Screening Visit, whichever is longer.

[0404] History of alcohol abuse or drug abuse within 5 years before the screening follow-up.

[0405] Patients who withdrew their consent during the screening period (after signing the informed consent form).

[0406] Unable or unwilling to complete the patient-reported outcomes (PRO) questionnaire.

[0407] Patients who meet any of the following conditions / circumstances: patients with short life expectancy; conditions / comorbidities that preclude the evaluation of efficacy endpoints (e.g., patients with chronic pain); patients who are investigators or any sub-investigators, research assistants, pharmacists, study coordinators, other staff directly involved in the conduct of the study, or their relatives, or employees of the applicable site / investigator or sponsor; individuals who are uncooperative or have any condition that may make the patient non-compliant with study procedures, etc., and individuals who have been institutionalized due to regulatory or legal order.

[0408] Pregnant or breastfeeding women.

[0409] Women of childbearing potential (WOCBP) who are not protected by one or more highly effective methods of contraception and / or women who are unwilling or unable to undergo pregnancy testing. Tuberculosis (TB)-related exclusions

[0410] Active TB or history of incompletely treated TB, regardless of screening Quantiferon result.

[0411] Quantiferon-positive patients (without active disease) were excluded from the study unless they met the following criteria: patients with a previously documented history of completed chemoprophylaxis for latent tuberculosis infection (e.g., acceptable treatment includes 9 months of oral isoniazid 300 mg daily or an equivalent regimen validated according to local guidelines) or a history of treatment for active tuberculosis infection (TBI) who had been consulted with an expert to exclude active TBI or the need for further treatment; patients without a previous history of chemoprophylaxis for latent TBI or treatment for active TBI who had been consulted with an expert to initiate an appropriate chemoprophylaxis regimen based on local epidemiology and applicable guidelines and had demonstrated adherence and tolerance to treatment for ≥1 month; or in either case, consultation with and prior approval of the sponsor was required.

[0412] Clinically significant abnormalities consistent with prior / active TB infection based on chest radiography with at least an anteroposterior view. Additional lateral views are recommended but not required.

[0413] Suspected extrapulmonary TB infection regardless of screening Quantiferon result.

[0414] Patients at high risk of TB infection, such as close contacts of individuals with active or latent TB.

[0415] Patients who received BCG vaccination within 12 months prior to screening. Other exclusion criteria

[0416] Patients with a history of invasive opportunistic infections including but not limited to histoplasmosis, listeriosis, coccidioidomycosis, candidiasis, Pneumocystis jiroveci, aspergillosis (even if resolved), or John Cunningham virus (progressive multifocal leukoencephalopathy).

[0417] Patients with fever (>38°C) associated with: infection within 4 weeks prior to the screening visit or one or more chronic, persistent or recurrent infections requiring active treatment with antibiotics, antivirals or antifungals, or other frequent recurrent infections deemed unacceptable by the investigator.

[0418] Patients with uncontrolled diabetes (defined as glycosylated hemoglobin (HbA1c) ≥ 9% at the screening visit).

[0419] Patients with non-healing or healing skin ulcers.

[0420] Patients who received any live attenuated vaccine (such as varicella-zoster vaccine, oral polio vaccine, or rubella vaccine) within 3 months prior to the baseline visit.

[0421] Patients who are positive for hepatitis B surface antigen (HBsAg) at screening; or positive for total hepatitis B core antibody (HBcAb) and negative for hepatitis B surface antibody (HBsAb); or positive for both HBcAb and HBsAb and the presence of HBV DNA.

[0422] Patients who are hepatitis C antibody (HCV Ab) positive.

[0423] Patients who test positive for human immunodeficiency virus (HIV) antibodies at screening or who have previously tested positive for HIV antibodies or are suspected of being HIV positive.

[0424] Patients with a history of recurrent or active herpes zoster.

[0425] Patients with a history of previous joint or prosthetic joint infection.

[0426] A history of previous or current malignancy, including lymphoproliferative disorders, other than adequately treated carcinoma in situ of the cervix, nonmetastatic squamous cell carcinoma of the skin, or basal cell carcinoma within 5 years before baseline follow-up.

[0427] A history of one or more other significant concomitant medical conditions that, in the investigator's judgment, would adversely affect the patient's participation in the study. These include, but are not limited to, cardiovascular disease (including stage III or IV heart failure according to the New York Heart Association classification), renal disease, neurologic disease (including demyelinating disease), active infectious disease, endocrine disease, gastrointestinal disease, hepatobiliary disease, metabolic disease, pulmonary disease, non-malignant lymphoproliferative disease, or one or more other lymphoid diseases.

[0428] Patients who had surgery within 4 weeks before the screening visit or were scheduled to undergo surgery during the study.

[0429] Patients with a history of systemic hypersensitivity reaction to any biologic drug (except local injection site reactions) and known hypersensitivity to any component of the sarrellumab product.

[0430] Patients with any of the following laboratory abnormalities at the screening visit: hemoglobin <8.5 g / dL; white blood cells <3000 / mm 3 Neutrophils <2000 / mm 3 Platelet count <150,000 cells / mm 3aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >1.5x upper limit of normal (ULN); bilirubin (total) >ULN, unless Gilbert's disease is diagnosed by genetic testing; severe uncontrolled hypercholesterolemia (>350 mg / dL, 9.1 mmol / L) or hypertriglyceridemia (>500 mg / dL, 5.6 mmol / L); and calculated creatinine clearance <30 mL / min (using the Cockroft-Gault formula).

[0431] Patients with a history of inflammatory bowel disease or severe diverticulitis or previous gastrointestinal perforation. Study Treatment Investigational medicinal products

[0432] Table 3 provides details of the investigational medicinal product (IMP). Placebo + 52-week GC gradual dose reduction group: W0 / W1: 15 mg; W2: 14 mg; W3 to W5: 12 mg; W6 / W7: 10 mg; W8 to W11: 9 mg; W12 to W15: 8 mg; W16 to W19: 7 mg; W20 to W23: 6 mg; W24 to W27: 5 mg; W28 to W31: 4 mg; W32 to 35: 3 mg; W36 to 43: 2 mg; W44 to W51: 1 mg. Preparations

[0433] The sarrelumab drug product is provided as a single-use 1.14 ml pre-filled glass syringe containing 131.6 mg / mL (150 mg), 175 mg / mL (200 mg) of sarrelumab, or placebo solution for SC injection. Preparation at the clinical site is not required. Route of administration

[0434] Sarrelumab is administered subcutaneously (SC) in the abdomen or thigh for self-injection, or in the upper arm (outer side) by a professional or lay caregiver. Preferably, the SC injection site alternates between the four quadrants of the abdomen (excluding the navel or lumbar area) or thigh (front and side). Each drug administration requires a single injection.

[0435] At the start of the study, patients and / or their lay caregivers were trained to prepare and administer the study medication. This training was recorded in the subject's study file. The investigator reviewed the patient's self-administration technique at Visit 2 (Week 0). For doses not administered at the study site, a log was provided to record information related to these injections. Dosage regimen

[0436] IMP (sarrellumab or matching placebo) was administered every 14 days according to the protocol IMP administration schedule; however, in special circumstances (e.g., pending laboratory test results, ongoing AEs, or patient scheduling difficulties), a ±3-day IMP administration window was allowed. For subsequent IMP administrations, the initial IMP administration schedule was followed again.

[0437] Maintain an interval of at least 11 days between 2 IMP (sarelumab and matching placebo) doses.

[0438] If a study visit was not scheduled on-site, the patient, qualified site personnel, and / or their caregiver(s) administered the dose as described above.

[0439] On the days that patients were on study visits, IMP was administered following clinical procedures and blood collection.

[0440] Monitor patients for at least 30 minutes (or up to 2 hours based on country-specific requirements) after each dose of sarrellumab for any signs or symptoms of a medical event. In cases where sarrellumab is administered by a caregiver or self-injection, instruct patients to monitor themselves for any signs or symptoms of a medical event. The total duration of treatment is 52 weeks. Dose changes / reductions

[0441] The sarrelumab dose could be reduced in a blinded manner to 150 mg every 2 weeks to treat neutropenia, thrombocytopenia, and / or elevated liver transaminases. Additionally, the sarrelumab dose could be temporarily interrupted. The decision to reduce the sarrelumab dose and / or temporarily interrupt the sarrelumab was at the investigator's discretion.

[0442] Between the protocol-planned site visits, interim visits may be required for IMP allocation. As an alternative to these visits, sarrellumab or matching placebo can be provided to patients from the site via a sponsor-approved courier permitted by local regulations and approved by the participant.

[0443] Post-trial use of sarrellumab complies with all applicable national and local laws and regulations, including safety reporting obligations. Prednisone or matching placebo Preparations

[0444] 1 and / or 5 mg overencapsulated tablets or overencapsulated matching placebo. Route of administration

[0445] Prednisone or matching placebo was administered orally. Dosage regimen

[0446] All patients received prednisone according to the assigned regimen. Patients received prednisone and / or prednisone-matched placebo to ensure adherence to the double-blind CS tapering schedule defined below. For the first 2 weeks after randomization, the initial prednisone dose was 15 mg / day in both groups.

[0447] For Group 1: Patients received tapering dose levels of prednisone from weeks 2 to 13. Starting from week 14, patients without flare-ups received prednisone-matched placebo.

[0448] For Group 2: From Week 2 to Week 51, patients will receive gradually decreasing dose levels of prednisone (prednisone or a combination of prednisone and placebo to prednisone).

[0449] Each double-blind prednisone taper had two phases: Phase 1: an initial 2-week period after randomization (starting at Week 0 and ending at Week 1), during which all patients received 15 mg of prednisone daily; and Phase 2: 50 weeks following Phase 1 (starting at Week 2 and ending at Week 51). Prednisone and matching placebo were used to maintain blinding of the taper in both treatment groups.

[0450] During the prednisone taper, patients are provided with a monthly kit containing four weekly blister packs clearly indicating the number of tablets to be taken each day. The monthly kit and blister packs are numbered, and it is important that the blister packs are used sequentially, and patients should take seven days of prednisone from each blister pack before starting the next. If a scheduled study visit occurs before the target date, patients should complete the blister pack assigned for that particular week before using the sequentially numbered blister pack assigned at the scheduled study visit. If tablets are lost or skipped, patients should not use the missed tablets until they resume using the blister pack as planned.

[0451] At baseline, patients were trained in the use of the prednisone treatment kit and weekly prednisone blister packs. This training included instructions for using the blister packs in the proper sequence and for using a "backup" row of tablets in case a tablet was lost during dosing.

[0452] The daily capsule contains prednisone, placebo, or a combination of the two. The number of tablets taken daily varies and is not consistent with the prednisone dose. During the tapering schedule, the number of tablets taken daily may increase or decrease, but not exceed six tablets per day. In case of flare-ups within the first 12 weeks, add prednisone and gradually taper

[0453] During the initial 12 weeks of prednisone taper, treatment of a flare prior to week 12 is permitted if it can be successfully treated with low-dose prednisone (≤5 mg / day) (to be added to the CS taper regimen) and provided all other sustained remission parameters are met. Addition of prednisone must be completed before week 12.

[0454] The prednisone for this add-on taper is provided in an open-label format consisting of 30-count blisters (1 mg each) in a child-resistant bag. The investigator determines the CS dose (maximum dose ≤5 mg / day) and the schedule / duration of the taper based on the patient's disease status. The number of tablets to be taken each day is written on the bag and recorded in the eCRF. Patient monitoring and close contact with the site are required to ensure that the patient is taking the correct amount of prednisone until the add-on taper is completed by Week 12. Non-investigational medicinal products

[0455] Prednisone for rescue therapy: If a patient experiences a disease flare or is unable to comply with the protocol-based prednisone taper (including the addition of 5 mg of prednisone before Week 12), the patient must discontinue the protocol-based prednisone taper and may receive commercial CS as a form of rescue therapy, based on the investigator's clinical judgment. Commercial CS will be reimbursed by the sponsor. Patients may continue for the entire 52-week double-blind period of the study and may continue to receive blinded sarrelumab or matching placebo injections (unless contraindicated for safety reasons) and complete the remaining study assessments. Once the investigator decides to place a patient on rescue therapy, the patient is not allowed to return to the protocol-based prednisone taper. Concomitant drug therapy

[0456] Concomitant medication is any treatment a patient receives concomitantly with any one or more IMPs.

[0457] Unless otherwise indicated, the use of any biologic agent for PMR during the study period was not permitted throughout the study treatment period and until 6 weeks after the last dose of sarrellumab or matching placebo. If any of these treatments were used, the patient would discontinue IMP treatment but would remain in the study and continue to be monitored for safety.

[0458] Administration of any live (attenuated) vaccines is contraindicated until 3 months after the last dose of sarrellumab or matching placebo.

[0459] Treatment with non-biological disease-modifying antirheumatic drugs [DMARDs] (such as alkylating agents, hydroxychloroquine, CsA, MMF, AZA, etc.) was not allowed during the study course, except for the purpose of rescue therapy.

[0460] During the study, corticosteroids were the preferred agent for patients who required rescue therapy at the investigator's discretion. Patients continued SC administration of sarrellumab or matching placebo only when CS was used as rescue therapy. If patients remained symptomatic despite CS rescue therapy, other treatment options, including non-biologic immunosuppressive agents, were available (patients must have had symptomatic PMR disease), and patients were discontinued from study treatment and considered non-responders.

[0461] Methotrexate dosing up to 15 mg / week was permitted if the dose was stable for at least 3 months prior to baseline. The dose remained stable (or, if necessary, reduced or discontinued for safety reasons) throughout the study treatment period and until 6 weeks after the last SC IMP (sarrellumab or matching placebo) administration.

[0462] Treatment with any IMP other than sarrellumab and protocol-defined CS was not permitted. steroids

[0463] There were two standardized prednisone taper schedules in the study, one lasting 14 weeks (Group 1) and the other lasting 52 weeks (Group 2). The total duration of prednisone therapy for each specific patient depended on the treatment group to which the patient was randomly assigned.

[0464] If a patient experiences an adverse event (AE) for a condition unrelated to PMR that requires the introduction of a new systemic CS medication, the new medication and the AE will be recorded on the patient's eCRF. In addition, the sponsor will be notified as soon as possible (e.g., within 24 hours) when the steroid dose is modified so that the patient's status regarding ongoing study participation can be discussed. Per-label intranasal, inhaled, ophthalmic, or topical CS will be permitted throughout the study. Nonsteroidal anti-inflammatory drugs and analgesics

[0465] Because treatment options for pain were limited, all analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), were permitted and withheld for 24 hours prior to efficacy assessments, including physical function and quality of life assessments.

[0466] Limit acetaminophen use to ≤ 4 g per 24 hours. Exercise special caution with coadministration of hepatotoxic drugs. Treatment of dyslipidemia

[0467] Treatment for dyslipidemia, such as statins, is allowed. The dose of dyslipidemia medication was stable for at least 6 weeks before the screening visit. Any changes and the reason for the change were recorded on the patient's electronic case report form (eCRF). Anti-IL-6 drugs (including sarrelumab) are known to increase serum total cholesterol, and this effect was closely monitored during the study. If a patient's cholesterol level was found to be significantly elevated or other lipid abnormalities were found during the treatment period of this study, cholesterol-lowering therapy with a statin or one or more other treatments for dyslipidemia was initiated according to local guidelines, or the dose was adjusted. Prevention and treatment of glucocorticoid-induced osteopenia / osteoporosis

[0468] Oral calcium, 25-hydroxyvitamin D supplementation, and bisphosphonate therapy (eg, alendronate 70 mg weekly or zoledronate 4 mg annually) for the prevention or treatment of glucocorticoid-induced osteoporosis were permitted. The dose and duration of treatment were in accordance with local practice or clinical guidelines as determined by the investigator. CYP substrates

[0469] In in vitro studies, IL-6 has been shown to reduce the expression of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, and CYP3A4 enzymes. Therefore, it is expected that for molecules that antagonize cytokine activity (such as sarrelumab), the formation of CYP450 enzymes may be normalized, and therefore when PMR patients start receiving sarrelumab, drugs metabolized by these CYP450 isoforms may have reduced levels. As a precautionary measure, if necessary, drugs that are metabolized by these cytochromes and have a narrow therapeutic index can be adjusted: the dose can be increased after starting sarrelumab to maintain efficacy, and the dose can be reduced after stopping sarrelumab. Some examples of CYP450 substrates with a narrow therapeutic index that require monitoring of effect are warfarin, or examples of drugs that require monitoring of drug concentrations include, but are not limited to, the following: warfarin, cyclosporine, theophylline, digoxin, antiepileptic drugs such as carbamazepine Divalproex Phenytoin or valproic acid or antiarrhythmic drugs, such as disopyramide Procainamide or quinidine Primary End Point Proportion of patients achieving sustained remission at week 52

[0470] Sustained remission at Week 52 was defined as meeting all of the following parameters: disease remission achieved no later than Week 12, with no disease flares from Week 12 to Week 52, and a sustained decrease in CRP (to <10 mg / L and no consecutive increases to ≥10 mg / L) from Week 12 to Week 52, and successful compliance with prednisone taper from Week 12 to Week 52. Sustained remission was also assessed between Week 16 and Week 52 and from Week 24 to Week 52.

[0471] Successful adherence to prednisone taper may include the use of any excess prednisone (beyond the per-protocol CS taper schedule) where the cumulative dose is less than or equal to 100 mg (or equivalent), such as those used to manage AEs not related to PMR.

[0472] Disease remission is defined as: resolution of PMR signs and symptoms and normalization of CRP (<10 mg / L). A single increase in CRP (≥10 mg / L) should not be considered as the absence of remission unless the CRP remains elevated (≥10 mg / L) for two consecutive study visits.

[0473] A flare was defined as: 1) active PMR with a recurrence of signs and symptoms due to an increase in the CS dose caused by PMR, or 2) active PMR with an increase in the ESR due to an increase in the CS dose caused by PMR.

[0474] An escalation of the CS dose was defined as any dose increase during a protocol-defined steroid taper or when prednisone therapy was restarted after completion of a protocol-defined taper. During the initial 12 weeks of prednisone taper, treatment of a flare prior to week 12 was permitted if the flare could be successfully treated with a low-dose (≤5 mg / day) prednisone addition taper (completed before week 12) and provided all other parameters for sustained remission were met.

[0475] Signs and Symptoms of PMR: Evaluation of clinical signs and symptoms by efficacy assessors at each study visit according to the assessment schedule should include, but not be limited to, the following: morning stiffness and / or pain in the neck, shoulder, and / or hip girdle; limited range of motion in the shoulder and / or hip girdle; constitutional symptoms such as fatigue, weight loss, and low-grade fever; and other features consistent with a PMR outbreak as judged by the clinician-investigator. Secondary efficacy endpoints Components of the composite measure of sustained remission at week 52

[0476] Patients who achieved disease remission at Week 12, Week 16 to Week 52, and Week 24 to Week 52; patients who had no disease flare-ups from Week 12 to Week 52; patients whose CRP normalized (reduced to <10 mg / L) and maintained normalization from Week 12 to Week 52, Week 16 to Week 52, and Week 24 to Week 52; and patients who successfully adhered to prednisone tapering from Week 12 to Week 52.

[0477] Successful adherence to prednisone taper may include the use of any excess prednisone (beyond the per-protocol CS taper schedule) where the cumulative dose is less than or equal to 100 mg (or equivalent), such as those used to manage AEs not related to PMR. Total cumulative corticosteroid (including prednisone) dose over 52 weeks

[0478] The total cumulative prednisone (or equivalent) dose for each group over the 52-week period was analyzed as a secondary endpoint. Time to first PMR outbreak

[0479] The duration from clinical remission to the first PMR flare was analyzed up to week 52 in each group. Composite glucocorticoid toxicity index and components

[0480] The Glucocorticoid Toxicity Index (GTI) is a composite scale designed to assess glucocorticoid-related morbidity and the potential steroid-sparing effects of treatment alternatives. The composite GTI and specific lists constitute the entire GTI. The composite GTI consists of nine domains and 31 items that assess potential side effects of glucocorticoids and includes assessments of body mass index (BMI), glucose tolerance, blood pressure, lipid metabolism, bone mineral density, glucocorticoid-induced myopathy, skin toxicity, neuropsychiatric toxicity, and infection. These are potential CS toxicities that may occur during the course of clinical trials and may vary depending on the degree of CS exposure and are weighted and scored.

[0481] The composite GTI and a specific list of domains of the GTI (except bone density, which was assessed only at baseline and week 52) were assessed at baseline, week 12 (visit 6), week 24 (visit 9), week 40, and week 52. Glucocorticoid (GC) toxicity or the change in GC toxicity compared to baseline data was scored for each domain (scores range from -36 to 439) based on information from laboratory, vital sign, and clinical assessments, as well as review of concomitant medications. The composite GTI was then reported as a total score and domain-specific scores to account for situations where improvements in some domains offset deterioration in other domains.

[0482] Bone mineral density was assessed using dual-energy X-ray absorptiometry (DXA) scans at baseline (Visit 2) and week 52 (Visit 12). Scans were performed within ±14 days of Visit 2 and -14 days of Visit 12 and were required to include the lumbosacral and femoral neck regions. However, if a baseline follow-up DXA scan (including assessment of the lumbosacral and femoral neck regions) was available within 12 weeks of baseline, a baseline follow-up DXA scan was not required.

[0483] The specific list consisted of 11 domains and 23 items that were not weighted and captured additional CS-related toxicities not found in the composite GTI (see Table 4 below). If information related to the domains / items in the specific list was available at the planned time points (baseline, week 12, week 24, week 40, and week 52), this information was collected, but no pre-specified assessments related to the domains in the specific list were required during the conduct of the study (unless justified). Table 4: Specific listing of glucocorticoid toxicity indices Other endpoints

[0484] GTI Overall Improvement Score (AIS) at Week 52.

[0485] GTI Cumulative Worsening Score (CWS) at Week 52.

[0486] Secondary safety endpoints included adverse events (AEs), laboratory safety variables, vital sign variables, antinuclear antibodies, and immunogenicity variables.

[0487] Functional sarrellumab concentration in serum.

[0488] Physician's global assessment of disease activity as measured by the MD-VAS.

[0489] Patient-reported outcomes (described in the next section).

[0490] Changes in ESR and CRP from Baseline to Week 52.

[0491] Changes in IL-6 levels and soluble IL-6 receptor (sIL-6R) through week 52.

[0492] Changes over time in markers of inflammation and disease activity as assessed in circulating immune cell types, circulating proteins, and gene expression changes. Patient-Reported Outcomes

[0493] Patients were asked to complete the patient-reported outcome (PRO) questionnaire described below at Visit 2 (baseline visit), Visit 6 (week 12), Visit 9 (week 24), and Visit 12 (week 52). The following measures were assessed. Chronic Disease Therapy Functional Assessment Fatigue Scale

[0494] As shown in Table 5 below, the Functional Assessment of Chronic Illness Therapy Fatigue Inventory (FACIT-Fatigue) is a general PRO tool that includes 13 items for measuring fatigue. Each item is rated by the patient on a 0 to 4 scale (0 = not at all, 1 = a little, 2 = a little, 3 = quite a bit, 4 = very much). The scores are summed to give a total score between 0 and 52. The recall period is the last 7 days. Table 5: FACIT-Fatigue Scale EQ-5D-3L

[0495] like Figure 2A-2B As shown, the EQ-5D-3L is a general PRO instrument for measuring health status (EuroQol Group, EuroQol-a new facility for the measurement of health-related quality of life, Health Policy 1990; 16(3): 199-208).

[0496] There are two components of the EQ-5D: a "today" health utility index score derived from 5 items (covering mobility, self-care, daily activities, pain / discomfort, and anxiety / depression), and a current ("at this moment") overall health status score derived from a single 0-100 visual analog scale (VAS). The items that make up the EQ-5D-3L health utility index score each have the same 3-point response scale (1 = no difficulty, 2 = moderate difficulty, 3 = severe difficulty). The VAS is anchored by "best imaginable health state" and "worst imaginable health state." Simple Form 36v2 (SF-36v2)

[0497] like Figure 3A-3CAs shown, the Short Form 36 v2 (SF-36 v2) is a short-form, general 36-item PRO instrument that assesses eight multi-item dimensions of health: physical functioning (PF; 10 items), social functioning (SF; 2 items), role limitations due to physical problems (RP; 4 items), role limitations due to emotional problems (RE; 3 items), mental health (MH; 5 items), energy / vitality (VT; 4 items), bodily pain (BP; 2 items), and global health perception (GH; 5 items) (Ware et al. The MOS 36-Item Short-Form Health Survey (SF-36): I. Conceptual Framework and Item Selection, Medical Care 1992; 30(6): 473-483). For each dimension, item scores were coded, summed, and converted to a scale ranging from 0 (the worst possible health state measured by the questionnaire) to 100 (the best possible health state). Two standardized summary scores can also be calculated from the SF-36v2; the physical summary (PCS) and the mental summary (MCS) (0-100 scale) (see Maruish ME (2011) User's manual for the SF-36v2 Health Survey (3rd ed.) Lincoln, RI: QualityMetrics, Inc.). HAQ-DI

[0498] The HAQ-DI was developed to assess functional status in adults with arthritis but is now commonly used in many rheumatic conditions (see Wolfe F “A brief clinical health assessment instrument: CLINHAQ,” Arthritis Rheum. 1989;32(Suppl):S9 and Wolfe F. “Data collection and utilization: a methodology for clinical practice and clinical research,” Rheumatoid arthritis: pathogenesis, assessment, outcome and treatment, New York: Marcel Dekker, 1994:463-514). It contains 25 items: 20 4-point Likert-scale questions assessing 8 physical dimensions of activities of daily living (dressing and grooming, getting up, eating, walking, washing, reaching, grasping, and chores and housework), 13 additional questions assessing the use of assistive devices, and 8 additional questions assessing help received from another person. The recall phase was for the most recent week. To calculate the HAQ-DI score, there are 3 steps: summing the 8 category scores by using the highest subcategory score in each category; adjusting for the use of aids / devices and / or help from another person when indicated; and dividing the summed category score by the number of categories answered (which must be at least 6) to obtain an HAQ-DI score of 0-3 (3 = worst functioning).

[0499] In addition, the HAQ-DI has two additional questions, measured on a 0-100 scale: How much pain did you have in the past week? Please rate your performance on a scale of 0 to 100 (0 representing "excellent" health and 100 representing "very poor" health). These questions (measuring pain and global assessment, respectively) are scored independently. Clinician-reported outcomes Physician's global assessment of disease activity-visual analog scale [MD-VAS]

[0500] like Figure 4As shown, efficacy assessors are asked to rate the patient's disease activity on an anchored 100 mm horizontal VAS, where 0 is considered inactive and 100 is considered most active (see Huskisson et al. "Vertical or Horizontal Visual Analogue Scales" Ann Rheum Dis. 1979 Dec;38(6):560). Other assessments PMR activity score (PMR-AS)

[0501] PMR-AS was calculated as the sum of CRP (mg / dL), visual analogue scale (VAS) for pain (0 to 10), VAS for physician assessment (0 to 10), duration of morning stiffness (MST [min] x 0.1), and ability to lift the upper limb (EUL [3-0]). Glucocorticoid toxicity index

[0502] The Glucocorticoid Toxicity Index (GTI) is a composite scale designed to assess glucocorticoid-related morbidity. The GTI Cumulative Worsening Score (CWS) reflects cumulative glucocorticoid toxicity, whether permanent or temporary. The GTI-CWS can only increase or remain unchanged over time. Lower scores indicate lower glucocorticoid toxicity. The GTI Integrated Improvement Score (AIS) reflects both worsening and improvement in glucocorticoid toxicity. New or worsening toxicity contributes a positive score, while improvement in existing toxicity contributes a negative score. Lower scores indicate lower glucocorticoid toxicity. Cumulative corticosteroid dose

[0503] Cumulative corticosteroid dose is a measure of a patient's exposure to corticosteroids over a period of time (eg, 14 weeks or 52 weeks). Pharmacodynamics, pharmacokinetics, and anti-drug antibodies Pharmacodynamic variables measured

[0504] Changes in ESR and CRP from Baseline to Week 52.

[0505] Changes in IL-6 levels and soluble IL-6 receptor (sIL-6R) through week 52.

[0506] The following changes in the markers of inflammation and disease activity assessed in circulating immune cell types, circulating proteins and gene expression changes over time: During the study, markers of inflammation were assessed in a portion of the patient population at V2 (baseline), V4 (week 4), V9 (week 24), as measured by immune cell phenotype. Approximately 80 patients (40 patients in each treatment group) were selected for this analysis. Disease activity assessment of PMR patients was assessed via evaluation of circulating proteins and gene expression. Serum or plasma samples were collected at V2 (baseline), V3 (week 2), V6 (week 12), V9 (week 24), V12 (week 52 EOT) for circulating protein measurement. DNA samples were collected at V2 (baseline) or any treatment or subsequent follow-up, and RNA samples were collected before administration at V2 (baseline) and / or V3 (week 2) for gene expression measurement. Pharmacokinetics and anti-drug antibodies

[0507] Pre-dose blood samples were collected at each study visit to determine serum sarrelumab concentrations (functional) and antibodies to sarrelumab and analyzed according to the bioanalytical method shown in Table 6. Pre-dose serum sarrelumab concentrations were collected at Week 0 and sarrelumab trough levels were collected at Weeks 2, 4, 12, 16, 24, 32, 52, and 58. In addition, a post-dose sample was obtained 4-7 days after Week 24 (Visit 9). Table 6: Summary of bioanalytical methods for functional sarrelumab and anti-sarrelumab antibodies Adverse events

[0508] Adverse events (AEs) are defined as any undesirable medical occurrence in patients administered a medicinal product or in clinical investigational patients that is not necessarily causally related to the treatment. The reconciliation of AEs between the GTI and clinical safety databases is part of routine data review monitoring activities. All AEs, regardless of severity or relationship to the IMP, are recorded from the signing of informed consent to the end of the study. result Demographic and other baseline characteristics

[0509] Demographic and participant characteristics at baseline were generally similar between treatment groups, with slightly more participants in the ≥75 to <85 year age group and slightly fewer participants in the ≥65 to <75 year age group in the placebo plus 52-week taper group compared with the sarrellumab 200 mg q2w plus 14-week taper group.

[0510] Baseline disease characteristics were generally well balanced between treatment groups, with the exception of the number of participants with other joint involvement, which was reported more frequently in the sarrelumab 200 mg q2w + 14-week taper group compared with the placebo + 52-week taper group (6 [10.3%] vs. 12 [20.0%]). The mean (SD) duration of PMR for all participants was 631.3 (752.0) days. Participants in the placebo + 52-week taper group had a longer duration of morning stiffness, as measured in minutes; however, the number of participants with morning stiffness duration >45 minutes was comparable between treatment groups. A detailed breakdown of patient demographics and baseline disease characteristics is provided in Table 7 below. Table 7: Patient demographics and characteristics *Date of diagnosis relative to baseline. Placebo plus 52 weeks of GC tapering, n = 50; sarrellumab 200 mg every 2 weeks plus 14 weeks of GC tapering, n = 54. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GC, glucocorticoid; PMR, polymyalgia rheumatica. Exposure

[0511] Cumulative exposure to double-blind treatment and the median duration of study treatment were similar between the sarrellumab 200 mg q2w followed by a 14-week taper and the placebo followed by a 52-week taper, with a cumulative exposure of 47.37 patient-years in the sarrellumab 200 mg q2w followed by a 14-week taper and 45.36 patient-years in the placebo followed by a 52-week taper. Overall Summary of Efficacy End Points

[0512] An overall summary of the efficacy endpoints is provided in Table 8. The results of this study demonstrate that treating participants with PMR with sarrelumab 200 mg q2w followed by a 14-week taper provided greater benefit compared to treatment with a 52-week CS taper alone. The study met its primary endpoint, as a higher proportion of participants in the sarrelumab 200 mg q2w followed by a 14-week taper achieved sustained remission at Week 52 compared to the placebo followed by a 52-week taper; this difference was statistically significant. The study also demonstrated that a higher proportion of patients in the sarrelumab group achieved sustained remission compared to the comparator group when assessed from Weeks 12, 16, and 24 to Week 52. Most patients who achieved sustained remission did indeed respond rapidly by Week 12, with some additional responses occurring between Weeks 16 and 24.

[0513] Results of a sensitivity analysis excluding CRP as the primary efficacy endpoint were consistent with those of the primary analysis. Most secondary endpoints were also achieved. Table 8 - Summary of Efficacy Endpoints - Intent-to-Treat (ITT) Population Primary efficacy endpoint

[0514] A higher proportion of participants achieved sustained remission at week 52 in the sarrelumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group. Seventeen participants (28.3%) in the sarrelumab 200 mg q2w + 14-week taper group and six (10.3%) in the placebo + 52-week taper group achieved sustained remission at week 52, for a proportion difference of 18.0 (95% CI: 4.15, 31.82). As shown in Table 9, the difference was statistically significant with a p-value of 0.0193. Table 9: Number of patients achieving sustained remission at Week 52 (%) - ITT population

[0515] Figure 23 A higher proportion of patients in the sarilumab group (compared to the comparator group) achieved sustained remission at weeks 16 to 52 (30.0% vs. 8.6%; difference [95% CI]: 21.4 [7.7, 35.0]; P = 0.0047) and at weeks 24 to 52 (31.7% vs. 10.3%; difference [95% CI]: 21.3 [7.2, 35.5]; P = 0.0063). This improvement in sustained remission rate with sarilumab was due to the occurrence of additional responses between weeks 12 and 24.

[0516] Similarly, a higher proportion of patients in the sarrelumab group (compared to the comparator group) achieved sustained remission across all independent components during each assessment period. As shown in Figure 24, the disease remission rate decreased slightly in both the sarrelumab group and the comparator group from the week 12 to week 52 assessment (46.7% vs. 37.9%) to the week 16 to week 52 (40.0% vs. 31.0%) and week 24 to week 52 (41.7% vs. 20.7%). Although the decrease in disease remission rate may be due to the absence or abnormality of CRP, the proportion of patients without signs and symptoms of PMR increased over time.

[0517] In the sarrellumab group, the proportion of patients who were free of disease flare-ups increased from the week 12 to week 52 assessment to the week 16 to week 52 and week 24 to week 52 assessments, while the proportion of patients with sustained CRP normalization or adherence to protocol-defined GC tapering remained the same across the three assessment periods, as shown in Figure 25. Sensitivity analyses of the primary endpoint were performed. These analyses included removing the acute-phase reactant CRP from the definition of sustained remission and an additional analysis that removed participants who discontinued study treatment due to an erroneous diagnosis of PMR.

[0518] As shown in Table 10, a higher proportion of participants in the sarrelumab 200 mg q2w + 14-week taper group achieved sustained remission (excluding the acute phase reactant CRP) at week 52 compared with the placebo + 52-week taper group (19 [13.8%] participants and 8 [31.7%] participants, respectively), with a proportion difference of 17.9 (95% CI: 3.13, 32.61). Consistent with the primary analysis, a statistically significant difference in favor of the sarrelumab 200 mg q2w + 14-week taper group was observed compared with the placebo + 52-week taper group, with a p-value of 0.0280. Table 10: Sensitivity Analysis: Number of Patients Achieving Sustained Remission (Excluding Acute Phase Reactants) at Week 52 (%) - ITT Population

[0519] Four participants were incorrectly diagnosed with PMR (two in the sarrelumab 200 mg q2w + 14-week taper group and two in the placebo + 52-week taper group). The proportion of participants achieving sustained remission at week 52 (excluding participants with an incorrect diagnosis of PMR) continued to be higher in the sarrelumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group (6 [10.9%] participants and 17 [29.3%] participants, respectively), for a proportion difference of 18.4 (95% CI: 4.08, 32.72). As shown in Table 11, consistent with the primary analysis, a statistically significant difference was observed in favor of the sarrelumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group, with a p-value of 0.0193. Table 11: Sensitivity Analysis: Number of Patients Achieving Sustained Remission at Week 52 (Excluding Patients with Incorrect PMR Diagnosis) (%) - ITT Population

[0520] A critical point analysis was also performed to assess the robustness of the conclusions of the primary endpoint analysis. Participants who did not achieve remission or received rescue therapy were considered non-responders. Participants who withdrew from the study before Week 52 and did not experience a flare prior to withdrawal were considered "missing" and were sequentially imputed for the critical point analysis. As shown in Table 12, 13 participants from the sarrelumab 200 mg q2w + 14-week taper group and 9 participants from the placebo + 52-week taper group were considered missing. Table 12: Tipping Point Analysis: Patient Accountability at Week 52 - ITT Population

[0521] The results of the critical point analysis are shown in Table 13. Table 13: Tipping Point Analysis: p-Values ​​for Sustained Remission at Week 52 - ITT Population

[0522] A post hoc analysis was performed to assess the effect of methotrexate on the primary efficacy endpoint, as shown in Table 14. There was no trend suggesting that methotrexate use affected the primary endpoint. Table 14 - Post hoc analysis: Summary of sustained remission at week 52 for patients receiving concomitant methotrexate during the 52-week treatment period - ITT population

[0523] like Figure 5 As shown, subgroup analyses of the primary endpoint were performed to assess the consistency of treatment effects. Subgroup analyses of the primary endpoint results showed numerical trends favoring the sarrellumab 200 mg q2w followed by 14-week taper compared with the placebo followed by 52-week taper, with the exception of participants with a baseline weight <60 kg; however, the sample size for this subgroup was very small. There were no statistically significant interactions between each subgroup and treatment group. Some subgroups had small sample sizes and low event counts. Secondary efficacy endpoints Components of sustained remission

[0524] As shown in Table 15, overall, a higher proportion of participants in the sarrelumab 200 mg q2w with 14-week taper group achieved sustained remission for each component compared with the placebo with 52-week taper group. A higher proportion of participants in the sarrelumab 200 mg q2w with 14-week taper group achieved disease remission within 12 weeks compared with the placebo with 52-week taper group (22 [37.9%] participants and 28 [46.7%] participants, respectively). A higher proportion of participants in the sarrelumab 200 mg q2w with 14-week taper group remained flare-free from week 12 to week 52 compared with the placebo with 52-week taper group (19 [32.8%] participants and 33 [55.0%] participants, respectively). A higher proportion of participants in the sarrellumab 200 mg q2w group followed by a 14-week taper achieved sustained CRP reductions from week 12 to week 52 compared with the placebo plus a 52-week taper group (26 [44.8%] participants and 40 [66.7%] participants, respectively). A higher proportion of patients in the sarrellumab 200 mg q2w group followed by a 14-week taper achieved successful adherence to prednisone taper from week 12 to week 52 compared with the placebo plus a 52-week taper group (14 [24.1%] participants and 30 [50.0%] participants, respectively). Table 15: Components of the Composite Measure of Sustained Remission at Week 52 - ITT Population

[0525] As shown in Table 16, after baseline follow-up, the number (%) of participants who were free of any signs and symptoms of PMR at each follow-up visit (excluding participants who received rescue therapy) was higher in the sarrellumab 200 mg q2w + 14-week taper group than in the placebo + 52-week taper group. At the end of treatment (Week 52), 27 participants (84.4%) in the sarrellumab 200 mg q2w + 14-week taper group and 8 participants (47.1%) in the placebo + 52-week taper group did not have any signs and symptoms of PMR (excluding participants who received rescue therapy). Table 16: Number (%) of patients without any signs and symptoms of PMR at follow-up (excluding patients who received rescue therapy) - ITT population Total cumulative corticosteroid (including prednisone) dose

[0526] Table 17 presents the cumulative CS dose during the treatment period. The placebo plus 52-week taper group had a greater expected cumulative CS dose compared to the sarrelumab 200 mg q2w plus 14-week taper group (14-week and 52-week CS tapers, respectively). The median expected cumulative CS dose (prednisone or corticosteroid dose equivalent) over the 52-week treatment period was 777 mg for the sarrelumab 200 mg q2w plus 14-week taper group and 2044 mg for the placebo plus 52-week taper group.

[0527] The actual cumulative CS dose was greater in the placebo plus 52-week taper group compared to the sarrelumab 200 mg q2w plus 14-week taper group due to the difference in the duration of the CS taper. The total median cumulative prednisone dose (i.e., the dose actually taken by participants) during the 52-week treatment period was 777 mg in the sarrelumab 200 mg q2w plus 14-week taper group, compared to 2044 mg in the placebo plus 52-week taper group.

[0528] The median difference between the actual and expected cumulative CS doses was significantly lower in the sarrelumab 200 mg q2w + 14-week taper group compared with the placebo + 52-week taper group (199.5 mg vs. 0.0 mg; p=0.0189). Table 17: Cumulative Corticosteroid Dose During the Treatment Period - ITT Population

[0529] Most of the difference between the actual cumulative CS dose and the expected cumulative CS dose was due to rescue therapy for PMR received by participants. As shown in Table 18, the cumulative number (%) of participants who received rescue therapy for PMR was lower in the sarrelumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group. During the 52-week treatment period, 34 participants (58.6%) in the placebo + 52-week taper group and 19 participants (32.2%) in the sarrelumab 200 mg q2w + 14-week taper group received rescue therapy for PMR. Table 18: Cumulative number of patients receiving rescue therapy due to PMR (%) - ITT population Time to first PMR outbreak

[0530] Figure 6Kaplan-Meier estimates of the time to first PMR flare after clinical remission were provided for up to 52 weeks. The time to first PMR flare was statistically significantly longer in participants treated with sarrelumab than in those treated with placebo, and the median was never reached in participants treated with sarrelumab. Forty-one participants (68.3%) in the sarrelumab 200 mg q2w + 14-week taper group and 30 participants (51.7%) in the placebo + 52-week taper group achieved clinical remission during the 52-week treatment period. Participants in the sarrelumab 200 mg q2w + 14-week taper group were less likely to experience a PMR flare after achieving clinical remission than those in the placebo + 52-week taper group (16.7% vs. 29.3%), with a hazard ratio of 0.56 (95% CI: 0.35 to 0.90; p=0.0153). The median value was not reached in the sarrellumab 200 mg q2w followed by a 14-week taper. A post hoc analysis of the time to first PMR flare after the clinical remission endpoint was performed to analyze the total time to first PMR flare calculated from the date of first clinical remission. The results of this post hoc analysis were consistent with the analysis of the total time to first PMR flare calculated from the date of randomization. Glucocorticoid Toxicity Index-Cumulative Worsening Score (CWS) and Overall Improvement Score (AIS)

[0531] As shown in Table 19, there was a numerical trend toward less cumulative worsening and greater overall improvement in the sarrelumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group. However, there was no significant difference in CWS between the sarrelumab 200 mg q2w + 14-week taper group and the placebo + 52-week taper group, with a LS mean difference (SE) of -4.90 (9.375) compared to placebo (95% CI: -23.477, 13.669; p = 0.6020). Table 19: Summary of Cumulative Exacerbation Scores During the 52-Week Treatment Period - ITT Population

[0532] Similarly, as shown in Table 20, there was no significant difference in AIS between the sarrellumab 200 mg q2w + 14-week taper group and the placebo + 52-week taper group, with an LS mean difference (SE) of -6.59 (8.811) compared to placebo (95% CI: -24.047, 10.862; p = 0.4559). Table 20: Summary of Composite Improvement Scores During the 52-Week Treatment Period - ITT Population Outcomes and Other End Points and Assessments PMR activity score

[0533] As shown in Table 21, a higher proportion of participants in the sarilumab plus 14-week taper group had low disease activity levels over time compared with the placebo plus 52-week taper group. At weeks 24 and 52, no participants in the sarilumab plus 14-week taper group had high levels of PMR activity, and a higher proportion of participants in the sarilumab plus 14-week taper group had low disease activity levels compared with the placebo plus 52-week taper group. Table 21 - Post hoc analysis: Number of patients (%) with high, moderate, and low levels of PMR activity over time - ITT population

[0534] As shown in Table 22, participants in the sarrelumab 200 mg q2w + 14-week taper group had a greater change from baseline in PMR-AS at Week 52 compared to the placebo + 52-week taper group (LS mean [SE] -10.27 [0.97] and -15.57 [0.94], respectively). The LS mean difference in PMR-AS in the sarrelumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group was statistically significant (-5.302, 95% CI: -8.006 to -2.597; p = 0.0002). Table 22: Change from Baseline in PMR Activity Score at Week 52 - ITT Population

[0535] like Figure 7 As shown, the greatest reductions in PMR activity were observed from baseline to Week 12 in both the sarrellumab 200 mg q2w + 14-week taper group and the placebo + 52-week taper group, with the reductions in the sarrellumab 200 mg q2w + 14-week taper group sustained through Week 52. MD-VAS

[0536] As shown in Table 23, participants in the sarrelumab 200 mg q2w + 14-week taper group had a greater reduction from baseline in the MD-VAS at week 52 compared to the placebo + 52-week taper group (LS mean [SE] -30.49 [3.46] and -40.58 [3.40], respectively). The LS mean difference in MD-VAS in the sarrelumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group was statistically significant (-10.097, 95% CI: -19.775, -0.419; p = 0.0411). Table 23: Change from Baseline in MD-VAS at Week 52 - ITT Population FACIT-Fatigue

[0537] As shown in Table 24, the change from baseline in the FACIT-Fatigue scale at Week 52 was numerically higher in the sarrelumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group (LS mean [SE] 4.17 [1.42] and 7.91 [1.33], respectively). The LS mean difference in the FACIT-Fatigue scale in the sarrelumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group was 3.740 (95% CI: -0.108, 7.588; p = 0.0567). Table 24: Change from Baseline in FACIT-Fatigue at Week 52 - ITT Population

[0538] Among patients treated with sarrellumab and placebo, the percentages of patients reporting an improvement greater than or equal to the MCID for FACIT-F scores at Week 52 are shown in Table 2. Figure 12 The MCID for FACIT-F is an improvement of greater than or equal to 4.0. These results suggest that treatment with sarrellumab resulted in a numerically greater improvement in FACIT-F scores (higher scores represent better function or less fatigue) than treatment with placebo.

[0539] Among patients treated with sarrellumab and placebo, the percentages of patients reporting FACIT-F scores greater than or equal to the normative value at baseline and Week 52 are shown in Table 2. Figure 13 The threshold for the criterion value was greater than or equal to 43.5. These results indicate that treatment with sarrelumab resulted in a numerically greater improvement in the FACIT-F score than treatment with placebo. EQ-5D-3L

[0540] As shown in Table 25, participants in the sarrellumab 200 mg q2w + 14-week taper group had a greater increase from baseline in the EQ-5D-3L single index utility score at week 52 compared to the placebo + 52-week taper group (LS mean [SE] -0.02 [0.04] and 0.11 [0.04], respectively). The LS mean difference in the EQ-5D-3L single index utility score in the sarrellumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group was statistically significant (0.130, 95% CI: 0.010, 0.250; p = 0.0336). Table 25: Change from Baseline in EQ-5D Single Index Utility at Week 52 - ITT Population

[0541] As shown in Table 26, participants in the sarrelumab 200 mg q2w + 14-week taper group had a greater increase from baseline in the EQ-5D-3L VAS score at week 52 compared to the placebo + 52-week taper group (LS mean [SE] -0.46 (3.68) and 8.37 [3.46], respectively). The LS mean difference in EQ-5D-3L VAS score in the sarrelumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group was 8.830 (95% CI: -1.191, 18.850; p = 0.0835). Table 26: Change from Baseline in EQ-5D VAS at Week 52 - ITT Population

[0542] The LSM changes from baseline in the EQ-5D index utility scores and EQ VAS scores at week 52 for patients treated with sarrellumab and placebo are shown in Figure 19 These results indicate that sarrelumab treatment resulted in a statistically greater improvement in the EQ-5D index utility score relative to baseline, with a LSM difference of 0.13 (P=0.0336) compared to placebo. These results also indicate that sarrelumab treatment resulted in a numerically greater improvement in the EQ VAS score relative to baseline (higher scores indicate better health). SF-36

[0543] As shown in Table 27, participants in the sarrellumab 200 mg q2w plus 14-week taper group had a greater increase from baseline in PCS at Week 52 compared with those in the placebo plus 52-week taper group (LS mean [SE] 2.87 [1.45] and 7.65 [1.34], respectively). Figure 8As shown, the LS mean difference in PCS in the sarrelumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group was statistically significant (4.784, 95% CI: 0.865, 8.703; p=0.0172). Table 27: Change from Baseline in SF-36 Physiological Summary Score at Week 52 - ITT Population

[0544] As shown in Table 28, participants in the sarrellumab 200 mg q2w plus 14-week taper group had a greater increase from baseline in MCS at Week 52 compared with those in the placebo plus 52-week taper group (LS mean [SE] -1.71 [1.57] and 3.04 [1.47], respectively). Figure 8 As shown, the LS mean difference in MCS scores in the sarrellumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group was statistically significant (4.748, 95% CI: 0.484, 9.013; p=0.0295). Table 28: Change from Baseline in SF-36 Mental Summary Score at Week 52 - ITT Population

[0545] Table 29 provides the change from baseline in LSM at Week 52 for sarrelumab compared to placebo in each of the following SF-36 domains: Physical Functioning (PF), Role Physical (RP), Bodily Pain (BP), Global Health (GH), Vitality (VT), Social Functioning (SF), Role Emotional (RE), and Mental Health (MH). Figure 9 As demonstrated, 5 of the 8 domains of the SF-36 showed that sarrelumab resulted in statistically significantly greater improvements compared to placebo (MH, RP, BP, SF, and VT). Table 29: LSM of SF-36 Domains by Sareptalumab and Placebo Treatment

[0546] The percentages of patients who reported an improvement greater than or equal to the MCID at Week 52 for various SF-36 measures (including PCS, MCS, PF, RP, BP, GH, VT, SF, RE, and MH) among those receiving sarrelumab and placebo are presented in Table 5. Figure 10More patients receiving sarrelumab reported statistically significant improvements greater than or equal to the MCID on the PCS (P = 0.0161) and five of the eight SF-36 domain scores. The MCID (improvement from baseline) for the PCS and MCS was 2.5. The MCID for each individual SF-36 domain was 5.0.

[0547] The percentages of patients with scores greater than or equal to the normative values ​​at baseline and Week 52 for various SF-36 measures (including PCS, MCS, PF, RP, BP, GH, VT, SF, RE, and MH) are reported in patients treated with sarrellumab and placebo. Figure 11 The thresholds were as follows: PCS and MCS ≥ 50.0; PF ≥ 66.0, RP ≥ 69.2, BP ≥ 66.4, GH ≥ 66.1, VT ≥ 58.8, SF ≥ 82.1, RE 81.9, and MH ≥ 77.8. These results indicate that numerically more patients receiving sarrelumab reported scores greater than or equal to the normative values ​​on the SF-36 MCS and four SF-36 domain scores. HAQ-DI

[0548] As shown in Table 30, participants in the sarrelumab 200 mg q2w + 14-week taper group had a numerically greater reduction from baseline in the HAQ-DI standardized score at Week 52 compared to the placebo + 52-week taper group (LS mean [SE] -0.15 [0.09] and -0.39 [0.09], respectively). The LS mean difference in HAQ-DI standardized score in the sarrelumab 200 mg q2w + 14-week taper group compared to the placebo + 52-week taper group was -0.246 (95% CI: -0.496, 0.005; p = 0.0543). Table 30: Change from Baseline in HAQ-DI Standardized Score at Week 52 - ITT Population

[0549] Among patients treated with sarrellumab and placebo, the percentages of patients who reported an improvement greater than or equal to the MCID at Week 52 for HAQ-DI scores are shown in Table 5. Figure 14 The MCID for the HAQ-DI is an improvement of greater than or equal to 0.22. These results suggest that treatment with sarrelumab resulted in a numerically greater improvement in HAQ-DI scores compared with treatment with placebo (lower HAQ-DI scores represent improvement).

[0550] Among patients treated with sarrellumab and placebo, the percentages of patients reporting HAQ-DI scores greater than or equal to the normative value at baseline and Week 52 are shown in Table 2. Figure 15 The threshold for the criterion value was less than or equal to 0.25. These results indicate that treatment with sarrelumab resulted in a numerically greater improvement in HAQ-DI scores than treatment with placebo. Patient global assessment of disease activity (PtGA)

[0551] The LSM changes from baseline in Patient Global Assessment of Disease Activity (PtGA) scores at Week 52 in patients treated with sarrellumab and placebo are shown in Figure 16 These results suggest that treatment with sarrellumab resulted in numerically greater improvements in PtGA scores compared with treatment with placebo (higher scores represent higher levels of disease activity or poorer overall health).

[0552] The percentages of patients who reported an improvement greater than the MCID in PtGA scores at Week 52 with sarrelumab and placebo are shown in Table 5. Figure 17 The MCID is an improvement greater than or equal to 10.0. These results indicate that treatment with sarrelumab resulted in a numerically greater improvement in PtGA scores than treatment with placebo. Visual Analog Scale (VAS) for pain

[0553] The LSM changes from baseline in pain visual analog scale (VAS) scores at Week 52 for patients treated with sarrelumab and placebo are shown in Figure 18 These results indicate that treatment with sarrelumab resulted in numerically greater improvements in pain VAS scores compared with treatment with placebo (higher scores represent greater pain intensity). Resolution of PMR signs and symptoms

[0554] The proportion of patients without any signs and symptoms of PMR at each follow-up visit with sarrelumab (200 mg Q2W + 14-week GC taper) and placebo (52-week GC treatment) is shown in Figure 20 The proportion of patients without signs and symptoms of PMR increased with sarrelumab compared to placebo at week 2 and continued to increase over time until week 52. At each follow-up visit after baseline, a higher proportion of patients in the sarrelumab group were free of any signs and symptoms of PMR. Figure 20 Compared with Figure 21 A greater difference between the two treatment groups was observed in the 2 studies because patients receiving rescue therapy were excluded from the Figure 21 Beyond the analysis. rescue therapy

[0555] The cumulative proportion of patients who received rescue therapy with sarrelumab (200 mg Q2W + 14-week GC taper) and placebo (52-week GC treatment) is shown in Figure 22 These results demonstrate that at every time point after baseline through Week 52, the cumulative proportion of patients requiring rescue therapy was higher in the placebo-treated group. During the study period, a higher proportion of patients in the placebo-treated group required additional GC compared with the sarelumab-treated group (32.2% vs. 58.6%; P = 0.0053 [Fisher's exact test]). In the subgroup of patients who required rescue GC, the median cumulative rescue GC dose over 52 weeks was lower in the sarelumab-treated group (1076.1 mg [range, 8-2108]) than in the placebo-treated group (1326.5 mg [range, 20-2484]; P = 0.5078). Pharmacodynamics, pharmacokinetics, and anti-drug antibodies Pharmacokinetic results

[0556] Following multiple SC administration of sarrellumab 200 mg q2w, observed trough concentrations of functional sarrellumab increased over time and reached steady-state at week 24, with an accumulation ratio of approximately 5-fold. Pharmacodynamic results

[0557] Following subcutaneous administration of sarrellumab, mean serum IL-6 concentrations in the sarrellumab 200 mg q2w followed by a 14-week taper increased to peak levels at week 12 and then declined with further treatment. Mean serum total sIL-6Rα concentrations increased rapidly by week 2 and reached steady-state at week 24.

[0558] At week 52, mean CRP levels decreased by 6.9 mg / dL from baseline in the sarrelumab 200 mg q2w followed by a 14-week taper, compared with a 1.7 mg / dL decrease in the placebo followed by a 52-week taper. These reductions were greater in the sarrelumab 200 mg q2w followed by a 14-week taper at all time points compared with the placebo followed by a 52-week taper. Immunogenicity

[0559] One participant in the placebo plus 52-week taper group and two participants in the sarrellumab 200 mg q2w plus 14 weeks group had a treatment-emergent positive ADA response. Adverse events Safety results

[0560] The overall incidence of SAEs was low in both treatment groups (8 [13.6%] participants in the sarelumab 200 mg + 14-week taper group and 12 [20.7%] participants in the placebo + 52-week taper group). The most frequently reported SAEs occurred in the infections and infestations SOC (3 [5.1%] participants in the sarelumab 200 mg + 14-week taper group and 3 [5.2%] participants in the placebo + 52-week taper group).

[0561] The overall incidence of TEAEs leading to permanent treatment discontinuation was low in both treatment groups (7 [11.9%] participants in the sarrelumab 200 mg q2w plus 14-week taper group and 4 [6.9%] participants in the placebo plus 52-week taper group). The most frequently reported TEAEs leading to treatment discontinuation occurred in the SOCs for infections and infestations (COVID-19, discitis, and pneumonia, each in 1 [1.7%] participant) and blood and lymphatic system disorders (neutropenia, 3 [5.1%] participants).

[0562] Overall, mean changes in clinical laboratory values ​​and vital signs were similar across study treatment groups, with the exception of neutropenia, which was observed at a higher rate in the sarrelumab 200 mg q2w + 14-week taper group. in conclusion

[0563] Due to extended recruitment timelines and the impact of the COVID-19 pandemic on enrollment, the sponsor halted enrollment in Study EFC15160 in July 2020. Due to the early termination of the study, 118 (117 treated) of the expected 280 participants were enrolled. All enrolled participants were allowed to complete the study as originally planned. Due to enrollment of fewer participants than initially planned, a protocol amendment was implemented to modify the Type I error rate from <0.01 to <0.05 before the database lock.

[0564] Overall, the results of this study suggest that treatment with sarrelumab 200 mg every 2 weeks followed by a 14-week taper provides greater benefit in participants with PMR compared with treatment with a 52-week CS taper alone. Despite accelerated corticosteroid taper in participants treated with sarrelumab, a significantly greater proportion of participants were able to achieve sustained remission at week 52 (10.3% of participants in the placebo plus 52-week taper group vs. 28.3% of participants in the sarrelumab 200 mg every 2 weeks followed by a 14-week taper; p=0.0193). This effect was consistent across pre-specified subgroups of age, sex, race, region, and BMI, all of which favored the sarrelumab 200 mg every 2 weeks followed by a 14-week taper. To further determine the robustness of this effect, a prespecified sensitivity analysis was performed that removed acute-phase reactants from the definition of sustained remission, and in this analysis, participants treated with sarrellumab had a consistent and statistically significant increase in the proportion of participants achieving complete remission at week 52 (13.8% in the placebo plus 52-week taper group vs. 31.7% in the sarrellumab 200 mg q2w plus 14-week taper group; p=0.0280).

[0565] The important secondary endpoint was to reduce cumulative steroid use in participants with PMR who were treated with sarrelumab and are known to be susceptible to adverse side effects of corticosteroid therapy. In this study, participants treated with sarrelumab used significantly fewer steroids compared to placebo (2044.0 mg in the placebo + 52-week taper group vs. 777.0 mg in the sarrelumab 200 mg q2w + 14-week taper group; p < 0.0001). In addition, the median difference between the actual cumulative CS dose and the expected cumulative CS dose was significantly lower in the sarrelumab group compared to the placebo group (median: 199.5 mg vs. 0.0 mg; p = 0.0189). This represents a clinically significant difference, and in this study, when comparing actual steroid use to expected steroid use, a favorable reduction in steroid use was observed in the sarrelumab group, influenced by an increased rate of flares in the placebo + 52-week taper group.

[0566] Most secondary endpoints were achieved. A greater proportion of participants in the sarrelumab 200 mg q2w + 14-week taper group achieved disease remission by week 12 (46.7% and 37.9% in the sarrelumab 200 mg q2w + 14-week taper group and the placebo + 52-week taper group, respectively). In addition, more sarrelumab-treated participants had no PMR flare after clinical remission compared with placebo (32.8% vs. 55.0%). While sarrelumab-treated participants never reached the median, the time to first PMR flare was statistically significantly longer in sarrelumab-treated participants. Finally, greater compliance with prednisone taper was observed in the sarrelumab + 14-week taper group compared with the placebo + 52-week taper group.

[0567] The number of participants without any signs and symptoms of PMR (excluding those who received rescue therapy) was higher at each follow-up visit in the sarrellumab 200 mg q2w plus 14-week taper group.

[0568] Participants in the sarrellumab 200 mg q2w followed by a 14-week taper had a 56% reduced risk of PMR flare after achieving clinical remission.

[0569] Participants in the sarrellumab 200 mg q2w + 14-week taper group showed a numerical trend toward reduced steroid toxicity in GTI, but this did not reach statistical significance.

[0570] Exploratory efficacy endpoints showed that sarrelumab treatment combined with a rapid 14-week corticosteroid taper resulted in favorable functional and symptomatic benefits compared with placebo with a 52-week corticosteroid taper.

[0571] The change from baseline in PMR activity scores at Week 52 favored sarrellumab with an LS mean difference of -5.302 (p=0.0002).

[0572] The change from baseline in MD-VAS score at week 52 favored sarrellumab with an LS mean difference of -10.097 (p=0.0411).

[0573] The change from baseline in FACIT-Fatigue score at Week 52 showed a favorable trend for sarrelumab with an LS mean difference of 3.740 (p=0.0567).

[0574] The change from baseline in EQ-5D score at week 52 favored sarrellumab, with an LS mean difference of 0.130 (p=0.0336).

[0575] The change from baseline in EQ5D-VAS score at week 52 showed a favorable trend for sarrelumab, with an LS mean difference of 8.830 (p=0.0835).

[0576] The change from baseline in the SF-36 physical health score at week 52 favored sarrellumab, with an LS mean difference of 4.487 (p=0.0172).

[0577] The change from baseline in the SF-36 mental health score at week 52 favored sarrellumab with an LS mean difference of 4.748 (p=0.0295).

[0578] The change from baseline in HAQ-DI score at Week 52 showed a favorable trend toward sarrellumab, with an LS mean difference of -0.246 (p=0.0543).

[0579] This study showed that sarrelumab 200 mg administered every 2 weeks in combination with a rapid 14-week taper of corticosteroids resulted in clinically relevant and statistically significant differences relative to placebo plus a 52-week CS taper in participants with PMR with respect to the primary endpoint, most secondary endpoints, and many exploratory endpoints.

[0580] In this study, sarrelumab demonstrated efficacy in patients with GC-resistant PMR. A greater proportion of patients treated with sarrelumab remained free of PMR signs and symptoms at every time point after baseline compared to those in the placebo group, confirming that sarrelumab provides a more rapid and sustained response to PMR activity compared to GC alone. Despite receiving fewer GCs than those in the placebo group, sarrelumab recipients required less rescue GC therapy than those in the placebo group.

[0581] The combination of sarrelumab 200 mg q2w with a rapid 14-week taper of CS in PMR revealed no new safety signals and was consistent with the known safety profile of sarrelumab. No deaths were reported. The safety observations from this study, when considered together with the observed clinical benefits, support the favorable risk-benefit ratio and clinical utility of sarrelumab for the treatment of PMR.

[0582] Sarrelumab is used to treat polymyalgia rheumatica (PMR) in adult patients who have had an inadequate response to corticosteroids or who cannot tolerate a corticosteroid taper. Example 2. Glucocorticoid-Free Resolution of Polymyalgia Rheumatica (PMR) Signs and Symptoms in Patients with a History of Flares Treated with Sareptalumab: An Analysis from SAPHYR (NCT03600818, EFC15160, Phase 3)

[0583] In the SAPHYR study (NCT03600818), a significantly greater proportion of patients with polymyalgia rheumatica (PMR) who received sarrellumab plus a glucocorticoid taper (GC) achieved sustained remission at Week 52 (W) compared to placebo plus a GC taper. Post-hoc data are shown for resolution of PMR signs and symptoms (S&S) over time and for GC-free resolution of PMR S&S. method

[0584] Patients enrolled between October 2018 and July 2020 received either sarrelumab 200 mg Q2W with a 14-week GC taper (sarrelumab group) or placebo Q2W with a 52-week GC taper (comparative group) for 52 weeks. All patients received prednisone 15 mg / day for 2 weeks, followed by a blinded prednisone taper. Patients who experienced a flare or were unable to adhere to the pre-protocol GC taper received rescue open-label GC. result

[0585] A total of 118 patients were enrolled (sarrelumab, n=60 [1 untreated]; comparator, n=58). At each follow-up visit after baseline, a higher proportion of patients in the sarrelumab group had no signs and symptoms of PMR compared with the comparator group (W52, observed cases [OC]: 56.5% vs. 81.3%; intention-to-treat [ITT]: 45.8% vs. 65%). At W52, for OC and ITT, 64.3% and 45% of patients in the sarrelumab group and 22.2% and 13.8% of patients in the comparator group had GC resolution without signs and symptoms of PMR, respectively. Figure 26 A lower proportion of patients in the sarrelumab group required rescue GC at W52 compared with the comparator group (58.6% vs. 31.7%).

[0586] From W4 to W52, a higher proportion of patients in the sarrelumab group had no signs and symptoms of PMR compared with the comparator group (OC, 72.2% vs. 92.9% at week 52; ITT, 44.8% vs. 65%) ( Figure 27 ).

[0587] Patients in the sarrelumab group were less likely to experience a flare after achieving clinical remission than those in the comparator group (29.3% vs 16%; HR 0.56; 95% CI 0.35-0.90; P = 0.0158). In the sarrelumab group, flare-ups were almost absent after W16, whereas in the comparator group, flare-ups continued to occur until W52 ( Figure 28 ). in conclusion

[0588] Compared with the 52-week GC taper, the addition of sarilumab to a short 14-week GC taper resulted in more rapid resolution of PMR signs and symptoms from Week 4 onward. In patients treated with sarilumab, GC-free resolution of PMR signs and symptoms was maintained from Week 16 to Week 52. Example 3. Effectiveness of interleukin-6 receptor inhibitors in polymyalgia rheumatica Research Overview

[0589] Interleukin-6 receptor (IL-6R) inhibition has been shown to be effective in giant cell arteritis, but data are limited in polymyalgia rheumatica (PMR). We conducted a retrospective study to evaluate the efficacy of IL-6R inhibitors (IL-6Ri; sarrelumab or tocilizumab) as third- and second-line treatment in patients with glucocorticoid (GC)-refractory PMR compared with conventional immunomodulatory (cIM) therapy. Materials and Methods Research objectives

[0590] To evaluate the therapeutic efficacy of IL-6R inhibitor therapy (IL-6Ri) (tocilizumab, sarrellumab) compared with conventional disease-modifying antirheumatic drug (cDMARD) therapy (methotrexate, azathioprine, leflunomide) in the third- and second-line treatment of GC-refractory PMR. Study Design

[0591] The study used an observational retrospective comparative cohort design. Adults with PMR were identified from fee-for-service Medicare drug and Part D prescription claims from 3 / 29 / 2016 to 6 / 30 / 2020, with PMR defined as 1 hospitalization or 2 outpatient claims (with a PMR diagnosis interval ≥30 days). Those who initiated IL-6Ri or cIM as 2nd and 3rd line PMR therapy and were continuously enrolled for 180 days before initiating therapy (baseline) were included. For the 3rd line cohort, the index date for the IL-6Ri group was the date of switching from cIM to IL-6Ri, and the index date for the cIM group was the date of switching from one cIM to another cIM. For the 2nd line cohort, the index date for the IL-6Ri group was the start date of IL-6Ri (without previous cIM), and the index date for the cIM group was the date of new cIM use. A 180-day washout period for the index drug applied to all cohorts. Patients were receiving GC (≤25 mg / day) on the index date and were excluded if they had evidence of seropositive rheumatoid arthritis, other inflammatory arthritis or connective tissue disease, multiple sclerosis, or malignancy. Patients receiving IL-6Ri and cIM were matched 1:1 for age, sex, and GC dose category, and propensity score matching was used to adjust for potential confounders.

[0592] The outcomes assessed using adjusted Cox proportional hazards models included GC discontinuation; GC discontinuation or low-dose GC (<2.5 mg / day); and nonpersistence in the 2nd-line group (interleukin-6Ri or cIM discontinuation, or switch), after matching to adjust for residual imbalance. Censorship occurred at 1 year, death, 60 days before the end of enrollment (interval ≤ 30 days), or when a comparator PMR therapy was added, and additional censoring was applied in sensitivity analyses for drug discontinuation and / or switch. Inclusion criteria 2-wire and 3-wire

[0593] In all previous data, the diagnosis of PMR occurred during a single hospitalization or the first of 2 outpatient visits.

[0594] Oral use of GC on the index date.

[0595] Patients were enrolled continuously from 180 days before the index date to 1 day after the index date (baseline period). Only 3 lines

[0596] cDMARD therapy during the baseline period before the index date.

[0597] cDMARD therapy on the index date. Exclusion criteria 2-wire and 3-wire

[0598] Aged <18 years at the index date.

[0599] Initiate both IL-6Ri and cDMARD therapy on the index date (concurrent use of multiple drugs within the cDMARD drug group will be allowed, but >1 cannot be started on the same day. Similarly, prior cDMARD use and new IL-6Ri use will be allowed, but both cannot be started on the same day).

[0600] GC dose >25 mg prednisone equivalents on the index date.

[0601] Seropositive rheumatoid arthritis.

[0602] Diagnosis of other inflammatory arthritis, connective tissue disease, multiple sclerosis, organ transplantation.

[0603] Actively treat malignant tumors. Only 2 lines

[0604] Patients with prior use of IL-6Ri or cDMARD based on available records (at least 180 days) were excluded. ending main

[0605] Discontinuation of oral GC therapy was defined as a gap in oral GC drug supply >60 days.

[0606] Discontinuation of oral GC therapy or achievement of minimum oral GC daily dose (≤2.5 mg prednisone equivalents / day). secondary

[0607] The cumulative oral GC dose during follow-up was estimated as the cumulative sum and as mg prednisone equivalent per patient during each week of follow-up.

[0608] Time to discontinuation of index therapy (interval > 60 days) (2-line cohort only). result

[0609] After matching, 409 3rd-line patients and 251 2nd-line patients were included in the analysis. As shown in Table 31, after matching, patient characteristics were generally well balanced between cohorts, with little difference between exposure groups. The median time from first PMR diagnosis to start of follow-up was approximately 1.75 years (3rd-line) and 0.90 years (2nd-line) and was similar between groups. As shown in Table 32, despite matching on GC category, IL-6Ri patients started receiving higher doses of GC. As shown in Table 33, after matching and adjustment, patients receiving IL-6Ri were more likely to achieve GC discontinuation or low-dose GC compared to cIM patients. The unadjusted outcomes for 2nd-line are shown in Table 34 and the unadjusted outcomes for 3rd-line are shown in Table 35. As Figure 29 As shown, time to IL-6Ri or cIM discontinuation or switch (non-persistence) was significantly longer in IL-6Ri patients compared to cIM patients (p=0.029). Table 31: Post-match characteristics of PMR patients stratified by 2nd- and 3rd-line therapy use Table 32: Weekly GC doses over time for third-line therapy Table 33: Outcomes associated with IL-6Ri compared with cIM therapy Table 34: Unadjusted Outcomes Associated with Second-Line IL-6Ri Versus cIM Therapy Table 35: Unadjusted Outcomes Associated with 3rd-Line IL-6Ri Versus cIM Therapy ending cDMARD IL-6Ri P-value Patients who discontinued glucocorticoids, n (%) 123(30％) 184(45％) <0.001 Patients who stopped taking glucocorticoids or took the minimum dose, n (%) 144(35％) 203(50％) <0.001 Patients who discontinued glucocorticoids (no censoring at one year), n (%) 145(35％) 193(47％) <0.001 Cumulative GC dose (mg prednisone equivalent / person-week) 0.9 Mean (SD) 48(32) 50(40) Median (IQR) 39(27,63) 41(25,67) in conclusion

[0610] IL-6Ri therapy is more effective as a steroid-sparing agent compared with cIM therapy in adults with PMR. Example 4. Effectiveness of interleukin-6 receptor inhibitors in polymyalgia rheumatica Research objectives

[0611] To evaluate the efficacy of IL-6R inhibitor therapy (IL-6Ri) (tocilizumab, sarrellumab) as third-line (3L) and second-line (2L) treatment options for GC-refractory PMR compared with cIM therapy (methotrexate, azathioprine, leflunomide). Materials and Methods Study Design

[0612] This retrospective observational cohort study included adult patients (≥50 years) with PMR identified from fee-for-service Medicare drug and Part D prescription claims data from January 1, 2006, to December 31, 2020.

[0613] Patients who initiated IL-6Ri or cIM as 2L and 3L PMR therapy (a proxy for GC refractory) and were continuously enrolled for ≥180 days before initiating therapy (baseline) were included as 2 separate cohorts.

[0614] The 3L cohort compared patients who previously received cIM and started a new IL-6Ri therapy (Exposure) with patients who started a new cIM therapy different from the previous CIM (Reference) for the treatment of PMR.

[0615] For the 3L cohort, using all available data, the index date was the date of initiation of IL-6Ri therapy after prior cIM therapy or the date of initiation of cIM therapy different from prior cIM therapy (without prior IL-6Ri).

[0616] The 2L cohort compared patients with PMR who had no prior IL-6Ri or cIM therapy and received a new IL-6Ri therapy (exposure) with a new cIM therapy (reference). For the 2L cohort, all available data were used, and the index date was the date of initiation of the first IL-6Ri or CIM without prior IL-6Ri or cIM.

[0617] Patients initiating IL-6Ri and new CIM were initially matched 1:3 for age, sex, and GC dose category (and, in the 3L cohort, recency of prior CIM therapy) and then 1:1 for propensity score (PS) to control for potential confounders. Inclusion and exclusion criteria

[0618] Patients with one inpatient or two outpatient PMR diagnoses separated by at least 30 days from any clinical specialty or request location, who were using oral GC at index, and who were continuously enrolled for 180 days prior to the index day (baseline period) were included in the study. Patients who were on CIM therapy at any time prior to the index day were eligible only for the 3L cohort.

[0619] Patients were excluded if they had evidence of seropositive rheumatoid arthritis (RA), adult-onset Still's disease, other arthritis or connective tissue diseases, organ transplantation, or active treatment for malignancy. end

[0620] The primary efficacy endpoints were discontinuation of oral GC therapy and a composite endpoint of GC discontinuation or minimal GC dose (<2 mg / day).

[0621] Secondary endpoints included the cumulative GC dose received over the follow-up period and, in the 2L comparator cohort only, persistence of the index PMR therapy (ie, IL-6Ri or cIM therapy). Statistical analysis

[0622] Within each comparison group, time to GC discontinuation and time to the composite endpoint (GC discontinuation or minimal GC dose) were compared using Cox proportional hazards models.

[0623] Cox proportional hazards models were used to estimate hazard ratios (HRs) (95% confidence intervals (CIs)) to compare IL-6Ri and CIM exposure groups, and to estimate pooled HRs to stratify individual HRs in the 3L and 2L cohorts.

[0624] Models were further adjusted for any covariates not balanced by PS matching based on a post-matching standardized mean difference (SMD) >0.10.

[0625] Three sensitivity analyses were performed that applied different censoring rules for discontinuation of index therapy, treatment switch, and at 12 months. result Patient characteristics

[0626] After direct matching and PS matching, 409 and 251 patients were included in each treatment arm for the 3L and 2L cohorts, respectively.

[0627] Patient characteristics were generally well balanced, with some differences between exposure groups. In the 3L cohort, IL-6Ri patients were slightly more likely to be in a higher GC dose category at index, less likely to have a claim code for seronegative RA, and more likely to have a claim code for concomitant giant cell arteritis (GCA) compared to CIM patients (Table 36). All other characteristics examined were well balanced (data not shown). In the 2L cohort, IL-6Ri patients were slightly younger, less likely to be enrolled in Medicare due to disability, and more likely to have a claim code for seronegative RA and GCA (Table 36).

[0628] The median time from the first PMR diagnosis observed in claims to the start of follow-up was approximately 1.75 years (3L cohort) and 0.90 years (2L cohort) and was similar between groups. Table 36: Post-math and PS-matched characteristics of patients with PMR, stratified by third-line and second-line therapy use Glucocorticoid withdrawal or minimum dose of glucocorticoids

[0629] Based on the HRs shown in Table 37, patients receiving IL-6Ri were more likely to discontinue GC (HR [95% CI]: 1.32 [1.09-1.58]) and achieve minimal or no GC use (1.30 [1.90-1.54]) compared with the cIM group, and the results remained statistically significant regardless of the censoring rules applied in the sensitivity analysis.

[0630] Compared with CIM initiators, IL-R6i initiators were more likely to discontinue GC use (3L group: 30.1% vs. 45.0%, and 2L group: 32.7% vs. 49.0%) and discontinue or achieve minimal dose of GC (3L group: 34.7% vs. 49.6%, and 2L group: 39.4% vs. 55.4%) (mean follow-up time for IL-6Ri initiators: 147 days and 163 days for 3L and 2L, respectively; mean follow-up time for CIM initiators: 138 days and 148 days for 3L and 2L, respectively).

[0631] There was no significant difference in the cumulative prednisone equivalent dose during follow-up between the groups.

[0632] Results of sensitivity analyses showed that different censoring rules produced similar results. The individual HRs comparing IL-6Ri with CIM therapy were similar in each of the 3L and 2L cohorts. Table 37: Pooled adjusted hazard ratios stratified by third-line and second-line therapy, and different censoring rules for multiple sensitivity analyses. Treatment persistence, continuity, and transition

[0633] After PS matching, persistence in 2L therapy trended in favor of IL-6Ri therapy compared with cIM therapy (p = 0.055; Figure 30 IL-6Ri initiators were less likely to switch therapy compared with cIM therapy (p = 0.0011; Figure 31 ). in conclusion

[0634] In elderly patients with PMR, IL-6Ri therapy was as effective as steroid-sparing agents compared with cIM therapy when used as 3L or 2L therapy. These results are consistent with the efficacy of IL-6Ri therapy in PMR. Example 5. Long-term safety of conventional and biological IL-6Ri immunomodulators as second- or third-line treatment for polymyalgia rheumatica

[0635] Data are presented on the safety of IL-6Ri and conventional immunomodulatory (CIM) therapy in PMR patients for up to 2 years (Y). Target

[0636] To evaluate the safety of IL-6Ri and CIM therapy in the second-line (2L) or third-line (3L) treatment of PMR. method

[0637] This was a retrospective study of US adults aged ≥50 years with 1 inpatient / 2 outpatient claims (whose PMR diagnosis interval was ≥30 days) from Medicare fee-for-service data (3 / 29 / 2016-6 / 30 / 2020). Patients received ≤25 mg prednisone (PS) equivalents and started IL-6Ri (tocilizumab / sarelumab) or CIM (methotrexate / leflunomide / azathioprine) as 2L / 3L therapy and were continuously enrolled for ≥180 days before index. For 2L, the index date was the start date of IL-6Ri / CIM, where IL-6Ri / CIM was not used previously. For 3L, the index date was the start date of IL-6Ri (with / without background CIM) or new CIM after the previous CIM. Follow-up was until the end of enrollment, death, treatment switch, or 2 years, whichever was earliest. Patients with seropositive rheumatoid arthritis, other arthritis or connective tissue diseases, giant cell arteritis, organ transplantation, or treatment for malignancy were excluded. Stratified by line of therapy, IL-6Ri patients were directly matched by age, sex, index date, baseline PS equivalent dose category (<2.5, 2.5-<5, 5-<10, 10-<15, 15-<20, 20-25 mg), and recency of prior CIM (3L only; 1-60, 61-180, 180+ days) using 1:3 variable ratio matching, followed by 1:1 propensity score matching using multivariable logistic regression to identify variables with a mean difference (SMD) greater than 0.1. We examined hospitalizations for infection (any and principal diagnosis), gastrointestinal perforation, major adverse cardiac events, malignancy, and drug-induced liver injury. With the exception of infection, patients with prior events were excluded from each outcome-specific analysis. Outcomes were identified using validated or previously used claims-based algorithms. Incidence rates per 100 patient-years are reported up to 2 years of follow-up, using exact Poisson for 95% CI (if < 5 events). Cox proportional hazards models were used to estimate the adjusted hazard ratio (aHR) for infection (accounting for a small number of other events). Sensitivity analyses examined events in Y1 and Y2 separately and stratified by 2L vs. 3L. result

[0638] In the final cohort, 451 matched patients in each group (2L: 183; 3L: 268) were well balanced for covariates. Residual imbalances were minimal for disability status, steroid dose category, and chronic lung disease. The event rates and aHRs are shown in Table 38; the aHR for IL-6Ri compared with CIM was not significant. Sensitivity analyses were consistent with the primary results and generally showed similar rates or numerically lower rates for IL-6Ri compared with CIM in Y2 and lower rates for CIM compared with IL-6Ri in Y1 for most outcomes. Table 38: Pooled incidence and aHR of safety events stratified by 2L / 3L in patients treated with IL-6Ri and CIM for up to 2 years of exposure. *aHR, adjusted hazard ratio, controlling for unbalanced covariates with SMD > 0.10; CI, confidence interval; CIM, conventional immunomodulatory therapy; NE, not estimated, insufficient sample size; PY, patient-years; IL-6Ri, interleukin-6 receptor inhibitor in conclusion

[0639] Serious adverse event rates were comparable with IL-6Ri versus CIM therapy in PMR up to 2 years of exposure.

Claims

1. An antibody or antigen-binding fragment thereof that specifically binds to an IL-6 receptor for use in a method of treating polymyalgia rheumatica (PMR) in a subject in need thereof.

2. The antibody or antigen-binding fragment thereof for use according to claim 1, wherein the subject suffers from PMR that is refractory to steroids or refractory to steroid taper.

3. The antibody or antigen-binding fragment thereof for use according to claim 1 or 2, wherein the subject has had an inadequate response to steroids or is unable to tolerate steroid tapering.

4. The antibody or antigen-binding fragment thereof for use according to claim 2 or 3, wherein the steroid comprises a corticosteroid.

5. The antibody or antigen-binding fragment thereof for use according to claim 4, wherein the corticosteroid comprises prednisone.

6. The antibody or antigen-binding fragment thereof for use according to claim 5, wherein the subject has previously been treated with prednisone at a dose of ≥7.5 mg / day, and / or ≤25 mg / day or ≤20 mg / day.

7. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is administered in combination with another therapeutic agent.

8. The antibody or antigen-binding fragment thereof for use as claimed in claim 7, wherein the therapeutic agent comprises a corticosteroid.

9. The antibody or antigen-binding fragment thereof for use according to claim 8, wherein the corticosteroid comprises prednisone.

10. The antibody or antigen-binding fragment thereof for use according to claim 9, wherein the prednisone is administered at a dose of about 15 mg / day.

11. The antibody or antigen-binding fragment thereof for use according to claim 10, wherein the dose of prednisone is discontinued or optionally tapered to <2.5 or 2.0 mg prednisone / day.

12. The antibody or antigen-binding fragment thereof for use according to claim 11, wherein discontinuation of the prednisone begins between about 10 weeks and about 20 weeks after administration of the first dose of the antibody, optionally wherein discontinuation of the prednisone begins about 14 weeks after administration of the first dose of the antibody.

13. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the subject has previously been treated with a disease-modifying antirheumatic drug (cDMARD).

14. The antibody or antigen-binding fragment thereof for use according to the preceding claim, wherein the subject is concomitantly treated with a cDMARD.

15. The antibody or antigen-binding fragment thereof for use according to claim 14, wherein the cDMARD is selected from the group consisting of methotrexate, azathioprine and leflunomide.

16. The antibody or antigen-binding fragment thereof for use according to claim 14 or 15, wherein the cDMARD is methotrexate.

17. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is administered in a dose of between about 150 mg and about 200 mg.

18. The antibody or antigen-binding fragment thereof for use according to claim 17, wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg.

19. The antibody or antigen-binding fragment thereof for use according to claim 17, wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg.

20. The antibody or antigen-binding fragment thereof for use according to any one of claims 1 to 17 and 19, wherein the antibody or antigen-binding fragment thereof is administered in an initial dose of about 200 mg and one or more secondary doses of about 200 mg administered every other week (q2w).

21. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4 and 5, and the light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7 and 8.

22. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO:

2.

23. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO:

10.

24. The antibody for use according to any one of the preceding claims, wherein the antibody is sarrellumab.

25. An antibody or antigen-binding fragment thereof that specifically binds to an IL-6 receptor for use in a method of reducing or eliminating dependence of a subject with polymyalgia rheumatica (PMR) on background therapy comprising a corticosteroid for treating PMR, the method comprising: (a) Select patients with PMR that is partially controlled or uncontrolled with background therapy containing corticosteroids; (b) administering to the patient a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to IL-6 receptor at a defined dose and at a defined frequency during an initial treatment period, while maintaining the subject's background PMR therapy during the initial treatment period; as well as (c) gradually reducing or eliminating the dose of corticosteroid administered to the subject during the subsequent treatment period, while continuing to administer the antibody or antigen-binding fragment thereof to the subject at the defined frequency and dose used during the initial treatment period.

26. The antibody or antigen-binding fragment thereof for use according to claim 25, wherein the corticosteroid comprises prednisone.

27. The antibody or antigen-binding fragment thereof for use according to claim 26, wherein the initial dose of prednisone is about 15 mg / day.

28. The antibody or antigen-binding fragment thereof for use according to any one of claims 25 to 27, wherein the subsequent treatment period is at least 14 weeks.

29. The antibody or antigen-binding fragment thereof for use according to any one of claims 25 to 28, wherein the subsequent treatment period is at least 52 weeks.

30. The antibody or antigen-binding fragment thereof for use according to any one of claims 25 to 29, wherein the antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg.

31. The antibody or antigen-binding fragment thereof for use according to any one of claims 25 to 30, wherein the antibody or antigen-binding fragment thereof is administered every other week (q2w).

32. The antibody or antigen-binding fragment thereof for use as described in any one of claims 25 to 31, wherein the antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4 and 5, and the light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7 and 8.

33. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the subject is seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP).

34. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the subject does not suffer from a disorder or disease selected from the group consisting of giant cell arteritis, rheumatoid arthritis, inflammatory arthritis, connective tissue disease, rhabdomyolysis, neuromuscular disease and active fibromyalgia.

35. The antibody or antigen-binding fragment thereof for use according to claim 34, wherein the connective tissue disease is selected from the group consisting of systemic lupus erythematosus, systemic sclerosis, vasculitis, myositis, mixed connective tissue disease and ankylosing spondylitis.

36. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein at least one symptom of polymyalgia rheumatica in the subject is improved following administration of the antibody or antigen-binding fragment thereof.

37. The antibody or antigen-binding fragment thereof for use according to claim 36, wherein the symptom is selected from the group consisting of: shoulder pain associated with inflammatory stiffness; hip pain associated with inflammatory stiffness; elevated C-reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR).

38. The antibody or antigen-binding fragment thereof for use according to any of the preceding claims, wherein treatment with the antibody or antigen-binding fragment thereof results in an improvement in at least one patient-reported outcome measure or clinician-reported outcome measure selected from the group consisting of the Functional Assessment of Chronic Illness Therapy Fatigue Inventory (FACIT-Fatigue), EuroQol Five Dimensions Three Levels Questionnaire (EQ-5D-3L) and Short Form-36 v2 (SF-36 v2), Health Assessment Questionnaire Disability Index (HAQ-DI), and Physician's Global Assessment of Disease Activity - Visual Analog Scale (MD-VAS).

39. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein treatment with the antibody or antigen-binding fragment thereof results in a reduction in the Glucocorticoid Toxicity Index (GTI) score.

40. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein treatment with the antibody or antigen-binding fragment thereof results in a decrease in the PMR activity score (PMR-AS).

41. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein treatment with the antibody or antigen-binding fragment thereof results in an increased time to first PMR outbreak.

42. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein treatment with the antibody or antigen-binding fragment thereof results in remission of PMR in the subject.

43. The antibody or antigen-binding fragment thereof for use according to claim 42, wherein the subject is in remission and is free of disease flares.

44. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein treatment with the antibody or antigen-binding fragment thereof results in increased resolution of PMR signs and symptoms or GC-free resolution of PMR signs and symptoms in the subject.

45. The antibody or antigen-binding fragment thereof for use according to claim 44, wherein resolution of PMR signs and symptoms is achieved 4 weeks after initiation of treatment with the antibody or antigen-binding fragment thereof.

46. ​​The antibody or antigen-binding fragment thereof for use according to claim 44, wherein GC-free regression of PMR signs and symptoms is maintained from week 16 to week 52 after initiation of treatment with the antibody or antigen-binding fragment thereof.

47. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is administered subcutaneously.

48. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen delivery device or an autoinjector.

49. The antibody or antigen-binding fragment thereof for use according to any one of the preceding claims, wherein the antibody or antigen-binding fragment thereof is administered using a pre-filled syringe containing about 175 mg / mL sarrelumab.

Images