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

Abstract

To provide an effective treatment for polymyalgia rheumatica (PMR) with fewer harmful side effects. [Solution] An antibody or an antigen-binding fragment thereof that specifically binds to the IL-6 receptor is provided for use in a method for treating polymyalgia rheumatica (PMR) in subjects requiring treatment for PMR.

Description

[Technical Field]

[0001] Related Application This application claims priority to U.S. Provisional Patent Application No. 63 / 327,850 filed on April 6, 2022, No. 63 / 350,761 filed on June 9, 2022, No. 63 / 389,317 filed on July 14, 2022, No. 63 / 424,035 filed on November 9, 2022, No. 63 / 424,627 filed on November 11, 2022, No. 63 / 445,329 filed on February 14, 2023, No. 63 / 445,331 filed on February 14, 2023, and No. 63 / 447,796 filed on February 23, 2023. The entire disclosures of each of these applications are incorporated herein by reference in their entirety.

[0002] Field The present disclosure relates to the field of therapeutic treatment of polymyalgia rheumatica (PMR). More specifically, the present disclosure relates to the use of an interleukin-6 receptor (IL-6R) antagonist, for example, an anti-IL-6R antibody, for treating polymyalgia rheumatica. [Background Art]

[0003] Polymyalgia rheumatica (PMR) is a chronic inflammatory disease of unknown cause characterized by pain and morning stiffness in the shoulders, neck, and pelvic girdle, often accompanied by low-grade fever, fatigue, malaise, and weight loss. The debilitating effects of this disease can significantly impact the quality of life for PMR patients. It typically affects people over 50 years of age, and its prevalence varies by age and population (Non-Patent Literature 1). In 2008, the number of PMR cases in the United States was estimated at 711,000 (Non-Patent Literature 2). Prevalence is higher in women than in men and increases dramatically with age. Based on the only population-based study on PMR in the United States, prevalence ranged from 21 per 100,000 people aged 50-54 to 4,070 per 100,000 people aged 90 and over (Non-Patent Literature 2). In Europe, a higher prevalence has been observed in Northern European populations compared to Southern European populations. Among patients aged 50 and over, the annual incidence rate was 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 (Non-Patent Literature 1).

[0004] The cause is unknown, but both genetic and environmental factors are thought to be involved. Studies suggest that inflammation of the joints and surrounding bursae may cause the pain and stiffness associated with PMR. There is no definitive test, but there are guidelines that are helpful in the clinical diagnosis of PMR (Non-Patent Literature 3).

[0005] PMR is typically treated with low-dose corticosteroids (CS), but a subset of patients are either steroid-dependent or unable to taper prednisone or its equivalent to less than 10 mg / day without symptom relapse, thus putting them at risk of complications from long-term steroid therapy. The 2015 American College of Rheumatology / European League Against Rheumatism (ACR / EULAR) guidelines recommend a minimum effective starting dose of 12.5–25 mg of prednisone (or its equivalent) per day (Non-Patent Literature 4). The average treatment duration is approximately 2–3 years. CS with gradual tapering rapidly reduces symptoms in most patients. However, one report (Non-Patent Literature 3) indicated that nearly half of PMR patients treated with CS did not respond adequately based on clinical laboratory tests and clinical markers of disease activity. Another report showed that among patients with baseline prednisone doses above 10 mg / day, remission occurred at one year. Only 30% of the cases yielded a solution (Non-Patent Document 5). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Gonzalez, G. et al., 2009, Arthritis Rheum.61(10):1454-61 [Non-Patent Document 2] Lawrence, RC 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. [Non-Patent Document 3] Dasgupta, B. et al., 2010, Rheumatology. 49(1): pp. 186-1890. [Non-Patent Document 4] Dejaco, C. et al., 2017, Rheumatology. 56(4): pp. 506-515. [Non-Patent Document 5] Caporali, R. et al., 2004, Ann Intern Med. 141(7): 493-500. [Non-Patent Document 6] Chatzigeorgiou C et al. “Comorbidity in polymyalgia rheumatica”, Reumatismo. March 2018, 27;70(1):35-43 [Overview of the project] [Problems that the invention aims to solve]

[0007] Current treatment protocols for PMR include long-term oral glucocorticoid therapy. One drawback of long-term oral glucocorticoid therapy is its potential association with comorbidities (Non-Patent Literature 6). There is still a need for effective treatments for PMR with fewer adverse side effects. [Means for solving the problem]

[0008] In one embodiment, a method is provided for treating polymyalgia rheumatica (PMR) in a subject requiring treatment for PMR, comprising administering an effective amount of an antibody or antigen-binding fragment that specifically binds to the IL-6 receptor.

[0009] 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.

[0010] In certain exemplary embodiments, the steroid includes a corticosteroid. In certain exemplary embodiments, the corticosteroid includes prednisone. In certain exemplary embodiments, the subject has been previously treated with prednisone at doses of 7.5 mg / day or more, and / or 25 mg / day or less, or 20 mg / day or less.

[0011] In certain exemplary embodiments, an 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 prednisone.

[0012] In certain exemplary embodiments, prednisone is administered at a dose of approximately 15 mg / day. In certain exemplary embodiments, administration of prednisone is discontinued or, if applicable, gradually reduced to less than 2.5 mg or less than 2.0 mg / day.

[0013] In certain exemplary embodiments, prednisone is discontinued approximately 10 to 20 weeks after the administration of the initial dose of the antibody. In certain exemplary embodiments, prednisone is discontinued approximately 14 weeks after the administration of the initial dose of the antibody.

[0014] In certain exemplary embodiments, the subject has been previously treated with a disease-modifying antirheumatic drug (cDMARD).

[0015] In a particular exemplary embodiment, the subjects are treated simultaneously with cDMARDs.

[0016] 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.

[0017] In a particular exemplary embodiment, the antibody or its antigen-binding fragment is administered in a dose of approximately 200 mg.

[0018] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered in an initial dose of approximately 200 mg, followed by one or more secondary doses of approximately 200 mg every other week (q2w).

[0019] In certain exemplary embodiments, the antibody or its antigen-binding fragment 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.

[0020] In certain exemplary embodiments, the antibody is sarilumab.

[0021] In one embodiment, a method is provided for treating polymyalgia rheumatica (PMR) in a subject requiring treatment for PMR, comprising administering an effective amount of an antibody or antigen-binding fragment that specifically binds to the IL-6 receptor, wherein the antibody or antigen-binding fragment 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.

[0022] In certain exemplary embodiments, the subject has PMR that is refractory to steroids or refractory to steroid tapering. In certain exemplary embodiments, the steroid includes a corticosteroid. In certain exemplary embodiments, the corticosteroid includes prednisone.

[0023] In certain exemplary embodiments, the subject has been previously treated with prednisone at a dose of 7.5 mg / day or higher.

[0024] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered in combination with another therapeutic agent.

[0025] 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 approximately 15 mg / day. In certain exemplary embodiments, the dose of prednisone is gradually reduced.

[0026] In a particular exemplary embodiment, the antibody or its antigen-binding fragment is used in approximately 200 mg It is administered by dose.

[0027] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered in an initial dose of approximately 200 mg, followed by one or more secondary doses of approximately 200 mg every other week (q2w).

[0028] In certain exemplary embodiments, the subjects are at least 50 years old.

[0029] In a particular exemplary embodiment, the subject has bilateral shoulder pain.

[0030] In certain exemplary embodiments, the subject has a C-reactive protein (CRP) level greater than 10 mg / L and / or an erythrocyte sedimentation rate (ESR) greater than 30 mm / hour.

[0031] In a particular exemplary embodiment, the subject has morning stiffness.

[0032] In certain exemplary embodiments, the subject does not have any affected joints other than the shoulder joint.

[0033] In certain exemplary embodiments, the subject has hip pain or limited range of motion.

[0034] In certain exemplary embodiments, subjects are seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptides (anti-CCP).

[0035] 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, neuropathic muscle disease, and active fibromyalgia. In certain exemplary embodiments, connective tissue disease is selected from the group consisting of systemic lupus erythematosus, systemic sclerosis, vasculitis, myositis, mixed connective tissue disease, and ankylosing spondylitis.

[0036] In certain exemplary embodiments, the subject has at least one shoulder having subdeltoid bursitis and / or biceps tendonitis and / or posterior or axillary shoulder joint synovitis, and at least one hip having synovitis and / or trochanteric bursitis.

[0037] In certain exemplary embodiments, at least one symptom of polymyalgia rheumatica in a subject improves after administration of an antibody or its antigen-binding fragment. In certain exemplary embodiments, the symptom is selected from the group consisting of shoulder pain with inflammatory stiffness; hip pain with inflammatory stiffness; elevated C-reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR).

[0038] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment 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 Disease Therapy - Fatigue Scale (FACIT-Fatigue), the EuroQol 5-Item 3-Level Questionnaire (EQ-5D-3L), and the Short form-36v2 (SF-36v2), the Health Assessment Questionnaire Disability Index (HAQ-DI), and the Physician's Global Assessment of Disease Activity - Visual Analog Scale (MD-VAS).

[0039] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment results in a reduction in the glucocorticoid toxicity index (GTI) score.

[0040] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment results in a decrease in the PMR activity score (PMR-AS). In certain exemplary embodiments, the decrease in PMR-AS is at least 3 points. In certain exemplary embodiments, the decrease in PMR-AS is at least 5 points.

[0041] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment results in an increase in the time to the first PMR flare. In certain exemplary embodiments, the symptoms of the PMR flare are selected from the group consisting of shoulder pain with inflammatory stiffness and pelvic girdle pain with inflammatory stiffness.

[0042] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered for at least 12 weeks. In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered for at least 52 weeks.

[0043] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment results in remission of PMR in a subject.

[0044] In certain exemplary embodiments, the subject has the absence of disease flares during remission. In certain exemplary embodiments, the symptoms of PMR flares are selected from the group consisting of shoulder pain with inflammatory stiffness and pelvic girdle pain with inflammatory stiffness. In certain exemplary embodiments, remission is achieved at week 12 after initiation of treatment with the antibody or its antigen-binding fragment. In certain exemplary embodiments, remission is sustained at week 52 after initiation of treatment with the antibody or its antigen-binding fragment. In certain exemplary embodiments, remission is achieved at week 12 after initiation of treatment with the antibody or its antigen-binding fragment and sustains until week 52. In yet other exemplary embodiments, remission (e.g., absence of disease flares) is achieved at week 16 after initiation of treatment with the antibody or its antigen-binding fragment and sustains until week 52, or at week 24 and sustains until week 52.

[0045] In a particular exemplary embodiment, the antibody or its antigen-binding fragment includes the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

[0046] In certain exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10.

[0047] In certain exemplary embodiments, the antibody is sarilumab.

[0048] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen-type delivery device, or an autoinjector.

[0049] In a particular exemplary embodiment, the antibody is administered using a pre-filled syringe containing approximately 175 mg / mL of sarilumab.

[0050] In another embodiment, a method is provided for treating polymyalgia rheumatica (PMR) in a subject requiring treatment for PMR, comprising administering a single initial dose of an antibody or antigen-binding fragment that specifically binds to the IL-6 receptor to the subject, followed by one or more secondary doses of the antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment 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.

[0051] In certain exemplary embodiments, the subject has PMR that is refractory to steroids or refractory to steroid tapering. In certain exemplary embodiments, the steroid includes a corticosteroid. In certain exemplary embodiments, the corticosteroid includes prednisone.

[0052] In certain exemplary embodiments, the subject has been previously treated with prednisone at a dose of 7.5 mg / day or higher.

[0053] 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 includes a corticosteroid. In certain exemplary embodiments, the corticosteroid includes prednisone. In certain exemplary embodiments, prednisone is administered at a dose of approximately 15 mg / day. In certain exemplary embodiments, the dose of prednisone is gradually reduced.

[0054] In certain exemplary embodiments, the initial and secondary doses of the antibody or its antigen-binding fragment are approximately 200 mg each.

[0055] In a particular exemplary embodiment, the secondary dose is administered every other week (q2w).

[0056] In certain exemplary embodiments, the subjects are at least 50 years old.

[0057] In a particular exemplary embodiment, the subject has bilateral shoulder pain.

[0058] In certain exemplary embodiments, the subject has a C-reactive protein (CRP) level greater than 10 mg / L and / or an erythrocyte sedimentation rate (ESR) greater than 30 mm / hour.

[0059] In a particular exemplary embodiment, the subject has morning stiffness.

[0060] In certain exemplary embodiments, the subject does not have any affected joints other than the shoulder joint.

[0061] In certain exemplary embodiments, the subject has hip pain or limited range of motion.

[0062] In certain exemplary embodiments, subjects are seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptides (anti-CCP).

[0063] In certain exemplary embodiments, the subject has at least one shoulder having subdeltoid bursitis and / or biceps tendonitis and / or posterior or axillary shoulder joint synovitis, and at least one hip having synovitis and / or trochanteric bursitis.

[0064] In certain exemplary embodiments, at least one symptom of polymyalgia rheumatica in a subject improves after administration of an antibody or its antigen-binding fragment. In certain exemplary embodiments, the symptom is selected from the group consisting of shoulder pain with inflammatory stiffness; hip pain with inflammatory stiffness; elevated C-reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR).

[0065] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment is used to assess the Functional Assessment of Chronic Disease Therapy and Fatigue Scale (FACIT-Fatigue), the EuroQol 5-Item 3-Level Questionnaire (EQ-5D-3L), and the Short Form-36v2 (SF-36v2), the Health Assessment Questionnaire Disability Index (HAQ-DI), and physician-administered disease activity assessments. Dynamic overall assessment – ​​resulting in improvement in at least one patient-reported outcome measure or clinician-reported outcome measure, selected from a group consisting of visual analog scales (MD-VAS).

[0066] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment results in a reduction in the glucocorticoid toxicity index (GTI) score.

[0067] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment results in a decrease in the PMR activity score (PMR-AS). In certain exemplary embodiments, the decrease in PMR-AS is at least 3 points. In certain exemplary embodiments, the decrease in PMR-AS is at least 5 points.

[0068] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment results in an increase in the time to the first PMR flare. In certain exemplary embodiments, the symptoms of the PMR flare are selected from the group consisting of shoulder pain with inflammatory stiffness and pelvic girdle pain with inflammatory stiffness.

[0069] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered for at least 12 weeks. In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered for at least 52 weeks.

[0070] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment results in remission of PMR in a subject.

[0071] In certain exemplary embodiments, the subject has no disease flares during remission. In certain exemplary embodiments, the symptoms of PMR flares are selected from the group consisting of shoulder pain with inflammatory stiffness and pelvic girdle pain with inflammatory stiffness. In certain exemplary embodiments, remission is achieved at week 12 after initiation of treatment with the antibody or its antigen-binding fragment. In certain exemplary embodiments, remission is maintained at week 16 after initiation of treatment with the antibody or its antigen-binding fragment. In certain exemplary embodiments, remission persists at week 24 after initiation of treatment with the antibody or its antigen-binding fragment. In certain exemplary embodiments, remission persists at week 52 after initiation of treatment with the antibody or its antigen-binding fragment.

[0072] In a particular exemplary embodiment, the antibody or its antigen-binding fragment includes the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

[0073] In certain exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10.

[0074] In certain exemplary embodiments, the antibody is sarilumab.

[0075] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen-type delivery device, or an autoinjector.

[0076] In a particular exemplary embodiment, the antibody is administered using a pre-filled syringe containing approximately 175 mg / mL of sarilumab.

[0077] In another aspect, corticosteroids are used to treat polymyalgia rheumatica (PMR). A method is provided for reducing or eliminating the dependence of a subject with PMR on a basic therapy including corticosteroids, comprising: (a) selecting a patient with PMR that is partially controlled or uncontrolled by a basic therapy including corticosteroids; (b) administering a prescribed dose of an effective amount of an antibody or antigen-binding fragment that specifically binds to the IL-6 receptor to the patient at a prescribed frequency over an initial treatment period, while maintaining the subject's basic PMR therapy over 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 to the subject at the prescribed frequency and dose used during the initial treatment period.

[0078] In certain exemplary embodiments, the antibody or its antigen-binding fragment 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.

[0079] In certain exemplary embodiments, the corticosteroid includes prednisone.

[0080] In a particular exemplary embodiment, the initial dose of prednisone is approximately 15 mg / day.

[0081] In a particular exemplary embodiment, the subsequent treatment period is at least 14 weeks.

[0082] In a particular exemplary embodiment, the subsequent treatment period is at least 52 weeks.

[0083] In a particular exemplary embodiment, the antibody or its antigen-binding fragment is administered in a dose of approximately 200 mg.

[0084] In a particular exemplary embodiment, the antibody or its antigen-binding fragment is administered every other week (q2w).

[0085] In certain exemplary embodiments, the subjects are at least 50 years old.

[0086] In a particular exemplary embodiment, the subject has bilateral shoulder pain.

[0087] In one exemplary embodiment, the subject has a C-reactive protein (CRP) level greater than 10 mg / L and / or an erythrocyte sedimentation rate (ESR) greater than 30 mm / hour.

[0088] In a particular exemplary embodiment, the subject has morning stiffness.

[0089] In certain exemplary embodiments, the subject does not have any affected joints other than the shoulder joint.

[0090] In certain exemplary embodiments, the subject has hip pain or limited range of motion.

[0091] In certain exemplary embodiments, subjects are seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptides (anti-CCP).

[0092] In certain exemplary embodiments, the subject has at least one shoulder having subdeltoid bursitis and / or biceps tendonitis and / or posterior or axillary shoulder joint synovitis, and at least one hip having synovitis and / or trochanteric bursitis.

[0093] In certain exemplary embodiments, at least one symptom of polymyalgia rheumatica in a subject improves after administration of an antibody or its antigen-binding fragment. In the embodiment, the symptoms are selected from the group consisting of shoulder pain with inflammatory stiffness; hip pain with inflammatory stiffness; elevated C-reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR).

[0094] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment 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 Disease Therapy - Fatigue Scale (FACIT-Fatigue), the EuroQol 5-Item 3-Level Questionnaire (EQ-5D-3L), and the Short form-36v2 (SF-36v2), the Health Assessment Questionnaire Disability Index (HAQ-DI), and the Physician's Global Assessment of Disease Activity - Visual Analog Scale (MD-VAS).

[0095] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment results in a reduction in the glucocorticoid toxicity index (GTI) score.

[0096] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment results in a decrease in the PMR activity score (PMR-AS). In certain exemplary embodiments, the decrease in PMR-AS is at least 3 points. In certain exemplary embodiments, the decrease in PMR-AS is at least 5 points.

[0097] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment results in an increase in the time to the first PMR flare. In certain exemplary embodiments, the symptoms of the PMR flare are selected from the group consisting of shoulder pain with inflammatory stiffness and pelvic girdle pain with inflammatory stiffness.

[0098] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered for at least 12 weeks. In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered for at least 52 weeks.

[0099] In certain exemplary embodiments, treatment with an antibody or its antigen-binding fragment results in remission of PMR in a subject.

[0100] In certain exemplary embodiments, the subject has no disease flares during remission. In certain exemplary embodiments, the symptoms of PMR flares are selected from the group consisting of shoulder pain with inflammatory stiffness and pelvic girdle pain with inflammatory stiffness. In certain exemplary embodiments, remission is achieved at week 12 after initiation of treatment with the antibody or its antigen-binding fragment. In certain exemplary embodiments, remission is sustained at week 52 after initiation of treatment with the antibody or its antigen-binding fragment. In certain exemplary embodiments, remission (e.g., no disease flares) is achieved at week 12 after initiation of treatment with the antibody or its antigen-binding fragment and persists until week 52. In yet other exemplary embodiments, remission (e.g., no disease flares) is achieved at week 16 after initiation of treatment with the antibody or its antigen-binding fragment and persists until week 52, or at week 24 and persists until week 52.

[0101] In certain exemplary embodiments, subjects treated with the antibody achieve increased resolution of PMR signs and symptoms, or resolution of PMR signs and symptoms without GC. In certain exemplary embodiments, resolution of PMR signs and symptoms was achieved from week 4 after the initiation of treatment with the antibody or its antigen-binding fragment. In certain exemplary embodiments, resolution of PMR signs and symptoms without GC was maintained from week 16 to week 52 after the initiation of treatment with the antibody or its antigen-binding fragment. In certain exemplary embodiments, Symptoms include morning stiffness and / or pain in the neck, shoulders, and / or pelvic girdle; limited range of motion in the shoulders and / or pelvic girdle; systemic symptoms, such as fatigue, weight loss, and low-grade fever; and other features that the clinician-investigator determines to be consistent with PMR.

[0102] In a particular exemplary embodiment, the antibody or its antigen-binding fragment includes the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

[0103] In certain exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10.

[0104] In certain exemplary embodiments, the antibody is sarilumab.

[0105] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen-type delivery device, or an autoinjector.

[0106] In a particular exemplary embodiment, the antibody is administered using a pre-filled syringe containing approximately 175 mg / mL of sarilumab.

[0107] In another embodiment, a method is provided for treating polymyalgia rheumatica (PMR) in a subject requiring treatment for PMR, comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to the IL-6 receptor, wherein the antibody or antigen-binding fragment 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, and the subject has had an insufficient response to steroids.

[0108] In certain exemplary embodiments, the steroid includes a corticosteroid, such as prednisone.

[0109] In a particular exemplary embodiment, the subject is an adult.

[0110] In a particular exemplary embodiment, the antibody or its antigen-binding fragment includes the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

[0111] In certain exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10.

[0112] In certain exemplary embodiments, the antibody is sarilumab.

[0113] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen-type delivery device, or an autoinjector.

[0114] In a particular exemplary embodiment, the antibody is administered using a pre-filled syringe containing approximately 175 mg / mL of sarilumab.

[0115] In another embodiment, a method for treating polymyalgia rheumatica (PMR) in a subject requiring treatment for PMR, comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to the IL-6 receptor, wherein the antibody or antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) sequences of SEQ ID NOs. 3, 4 and 5, and SEQ ID NOs. 6, 7 and A method is provided that includes eight light chain complementarity-determining region (LCDR) sequences, and in which the subject is unable to tolerate steroid tapering.

[0116] In certain exemplary embodiments, the steroid includes a corticosteroid, such as prednisone.

[0117] In a particular exemplary embodiment, the subject is an adult.

[0118] In a particular exemplary embodiment, the antibody or its antigen-binding fragment includes the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

[0119] In certain exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10.

[0120] In certain exemplary embodiments, the antibody is sarilumab.

[0121] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen-type delivery device, or an autoinjector.

[0122] In a particular exemplary embodiment, the antibody is administered using a pre-filled syringe containing approximately 175 mg / mL of sarilumab.

[0123] In another embodiment, a method is provided for treating polymyalgia rheumatica (PMR) in a subject requiring treatment for PMR, comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to the IL-6 receptor, wherein the antibody or antigen-binding fragment 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, wherein the subject has had an insufficient response to steroids or is unable to tolerate steroid tapering.

[0124] In certain exemplary embodiments, the steroid includes a corticosteroid, such as prednisone.

[0125] In a particular exemplary embodiment, the subject is an adult.

[0126] In another embodiment, a method is provided for treating polymyalgia rheumatica (PMR) in an adult subject requiring treatment for PMR, comprising administering an effective amount of an antibody or antigen-binding fragment thereof that specifically binds to the IL-6 receptor, wherein the antibody or antigen-binding fragment 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, wherein the subject has had an inadequate response to corticosteroids or is unable to tolerate corticosteroid tapering.

[0127] In a particular exemplary embodiment, the antibody or its antigen-binding fragment includes the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

[0128] In certain exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10.

[0129] In certain exemplary embodiments, the antibody is sarilumab.

[0130] In another context, a method is provided for treating polymyalgia rheumatica (PMR) in an adult subject requiring treatment for PMR, comprising administering an effective dose of sarilumab, wherein the subject has had an inadequate response to corticosteroids or is unable to tolerate corticosteroid tapering.

[0131] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen-type delivery device, or an autoinjector.

[0132] In a particular exemplary embodiment, the antibody is administered using a pre-filled syringe containing approximately 175 mg / mL of sarilumab.

[0133] In another embodiment, a method is provided for treating polymyalgia rheumatica (PMR) in a subject requiring treatment for PMR, comprising administering a single initial dose of an antibody or antigen-binding fragment that specifically binds to the IL-6 receptor to the subject, followed by one or more secondary doses of the antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment 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, and the subject has had an insufficient response to steroids.

[0134] In certain exemplary embodiments, the steroid includes a corticosteroid, such as prednisone.

[0135] In a particular exemplary embodiment, the subject is an adult.

[0136] In a particular exemplary embodiment, the antibody or its antigen-binding fragment includes the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

[0137] In certain exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10.

[0138] In certain exemplary embodiments, the antibody is sarilumab.

[0139] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen-type delivery device, or an autoinjector.

[0140] In a particular exemplary embodiment, the antibody is administered using a pre-filled syringe containing approximately 175 mg / mL of sarilumab.

[0141] In another embodiment, a method is provided for treating polymyalgia rheumatica (PMR) in a subject requiring treatment for PMR, comprising administering a single initial dose of an antibody or antigen-binding fragment that specifically binds to the IL-6 receptor to the subject, followed by one or more secondary doses of the antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment 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, and the subject is unable to tolerate steroid tapering.

[0142] In certain exemplary embodiments, the steroid is a corticosteroid, for example, pre- Includes donison.

[0143] In a particular exemplary embodiment, the subject is an adult.

[0144] In a particular exemplary embodiment, the antibody or its antigen-binding fragment includes the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

[0145] In certain exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10.

[0146] In certain exemplary embodiments, the antibody is sarilumab.

[0147] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen-type delivery device, or an autoinjector.

[0148] In a particular exemplary embodiment, the antibody is administered using a pre-filled syringe containing approximately 175 mg / mL of sarilumab.

[0149] In another embodiment, a method is provided for treating polymyalgia rheumatica (PMR) in a subject requiring treatment for PMR, comprising administering a single initial dose of an antibody or antigen-binding fragment that specifically binds to the IL-6 receptor to the subject, followed by one or more secondary doses of the antibody or antigen-binding fragment, wherein the antibody or antigen-binding fragment 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, wherein the subject has had an inadequate response to steroids or is unable to tolerate steroid tapering.

[0150] In certain exemplary embodiments, the steroid includes a corticosteroid, such as prednisone.

[0151] In a particular exemplary embodiment, the subject is an adult.

[0152] In a particular exemplary embodiment, the antibody or its antigen-binding fragment includes the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

[0153] In certain exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10.

[0154] In certain exemplary embodiments, the antibody is sarilumab.

[0155] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered subcutaneously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen-type delivery device, or an autoinjector.

[0156] In a particular exemplary embodiment, the antibody is administered using a pre-filled syringe containing approximately 175 mg / mL of sarilumab.

[0157] In another embodiment, a method for treating polymyalgia rheumatica (PMR) in a subject requiring treatment for PMR, comprising an antibody or other antibody that specifically binds to the IL-6 receptor. A method is provided comprising administering an effective amount of a proto-binding fragment, wherein the antibody or its antigen-binding fragment 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, or the antibody or its antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) sequences of SEQ ID NOs. 17, 18, and 19 and the light chain complementarity-determining region (LCDR) sequences of SEQ ID NOs. 14, 15, and 16.

[0158] In a particular exemplary embodiment, the antibody or its antigen-binding fragment includes the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

[0159] In certain exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10.

[0160] In certain exemplary embodiments, the antibody is sarilumab.

[0161] In certain exemplary embodiments, the antibody or its antigen-binding fragment includes a heavy chain complementarity-determining region (HCDR) and / or light chain complementarity-determining region (LCDR) of the HCVR containing the amino acid sequence of SEQ ID NO: 13, and a light chain complementarity-determining region (LCDR) of the LCVR containing the amino acid sequence of SEQ ID NO: 12.

[0162] In certain exemplary embodiments, the antibody or its antigen-binding fragment comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 13 and a light chain containing the amino acid sequence of SEQ ID NO: 12.

[0163] In certain exemplary embodiments, the antibody or its antigen-binding fragment is tocilizumab.

[0164] In certain exemplary embodiments, the antibody or its antigen-binding fragment is administered subcutaneously or intravenously. In certain exemplary embodiments, the pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen-type delivery device, or an autoinjector.

[0165] In certain exemplary embodiments, an antibody or its antigen-binding fragment is administered in combination with another therapeutic agent. In certain exemplary embodiments, the therapeutic agent includes a corticosteroid. In certain exemplary embodiments, the corticosteroid is a glucocorticoid. In certain exemplary embodiments, the glucocorticoid is prednisone or an equivalent.

[0166] In certain exemplary embodiments, the glucocorticoid dose is gradually reduced. In certain exemplary embodiments, the subject can reduce their total glucocorticoid exposure. In certain exemplary embodiments, the subject can achieve a minimum glucocorticoid dose of 2.5 mg or less of prednisone or its equivalent per day. In certain exemplary embodiments, the subject can achieve a minimum glucocorticoid dose of 2.0 mg or less of prednisone or its equivalent per day.

[0167] In certain exemplary embodiments, the use of antibodies or their antigen-binding fragments results in a greater reduction in glucocorticoid exposure than the use of conventional immunomodulatory (cIM) therapies.

[0168] In certain exemplary embodiments, the subject may discontinue glucocorticoid therapy. In certain exemplary embodiments, discontinuation of glucocorticoid therapy is defined as a absence of glucocorticoid use for more than 60 days.

[0169] In certain exemplary embodiments, the time to target discontinuity is longer when using antibodies or their antigen-binding fragments than when using conventional immunomodulatory (cIM) therapy.

[0170] In certain exemplary embodiments, an antibody or its antigen-binding fragment is a second-line treatment. In certain exemplary embodiments, an antibody or its antigen-binding fragment is a third-line treatment.

[0171] In certain exemplary embodiments, the method includes administering a single initial dose of an antibody or antigen-binding fragment that specifically binds to the IL-6 receptor to a target, followed by the administration of one or more secondary doses of the antibody or antigen-binding fragment.

[0172] In another embodiment, a method for reducing or eliminating the dependence of a subject having polymyalgia rheumatica (PMR) on a glucocorticoid-based basal therapy for the treatment of PMR, comprising: (a) selecting a patient having PMR that is partially controlled or uncontrolled with a glucocorticoid-based basal therapy; and (b) administering to the patient a prescribed dose of a therapeutically effective amount of an antibody or antigen-binding fragment that specifically binds to the IL-6 receptor at a prescribed frequency over an initial treatment period, while maintaining the subject's basal PMR therapy over the initial treatment period, wherein the antibody or antigen-binding fragment is the heavy chain of SEQ ID NOs: 3, 4, and 5 A method is provided comprising (c) administering an antibody or its antigen-binding fragment that includes a complementarity-determining region (HCDR) sequence and the light chain complementarity-determining region (LCDR) sequences of SEQ ID NOs. 6, 7, and 8, or an antibody or its antigen-binding fragment that includes a heavy chain complementarity-determining region (HCDR) sequence of SEQ ID NOs. 17, 18, and 19 and the light chain complementarity-determining region (LCDR) sequences of SEQ ID NOs. 14, 15, and 16, and (c) continuing to administer the antibody or its antigen-binding fragment to the subject at the prescribed frequency and dose used during the initial treatment period, while gradually reducing or eliminating the amount of glucocorticoid administered to the subject throughout the course of the subsequent treatment period.

[0173] In certain exemplary embodiments, the glucocorticoid includes prednisone or an equivalent.

[0174] In certain exemplary embodiments, at least one symptom of polymyalgia rheumatica in a subject improves after administration of an antibody or its antigen-binding fragment. In certain exemplary embodiments, the symptom is selected from the group consisting of shoulder pain with inflammatory stiffness; hip pain with inflammatory stiffness; elevated C-reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR).

[0175] The foregoing and other features and advantages of this disclosure will be better understood by receiving the following detailed description of exemplary embodiments in conjunction with the accompanying drawings. The patent file includes at least one drawing / photograph drawn in color. A copy of this patent, including the color drawing / photograph, will be provided by the Patent Office upon request and payment of the necessary fees. [Brief explanation of the drawing]

[0176] [Figure 1] Figure 1 is a schematic diagram illustrating the design of Example 1. This study was a randomized, double-blind, placebo-controlled trial aimed at evaluating the efficacy and safety of sarilumab in patients with polymyalgia rheumatica. The study included two groups of patients with active PMR. Subjects in Group 1 received sarilumab 200 mg q2w, with corticosteroid tapering over 14 weeks. Subjects in Group 2 received a placebo equivalent to sarilumab q2w, with corticosteroid tapering over 52 weeks. All patients received either sarilumab 200 mg or placebo for 52 weeks. [Figure 2A] Figures 2A-2B show the questionnaire used for the Euroqol-5-item questionnaire, a 3-level version (EQ-5D-3L), a common PRO tool for measuring health status. [Figure 2B] Figures 2A-2B show the questionnaire used for the Euroqol-5-item questionnaire, a 3-level version (EQ-5D-3L), a common PRO tool for measuring health status. [Figure 3A] Figures 3A-3C show the Short Form 36v2 (SF-36v2) questionnaire, a simplified version of a common 36-item PRO tool that assesses eight aspects of health: physical functioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, energy / vitality, physical pain, and perception of overall health. [Figure 3B]Figures 3A-3C show the Short Form 36v2 (SF-36v2) questionnaire, a simplified version of a common 36-item PRO tool that assesses eight aspects of health: physical functioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, energy / vitality, physical pain, and perception of overall health. [Figure 3C] Figures 3A-3C show the Short Form 36v2 (SF-36v2) questionnaire, a simplified version of a common 36-item PRO tool that assesses eight aspects of health: physical functioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, energy / vitality, physical pain, and perception of overall health. [Figure 4] Figure 4 shows a questionnaire for the physician's overall assessment of disease activity—a visual analog scale [MD-VAS]—where the patient's disease activity is assessed on a fixed 100 mm horizontal VAS, with 0 considered as no activity and 100 as the highest level of activity. [Figure 5] Figure 5 shows a forest plot for a subgroup analysis of the proportion of patients who achieved sustained remission at week 52. Subgroup analyses were performed to assess the consistency of treatment efficacy. Subgroup analyses of the primary endpoint results showed a numerical trend indicating that the sarilumab 200 mg q2w + 14-week tapering group was better than the placebo + 52-week tapering group, excluding subjects with baseline weight less than 60 kg; however, the sample size of this subgroup was very small. [Figure 6] Figure 6 shows Kaplan-Meier plots for the time to the first PMR flare after clinical remission up to week 52 for the ITT population. Subjects in the sarilumab 200 mg q2w + 14-week tapering group were less likely to have a PMR flare after achieving clinical remission (16.7% vs. 29.3%) compared to subjects in the placebo + 52-week tapering group, with a hazard ratio of 0.56 (95% CI: 0.35~0.90; p=0.0153). [Figure 7]Figure 7 shows a plot of the mean change in PMR activity score over time from baseline for the ITT population. In both the sarilumab 200 mg q2w + 14 weeks tapering group and the placebo + 52 weeks tapering group, the greatest decrease in PMR activity occurred from baseline to week 12, and in the sarilumab 200 mg q2w + 14 weeks tapering group, the decrease continued until week 52. [Figure 8] Figure 8 shows the least squares mean (LSM) summary scores for physical components (PCS) and mental components (MCS) of the SF-36 in graph form. The LSM difference in PCS between the sarilumab 200 mg q2w + 14-week tapering group and the placebo + 52-week tapering group was statistically significant (4.784, 95% CI: 0.865, 8.703; p=0.0172). The LSM difference in MCS scores between the sarilumab 200 mg q2w + 14-week tapering group and the placebo + 52-week tapering group was also statistically significant (4.748, 95% CI: 0.484, 9.013; p=0.0295). [Figure 9] Figure 9 graphically shows the statistical significance of baseline-to-baseline improvement with sarilumab compared to placebo in various SF-36 domains. The SF-36 domains include physical function (PF), physical role (RP), physical pain (BP), overall health (GH), vitality (VT), social functioning (SF), emotional role (RE), and mental health (MH). As shown in Figure 9, five of the eight SF-36 domains (MH, RP, BP, SF, and VT) showed statistically significantly greater improvement with sarilumab compared to placebo. [Figure 10]Figure 10 graphically shows the percentage of patients who reported a clinically significant minimum difference (MCID) or greater improvement at week 52 for various SF-36 metrics, including PCS, MCS, PF, RP, BP, GH, VT, SF, RE, and MH, with treatment by sarilumab and placebo. The MCID (improvement from baseline) was 2.5 for PCS and MCS. The MCID for individual SF-36 domains was 5.0. These results indicate that more patients treated with sarilumab reported a statistically significant improvement of MCID or greater for PCS (P=0.0161) and five of the eight SF-36 domain scores. [Figure 11] Figure 11 graphically shows the percentage of patients treated with sarilumab and placebo who reported above-normal scores at baseline and at week 52 for various SF-36 metrics, including PCS, MCS, PF, RP, BP, GH, VT, SF, RE, and MH. 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 a numerically higher percentage of patients treated with sarilumab reported above-normal scores for the SF-36 MCS and the four SF-36 domain scores. [Figure 12] Figure 12 graphically shows the percentage of patients treated with sarilumab and placebo who reported an improvement of MCID or higher in their FACIT-F score at week 52. An MCID of 4.0 or higher in FACIT-F indicated an improvement of 4.0 or higher. These results indicate that sarilumab treatment led to a greater numerical improvement in the FACIT-F score than placebo treatment (higher scores indicate better function or less fatigue). [Figure 13]Figure 13 graphically shows the percentage of patients treated with sarilumab and placebo who reported having a FACIT-F score above the normal range at baseline and at week 52. The normal range threshold was 43.5 or higher. These results indicate that sarilumab treatment led to a greater numerical improvement in the FACIT-F score compared to placebo treatment. [Figure 14] Figure 14 graphically shows the percentage of patients treated with sarilumab and placebo who reported an improvement of 0.22 or greater in their HAQ-DI score at week 52. An HAQ-DI MCID improvement of 0.22 or greater was observed. These results indicate that sarilumab treatment led to a numerically greater improvement in the HAQ-DI score than placebo treatment (lower HAQ-DI scores indicate greater improvement). [Figure 15] Figure 15 graphically shows the percentage of patients treated with sarilumab and placebo who reported having an HAQ-DI score above the normal range at baseline and at week 52. The normal range threshold was ≤0.25. These results indicate that sarilumab treatment led to a greater numerical improvement in the HAQ-DI score than placebo treatment (lower HAQ-DI score indicates greater improvement). [Figure 16] Figure 16 graphically shows the change in the patient's Global Assessment of Disease Activity (PtGA) score from baseline to LSM at week 52 for patients treated with sarilumab and placebo. These results indicate that treatment with sarilumab resulted in a significantly greater numerical improvement in the PtGA score compared to treatment with placebo (a higher score indicates a higher level of disease activity or poorer overall health). [Figure 17] Figure 17 graphically shows the percentage of patients treated with sarilumab and placebo who reported an improvement in their PtGA score above MCID at week 52. An improvement of 10.0 or more in MCID was observed. These results indicate that treatment with sarilumab led to a significantly greater numerical improvement in PtGA score compared to treatment with placebo. [Figure 18]Figure 18 graphically shows the change from baseline to long-term pain score (LSM) of the Visual Analog Scale (VAS) at week 52 for patients treated with sarilumab and placebo. These results indicate that treatment with sarilumab resulted in a significantly greater numerical improvement in pain VAS scores compared to treatment with placebo (higher scores indicate greater pain intensity). [Figure 19] Figure 19 graphically shows the long-term minimum standard (LSM) changes from baseline in the EQ-5D utility score and EQ VAS score at week 52 for patients treated with sarilumab and placebo. These results indicate that sarilumab treatment led to a statistically greater improvement in the EQ-5D utility score from baseline, with an LSM difference of 0.13 compared to placebo (P=0.0336). These results also show that sarilumab treatment led to a numerically greater improvement in the EQ VAS score from baseline (higher scores indicate better health). [Figure 20] Figure 20 graphically shows the percentage of patients who did not show signs and symptoms of post-metabolic malformation (PMR) at each visit after receiving sarilumab (200 mg Q2W + 14 weeks of GC tapering) or placebo (52 weeks of GC treatment). The percentage of patients who did not show signs and symptoms of PMR increased in the sarilumab group compared to the placebo group at week 2 and continued to increase over time until week 52. The percentage of patients who did not show signs and symptoms of PMR at each visit after baseline was higher in the sarilumab group compared to the placebo group. [Figure 21]Figure 21 graphs the proportion of patients who did not show signs and symptoms of post-metabolic regurgitation (PMR) at each visit, excluding patients who received rescue therapy, and who received either sarilumab (200 mg Q2W + 14 weeks of GC tapering) or placebo (52 weeks of GC treatment). The proportion of patients who did not show signs and symptoms of PMR increased with sarilumab treatment compared to placebo at week 2 and continued to increase over time until week 52. The proportion of patients who did not show signs and symptoms of PMR at each visit after baseline was higher in the sarilumab treatment group. Furthermore, the difference between the two treatment groups was observed to be larger in Figure 21 than in Figure 20, because patients who received rescue therapy were excluded from the analysis in Figure 21. [Figure 22] Figure 22 graphically shows the cumulative proportion of patients who received rescue therapy after being treated with sarilumab (200 mg Q2W + 14 weeks of GC tapering) and placebo (52 weeks of GC treatment). These results indicate that the cumulative proportion of patients requiring rescue therapy was higher in the placebo group at each time point from baseline to week 52. [Figure 23] Figure 23 shows a graph of the percentage of patients who achieved sustained remission at week 52 among those treated with sarilumab and placebo, evaluated from week 12 to week 52, from week 16 to week 52, and from week 24 to week 52. [Figure 24] Figures 24A-24B graphically show the percentage of patients treated with sarilumab and placebo who achieved disease remission (A) or flare-free status (B) at week 52, evaluated from week 12 to week 52, from week 16 to week 52, and from week 24 to week 52. [Figure 25] Figures 25A-25B graphically show the percentage of patients treated with sarilumab and placebo who achieved sustained normalization of CRP (A) or maintenance of steroid tapering (B) at week 52, evaluated from week 12 to week 52, from week 16 to week 52, and from week 24 to week 52. [Figure 26]Figure 26 shows a graph of the percentage of patients treated with sarilumab or placebo whose signs and symptoms of PMR resolved without GC, broken down by time of visit (not rescue therapy at the time of visit). [Figure 27] Figure 27 shows a graph of the percentage of patients treated with sarilumab or placebo who did not show signs and symptoms of post-metastatic regurgitation (PMR), broken down by time of visit. [Figure 28] Figure 28 graphically shows the time to the first flare after achieving clinical remission, compared to the control arm. [Figure 29] Figure 29 graphically shows the time to discontinuation (discontinuation or switching of the IL-6 inhibitor or conventional immunomodulator) with IL-6 inhibitors (IL-6Ri) compared to conventional immunomodulators (cIM). These results indicate that the time to discontinuation was significantly longer in the IL-6Ri group than in the cIM group (p=0.029). [Figure 30] Figure 30 graphically shows the time and continuation of index PMR therapy (either IL-6Ri (sarilumab or tocilizumab) or CIM therapy), which represents the survival curve for continuation after propensity score matching in the second-line treatment cohort. CIM: Conventional immunomodulatory agent; IL-6Ri: Interleukin-6 receptor inhibitor; PS: Propensity score; 2L: Second-line treatment. [Figure 31] Figure 31 graphs time and non-switching therapy, showing survival curves for switching treatments after PS matching for the second-line treatment cohort. CIM, conventional immunomodulatory agent; IL-6Ri, interleukin-6 receptor inhibitor; PS, propensity score; 2L, second-line treatment. [Modes for carrying out the invention]

[0177] Before describing this disclosure, it should be understood that this disclosure is not limited to the specific methods and experimental conditions described, as such methods and conditions may change. It should also be understood that the terms used herein are used solely to describe specific embodiments and are not intended to limit them, as the scope of this disclosure is limited only by the appended claims.

[0178] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure pertains.

[0179] As used herein, the term “about” means that, when used in reference to a specific stated number, the difference between that value and the stated value is 1% or less. For example, as used herein, the expression “about 100” includes 99 and 101, as well as all values ​​in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0180] As used herein, terms such as “to treat” and “to treat” mean to alleviate symptoms, to temporarily or permanently eliminate the cause of symptoms, or to prevent or delay the onset of symptoms of the disorder or condition mentioned.

[0181] As used herein, the term “PMR flare” refers to an increase in PMR symptoms. PMR symptoms can be selected from a group consisting of shoulder pain with inflammatory stiffness and pelvic girdle pain with inflammatory stiffness.

[0182] Any methods and materials similar or equivalent to those described herein may be used in carrying out the disclosures herein, but typical methods and materials are described below. All publications mentioned herein are incorporated herein by reference in their entirety.

[0183] This disclosure provides methods and compositions for treating polymyalgia rheumatica (PMR).

[0184] Polymyalgia rheumatica is a chronic inflammatory disease that occurs almost exclusively in people over 50 years of age (Guggino et al., Pathogenesis of Polymyalgia Rheumatica. Reumatismo 2018, 70(1):10-17, and Chatzigeorgiou C et al., Comorbidity in polymyalgia rheumatica. Reumatismo. 2018, 3 Month 27; 70(1): pp. 35-43 (These are incorporated herein by reference in their entirety). Polymyalgia rheumatica presents with pain and stiffness of the shoulder and possibly the hip, elevated inflammatory markers (though sometimes normal), and a characteristic dramatic response to corticosteroids. Diagnostic criteria for 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 (this entire work is incorporated herein by reference). Classification criteria include patients aged 50 years or older presenting with bilateral shoulder pain (not better explained by other diagnoses), elevated C-reactive protein (CRP) levels and / or elevated erythrocyte sedimentation rate (ESR). Further criteria include the presence of morning stiffness lasting longer than 45 minutes and the development of new symptoms involving the hip joint (e.g., pain, tenderness, and limited range of motion). Further classification criteria include the absence of peripheral synovitis, the absence of rheumatoid arthritis (RA) serological tests (rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), or both), and the absence of peripheral arthralgia. Further classification criteria include musculoskeletal ultrasound findings of bilateral shoulder abnormalities (subacromial bursitis / long head of biceps tendinitis / glenohumeral joint exudate) or abnormalities of one shoulder and the buttocks (hip joint exudate, trochanteric bursitis).

[0185] The following are the classification criteria for the diagnosis of polymyalgia rheumatica. These criteria are incorporated herein by reference in their entirety by the European League Against Rheumatism and the American College of Rheumatology, Dasgupta B et al., 2012, provisional classification criteria for polymyalgia rheumatism:a European League Against Rheumatism / American College of See also Rheumatology collaborative initiative, Annals of the Rheumatic Diseases 2012;71:484-492. Classification criteria include patients aged 50 years or older presenting with bilateral shoulder pain (not better explained by other diagnoses), elevated C-reactive protein (CRP) levels, and / or elevated erythrocyte sedimentation rate (ESR). Further criteria include the presence of morning stiffness lasting more than 45 minutes, and the development of new hip-related symptoms (e.g., pain, tenderness, and limited range of motion) (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-Endorsed-Criteria, which are incorporated herein by reference in their entirety).

[0186] IL-6 directly interacts with the IL-6Rα subunit, and the IL-6 / IL-6Rα pair forms a high-affinity complex with the glycoprotein 130 (gp130) subunit to initiate intracellular signaling via the Janus kinase (JAK)-signaling factor-activator (STAT) (JAK / STAT) pathway and the Ras / Raf / mitogen-activated protein kinase (MAPK) pathway. IL-6Rα also exists in a soluble form, which is involved in transsignaling and allows IL-6 to influence IL-6Rα-non-expressing cells, including synovial cells in the joints.

[0187] Sarilumab (SAR153191), also known as REGN88, is a fully human recombinant IgG1 kappa monoclonal antibody against the alpha subunit of the IL-6 receptor complex (IL-6Rα). Sarilumab blocks IL-6 binding and inhibits the cytokine-mediated signaling cascade. Sarilumab is also known by the trade name KEVZARA®.

[0188] Tocilizumab (TCZ) is a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody that binds to membrane-bound and soluble IL-6 receptors to inhibit IL-6 signaling. Tocilizumab is also known by the trade name ACTEMA®.

[0189] Methods for improving patient-reported outcome (PRO) and clinician-reported outcome (ClinRO) scales related to PMR A method is provided for improving one or more patient-reported outcome (PRO) measures related to PMR in subjects requiring improvement in one or more PMR-related PRO measures, comprising administering a pharmaceutical composition containing an IL-6R antagonist to the subject. A method is also provided for improving one or more clinician-reported outcome (ClinRO) measures related to PMR in subjects requiring improvement in one or more ClinRO measures, comprising administering a pharmaceutical composition containing an IL-6R antagonist to the subject.

[0190] Examples of PMR-related PRO scales include (1) Functional Assessment of Chronic Disease Therapy and Fatigue Scale (FACIT-Fatigue), (2) EuroQol 5-Item 3-Level Questionnaire (EQ-5D-3L), (3) Short Form-36v2 (SF-36v2), (4) Health Assessment Questionnaire Disability Index (HAQ-DI), (5) Patient Global Assessment of Disease Activity (PtGA), and (6) Pain Visual Analog Scale (Pain-VAS).

[0191] "Improvement in PMR-related PRO measures" means an increase from baseline in one or more of the following: FACIT-Fatigue score, EQ-5D-3L score, or SF-36v2 score, and / or a decrease from baseline in one or more of the following: HAQ-DI score, PtGA score, or Pain-VAS score. As used herein, the term "baseline" with respect to PMR-related PRO measures means the numerical value of the PRO measure for a patient before or at the time of administration of a pharmaceutical composition containing an IL-6R antagonist.

[0192] Examples of PMR-related ClinRO scales include the physician's overall assessment of disease activity—visual analog scale (MD-VAS).

[0193] "Improvement in the PMR-related ClinRO scale" means a decrease in the MD-VAS score from baseline. As used herein, the term "baseline" means the ClinRO scale score for a patient before or at the time of administration of a pharmaceutical composition containing an IL-6R antagonist, with respect to the PMR-related ClinRO scale.

[0194] To determine whether PMR-related parameters have “improved,” the parameters are quantified at baseline and at points after administration of the pharmaceutical composition described herein. For example, PMR-related parameters are quantified on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, or weeks 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18 after the initial treatment with the pharmaceutical composition. Measurements can be taken at weeks 19, 19, 20, 21, 22, 23, 24, 32, 40, 52, or later. The difference between the parameter value at a specific point in time after the start of treatment and the baseline parameter value is used to demonstrate whether or not there has been an "improvement" in the PMR-related parameter (e.g., an increase or decrease, depending on the specific parameter being measured).

[0195] As used herein, the terms “obtain” or “acquire” refer to obtaining ownership of a physical entity or value, such as a numerical value, by “directly obtaining” or “indirectly obtaining” a physical entity or value, such as a PMR-related parameter. “Directly obtaining” means performing a process (e.g., performing a synthesis method or an analytical method) to obtain a physical entity or value. “Indirectly obtaining” means receiving a physical entity or value from another entity or source (e.g., a laboratory that is not a party to the acquisition of the physical entity or value). Directly obtaining a physical entity involves performing a process that involves a physical change of a physical substance, such as a starting material. Exemplary changes include producing a physical entity from two or more starting materials, shearing or fragmenting a substance, separating or purifying a substance, combining two or more distinct entities into a mixture, and performing a chemical reaction that involves breaking or forming covalent or non-covalent bonds. Obtaining a value directly involves performing a process that includes a physical change of the sample or another substance, for example, performing an analytical process (sometimes referred to herein as “physical analysis”) that includes a physical change of a substance, such as a sample, analyte, or reagent.

[0196] Information obtained indirectly may be provided in the form of reports, for example, in paper or electronic format, or provided, for example, from online databases or applications ("apps"). Reports or information may be provided, for example, by healthcare institutions such as hospitals or clinics, or by healthcare providers such as doctors or nurses.

[0197] Functional assessment of chronic disease therapy and fatigue scale According to a specific embodiment, administration of an IL-6R antagonist to a patient results in an elevation from baseline in the Functional Assessment of Chronic Disease Therapy Fatigue Scale (FACIT-Fatigue) score. FACIT-Fatigue is a common PRO tool that includes 13 items for measuring fatigue. Each item is rated by the patient on a scale of 0 to 4 (0=not at all, 1=a little, 2=somewhat, 3=quite, 4=very). The scores are tallied to obtain a total score between 0 and 52. The recall period is the most recent 7 days.

[0198] A therapeutic method is provided that results in an increase in the FACIT-Fatigue score from baseline. For example, administration of an IL-6R antagonist to a subject requiring IL-6R antagonist administration will result in an increase of approximately 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 points in the FACIT-Fatigue score from baseline.

[0199] EuroQol-5 Questionnaire, 3-Level Version (EQ-5D-3L) According to certain embodiments, administration of an IL-6R antagonist to a patient results in an increase from baseline in EQ-5D-3L. EQ-5D-3L is a common 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): pp. 199-208). EQ-5D has two components: one is mobility, self-care, daily activities, pain / discomfort, and "today's" anxiety / depression. One is a health utility index score derived from five items, and the other is a current ("right now") overall health status score derived from a single 0-100 visual analog scale (VAS). The EQ-5D index utility score is fixed at 0 for death and 1 for perfect health. The VAS is fixed for "best imaginable health" and "worst imaginable health."

[0200] Treatment methods are provided that result in an increase in the EQ VAS score from baseline. For example, administration of an IL-6R antagonist to a subject requiring IL-6R antagonist administration results in an increase of approximately 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, 5 This triggers an increase of 2, 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.

[0201] Treatment methods are provided that result in an increase from baseline in the EQ-5D Index utility score. For example, administration of an IL-6R antagonist to a subject requiring IL-6R antagonist administration will result in an increase of approximately 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 from baseline in the EQ-5D Index utility score.

[0202] Short form 36v2 (SF-36v2) In a particular embodiment, administration of an IL-6R antagonist to a patient results in an elevation from baseline on the Short form 36v2 (SF-36v2). The Short form 36v2 (SF-36v2) is a simplified, general 36-item PRO scale that assesses multi-choice items from eight aspects of health: physical functioning (PF; 10 items), social functioning (SF; 2 items), role limitation due to physical problems (RP; 4 items), role limitation due to emotional problems (RE; 3 items), mental health (MH; 5 items), energy / vitality (VT; 4 items), physical pain (BP; 2 items), and perception of overall health status (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): pp. 473-483). For each aspect, item scores are coded, summed, and converted to a scale from 0 (worst health condition as measured by the questionnaire) to 100 (best health condition). Two standardized summary scores can also be calculated from the SF-36v2, namely the Physical Element Summary (PCS) and Mental Element Summary (MCS) on a scale of 0 to 100 (see Maruish ME (2011), "User's manual for the SF-36v2 Health Survey (3rd edition)," Lincoln, RI: QualityMetric Incorporated).

[0203] Treatment methods are provided that result in an increase in the SF-36v2 score from baseline. For example, administration of an IL-6R antagonist to a subject requiring IL-6R antagonist administration results in an increase of approximately 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, 3 from baseline in the SF-36v2 score. This triggers an increase of 5, 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.

[0204] Health Assessment Questionnaire Disability Index (HAQ-DI) The HAQ-DI was developed to assess the physical functioning status of adults with arthritis, but is now commonly used for many rheumatic diseases (see Wolfe F, "A brief clinical health assessment instrument: CLINHAQ," Arthritis Rheum. 1989; Vol. 32 (Supplement): 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: pp. 463-514). It includes the following 25 items: 20 4-point Likert scale questions assessing eight physical aspects of activities of daily living (dressing and grooming, standing, eating, walking, hygiene, reaching, grasping, errands and chores), 13 supplemental questions assessing the use of assistive devices, and 8 supplemental questions assessing assistance received from others. The recall period is the most recent week. The HAQ-DI score is calculated in three steps: sum the eight category scores by using the highest subcategory score from each category; adjust as needed for the use of assistive devices / apparatus and / or assistance from others; and divide the summed category scores by the number of categories answered (must be a minimum of 6) to obtain an HAQ-DI score from 0 to 3 (3 = worst function). In addition, the HAQ-DI has two additional questions measured on a scale of 0 to 100: how much pain you have experienced in the past week and rate your condition on a scale of 0 to 100 (0 represents "very good" and 100 represents "very poor"). These questions measure pain and overall assessment respectively and are scored independently.

[0205] Treatment methods are provided that result in a reduction of the HAQ-DI score from baseline. For example, administration of an IL-6R antagonist to a subject requiring IL-6R antagonist administration results in a reduction of approximately 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, 4 Causes a decrease of 4, 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.

[0206] Patient-to-Patient Global Assessment (PtGA) The Patient-to-Governance Assessment (PtGA) is a single-question assessment with a score of 0 to 100 that focuses on the patient's overall health status or disease activity. A higher score indicates a higher level of disease activity or poorer overall health.

[0207] Treatment methods are provided that result in a decrease in the PtGA score from baseline. For example, Administration of an IL-6R antagonist to patients requiring IL-6R antagonist therapy resulted in an improvement of approximately 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, 4 from baseline in the PtGA score. Causes a decrease of 5, 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.

[0208] Pain Visual Analog Scale (VAS) The Pain VAS is a one-dimensional pain intensity scale based on patient reports (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.

[0209] Treatment methods are provided that result in a reduction of the pain VAS score from baseline. For example, administration of an IL-6R antagonist to a subject requiring IL-6R antagonist administration results in a reduction of approximately 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, 4 Causes a decrease of 4, 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.

[0210] Physician's overall assessment of disease activity - Visual Analog Scale [MD-VAS] In the MD-VAS, physicians assess a patient's disease activity using a fixed 100mm horizontal VAS, where 0 is considered inactive and 100 is considered the most active (see Huskisson et al., "Vertical or Horizontal Visual Analogue Scales," Ann Rheum Dis. December 1979; 38(6): 560).

[0211] Treatment methods are provided that result in a reduction of the MD-VAS score from baseline. For example, administration of an IL-6R antagonist to a subject requiring IL-6R antagonist administration results in a reduction of approximately 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, 4 Causes a decrease of 4, 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.

[0212] 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 dose of corticosteroids, and time to PMR flare.

[0213] PMR Activity Score (PMR-AS) PMR-AS is calculated as the sum of CRP (mg / dL), visual analog score (VAS) for pain (0-10), VAS as assessed by a physician (0-10), duration of morning stiffness (MST [minutes] × 0.1), and upper limb elevation ability (EUL [3-0]).

[0214] Treatment methods are provided that result in a reduction of the PMR-AS score from baseline. For example, administration of an IL-6R antagonist to a subject requiring IL-6R antagonist administration results in a reduction of approximately 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, 4 Causes a decrease of 4, 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.

[0215] Glucocorticoid toxicity indicators The Glucocorticoid Toxicity Index (GTI) is a composite scale designed to assess glucocorticoid-related morbidity. The GTI-Cumulative Worsening Score (CWS) captures cumulative glucocorticoid toxicity, whether it is permanent or transient. The GTI-CWS either increases over time or remains unchanged. A lower score indicates lower glucocorticoid toxicity. The GTI-Overall Improvement Score (AIS) captures both worsening and improving glucocorticoid toxicity. New toxicity or worsening of toxicity contributes to a positive score, while improvement in existing toxicity contributes to a negative score. A lower score indicates lower glucocorticoid toxicity.

[0216] Treatment methods are provided that result in a reduction from baseline in the GTI-CWS or GTI-AIS score. For example, administration of an IL-6R antagonist to subjects requiring IL-6R antagonist administration results in a reduction of approximately 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, 4 Causes a decrease of 2, 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.

[0217] Cumulative dose of corticosteroids The cumulative dose of corticosteroids over a certain period of time is, for example, approximately 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, 4 This is a measure of a patient's exposure to corticosteroids over 8, 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.

[0218] Treatment with an IL-6R antagonist provides a therapeutic method that reduces the cumulative dose of corticosteroids over a period of time compared to treatment without an IL-6R antagonist. For example, administration of an IL-6R antagonist to a subject requiring IL-6R antagonist treatment results in a reduction of approximately 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 of the cumulative dose of corticosteroids.

[0219] Time until PMR flare Treatment methods are provided that result in an increase in the time until patients experience a PMR flare. For example, administration of an IL-6R antagonist to subjects requiring IL-6R antagonist administration increases the time until patients experience a PMR flare by approximately 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 This can cause an increase of 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 weeks.

[0220] Methods of administration and formulation The methods described herein involve administering a therapeutically effective dose of an anti-IL-6R antibody to a target. As used herein, the term “therapeutic dose” means a dose of the therapeutic agent that results in treatment of polymyalgia rheumatica. As used herein, “treatment” means 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 particular biomarker) that correlates with the underlying pathological mechanism causing the condition or symptoms. For example, the following symptoms or conditions are associated with polymyalgia rheumatica: bilateral shoulder pain, hip pain or tenderness and limited range of motion in the hip, elevated C-reactive protein (CRP) levels, elevated erythrocyte sedimentation rate (ESR), and the presence of morning stiffness lasting for several minutes (e.g., 30 or 45 minutes).

[0221] In various embodiments, “improvement” of PMR-related symptoms refers to a reduction in the incidence of PMR symptoms that may correlate with an improvement in one or more P-related tests, scores, or metrics (as described herein). For example, improvement may correlate with an increase over time from baseline of one or more of the following: 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 PMR-related parameters means the numerical value of the PMR-related parameter for a patient before or at the time of administration of the antibody described herein.

[0222] A detectable “improvement” may also be detected using at least one of the tests, scores, or metrics described herein. In various embodiments, improvement is detected by a reduction in PMR symptoms, selected from a group consisting of morning stiffness, neck pain, shoulder pain, pelvic girdle pain, limited range of motion in the shoulders, limited range of motion in the pelvic girdle, systemic symptoms (e.g., fatigue, weight loss, and low-grade fever), and other features that the clinician-investigator judges to be consistent with PMR flare. In various embodiments, improvement is detected by using at least one selected from a group consisting of the Patient Reported Outcomes (PRO) Questionnaire, the Functional Assessment of Chronic Disease Therapy-Fatigue Scale (FACIT-Fatigue), EQ-5D-3L, Short Form 36v2, HAQ-DI, PMR-AS, ​​and a physician’s overall assessment of disease activity (e.g., a Visual Analog Scale [MD-VAS]).

[0223] 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) remission of the disease, in particular up to week 12 after initiation of treatment with a therapeutically effective dose of anti-IL-6R antibody (i.e., absence of signs and symptoms of PMR in the subject); (ii) absence of disease flares; (iii) normalization of C-reactive protein, in particular from week 12 to week 52; or (iv) adherence to a steroid tapering protocol, in particular a glucocorticoid tapering protocol (e.g., prednisone tapering), in particular from week 12 to week 52.

[0224] In another example, if the dose of anti-IL-6R antibody does not result in a detectable improvement in one or more parameters or symptoms associated with PMR, or does not produce a biological effect that correlates with the underlying pathological mechanism causing the PMR condition or symptoms, then the treatment is considered ineffective.

[0225] In various embodiments, the IL-6R antibody is administered subcutaneously. In various embodiments, the IL-6R antibody is sarilumab.

[0226] 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., body weight or body surface area) of the subject, the route of administration, and other factors well known to those skilled in the art.

[0227] In various embodiments, the dose is a fixed dose regardless of the subject's body weight or surface area. In various embodiments, the subject is at least 50 years old. In various embodiments, the subject is older than 50 years old.

[0228] The present disclosure provides methods of using a therapeutic composition comprising an anti-IL-6R antibody or an antigen-binding fragment thereof, and optionally one or more additional therapeutic agents. The therapeutic composition of the present invention is administered together with suitable carriers, excipients, and / or other agents that are incorporated into the formulation to provide improved transport, delivery, tolerability, and the like. Many suitable formulations can be found in formulary compendia known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, vesicles containing lipids (cationic or anionic) (e.g., LIPOFECTIN®), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsion carbowaxes (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax.

[0229] Various delivery systems, for example, encapsulation in liposomes, microparticles, microcapsules, Receptor-mediated endocytosis is known and can be used for administering the pharmaceutical composition provided herein. Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition can be administered by any convenient route, for example by infusion or bolus injection, by absorption through the inner lining of epithelium or mucocutaneous tissue (e.g., oral mucosa, rectal and intestinal mucosa, etc.), and can also be administered together with other biologically active agents. Administration can be systemic or local. The IL-6R antibody can be administered subcutaneously.

[0230] In addition, the pharmaceutical composition can also be delivered in a form enclosed within vesicles such as liposomes. In certain specific embodiments, the pharmaceutical composition can be delivered with a controlled release system, for example, using a pump or a polymeric material. In certain specific embodiments, the controlled release system can be placed near the target of the composition, and thus only a fraction of a systemic dose is required.

[0231] Injectable preparations include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injection, local injection, infusion, and the like. These injectable preparations can be prepared by known methods. For example, an injectable preparation can be prepared, for example, by dissolving, suspending or emulsifying the above antibody or a salt thereof in a sterile aqueous medium or oily medium conventionally used for injection. As aqueous media for injection, for example, physiological saline, isotonic solutions containing glucose and other adjuvants, and the like can be mentioned, and these can be used in combination with an appropriate solubilizing agent, for example, an alcohol (e.g., ethanol), a polyhydric alcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)] and the like. As the oily medium, for example, sesame oil, soybean oil and the like are used, and these can be used in combination with a solubilizing agent, for example, benzyl benzoate and benzyl alcohol. The injection prepared in this way can be filled into a suitable ampoule.

[0232] Antibodies are typically formulated as described herein and in International Publication No. WO2011 / 085158, and these are incorporated herein by reference in their entirety.

[0233] In various embodiments, the antibody is - Approximately 21 mM histidine - Approximately 45 mM arginine - Approximately 0.2% (w / v) of polysorbate 20 - Approximately 5% (w / v) sucrose, and - Antibodies at approximately 100 mg / mL to 200 mg / mL It is administered as an aqueous buffer solution with a pH of approximately 6.0 containing [the substance].

[0234] In another embodiment, the antibody is - Approximately 21 mM histidine - Approximately 45 mM arginine - Approximately 0.2% (w / v) of polysorbate 20 - Approximately 5% (w / v) sucrose, and - At least approximately 130 mg / mL of antibody It is administered as an aqueous buffer solution with a pH of approximately 6.0 containing [the substance].

[0235] In another embodiment, the antibody is - Approximately 21 mM histidine - Approximately 45 mM arginine - Approximately 0.2% (w / v) of polysorbate 20 - Approximately 5% (w / v) sucrose, and - Approximately 131.6 mg / mL of antibody It is administered as an aqueous buffer solution with a pH of approximately 6.0 containing [the substance].

[0236] In another embodiment, the antibody is - Approximately 21 mM histidine - Approximately 45 mM arginine - Approximately 0.2% (w / v) of polysorbate 20 - about 5% (w / v) sucrose; and - about 175 mg / mL of the antibody is administered as an aqueous buffer having a pH of about 6.0.

[0237] In other embodiments, the antibody is - 21 mM histidine - 45 mM arginine - 0.2% (w / v) polysorbate 20 - 5% (w / v) sucrose, and - between 100 mg / mL to 200 mg / mL of the antibody is administered as an aqueous buffer having a pH of 6.0.

[0238] In another embodiment, the antibody is - 21 mM histidine - 45 mM arginine - 0.2% (w / v) polysorbate 20 - 5% (w / v) sucrose, and - at least 130 mg / mL of the antibody is administered as an aqueous buffer having a pH of 6.0.

[0239] In another embodiment, the antibody is - 21 mM histidine - 45 mM arginine - 0.2% (w / v) polysorbate 20 - 5% (w / v) sucrose, and - 131.6 mg / mL of the antibody is administered as an aqueous buffer having a pH of 6.0.

[0240] In another embodiment, the antibody is - 21 mM histidine - 45 mM arginine - 0.2% (w / v) polysorbate 20 - 5% (w / v) sucrose; and - 175 mg / mL of the antibody It is administered as an aqueous buffer solution with a pH of 6.0 containing [the substance].

[0241] In various embodiments, the antibody is administered in a stable pharmaceutical formulation containing (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 is determined by size exclusion chromatography after storage at 45°C for one month. Typically, at least 90% of the natural antibodies are recovered. In various embodiments, approximately 200 mg of antibody (e.g., sarilumab) is administered to the subject. In various embodiments, approximately 150 mg of antibody (e.g., sarilumab) is administered to the subject.

[0242] In various embodiments, the antibody is administered in a stable pharmaceutical formulation containing (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, the formulation having a pH of about 5.8, about 6.0, or about 6.2, and at least 90% of the native antibody is recovered by determination by size exclusion chromatography after storage at 45°C for one month. In various embodiments, about 200 mg of antibody (e.g., sarilumab) is administered to the subject. In various embodiments, about 150 mg of antibody (e.g., sarilumab) is administered to the subject.

[0243] Advantageously, the above-mentioned pharmaceutical compositions for oral or parenteral use are prepared as unit dose dosage forms suitable for adapting to the dose of the active ingredient. Such unit dose dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, and the like.

[0244] In various embodiments, an anti-IL-6R antibody (or a pharmaceutical formulation containing this antibody) can be administered to a patient using any acceptable device or mechanism. For example, administration can be achieved using a syringe and needle, or using a reusable pen and / or autoinjector delivery device. The methods of the present disclosure include the use of numerous reusable pen and / or autoinjector delivery devices for administering an anti-IL-6R antibody (or a pharmaceutical formulation containing the same). Examples of such devices include AUTOPEN® (Owen Mumford, Inc., Woodstock, UK), DISETRONIC® pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX® 75 / 25 pen, HUMALOG® pen, HUMALIN® 70 / 30 pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN® I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR® (Novo Nordisk, Copenhagen, Denmark), BD® pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN®, OPTIPEN PRO®, and OPTIPEN This includes, but is not limited to, STARLET® and OPTICLIK® (Sanofi-Aventis, Frankfurt, Germany).Examples of disposable pen and / or auto-injector delivery devices applicable to the subcutaneous delivery of the pharmaceutical compositions of this disclosure include, but are not limited to, the SOLOSTAR® pen (Sanofi-Aventis), FLEXPEN® (Novo Nordisk), and KWIKPEN® (Eli Lilly), the SURECLICK® auto-injector (Amgen, Thousand Oaks, CA), PENLET® (Haselmeier, Stuttgart, Germany), EPIPEN® (Dey, LP), and the HUMIRA® pen (AbbVie Inc., North Chicago, IL).

[0245] In various embodiments, the antibody is administered in a pre-filled syringe. In various embodiments, the antibody is administered in a pre-filled syringe that includes a safety system. For example, the safety system prevents accidental needle stick injuries. In various embodiments, the antibody is administered in a pre-filled syringe that includes the ERIS safety system (West Pharmaceutical Services Inc).

[0246] In various embodiments, the antibody is administered by an autoinjector. In various embodiments, the antibody is administered by an autoinjector featuring PUSHCLICK® technology (SHL Group). In various embodiments, the autoinjector is a device comprising a syringe that enables the administration of a certain dose of a composition and / or antibody to a subject.

[0247] The use of microinfusers for delivering anti-IL-6R antibodies (or pharmaceutical formulations containing such antibodies) to patients is also assumed herein. As used herein, the term “microinfuser” means a subcutaneous delivery device designed to slowly administer large volumes (e.g., up to approximately 2.5 mL or more) of a therapeutic formulation over a prolonged period (e.g., approximately 10, 15, 20, 25, 30 minutes or more). Microinfusers are particularly useful for delivering large volumes of therapeutic proteins contained in high concentrations (e.g., approximately 100, 125, 150, 175, 200 mg / mL or more) and / or viscous solutions.

[0248] In various embodiments, an inadequate response to pretreatment refers to a subject whose pain is not adequately controlled after receiving pretreatment at a typical maximum tolerable dose. In one embodiment, an inadequate response to pretreatment refers to a subject who, despite pretreatment, exhibits moderate or severe disease activity and features of a poor prognosis. In various embodiments, an inadequate response to pretreatment refers to a subject who, despite pretreatment, has pain symptoms (e.g., any of the symptoms listed herein) that have not improved or have worsened.

[0249] Dosage The amount of IL-6R antagonist (e.g., anti-IL-6R antibody) administered to a subject according to the methods described herein is generally a therapeutically effective dose. As used herein, the term “therapeutically effective dose” means the amount of IL-6R antagonist that results in improvement of one or more PMR-related PRO or ClinRO measures (as defined elsewhere herein). “Therapeutically effective dose” also includes the amount of IL-6R antagonist that inhibits, prevents, mitigates, or delays the progression of PMR in the subject. In some embodiments, the therapeutically effective dose of anti-IL-6R antibody reduces the dose of corticosteroid (e.g., prednisone) administered to the subject. In the case of anti-IL-6R antibodies, the effective therapeutic dose ranges from approximately 0.05 mg to approximately 700 mg, for example, approximately 0.05 mg, approximately 0.1 mg, approximately 1.0 mg, approximately 1.5 mg, approximately 2.0 mg, approximately 3.0 mg, approximately 5.0 mg, approximately 7.0 mg, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg , about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 41 0mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about The anti-IL-6R antibody may be 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, or approximately 700 mg. In certain embodiments, 200 mg of anti-IL-6R antibody is administered. In certain embodiments, 150 mg of anti-IL-6R antibody is administered. In certain embodiments, 300 mg of anti-IL-6R antibody is administered.

[0250] The amount of IL-6R antagonist contained in each dose can be expressed in milligrams of antibody per kilogram of the subject's body weight (i.e., mg / kg). For example, an IL-6R antagonist can be administered to a patient at a dose of approximately 0.0001 to 10 mg / kg per kg of body weight. For instance, an IL-6R antagonist can be administered at doses of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, or 6 mg / kg.

[0251] In certain embodiments, the initial dose is approximately the same as the loading dose. In certain embodiments, the initial dose is approximately 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, 2.5 times, 3.0 times, or more than the loading dose.

[0252] In certain embodiments, two or more doses (e.g., two, three, four, or five or more doses) are administered as an “initial dose” or “loading dose” at the start of the treatment regimen, followed by subsequent doses administered at a lower frequency (e.g., “maintenance dose”). In one embodiment, the maintenance dose may be lower than the loading dose or initial dose.

[0253] In certain exemplary embodiments, the IL-6R antagonist is administered in doses of approximately 150 mg or approximately 200 mg. In particularly exemplary embodiments, the IL-6R antagonist is administered in an initial dose of approximately 200 mg and one or more secondary or maintenance doses of approximately 200 mg, with the secondary dose administered every other week (q2w).

[0254] In certain exemplary embodiments, the subject is an adult, and the IL-6R antagonist is administered in doses of approximately 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg. In exemplary embodiments, the subject is an adult, and the IL-6R antagonist is administered in an initial dose of approximately 600 mg and one or more secondary or maintenance doses of approximately 300 mg, with the secondary dose administered every other week (q2w). In other exemplary embodiments, the subject is an adult, and the IL-6R antagonist is administered in an initial dose of approximately 400 mg and one or more secondary or maintenance doses of approximately 200 mg, with the secondary dose administered every other week (q2w). In a particular embodiment, the subjects are adults, and the initial dose contains approximately 300 mg of IL-6R antagonist, with one or more subsequent doses containing approximately 300 mg of IL-6R antagonist administered every other week.

[0255] In certain exemplary embodiments, the IL-6R antagonist is administered at a concentration of 150 mg / mL using a pre-filled device. In some embodiments, a 150 mg / mL IL-6R antagonist solution in a pre-filled device is used to deliver approximately 300 mg of IL-6R antagonist in a 2 mL injection. In certain exemplary embodiments, the IL-6R antagonist is administered at a concentration of 175 mg / mL using a pre-filled device. In some embodiments, a 175 mg / mL IL-6R antagonist solution in a pre-filled device is used to deliver approximately 200 mg of IL-6R antagonist in a 1.14 mL injection. In certain exemplary embodiments, the IL-6R antagonist is administered at a concentration of 131 mg / mL using a pre-filled device. In some embodiments, a 131 mg / mL IL-6R antagonist solution in a pre-filled device is used to deliver approximately 150 mg of IL-6R antagonist in a 1.14 mL injection.

[0256] Combination therapy Certain embodiments of the methods described herein are combined with an IL-6R antagonist. This includes administering one or more additional therapeutic agents in combination with the IL-6R antagonist. As used herein, the expression “in combination with” means that the additional therapeutic agent is administered before, after, or concurrently with the pharmaceutical composition comprising the IL-6R antagonist. In some embodiments, the term “in combination with” includes sequential or simultaneous administration of the IL-6R antagonist and the second therapeutic agent. A method is provided for treating PMR or related conditions or complications, comprising the administration of the IL-6R antagonist in combination with a second therapeutic agent for additive or synergistic activity.

[0257] For example, when administered "before" a pharmaceutical composition containing an IL-6R antagonist, the additional therapeutic agent may be administered approximately 72 hours, 60 hours, 48 ​​hours, 36 hours, 24 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 10 minutes prior to the administration of the pharmaceutical composition containing the IL-6R antagonist. When administered "after" a pharmaceutical composition containing an IL-6R antagonist, the additional therapeutic agent may be administered approximately 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours prior, 6 hours prior, 8 hours prior, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours prior, or 72 hours prior to the administration of the pharmaceutical composition containing the IL-6R antagonist. "Concurrent" administration with a pharmaceutical composition containing an IL-6R antagonist means that the additional therapeutic agent is administered to the subject in a different dosage form within 5 minutes (before, after, or concurrently) of the administration of the pharmaceutical composition containing the IL-6R antagonist, or as a single combination formulation containing both the additional therapeutic agent and the IL-6R antagonist.

[0258] In exemplary embodiments, additional therapeutic agents administered in combination with an IL-6R antagonist constitute the basal therapy. In some embodiments, the basal therapy includes a steroid. In exemplary embodiments, the basal therapy is a corticosteroid. Corticosteroids are steroid hormones produced in the adrenal cortex of vertebrates, and synthetic analogs of these hormones. Corticosteroids include prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, thixocortol pivalate, prednisolone, and methylprednisolone. In some embodiments, the corticosteroid is prednisone. According to other embodiments, corticosteroids also include triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortone, hydrocortisone-17-valerate, halomethasone, alclomethasone dipropionate, and betamethasone valerate. The following can be selected: acid esters, betamethasone dipropionate, prednicarbate, clobetazone-17-butyrate, clobetasol-17-propionate, fluocortone caproate, fluocortone pivalate, fluprednidenine acetate, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-butyrate propionate, ciclesonide, and prednicarbate.

[0259] In certain embodiments, the method leads to a reduction in the need for basic therapy. Reducing the dose of basic therapy is also called “tasking.” For example, in certain embodiments, the method leads to a reduction in the dose and / or frequency of basic therapy. In exemplary embodiments, the method leads to a reduction in the dose and / or frequency of corticosteroid basic therapy.

[0260] In certain embodiments, this method leads to the discontinuation of basic therapy. In exemplary embodiments, this method leads to the discontinuation of corticosteroid basic therapy.

[0261] In certain embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in subjects who have an inadequate response to basic therapy, particularly steroids such as corticosteroids. In exemplary embodiments, the method leads to the treatment of PMR (or one or more symptoms of PMR) while reducing or eliminating the need for corticosteroid basic therapy.

[0262] In certain embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in subjects who cannot tolerate tapering of basic therapy, particularly steroid tapering such as corticosteroid tapering. In exemplary embodiments, the method leads to the treatment of PMR (or one or more symptoms of PMR) after reducing or eliminating the need for corticosteroid basic therapy.

[0263] In certain embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in subjects who have an inadequate response to basic therapy, particularly steroids such as corticosteroids, and / or who cannot tolerate tapering of basic therapy, particularly steroid tapering such as corticosteroid tapering. In exemplary embodiments, the treatment of PMR (or one or more symptoms of PMR) is led by reducing or eliminating the need for corticosteroid basic therapy. In some embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in adult subjects who have an inadequate response to corticosteroids or cannot tolerate corticosteroid tapering.

[0264] In some embodiments, corticosteroid basal therapy can be administered from about 7.5 mg / day to about 80 mg / day. In certain embodiments, corticosteroid basal therapy can be administered from 15 mg / day to 20 mg / day, from about 20 mg / day to about 50 mg / day, and from about 35 mg / day to about 80 mg / day. In some embodiments, corticosteroid basal therapy is administered in doses of about 7.5 mg / day, about 10 mg / day, about 12.5 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 55 mg / day, about 60 mg / day, about 65 mg / day, about 70 mg / day, about 75 mg / day, or about 80 mg / day. In one exemplary embodiment, corticosteroid basal therapy is administered in a dose of about 15 mg / day.

[0265] In some embodiments, the dose of the basal therapy is tapered in conjunction with treatment with an IL-6R antagonist. Patients with polymyalgia rheumatica who are tapering their daily dose of corticosteroid treatment to a lower dose of corticosteroids may experience at least one flare episode, for example, by reducing the dose until they no longer experience shoulder pain, pelvic pain, or both, along with inflammatory stiffness lasting longer than a certain period in the morning (e.g., 45 minutes). As described herein, treatment with an IL-6R antibody or antibody fragment can mitigate flare episodes as the daily dose of the corticosteroid treatment in question is tapered or reduced over time.

[0266] Additional therapeutic agents may include, for example, another IL-6R antagonist, an IL-6 antagonist, or a steroid. In one exemplary embodiment, the additional therapeutic agent is a corticosteroid. In a further exemplary embodiment, the additional therapeutic agent is prednisone.

[0267] In some embodiments, the additional therapeutic agent administered in combination with the 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 live) viral vaccine or a live (e.g., attenuated live) bacterial vaccine.

[0268] Suitable vaccines include those for 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)), and 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 (e.g., IIV (also called IIV3, IIV4, RIV3, RIV4, 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 disease (e.g., MenACWY (Menactra, Menveo), MenB (Bexsero, Trumenba)), mumps (e.g., MMR (MMRII), MMRV (ProQuad), pertussis (e.g., DTaP (Daptacel, Infanrix), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), pneumococcus (e.g., PCV13 (Prevnar13), PPSV23 (Pneumovax 23)), polio (e.g., Polio (Ipol), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), rabies virus (e.g., Rabab (Imovax)) Rabab, 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)) This includes, but is not limited to, vaccines for varicella (e.g., VAR (Varivax), MMRV (ProQuad)) and yellow fever (e.g., YF (YF-Vax)). Preferred vaccines are also listed in the Centers for Disease Control's vaccine list, which is incorporated herein in its entirety for all purposes (cdc.gov / vaccines / vpd / vaccines-list.html). In some embodiments, the vaccine is for tetanus, diphtheria, pertussis and / or seasonal trivalent / quadrivalent influenza vaccines.

[0269] 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, the treatment is carried out by the vaccine. The subjects are treated simultaneously with an IL-6R antagonist for PMR.

[0270] In certain embodiments, treatment with an IL-6R antagonist is interrupted or terminated before treatment with a vaccine. In certain embodiments, treatment with an IL-6R antagonist is interrupted approximately 1 to 9 weeks before vaccine administration (e.g., approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9 weeks or earlier). In some embodiments, treatment with an IL-6R antagonist is approximately 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 of the vaccine administration. It will be interrupted approximately 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, or 60 days prior.

[0271] In certain embodiments, treatment with an IL-6R antagonist is resumed after treatment with a vaccine. In certain embodiments, treatment with an IL-6R antagonist is resumed approximately 1 to 14 weeks after vaccine administration (e.g., approximately 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 weeks or later). In some embodiments, treatment with an IL-6R antagonist is approximately 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 It will resume after approximately 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, or 90 days.

[0272] In certain embodiments, the efficacy of the IL-6R antagonist is not diminished by administration in combination with the vaccine or by subsequent administration of the vaccine.

[0273] In some embodiments, the efficacy of the vaccine is not diminished by administration in combination with an IL-6R antagonist, or by administration of an IL-6R antagonist before and / or after the vaccine. In some embodiments, when the vaccine is administered co-administered with an IL-6R antagonist, the subject develops a serum protective neutralizing titer against the vaccine.

[0274] In certain exemplary embodiments, the vaccine described herein is administered to a subject, and the subject is administered at least one dose of an IL-6R antagonist before, during, or after the administration of the vaccine.

[0275] Administration regimen According to certain embodiments, multiple doses of an IL-6R antagonist can be administered to a subject over a specified time course. Such a method includes administering multiple doses of the IL-6R antagonist sequentially to a subject. As used herein, “administer sequentially” means that each dose of the IL-6R antagonist is administered at different times. For example, this means that the drug is administered to the subject on different days separated by a predetermined interval (e.g., several hours, several days, several weeks, or several months). A method is provided which involves sequentially administering to a patient a single initial dose of the IL-6R antagonist, followed by one or more secondary doses of the IL-6R antagonist, and optionally, one or more tertiary doses of the IL-6R antagonist.

[0276] A method is provided comprising administering a pharmaceutical composition containing an IL-6R antagonist to a subject at a frequency of approximately four times a week, twice a week, once a week (q1w), once every two weeks (once 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 (once a month 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 at a frequency less frequent than that insofar as a therapeutic response is achieved.

[0277] In certain embodiments involving the administration of a pharmaceutical composition containing anti-IL-6R, a weekly dose of approximately 150 mg or approximately 200 mg may be used. In other embodiments involving the administration of a pharmaceutical composition containing anti-IL-6R antibody, a dose of approximately 150 mg or approximately 200 mg may be used every two weeks (every two weeks is interchangeable with every other week, every two weeks, or q2w). In other embodiments involving the administration of a pharmaceutical composition containing anti-IL-6R antibody, a dose of approximately 150 mg or approximately 200 mg may be used every three weeks. In other embodiments involving the administration of a pharmaceutical composition containing anti-IL-6R antibody, a dose of approximately 150 mg or approximately 200 mg may be used every four weeks (monthly dose). In other embodiments involving the administration of a pharmaceutical composition containing anti-IL-6R antibody, a dose of approximately 150 mg or approximately 200 mg may be used every five weeks. In other embodiments involving the administration of a pharmaceutical composition containing an anti-IL-6R antibody, a dose of about 150 mg or about 200 mg once every six weeks may be used. In certain exemplary embodiments, the route of administration is subcutaneous.

[0278] The terms "week" or "weeks" refer to a period of (n × 7 days) ± 3 days, for example, (n × 7 days) ± 2 days, (n × 7 days) ± 1 day, or (n × 7 days), where "n" is the number of weeks, for example, 1, 2, 3, 4, 5, 6, 8, 12 or more.

[0279] The terms “initial dose,” “secondary dose,” and “tertiary dose” refer to the chronological order of administration of the IL-6R antagonist. Thus, the “initial dose” is the dose administered at the start of the treatment regimen (also called the “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 secondary dose. The initial, secondary, and tertiary doses may all contain the same amount of IL-6R antagonist, or they may differ from one another in terms of the frequency of administration. However, in certain embodiments, the amounts of IL-6R antagonist contained in the initial, secondary, and / or tertiary doses may differ from one another throughout the course of treatment (e.g., adjusted upward or downward as appropriate). In certain embodiments, two or more doses (e.g., two, three, four, or five) may be administered as a “loading dose” at the start of the treatment regimen, followed by subsequent doses administered at a lower frequency (e.g., “maintenance doses”). In one embodiment, the maintenance dose may be lower than the loading dose. In one embodiment, the secondary dose / maintenance dose may be equal to the initial dose / loading dose. For example, one or more initial doses / loading doses of 150 mg or 200 mg of an IL-6R antagonist may be administered, followed by secondary doses / maintenance doses of approximately 150 mg or approximately 200 mg, respectively. In one embodiment, the loading dose may be divided into two or more doses administered at different time points, for example, two loading doses in which the second loading dose is administered two weeks after the first loading dose.

[0280] In some embodiments, the initial dose comprises 200 mg of antibody or its antigen-binding fragment, and one or more secondary doses comprise 200 mg of antibody or its antigen-binding fragment administered every two weeks (every two weeks can be used interchangeably with every other week, every two weeks, or q2w).

[0281] In one exemplary embodiment, each secondary and / or tertiary dose is administered 1 to 14 weeks after the preceding dose (e.g., 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5 weeks later, or later). The phrase “previous dose” means the dose of the IL-6R antagonist administered to the patient in a multi-dose sequence immediately before the next dose in a sequence without dose intervention.

[0282] The method may involve administering any number of secondary and / or tertiary doses of an IL-6R antagonist to a patient. For example, in one particular embodiment, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., two, three, four, five, six, seven, eight, or more) secondary doses are administered to the patient. Similarly, in one particular embodiment, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., two, three, four, five, six, seven, eight, or more) tertiary doses are administered to the patient.

[0283] In embodiments including multiple secondary doses, each secondary dose may be administered at the same frequency as the other secondary doses. For example, each secondary dose may be administered to the patient 1 to 2 weeks after the previous dose. Similarly, in embodiments including multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dose may be administered to the patient 2 to 4 weeks after the previous dose. Alternatively, the frequency at which secondary and / or tertiary doses are administered to the patient may vary throughout the course of the treatment plan. The frequency of administration may also be adjusted by the physician during the course of treatment according to the individual patient's needs after clinical examinations.

[0284] A method is provided for treating PMR or related conditions, comprising sequential administration of an IL-6R antagonist and a second therapeutic agent to a patient. In some embodiments, the method includes administering one or more doses of an IL-6R antagonist followed by one or more doses (e.g., two, three, four, five, six, seven, eight, or more) of a second therapeutic agent. For example, after administering one or more doses of an IL-6R antagonist ranging from about 150 mg to about 200 mg, one or more doses (e.g., two, three, four, five, six, seven, eight, or more) of a second therapeutic agent (e.g., a corticosteroid) can be administered to treat, alleviate, reduce or improve one or more symptoms of PMR. In some embodiments, an IL-6R antagonist is administered in one or more doses (e.g., two, three, four, five, six, seven, eight, or more) resulting in improvement of one or more PMR-related parameters, followed by the administration of a second therapeutic agent to prevent recurrence of at least one symptom of PMR. Alternative embodiments relate to the co-administration of an IL-6R antagonist and a second therapeutic agent. For example, one or more doses of the IL-6R antagonist (e.g., two, three, four, five, six, seven, eight, or more) are administered, and the second therapeutic agent is administered in separate doses at a frequency similar to or different from that of the IL-6R antagonist. In some embodiments, the second therapeutic agent is administered before, after, or concurrently with the IL-6R antagonist.

[0285] In a particular embodiment, the IL-6R antagonist was administered for 12 weeks, 14 weeks, and 16 weeks. The drug is administered every other week for 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 weeks or longer. In a particular embodiment, 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.

[0286] Treatment group The methods provided herein include administering a therapeutic composition comprising an IL-6R antagonist to a subject requiring the administration of such a therapeutic composition. The expression “subject requiring it” means a human or non-human animal exhibiting one or more symptoms or signs of PMR, or having been diagnosed with PMR.

[0287] In one relevant embodiment, the “subject requiring it” may be a subject who has been prescribed or is currently taking steroids prior to receiving the IL-6R antagonist. In some embodiments, the subject may be a subject who has been prescribed or is currently taking corticosteroids prior to receiving the IL-6R antagonist. In some embodiments, the subject is currently taking prednisone. For example, a method is provided comprising administering an IL-6R antagonist to a subject who has been regularly taking prednisone for eight weeks or more immediately prior to administration of the IL-6R antagonist (such prior treatment is referred to herein as “basic treatment”). In an exemplary embodiment, the subject is regularly taking prednisone at a dose of at least 7.5 mg / day and no more than 20 mg / day.

[0288] In yet another embodiment, the amount of corticosteroid, such as prednisone, is gradually reduced before or after the initiation of IL-6R antagonist administration.

[0289] In another exemplary embodiment, “the subject requiring it” has a diagnosis of PMR that is refractory to steroids prior to receiving an IL-6R antagonist. In some embodiments, the subject’s PMR symptoms persist despite treatment with steroids. In yet another exemplary embodiment, “the subject requiring it” has a diagnosis of PMR that is refractory to corticosteroids (e.g., prednisone) prior to receiving an IL-6R antagonist. In some embodiments, the subject’s PMR symptoms persist despite treatment with corticosteroids (e.g., prednisone).

[0290] In another exemplary embodiment, the subject requiring it has a diagnosis of PMR refractory to steroid tapering before receiving an IL-6R antagonist. In some embodiments, the subject experiences a PMR flare when steroid tapering is attempted. In one exemplary embodiment, the subject is refractory to corticosteroid (e.g., prednisone) tapering and experiences a PMR flare when corticosteroid (e.g., prednisone) tapering is attempted.

[0291] In another embodiment, “the subject who needs it” is a subject whose PMR is not adequately controlled with steroids. In yet another embodiment, “the subject who needs it” is a subject whose PMR is not adequately controlled with corticosteroids (e.g., prednisone). In some embodiments, “the subject who needs it” is a subject for whom steroids are not recommended (i.e., the subject is experiencing adverse effects associated with steroids or is receiving a drug therapy that cannot be combined with steroid therapy). In some embodiments, “the subject who needs it” is a subject for whom corticosteroids (e.g., prednisone) are not recommended (i.e., the subject is experiencing adverse effects associated with corticosteroids (e.g., prednisone) or is receiving a drug therapy that cannot be combined with corticosteroids (e.g., prednisone).

[0292] In a further exemplary embodiment, “the subject requiring it” is a subject for whom steroids are not medically recommended (i.e., the subject has an allergy, a history of adverse reactions, or other medical history for which steroid administration is not recommended). In an exemplary embodiment, the subject is a subject for whom corticosteroids (e.g., prednisone) are not medically recommended (i.e., the subject has an allergy, a history of adverse reactions, or other medical history for which corticosteroids (e.g., prednisone) administration is not recommended).

[0293] In a further exemplary embodiment, the “subject requiring it” is a subject that has had an inadequate response to one or more steroids. In an exemplary embodiment, the subject is a subject that has had an inadequate response to a corticosteroid (e.g., prednisone).

[0294] In a further exemplary embodiment, the subject who needs it is a subject who cannot tolerate steroid tapering. In an exemplary embodiment, the subject is a subject who cannot tolerate corticosteroid tapering (e.g., prednisone tapering).

[0295] In a further exemplary embodiment, “the subject requiring it” is a subject that has an inadequate response to steroids and / or cannot tolerate steroid tapering. In an exemplary embodiment, the subject is a subject that has an inadequate response to corticosteroids (e.g., prednisone) and / or cannot tolerate corticosteroid tapering (e.g., prednisone tapering).

[0296] In some exemplary embodiments, the subjects requiring it are at least 50 years old. In exemplary embodiments, the subjects are older than 50 years old. In other exemplary embodiments, the subjects have bilateral shoulder pain. In yet another exemplary embodiment, the subjects have C-reactive protein (CRP) levels greater than 10 mg / L and / or erythrocyte sedimentation rate (ESR) greater than 30 mm / hour. In some exemplary embodiments, the subjects have morning stiffness. In another exemplary embodiment, the subjects have no affected joints other than the shoulder joint. In yet another exemplary embodiment, the subjects have hip pain or limited range of motion. In some exemplary embodiments, the subjects are seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP). In another exemplary embodiment, the subjects have at least one shoulder with subdeltoid bursitis and / or biceps tendonitis and / or posterior or axillary shoulder joint synovitis, and at least one hip with synovitis and / or trochanteric bursitis.

[0297] Methods for evaluating pharmacodynamic PMR-related parameters A method is provided for evaluating one or more pharmacodynamic PMR-related parameters in subjects requiring administration of a pharmaceutical composition containing an IL-6R antagonist, as induced by the administration of the pharmaceutical composition. A reduction in the incidence of PMR symptoms, or improvement in PMR-related PRO or ClinRO scales, may correlate with an improvement in one or more pharmacodynamic PMR-related parameters; however, such correlations are not necessarily observed in all cases.

[0298] Examples of “pharmacodynamic PMR-related parameters” include, for example, (a) biomarker expression levels and (b) analysis of serum proteins and RNA. “Improvement of pharmacodynamic PMR-related parameters” means, for example, a decrease from baseline in one or more levels of IL-6, IL6R, and C-reactive protein (CRP), or a decrease in erythrocyte sedimentation rate (ESR). Where used herein, the term “baseline” refers to the pharmacodynamic PMR-related parameters as described herein. This refers to the numerical values ​​of pharmacodynamic PMR-related parameters in patients before or during administration of the pharmaceutical composition.

[0299] To evaluate pharmacodynamic PMR-related parameters, the parameters are quantified at baseline and after administration of the pharmaceutical composition. For example, pharmacodynamic PMR-related parameters can be measured approximately 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 14 days, or approximately 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, or later, after the initial treatment with the pharmaceutical composition. The difference between the parameter value at a specific point in time after the start of treatment and the parameter value at baseline is used to determine whether there has been a change, e.g., an "improvement" (e.g., an increase or decrease, depending on the specific parameter being measured) in the pharmacodynamic PMR-related parameter.

[0300] In certain embodiments, administration of an IL-6R antagonist to a patient can cause changes in the expression of specific biomarkers, e.g., a decrease or increase. PMR-related biomarkers include, but are not limited to, total IL-6, IL-6R, and C-reactive protein (CRP). For example, administration of an IL-6R antagonist to a PMR patient may cause a decrease in IL-6, IL-6R, or C-reactive protein (CRP) levels. This decrease can be detected approximately 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or later after administration of the IL-6R antagonist. The expression of biomarkers can be assayed by methods known in the art. For example, protein levels can be measured by ELISA (enzyme-linked immunosorbent assay). RNA levels can be measured, for example, by reverse transcription-linked polymerase chain reaction (RT-PCR).

[0301] Biomarker expression can be assayed by detecting proteins or RNA in serum, as discussed above. Serum samples can also be used to monitor for further protein or RNA biomarkers related to responses to treatment with IL-6R antagonists or IL-6 signaling. In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), e.g., the RNA level of a biomarker; in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).

[0302] Interleukin-6 receptor antagonist This disclosure includes a method comprising administering an antibody or an antigen-binding fragment thereof that specifically binds to hIL-6R. As used herein, the term "hIL-6R" means a human cytokine receptor that specifically binds to human interleukin-6 (IL-6). In certain embodiments, the antibody administered to the patient specifically binds to the extracellular domain of hIL-6R.

[0303] As used herein, the term “antibody” refers to an immunoglobulin molecule comprising four polypeptide chains interconnected by disulfide bonds, namely two heavy (H) chains and two light (L) chains, and their polymer (e.g., IgM). Each heavy chain contains a heavy chain variable region (HCVR or V) as used herein. H It includes the heavy chain steady region (abbreviated as C). The heavy chain steady region is C H 1, C H 2 and C H It contains three domains. Each light chain is a light chain Variable region (LCVR or V in this specification) L It includes a light chain constant region (abbreviated as C). The light chain constant region consists of one domain (C L 1) consists of V H and V LThe regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each V H and V L is composed of three CDRs and four FRs, which are arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of an antibody (or antigen-binding portion thereof) may be identical to human germline sequences, or may be naturally or artificially modified. Amino acid consensus sequences can be defined based on parallel analysis of two or more CDRs.

[0304] The term "antibody", as used herein, also includes antigen-binding fragments of intact antibody molecules. Terms such as "antigen-binding portion of an antibody" and "antigen-binding fragment of an antibody", as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from intact antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques, including, for example, the manipulation and expression of DNA encoding the variable domains and optionally constant domains of an antibody. Such DNA is known and / or is readily available from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. For example, DNA can be sequenced and manipulated chemically or using molecular biology techniques to modify, add or delete amino acids, to arrange one or more variable and / or constant domains in a suitable configuration, to introduce codons, or to create cysteine residues.

[0305] 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 mimicking the hypervariable region of an antibody (e.g., isolated complementarity-determining regions (CDRs), e.g., CDR3 peptides) or a constrained FR3-CDR3-FR4 peptide. Other manipulated molecules, such as domain-specific antibodies, single-domain antibodies, domain deletion antibodies, chimeric antibodies, CDR graft antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies and divalent nanobodies), small molecule modular immunotherapy drugs (SMIPs), and shark variable IgNAR domains, also fall within the scope of the expression “antigen-binding fragment” as used herein.

[0306] The antigen-binding fragment of an antibody typically contains at least one variable domain. The variable domain may be of any size or amino acid composition and generally contains at least one CDR adjacent to or within one or more framework sequences. L V associated with the domain H In an antigen-binding fragment having a domain, V H and V L The domains may be positioned in any suitable arrangement relative to each other. For example, the variable region may be a dimer, V H -V H , V H -V L or V L -V L It may contain a dimer. Alternatively, the antigen-binding fragment of the antibody may be a monomer V H or V L It may contain a domain.

[0307] In certain embodiments, the antigen-binding fragment of the antibody may include at least one variable domain covalently bound to at least one constant domain. Non-limiting exemplary configurations of variable and constant domains that can be found within the antigen-binding fragment of the antibody include (i)VH -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 -CL;(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 This includes. In any configuration of variable and constant domains, including any of the exemplary configurations described above, the variable and constant domains may be directly linked to each other or linked by a complete or partial hinge or linker region. The hinge region may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids so that a mobile or semi-mobile binding occurs between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, the antigen-binding fragment of the antibody may, in various embodiments, be linked to each other and / or one or more monomers V H Or V LThe material may also contain homodimers or heterodimers (or other polymers) of either the variable domain or the constant domain configuration described above, which are non-covalently bonded to the domain (for example, by disulfide bonds).

[0308] In certain embodiments, the antibody or antibody fragment for use in the methods disclosed herein may be a monospecific antibody. In certain embodiments, the antibody or antibody fragment for use in the methods disclosed herein may be a multispecific antibody, which may be specific to a different epitope of one target polypeptide, or may contain antigen-binding domains specific to epitopes of two or more target polypeptides. An exemplary bispecific antibody format that may be used in connection with a particular embodiment is a first immunoglobulin (Ig) C H 3 domains and 2nd Ig C H This involves the use of three domains, where the first and second Ig C H The three domains differ from each other in at least one amino acid, and this difference in at least one amino acid reduces the binding of the bispecific antibody to protein A compared to a bispecific antibody lacking amino acid differences. In one embodiment, the first Ig C H The 3 domains bind to protein A, and the second Ig C H The 3 domains contain mutations that reduce or eliminate protein A binding, such as the H95R modification (according to IMGT exon numbering; H435R according to EU numbering). Second C H 3 may further include Y96F modification (by IMGT; Y436F by EU). Second C HFurther modifications that may be found within 3 include: D16E, L18M, N44S, K52N, V57M, and V82I for IgG1 antibodies (according to IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU); N44S, K52N, and V82I for IgG2 antibodies (according to IMGT; N384S, K392N, and V422I by EU); and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I for IgG4 antibodies (according to IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU). Modifications of the bispecific antibody formats described above are conceivable within the scope of certain specific embodiments. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be adapted in various embodiments for use in relation to an antigen-binding fragment of an anti-IL-6R antibody using conventional methods available in the art.

[0309] The fully human anti-IL-6R antibodies disclosed herein may include one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR region of the heavy and light chain variable domains compared to the corresponding germline sequence. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with germline sequences available, for example, from publicly available antibody sequence databases. This disclosure includes antibodies derived from any of the amino acid sequences disclosed herein, and their antigen-binding fragments, wherein one or more amino acids in the framework and / or CDR region are reverse-mutated to the corresponding germline residue, or to a conserved amino acid substitution (natural or unnatural) of the corresponding germline residue (such sequence changes are referred to herein as “germline reverse mutations”). Those skilled in the art will be familiar with the information disclosed herein. Starting from the shown heavy and light chain variable region sequences, a large number of antibody and antigen-binding fragments containing one or more individual germline reverse mutations or combinations thereof can be easily constructed. In a particular embodiment, V H and / or V L All framework residues and / or CDR residues within a domain are reverse-mutated to germline sequences. In other embodiments, only specific residues are reverse-mutated to germline sequences, for example, only mutated residues found in the first eight amino acids of FR1 or the last eight amino acids of FR4, or only mutated residues found in CDR1, CDR2, or CDR3. Furthermore, antibodies that may contain any combination of two or more germline reverse mutations within the framework and / or CDR regions, i.e., antibodies in which specific individual residues are reverse-mutated to germline sequences, while certain other residues that are not germline sequences are maintained, are also included herein. Once obtained, antibodies and antigen-binding fragments containing one or more germline reverse mutations can be easily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced (in some cases) of the biological properties of the antagonist or agonist, or decreased immunogenicity. Antibodies and antigen-binding fragments obtained by this general method are included within the scope of this disclosure.

[0310] The constant region of an antibody is crucial for its ability to bind to complement and mediate cell-dependent cytotoxicity. Therefore, antibody isotypes can be selected based on whether or not it is desirable for the antibody to mediate cytotoxicity.

[0311] As used herein, the term “human antibody” is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, the human antibodies characterized in this disclosure may, in various embodiments, include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutation in vivo), such as CDRs and, in some embodiments, CDR3. 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, such as mouse, have been transplanted into a human framework sequence.

[0312] As used herein, the term “recombinant human antibody” is intended to include all human antibodies prepared, expressed, produced or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into host cells (as further described below), antibodies isolated from a recombinant combinatorial human antibody library (as further described below), antibodies isolated from an animal transgenic to a human immunoglobulin gene (e.g., mouse), or antibodies prepared, expressed, produced or isolated by any other means involving splicing of the human immunoglobulin gene sequence to another DNA sequence. Such recombinant human antibodies have a variable region and a constant region derived from a human germline immunoglobulin sequence. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or in vivo somatic mutagenesis if an animal transgenic to a human Ig sequence is used), and therefore the V of the recombinant antibody H and V L The amino acid sequence of the region is human germline V H and V L Although derived from and related to the sequence, it is a sequence that does not naturally exist in the human antibody germline repertoire in vivo.

[0313] Human antibodies can exist in two forms related to the heterogeneity of the hinge. In one embodiment, the immunoglobulin molecule comprises a stable quad-chain construct of about 150–160 kDa, in which the dimer is held together by interchain heavy-chain disulfide bonds. In another embodiment, the dimer is not linked via interchain disulfide bonds and is of about 75–80 kDa. The molecule is formed from covalently bonded light and heavy chains (half-antibodies). In certain embodiments, these forms were extremely difficult to separate, even after affinity purification.

[0314] The frequency of occurrence of the second form in various intact IgG isotypes is attributable to structural differences related to the hinge region isotype of the antibody, but is not limited to these differences. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the occurrence of the second form to the level typically observed using the human IgG1 hinge. In various embodiments of this disclosure, the hinge, C H 2 or C H The range includes antibodies having one or more mutations in three regions, and these mutations may be desirable, for example, to improve the yield of the desired antibody form during production.

[0315] As used herein, “isolated antibody” means an antibody that has been identified and isolated and / or recovered from at least one component of its natural environment. For example, an antibody isolated or withdrawn from at least one component of an organism, or from a tissue or cell in which antibodies are naturally present or 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 subjected to at least one purification or isolation step. In various embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0316] Terms such as "specifically bind" mean that the antibody or its antigen-binding fragment forms a complex with an antigen that is relatively stable 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 and surface plasmon resonance. For example, as used herein, an antibody that "specifically binds" to IL-6R is one with a K content of less than approximately 1000 nM, less than approximately 500 nM, less than approximately 300 nM, less than approximately 200 nM, less than approximately 100 nM, less than approximately 90 nM, less than approximately 80 nM, less than approximately 70 nM, less than approximately 60 nM, less than approximately 50 nM, less than approximately 40 nM, less than approximately 30 nM, less than approximately 20 nM, less than approximately 10 nM, less than approximately 5 nM, less than approximately 4 nM, less than approximately 3 nM, less than approximately 2 nM, less than approximately 1 nM, or about 0.5 nM of K. D in, The present invention comprises an antibody that binds to IL-6R (e.g., human IL-6R) or a portion thereof. In some embodiments, the antibody has a K content of about 0.1 nM to about 1000 nM or about 1 nM to about 100 nM. D Then, it binds to IL-6R (e.g., human IL-6Rα). In some embodiments, the antibody is K at approximately 1 pM to 100 pM or approximately 40 pM to 60 pM. D It then binds to IL-6R (for example, human IL-6Rα). Furthermore, it achieves specific binding at least approximately 1 × 10⁻⁶ times. -6 It can also be characterized by a dissociation constant of M or less. In other embodiments, the dissociation constant is at least about 1 × 10⁻⁶. -7 M, 1×10 -8 M, or 1 × 10 -9 M is the case. However, isolated antibodies that specifically bind to human IL-6R may exhibit cross-reactivity to other antigens, such as IL-6R molecules from other (non-human) species.

[0317] As used herein, the term "surface plasmon resonance" refers to an optical phenomenon that enables real-time interaction analysis by detecting changes in protein concentration within a biosensor matrix, for example, using the BIACORE® system (Biacore Life Sciences division, GE Healthcare, Piscataway, NJ).

[0318] "K D When used herein, the term "equilibrium dissociation constant of antibody-antigen interactions" is intended to refer to the equilibrium dissociation constant of antibody-antigen interactions.

[0319] The term "epitope" refers to a specific region within the variable area of ​​an antibody molecule, known as a paratope. An epitope refers to an antigenic determinant that interacts with a heteroantigen-binding site. A single antigen may have multiple epitopes. Therefore, different antibodies may bind to different regions on one antigen and 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. Linear epitopes are produced by adjacent amino acid residues in a polypeptide chain. In certain circumstances, epitopes can include sugar, phosphoryl, or sulfonyl groups on the antigen.

[0320] Anti-IL-6R antibodies useful in the methods described herein may, in various embodiments, include one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR region of the heavy and light chain variable domains compared to the corresponding germline sequence from which the antibody is derived. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with germline sequences available, for example, from publicly available antibody sequence databases. In various embodiments, this disclosure includes methods involving the use of an antibody derived from one of the amino acid sequences disclosed herein, and its antigen-binding fragment, wherein one or more amino acids in the framework and / or CDR region are mutated to a corresponding residue in the germline sequence from which the antibody is derived, or a corresponding residue in another human germline sequence, or a conserved amino acid substitution of a corresponding germline residue (such sequence changes are collectively referred to herein as “germline mutations”). A number of antibodies and antigen-binding fragments containing one or more individual germline mutations or combinations thereof can be constructed. In certain embodiments, V H and / or V LIn other embodiments, all of the framework and / or CDR residues within the domain are reversed to residues found in the original germline sequence from which the antibody originated. In other embodiments, only specific residues are reversed to the original germline sequence. For example, only mutated residues found in the first eight amino acids of FR1 or the last eight amino acids of FR4, or only mutated residues found in CDR1, CDR2, or CDR3 are reversed. In other embodiments, one or more framework and / or CDR residues are mutated to corresponding residues in a different germline sequence (i.e., a germline sequence different from the original germline sequence from which the antibody originated). Furthermore, the antibody may contain any combination of two or more germline mutations within the framework and / or CDR region, for example, by mutating specific individual residues to corresponding residues in a specific germline sequence, while maintaining or mutating other specific residues that are different from the original germline sequence to corresponding residues in a different germline sequence. Once obtained, antibody and antigen-binding fragments containing one or more germ cell mutations can be readily tested for one or more desired properties, such as improved binding specificity, increased binding affinity, improved or enhanced (in some cases) of the biological properties of the antagonist or agonist, or decreased immunogenicity. The use of antibody and antigen-binding fragments obtained by this general method is included in the scope of this disclosure.

[0321] The Disclosure also includes methods involving the use of an anti-IL-6R antibody comprising a variant of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the Disclosure includes the use of an anti-IL-6R antibody comprising an HCVR, LCVR, and / or CDR amino acid sequence having, for example, 10 or fewer, 8 or fewer, 6 or fewer, or 4 or fewer conservative amino acid substitutions compared to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0322] According to this disclosure, the anti-IL-6R antibody or its antigen-binding fragment includes, in various embodiments, a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR), which include one of the amino acid sequences of the anti-IL-6R antibody 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 its antigen-binding fragment comprises a heavy chain complementarity-determining region (HCDR) of the HCVR containing the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity-determining region (LCDR) of the LCVR containing the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), where HCDR1 contains the amino acid sequence of SEQ ID NO: 3, HCDR2 contains the amino acid sequence of SEQ ID NO: 4, HCDR3 contains the amino acid sequence of SEQ ID NO: 5, LCDR1 contains the amino acid sequence of SEQ ID NO: 6, LCDR2 contains the amino acid sequence of SEQ ID NO: 7, and LCDR3 contains the amino acid sequence of SEQ ID NO: 8. In yet another embodiment, the anti-IL-6R antibody or its antigen-binding fragment comprises an HCVR containing the amino acid sequence of SEQ ID NO: 1 and an LCVR containing the amino acid sequence of SEQ ID NO: 2.

[0323] In another embodiment, the anti-IL-6R antibody or its antigen-binding fragment comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10. In some embodiments, the extracellular domain of hIL-6R contains the amino acid sequence of SEQ ID NO: 11. According to certain exemplary embodiments, the method of the present disclosure involves the use of an anti-IL-6R antibody or its bioequivalent, referred to as sarilumab, which is known in the art.

[0324] The amino acid sequence of Sequence ID No. 1 is: [ka] (CDR numbering is highlighted; IMGT numbering is bold; Kabat numbering is underlined; Chothia numbering is italicized).

[0325] The amino acid sequence of Sequence ID No. 2 is: [ka] (CDR numbering is highlighted; IMGT numbering is bold; Kabat numbering is underlined; Chothia numbering is italicized).

[0326] The amino acid sequence of sequence number 3 is RFTFDDYA (CDR-H1 according to IMGT numbering).

[0327] The amino acid sequence of sequence number 4 is ISWNSGRI (CDR-H2 according to IMGT numbering).

[0328] The amino acid sequence of sequence number 5 is AKGRDSFDI (CDR-H3 according to IMGT numbering).

[0329] The amino acid sequence of sequence number 6 is QGISSW (CDR-L1 according to IMGT numbering).

[0330] The amino acid sequence of sequence number 7 is GAS (CDR-L2 according to IMGT numbering). .

[0331] The amino acid sequence of sequence number 8 is QQANSFPYT (CDR-L3 according to IMGT numbering).

[0332] The amino acid sequence of sequence number 9 is: [ka] (CDR numbering is highlighted; IMGT numbering is bold; Kabat numbering is underlined; Chothia numbering is italicized).

[0333] The amino acid sequence of sequence number 10 is: [ka] (CDR numbering is highlighted; IMGT numbering is bold; Kabat numbering is underlined; Chothia numbering is italicized).

[0334] The amino acid sequence of sequence number 11 is: MVAVGCALLAALLAAPGAALAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLA VPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITTVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTNKDDDNILFRDSANATSLPVQD That is the case.

[0335] According to this disclosure, the anti-IL-6R antibody or its antigen-binding fragment includes, in various embodiments, a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR), which include one of the amino acid sequences of the anti-IL-6R antibody described in U.S. Patent No. 7,521,052, which is incorporated herein by reference in its entirety. The hybridoma cell line producing cilizumab (TCZ) was internationally deposited as FERM BP-2998 at the International Patent Organism Depository (AIST Tsukuba Central 6,1-1,Higashi 1-chome,Tsukuba-shi,Ibaraki Pref.) on July 12, 1989, under the Budapest Convention. In certain embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (HCDR) and / or light chain complementarity-determining region (LCDR) of HCVR containing the amino acid sequence of SEQ ID NO: 13, and a light chain complementarity-determining region (LCDR) of LCVR containing the amino acid sequence of SEQ ID NO: 12. In a particular embodiment, the anti-IL-6R antibody or its antigen-binding fragment comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), where 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 its antigen-binding fragment 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.

[0336] In another embodiment, the anti-IL-6R antibody or its antigen-binding fragment comprises a heavy chain containing the amino acid sequence of the heavy chain of TCZ and a light chain containing 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. In certain exemplary embodiments, the method of the present disclosure comprises the use of an anti-IL-6R antibody or its bioequivalent, referred to as tocilizumab, which is known in the art.

[0337] The amino acid sequence of sequence number 12 is: DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC That is the case.

[0338] The amino acid sequence of sequence number 13 is: VQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQG SLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG That is the case.

[0339] The amino acid sequence of sequence number 14 is RASQDISSYLN.

[0340] The amino acid sequence of sequence number 15 is YTSRLHS.

[0341] The amino acid sequence of sequence number 16 is QQGNTLPYT.

[0342] The amino acid sequence of sequence number 17 is SDHAWS.

[0343] The amino acid sequence of sequence number 18 is YISYSGITTYNPSLK.

[0344] The amino acid sequence of sequence number 19 is SLARTTAMDY.

[0345] As used herein, the term “bioequivalence” refers to a molecule that, after administration at the same molar dose under similar conditions (e.g., the same route of administration), exhibits comparable bioavailability (rate and degree of availability), and as a result, can be expected to have essentially the same efficacy and safety as a comparator molecule. Two pharmaceutical compositions containing an anti-IL-6R antibody are bioequivalent if they are pharmaceutically equivalent, meaning they contain the same amount of active ingredient (e.g., IL-6R antibody) in the same dosage form for the same route of administration and meet the same or equivalent criteria. Bioequivalence can be determined, for example, by an in vivo study comparing the pharmacokinetic parameters of the two compositions. Parameters commonly used in bioequivalence studies include the maximum plasma concentration (Cmax) and the area under the plasma drug concentration-time curve (AUC).

[0346] Disclosure in a particular embodiment relates to a method of administering an antibody comprising a heavy chain variable region including SEQ ID NO: 1 and a light chain variable region including SEQ ID NO: 2.

[0347] This disclosure provides pharmaceutical compositions comprising such antibodies, and methods for using these compositions.

[0348] In various embodiments, the antibody comprises a heavy chain variable region containing SEQ ID NO: 1 and a light chain variable region containing SEQ ID NO: 2, and is an antibody that specifically binds to the human interleukin-6 receptor (hIL-6R). See International Publication No. WO2007 / 143168, the entirety of which is incorporated herein by reference. In one embodiment, the antibody comprises a heavy chain variable region containing SEQ ID NO: 9 and a light chain variable region containing SEQ ID NO: 10. In various embodiments, the antibody is sarilumab, also known by the trade name KEVZARA®. [Examples]

[0349] A randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of sarilumab in patients with polymyalgia rheumatica (NCT03600818, EFC15160, Phase 3). material and method Number of testing facilities and countries A total of 70 sites enrolled at least one participant, and at least one participant was randomized from 60 of these sites. The sites were located in 17 countries (Australia, Argentina, Belgium, Canada, Estonia, France, Germany, Hungary, Israel, Italy, Japan, Netherlands, Russia, Spain, Switzerland, the United Kingdom, and the United States).

[0350] Argument The EFC15160 trial was a 52-week double-blind, placebo-controlled, randomized trial to evaluate the efficacy and safety of sarilumab in patients with active polymyalgia rheumatica (PMR). This study was designed as a trial. The 52-week trial treatment period reflected the usual duration and standard therapy required to ensure sustained remission in the majority of PMR patients (therefore, the primary endpoint, sustained remission, was at week 52). The ability to rapidly tape off CS within 14 weeks of the start of therapy (in contrast to the usual tapering regimen of one year or more) while maintaining disease remission represents a clinically significant benefit compared to usual care.

[0351] the purpose Main purpose The efficacy of sarilumab in patients with post-symptomatic remission (PMR) will be evaluated by comparing a regimen of sarilumab combined with 14 weeks of corticosteroid (CS) tapering with a regimen of placebo combined with 52 weeks of CS tapering, and by assessing the proportion of patients who maintained remission at week 52.

[0352] Secondary purpose In patients with PMR, the efficacy of sarilumab (with 14 weeks of CS tapering) will be demonstrated compared to placebo (with 52 weeks of CS tapering) in the following respects: clinical response over time (e.g., components of sustained remission, disease remission rate, and time to first disease flare) and cumulative exposure to corticosteroids (including prednisone).

[0353] To evaluate the safety (including immunogenicity) and tolerability of sarilumab in patients with PMR.

[0354] Measure the serum sarilumab concentration in PMR patients.

[0355] The effect of sarilumab on reducing glucocorticoid toxicity will be evaluated using the Combined Glucocorticoid Toxicity Index (GTI) questionnaire.

[0356] exploratory purpose To evaluate the effect of sarilumab on physician assessment of disease activity as measured by a visual analog scale (MD-VAS).

[0357] To evaluate the effects of sarilumab on various PRO concepts, including fatigue (measured by the FACIT-Fatigue scale), health status (measured by EQ-5D-3L and SF-36v2), physical function (measured by HAQ-DI), pain (measured via HAQ-DI and visual analog scale [VAS]), and patient assessment of disease activity (measured via HAQ-DI and VAS).

[0358] To evaluate the impact of ESR / CRP levels on remission.

[0359] To characterize disease activity in PMR patients undergoing steroid tapering or sarilumab treatment in a subset of patients using a comprehensive approach to assess circulating immune cell types.

[0360] To characterize disease activity in PMR patients undergoing steroid tapering or sarilumab treatment by evaluating circulating proteins, genetics, and gene expression in patients who consent to this voluntary selection portion of the study.

[0361] Test design This study was a 52-week, multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of sarilumab in patients with active PMR. Ta.

[0362] As shown in Figure 1, active PMR patients who met the participation criteria were randomly assigned to one of two parallel treatment groups, each receiving either sarilumab 200 mg or placebo in combination with a protocol-specified 14-week or 52-week CS tapering regimen in a 1:1 ratio: Group 1: sarilumab 200 mg q2w and 14-week CS tapering; Group 2: placebo corresponding to sarilumab q2w and 52-week CS tapering. All patients received either sarilumab 200 mg or placebo for 52 weeks.

[0363] All patients received prednisone treatment (CS tapering) with different regimens depending on their assigned group. Prior to randomization and the initiation of the study treatment, corticosteroid therapy was optimized to minimize the risk of serious adverse events associated with corticosteroid tapering. The initial dose of prednisone in both groups was 15 mg / day for the first two weeks after randomization, followed by prednisone and / or a placebo equivalent to prednisone to ensure the double-blind CS tapering regimen described below.

[0364] Group 1: From week 2 to week 13, patients received prednisone at gradually decreasing dose levels (from prednisone or a combination of prednisone and placebo to prednisone). From week 14 onward, patients without flare received a placebo equivalent to prednisone.

[0365] Group 2: From week 2 to week 51, patients received prednisone at gradually decreasing dose levels (prednisone or prednisone in combination with placebo).

[0366] At each facility visit, the patient's condition was assessed, and it was determined whether the patient could adhere to the prednisone tapering schedule specified in the protocol. During the first 12 weeks of prednisone tapering, if treatment with a low-dose (5 mg / day or less) additional prednisone tapering regimen (completed before week 12) was successful and all other sustained remission parameters were met, treatment for one flare was permitted.

[0367] For patients who experienced a disease flare during the study period and required rescue therapy (such as corticosteroids) at the discretion of the principal investigator, sarilumab or the corresponding placebo may be continued in a double-blind manner for the entire 52-week treatment period, provided that corticosteroids were used as rescue therapy. Treatment with non-biological immunosuppressants (e.g., alkylating agents, hydroxychloroquine, CsA, MMF, AZA) was not permitted during the study period except when used for rescue therapy.

[0368] During the study period, corticosteroids were the first-line treatment for patients requiring rescue therapy at the discretion of the principal investigator. Patients were allowed to continue sarilumab or the corresponding placebo (sarilumab) only if they were using CS as rescue therapy. If a patient's symptoms persisted despite CS rescue therapy, other treatment options, including nonbiological immunosuppressants, may be used (patients must have symptomatic PMR disease), and such patients were discontinued from the study and considered non-responders.

[0369] The total duration of study participation for each patient was a maximum of 62 weeks; the screening period was a maximum of 4 weeks, the treatment period a maximum of 52 weeks, and the post-treatment follow-up period a maximum of 6 weeks. The last patient's final visit was when the last patient completed the 52-week double-blind treatment period and the 6-week follow-up period (13th visit / end of study (EOS)). The end of the clinical trial was defined as the last patient's final visit. The event schedule is shown in Table 1 below.

[0370] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0371] The exam ended early, but this was due to the global COVID-19 pandemic, which affected the recruitment schedule. This was due to the prolonged duration of the treatment. Approximately 118 patients who met the eligibility criteria were enrolled and randomly assigned to one of two parallel groups, receiving either sarilumab 200 mg q2w with 14 weeks of tapered prednisone (Group 1) or a placebo equivalent to sarilumab with 52 weeks of tapered prednisone (Group 2) in a 1:1 ratio. As shown in Table 2, 117 of the 118 randomized patients received treatment.

[0372] [Table 2]

[0373] Examination Committee When ultrasound was used to diagnose PMR and determine patient eligibility, a group of rheumatologists specializing in the performance and interpretation of shoulder and hip diagnostic ultrasounds reviewed the ultrasound images to confirm the diagnosis. Furthermore, rheumatologists from the same group assisted in the accreditation of facilities wishing to offer the option of using ultrasound to diagnose patients with PMR.

[0374] Inclusion Criteria Informed consent in writing with signatures.

[0375] The following are the European League against Rheumatism / American College of Rheumatology Diagnosis of PMR according to the Rheumatology (EULAR / ACR) classification criteria (all criteria must be met): a) age 50 years or older at diagnosis, b) bilateral shoulder pain, and elevated acute-phase reaction substances (CRP greater than 10 mg / L and / or ESR greater than 30 mm / hour).

[0376] In addition, one of the following: - A diagnostic score of 4 or higher (excluding ultrasound) based on the following: Morning stiffness lasting more than 45 minutes: 2 points; Hip pain or limited range of motion: 1 point; Seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP): 2 points; and no other affected joints: 1 point; or - A diagnostic score of 5 or higher (excluding ultrasound) based on the following: Morning stiffness lasting more than 45 minutes: 2 points; Hip pain or limited range of motion: 1 point; Seronegative for RF and anti-CCP: 2 points; and no other affected joints: 1 point; At least one shoulder with subdeltoid bursitis and / or biceps tendonitis and / or shoulder joint synovitis (posterior or axillary), and a small shoulder with synovitis and / or trochanteric bursitis. One hip joint (even if absent): 1 point (confirmed by ultrasound); both shoulders with subdeltoid bursitis, biceps tendonitis, or shoulder joint synovitis: 1 point (confirmed by ultrasound).

[0377] Patients must be receiving prednisone at a dose of at least 7.5 mg / day (or equivalent) and no more than 20 mg / day at the time of screening and during the screening period.

[0378] Patients must be willing and able to receive 15 mg / day of prednisone at the time of randomization.

[0379] Patients must have a history of receiving treatment with 10 mg / day or more of prednisone or an equivalent for at least 8 weeks.

[0380] Patients must have experienced at least one episode of a clear PMR flare within 12 weeks prior to screening while attempting tapering of prednisone at 7.5 mg / day or equivalent. A clear PMR flare is defined as shoulder and / or pelvic girdle pain accompanied by inflammatory stiffness.

[0381] Patients must have an ESR of 30 mm / hour or higher, or a CRP of 10 mg / L or higher, within 12 weeks prior to screening, in relation to PMR disease activity.

[0382] Exclusion criteria Patients who met all of the above inclusion criteria were screened against the following exclusion criteria.

[0383] Diagnosis of giant cell arteritis (GCA) (e.g., persistent or recurrent focal headache, tenderness of the temporal artery or scalp, jaw claudication, limb claudication, blurred vision or visual impairment, symptoms of stroke).

[0384] 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.

[0385] Simultaneous diagnosis of rhabdomyolysis or neuropathic muscle disease.

[0386] Simultaneous diagnosis of active fibromyalgia.

[0387] Inadequately treated hypothyroidism.

[0388] Organ transplant recipient.

[0389] A history of or concurrent use of immunosuppressive therapy (within the periods specified below), including but not limited to the following: Janus kinase (JAK) inhibitors within 4 weeks from baseline (e.g., tofacitinib); cell depletion agents for which there is no evidence of B cell recovery to baseline levels (e.g., anti-CD20); anakinra within 1 week from baseline; abatacept within 8 weeks from baseline; tumor necrosis factor (TNF) inhibitors within 2 to 8 weeks (etanercept within 2 weeks, infliximab, certolizumab, golimumab, or adalimumab) or after at least 5 half-lives, whichever is longer; alkylating agents including cyclophosphamide (CYC) within 6 months from baseline; and cyclosporine (CsA), azathioprine (AZA), mycophenolate mofetil (MMF), or leflunomide within 4 weeks from baseline.

[0390] Treatment failure, including inadequate response, intolerance, or contraindication to a biological IL-6 antagonist (previous IL-6 antagonist treatments terminated for reasons unrelated to treatment failure at least 3 months prior to baseline are not excluded).

[0391] Unstable methotrexate (MTX) dose and / or MTX dose exceeding 15 mg / week within 3 months from baseline.

[0392] Concurrent use of systemic CS for conditions other than PMR.

[0393] Participation in a clinical study evaluating the investigational drug or treatment within 5 half-lives or 60 days, whichever is longer, from the screening visit.

[0394] A history of alcohol or drug abuse within the five years prior to the screening visit.

[0395] Patients who withdrew their consent during the screening period (after signing informed consent).

[0396] Unable to complete or unwilling to complete the Patient-Reported Outcome (PRO) Questionnaire.

[0397] Patients meeting any of the following conditions / circumstances: patients with a short estimated life expectancy; conditions / comorbidities that make efficacy evaluation impossible (e.g., patients with chronic pain); patients who are the principal investigator, clinical investigator, research assistant, pharmacist, study coordinator, other staff or their relatives, or, where applicable, employees of the study site / principal investigator or sponsor; patients who are uncooperative or in a situation where they may not comply with study procedures, and those confined to the facility by regulatory or legal orders.

[0398] Pregnant or breastfeeding women.

[0399] Women of childbearing age (WOCBP) who are not protected by highly effective contraception and / or women who are unwilling or unable to take a pregnancy test.

[0400] Exclusions related to tuberculosis (TB) Regardless of the results of the screening QuantiFERON test, the patient has active TB or a history of TB that was not fully treated.

[0401] Patients who test positive for QuantiFERON (without active disease) will be excluded from the study unless they meet the following conditions: they have a record of completing chemoprevention for latent tuberculosis infection (e.g., acceptable treatment including isoniazid 300 mg orally once daily for 9 months or an equivalent proven regimen, in accordance with local guidelines), or they have been treated for active tuberculosis infection (TBI) and have been consulted by a specialist who has determined that they do not have active TBI and do not require further treatment; they have never received chemoprevention for latent TBI or treatment for active TBI, but have been consulted by a specialist to initiate an appropriate chemoprevention regimen based on local epidemiology and applicable guidelines and have demonstrated compliance and tolerance to the treatment for at least one month; or, in any of the above scenarios, patients require consultation and prior approval from the sponsor.

[0402] Clinically significant abnormalities consistent with a history of / active TB infection, based on chest X-rays with at least posterior-anterior views. Additional lateral views are recommended but not required.

[0403] Regardless of the results of the screening QuantiFERON test, extrapulmonary TB infection is suspected.

[0404] Patients at high risk of contracting TB, such as those with close contact with individuals who have active or latent TB.

[0405] Patients who received the Bacille Calmette Guerin vaccine within 12 months prior to screening.

[0406] Other exclusion criteria Patients with a history of invasive opportunistic infections, including but not limited to histoplasmosis, listeriosis, coccidioidomycosis, candidiasis, Pneumocystis jirovecii infection, aspergillosis (even after recovery), or John Cunningham virus (progressive multifocal leukoencephalopathy).

[0407] Patients who have developed a chronic, persistent, or recurrent infection with fever (above 38°C) associated with an infection and who required aggressive treatment with antibiotics, antiviral drugs, or antifungal drugs within four weeks prior to the screening visit, or patients who have developed other frequent recurrent infections that are deemed unacceptable by the principal investigator.

[0408] Patients with poorly controlled diabetes, defined as those with glycated hemoglobin (HbA1c) levels of 9% or higher at the time of their screening visit.

[0409] Patients with skin ulcers that have not healed or are in the healing process.

[0410] Patients who received any attenuated live vaccine, such as varicella-zoster vaccine, oral polio vaccine, or rubella vaccine, within three months prior to their baseline visit.

[0411] Patients who are positive for hepatitis B surface antigen (HBsAg) at the time of screening, or who are positive for hepatitis B core antibody (HBcAb) and negative for hepatitis B surface antibody (HBsAb), or who are positive for both HBcAb and HBsAb and have the presence of HBV DNA.

[0412] Patients who test positive for hepatitis C antibody (HCV Ab).

[0413] Patients who tested positive for human immunodeficiency virus (HIV) antibodies at the time of screening, patients who previously tested positive for HIV antibodies, or patients suspected of being HIV-positive.

[0414] Patients with a history of recurrent herpes zoster or active herpes zoster.

[0415] Patients with a history of joint or prosthetic joint infection.

[0416] Patients with a history or current medical history of malignant tumors, including lymphoproliferative disorders, other than appropriately treated cervical carcinoma in situ, non-metastatic squamous cell carcinoma of the skin, or basal cell carcinoma, within the five years prior to their baseline visit.

[0417] Patients with a history or current medical condition of other serious complications that the principal investigator believes may adversely affect their participation in this study. This includes cardiovascular disease (including stage III or IV heart failure according to the New York Heart Association classification), renal disease, neurological disorders (including demyelinating diseases), and activity-related illnesses. This includes, but is not limited to, sexually transmitted infections, endocrine disorders, gastrointestinal disorders, hepatobiliary disorders, metabolic disorders, lung diseases, non-malignant lymphoproliferative disorders, or other lymphoid disorders.

[0418] Patients who have undergone surgery within four weeks prior to their screening visit, or who have surgery scheduled during the trial period.

[0419] Patients with a history of systemic hypersensitivity reactions other than local injection site reactions to any biological agent, and with known hypersensitivity to any component of sarilumab.

[0420] Patients with any of the following abnormal clinical laboratory values ​​at the time of screening visit: hemoglobin <8.5 g / dL; white blood cell count <3000 / mm³ 3 Neutrophil count < 2000 / mm³ 3 Platelet count <150,000 cells / mm 3 Patients with: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 times the upper limit of normal (ULN); total bilirubin > ULN, except when Gilbert's disease is confirmed by genetic testing; presence of poorly controlled severe 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).

[0421] Patients with a history of inflammatory bowel disease, severe diverticulitis, or gastrointestinal perforation.

[0422] Test treatment Investigational drug products Table 3 shows the details of the investigational drug product (IMP).

[0423] [Table 3]

[0424] formulation Sarilumab preparations are available in doses of 131.6 mg / mL (150 mg) and 175 mg / mL (200 mg). It was provided as a 1.14 ml pre-filled glass syringe containing sarilumab (mg) or placebo SC injection solution. No in-situ preparation was required.

[0425] Route of administration Sarilumab is administered subcutaneously (SC) by a professional or non-professional caregiver to the abdomen, thigh, or upper arm (lateral) during self-injection. It was preferred that SC injection sites alternate between the four quadrants of the abdomen (excluding the navel or lumbar region) or the thigh (anterior and lateral). Each drug administration required one injection.

[0426] Patients and / or their non-specialized caregivers were trained to prepare and administer the study drug at the start of the study. This training was recorded in the study file. Study staff checked the patient's self-administration technique during the second visit (Week 0). For doses not administered at the study site, a logbook was provided to record information about those injections.

[0427] Medication regimen IMP (sarilumab or corresponding placebo) was administered every 14 days according to the protocol's IMP administration schedule; however, in exceptional circumstances (e.g., pending clinical test results, ongoing adverse events, or patient scheduling difficulties), a ±3 day time frame for IMP administration was permitted. Subsequent IMP administrations followed the initial IMP administration schedule again.

[0428] A minimum interval of 11 days was maintained between the two IMP (sarilumab and the corresponding placebo) doses.

[0429] If a patient was unable to attend the trial as scheduled, the patient, a qualified staff member at the trial site, and / or their caregiver administered the dose as described above.

[0430] On the day the patient came to the hospital for the trial, IMP was administered following the examination procedure and blood sampling.

[0431] Patients were monitored for signs or symptoms of medical events for at least 30 minutes (or up to 2 hours, depending on country-specific requirements) after each dose of sarilumab. If injections were administered by a caregiver or self-injection, patients were instructed to monitor themselves for signs or symptoms of medical events. The total treatment period was 52 weeks.

[0432] Dosage change / reduction For the treatment of neutropenia, thrombocytopenia, and / or elevated hepatic transaminases, sarilumab could be reduced to 150 mg q2w under blinded conditions. In addition, temporary discontinuation of sarilumab administration was permitted. Dose reduction and / or temporary discontinuation of sarilumab was determined by the principal investigator.

[0433] Intermediate visits may be required between the scheduled visits specified in the protocol for the distribution of IMP. As an alternative to these visits, if permitted by local regulations and approved for the relevant application, sarilumab or the corresponding placebo may be delivered from the site to the patient via a courier company approved by the clinical trial sponsor.

[0434] The acquisition of sarilumab after the trial was conducted in compliance with all applicable national and local laws and regulations, including safety reporting requirements.

[0435] Prednisone or the corresponding placebo formulation 1 mg and / or 5 mg over-encapsulated tablets or corresponding over-encapsulated placebos.

[0436] Route of administration Prednisone or the corresponding placebo was administered orally.

[0437] Medication regimen All patients received prednisone treatment with different regimens depending on the assigned group. Patients received prednisone and / or a placebo equivalent to prednisone to ensure that the double-blind CS tapering regimen specified below was maintained. The initial dose of prednisone in both groups was 15 mg / day for the first two weeks after randomization.

[0438] For Group 1: From week 2 to week 13, patients received prednisone with gradually reduced doses. From week 14 onward, patients without flare received a placebo equivalent to prednisone.

[0439] Group 2: From week 2 to week 51, patients receive a gradual reduction in the dose of prednisone (from prednisone or prednisone and placebo to prednisone alone).

[0440] Each double-blind prednisone tapering regimen had two phases: Phase 1: For the first two weeks after randomization (from the start of week 0 to the end of week 1), all patients received 15 mg / day of prednisone; and Phase 2: For 50 weeks following Phase 1 (from the start of week 2 to the end of week 51), prednisone and the corresponding placebo were used, maintaining blindness of the tapering regimen in both treatment arms.

[0441] During prednisone tapering, patients were provided with a monthly kit containing a four-week supply of blister packs clearly indicating the number of tablets to be taken per day. The monthly kits and blister packs were numbered, and it was important that the blister packs be used in order, with the patient taking seven days' worth of prednisone from each blister before starting the next blister pack. If a scheduled visit occurred earlier than the target date, the patient was instructed to complete the use of the blister packs assigned to that particular week before using the consecutively numbered blister packs distributed at the scheduled visit. If a tablet was missed or omitted, the patient should restart the blister pack as scheduled without using the missed tablet.

[0442] Patients received training on the use of the prednisone treatment kit and weekly prednisone blister packs upon their baseline visit. This training included instructions on using the blister packs in the correct order and using tablets from the "spare" column if tablets were lost during administration.

[0443] The daily encapsulated dose contained prednisone, placebo, or a combination of both. The number of tablets taken daily varied but did not correspond to the prednisone dose. The number of tablets taken daily may increase or decrease during the tapering schedule, but should not exceed six tablets per day.

[0444] Additional dose of prednisone to tapered off in case of flare within the first 12 weeks. During the first 12 weeks of prednisone tapering, treatment for one flare prior to week 12 was permitted, provided that all other sustained remission parameters were met, if it was deemed that the flare could be successfully managed with a low dose of prednisone (5 mg / day or less) added to the CS tapering regimen. Additional prednisone treatment must be completed by week 12.

[0445] The prednisone supplement for this tapering regimen was provided in an open-label format, consisting of 30 blisters (1 mg each) in a pediatric safety wallet. The dosage of CS (maximum dose (5 mg / day or less)) and the tapering schedule / duration were determined by the principal investigator based on the patient's condition. The amount of tablets to be taken daily was clearly indicated in the wallet and recorded in the eCRF. Patients were monitored and kept in close contact with the facility until the tapering regimen was completed before week 12 to ensure that patients were taking the correct amount of prednisone.

[0446] Non-investigational drug products Prednisone for rescue therapy: If a patient experienced a disease flare or failed to adhere to the protocol-based prednisone tapering schedule, including an additional 5 mg of prednisone, by week 12, the patient had to discontinue the protocol-based prednisone tapering and, at the clinical discretion of the investigator, could instead receive commercially available sarilumab as a form of rescue therapy. The sponsor reimbursed the cost of the commercially available sarilumab. Patients could continue the double-blind period of the study for the entire 52 weeks and, unless contraindicated for safety concerns, could continue blinded sarilumab or corresponding placebo injections to complete the remaining study evaluation. After receiving rescue therapy at the discretion of the investigator, patients were not permitted to return to the protocol-based prednisone tapering regimen.

[0447] Concomitant medications Concomitant medications refer to any treatment a patient receives simultaneously with any IMP (Immune Pulmonary Patch).

[0448] During the study period, the use of biological agents for PMR treatment was not permitted throughout the study treatment period and until 6 weeks after the last dose of sarilumab or the corresponding placebo, unless otherwise specified. If either of these treatments was used, IMP treatment for the patient was discontinued, but the patient continued the study and safety monitoring continued.

[0449] The administration of any live (attenuated) vaccine was contraindicated until 3 months after the last dose of sarilumab or the corresponding placebo.

[0450] Treatment with nonbiological disease-modifying antirheumatic drugs [DMARDs] (alkylating agents, hydroxychloroquine, CsA, MMF, AZA) was not permitted during the study period, except when used as rescue therapy.

[0451] During the study period, corticosteroids were the first-line treatment for patients who required rescue therapy at the discretion of the principal investigator. Patients were allowed to continue sarilumab or the corresponding placebo (sarilumab) only if they were using CS as rescue therapy. If symptoms persisted despite CS rescue therapy, other treatment options, including nonbiological immunosuppressants, may be used (patients must have symptomatic PMR disease), and such patients were discontinued from the study and considered non-responders.

[0452] If the dose had been stable for at least 3 months prior to baseline, administration of methotrexate not exceeding 15 mg / week was permitted. The dose remained stable throughout the study treatment period and up to 6 weeks after the last IMP (sarilumab or corresponding placebo) SC administration (though dose reduction or discontinuation was permitted for safety reasons if applicable).

[0453] Treatment with IMP other than sarilumab and CS as specified in the protocol was not permitted.

[0454] steroid This study included two standardized prednisone tapering regimens, one administered for 14 weeks (Group 1) and the other for 52 weeks (Group 2). The total duration of prednisone therapy for individual patients depended on the treatment group to which patients were randomly assigned.

[0455] If a patient developed an adverse event (AE) unrelated to PMR and required the initiation of new systemic steroid therapy, the new therapy and AE were recorded in the patient's eCRF. Furthermore, changes in steroid dosage were notified to the sponsor as soon as possible (e.g., within 24 hours) to review the patient's condition regarding ongoing trial participation. Throughout the trial, intranasal, inhaled, ophthalmic, or topical steroids were permitted as labeled.

[0456] Nonsteroidal anti-inflammatory drugs and analgesics Due to limited treatment options for pain, all analgesics, including nonsteroidal anti-inflammatory drugs (NSAIDs), were permitted. These analgesics were withheld for 24 hours prior to efficacy assessments, including assessments of physical function and quality of life.

[0457] Acetaminophen use was limited to 4g or less every 24 hours. Particular attention was paid to concomitant use with hepatotoxic drugs.

[0458] Treatment for dyslipidemia Treatment for dyslipidemia, such as statins, was permitted. The dosage of dyslipidemia-related drug therapy was to be stable for at least six weeks prior to the screening visit. All changes and reasons for changes were recorded in the patient's electronic case report form (eCRF). Anti-IL-6 drugs, including sarilumab, are known to increase serum total cholesterol, and this effect was carefully monitored throughout the study. If a significant increase in cholesterol levels or other dyslipidemia was observed in a patient during the treatment period of this study, cholesterol-lowering therapy with statins or other treatments for dyslipidemia were initiated or their dosages were adjusted in accordance with local guidelines.

[0459] Prevention and treatment of glucocorticoid-induced osteopenia / osteoporosis Oral calcium, 25-hydroxyvitamin D supplementation, and bisphosphonate therapy (e.g., alendronate 70 mg once weekly or zoledronic acid 4 mg once annually) were permitted for the prevention or treatment of glucocorticoid-induced osteoporosis. Dosage and duration of treatment were at the discretion of the principal investigator, in accordance with local clinical practice or guidelines.

[0460] CYP substrate In vitro studies have shown that IL-6 reduces the expression of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, and CYP3A4 enzymes. Therefore, it was anticipated that cytokine-antagonizing molecules such as sarilumab would normalize CYP450 enzyme formation, resulting in reduced levels of drugs metabolized by these CYP450 isoforms when PMR patients began receiving sarilumab. As a precautionary measure, adjustments were made as needed for drugs with narrow therapeutic ranges metabolized via these cytochromes: doses were increased to maintain efficacy after initiation of sarilumab administration and decreased after discontinuation of sarilumab administration. Warfarin is one example of a CYP450 substrate with a narrow therapeutic range that requires monitoring of its effects, or other drugs that require monitoring of their concentration, such as warfarin, cyclosporine, theophylline, digoxin, antiepileptic drugs such as carbamazepine (CARBATROL®, Tegretol®), divalproex (DEPAKOTE®), phenytoin (DILANTIN®), or valproic acid (DEPAKENE®); or antiarrhythmic drugs such as disopinion. Examples include, but are not limited to, lamids (NORPACE®), procainamides (PROCAN®, PRONESTEL®), or quinidines (QUINIDEX®, QUIN RELEASE QUIN-G®).

[0461] Key evaluation criteria Percentage of patients who achieved sustained remission at week 52 Sustained remission at week 52 is defined as meeting all of the following parameters: achieving disease remission by week 12, no disease flare observed from week 12 to week 52, a sustained decrease in CRP (below 10 mg / L and no continuous increase above 10 mg / L) from week 12 to week 52, and successful adherence to prednisone tapering from week 12 to week 52. Sustained remission was also evaluated from week 16 to week 52 and from week 24 to week 52.

[0462] Successful adherence to prednisone tapering includes the use of excess prednisone (exceeding the protocol-followed CS tapering regimen) with a cumulative dose of 100 mg (or equivalent) or less, such as when used to manage AEs not related to PMR.

[0463] Disease remission was defined as the disappearance of signs and symptoms of PMR, as well as normalization of CRP levels (<10 mg / L). A single elevation of CRP (≥10 mg / L) was not considered a failure of remission unless the elevation of CRP (≥10 mg / L) persisted during two consecutive trial visits.

[0464] A flare is defined as either 1) a recurrence of signs and symptoms caused by active PMR plus an increase in CS dose due to PMR, or 2) an increase in ESR caused by active PMR plus an increase in CS dose due to PMR.

[0465] An increase in CS dose is defined as follows: an increase during steroid tapering as defined in the protocol, or the resumption of prednisone therapy after completion of tapering as defined in the protocol. During the first 12 weeks of prednisone tapering, treatment for one flare prior to week 12 was permitted if treatment with a low-dose (≤5 mg / day) prednisone add-on tapering regimen (completed before week 12) was successful and all other sustained remission parameters were met.

[0466] Signs and symptoms of PMR: When the efficacy evaluator assesses clinical signs and symptoms at each visit in accordance with the evaluation schedule, the following should be included, but are not limited to: morning stiffness and / or pain in the neck, shoulders and / or pelvic girdle; limited range of motion in the shoulders and / or pelvic girdle; systemic symptoms, e.g., fatigue, weight loss and low-grade fever; and any other features that the clinician-investigator judges to be consistent with a PMR flare.

[0467] Secondary evaluation items for efficacy Components of the composite index for sustained remission at week 52 Patients who achieved disease remission by week 12, between weeks 16 and 52, and between weeks 24 and 52; patients who did not experience disease flares between weeks 12 and 52; patients whose CRP levels remained normalized (decreased to less than 10 mg / L) between weeks 12 and 52, between weeks 16 and 52, and between weeks 24 and 52; and patients who successfully adhered to prednisone tapering between weeks 12 and 52.

[0468] Successful adherence to prednisone tapering includes the use of excess prednisone (exceeding the protocol-followed CS tapering regimen) with a cumulative dose of 100 mg (or equivalent) or less, such as when used to manage AEs not related to PMR.

[0469] Total cumulative dose of corticosteroids (including prednisone) over 52 weeks For each group, the total cumulative dose of prednisone (or its equivalent) over 52 weeks was analyzed as a secondary endpoint.

[0470] Time until the first PMR flare The time from clinical remission to the first PMR flare at week 52 was analyzed for each group.

[0471] Complex glucocorticoid toxicity index and components The Glucocorticoid Toxicity Index (GTI) is a composite index designed to assess glucocorticoid-related morbidity and the potential steroid-saving effects of alternative treatments. The composite GTI and specific lists constitute the overall GTI. The composite GTI consists of nine areas and 31 items that assess potential side effects of glucocorticoids, including body mass index (BMI), glucose tolerance, blood pressure, lipid metabolism, bone mineral density, glucocorticoid-induced myopathy, skin toxicity, neuropsychotoxicity, and infection assessment. These are CS toxicities that are likely to occur during clinical trials and may vary depending on the degree of CS exposure, and were weighted and scored accordingly.

[0472] At baseline, week 12 (6th visit), week 24 (9th visit), week 40, and week 52, the specific list of domains and GTIs of the composite GTI were evaluated (excluding bone mineral density, which was evaluated only at baseline and week 52). Based on information obtained from clinical laboratory tests, vital signs, clinical assessments, and concomitant medication reviews, changes in glucocorticoid (GC) toxicity or GC toxicity in each domain (compared to baseline data) were scored (scores ranging from -36 to 439). Subsequently, the composite GTI was reported as both a total score and a domain-specific score to consider scenarios where improvement in a particular domain compensated for deterioration in other domains.

[0473] Bone mineral density was assessed using dual-energy DXA scans at baseline (second visit) and week 52 (twelfth visit). Scans were required to be performed within ±14 days of the second visit and within -14 days of the twelfth visit, and should include the lumbosacral and femoral neck regions. However, if a DXA scan including lumbosacral and femoral neck assessment was available within 12 weeks of baseline, a DXA scan at the baseline visit was not required.

[0474] The specific list consists of 11 unweighted domains and 23 items to identify other CS-related toxicities not included in the composite GTI (see Table 4 below). Information related to the domains / items of the specific list was collected at scheduled time points (baseline, week 12, week 24, week 40, and week 52) if available, but pre-specified assessments related to the domains of the specific list were not required in the conduct of this study unless there was a specific reason.

[0475] [Table 4-1] [Table 4-2]

[0476] Other evaluation items GTI Overall Improvement Score (AIS) for Week 52.

[0477] GTI Cumulative Worsening Score (CWS) for week 52.

[0478] Secondary safety endpoints: Adverse events (AEs), clinical laboratory safety variables, vital sign variables, antinuclear antibodies, and immunogenicity variables.

[0479] Functional sarilumab concentration in serum.

[0480] Overall assessment of disease activity by a physician, measured using MD-VAS.

[0481] Patient-reported outcomes (described in the following sections).

[0482] Changes in ESR and CRP from baseline to week 52.

[0483] Changes in IL-6 levels and soluble IL-6 receptor (sIL-6R) up to week 52.

[0484] Time-course changes in markers of inflammation and disease activity, assessed by changes in circulating immune cell types, circulating proteins, and gene expression.

[0485] Patient-reported outcomes Patients were asked to complete the patient-reported outcome (PRO) questionnaire described below at their second visit (baseline visit), sixth visit (week 12), ninth visit (week 24), and twelfth visit (week 52). The following metrics were evaluated.

[0486] Functional assessment of chronic disease therapy and fatigue scale As shown in Table 5 below, the Functional Assessment of Fatigue in Chronic Disease Therapy (FACIT-Fatigue) is a common PRO tool containing 13 items for measuring fatigue. Each item is rated by the patient on a scale of 0 to 4 (0=not at all, 1=a little, 2=somewhat, 3=quite, 4=very). The scores are tallied to obtain a total score between 0 and 52. The recall period was the most recent 7 days.

[0487] [Table 5]

[0488] EQ-5D-3L As shown in Figures 2A-B, the EQ-5D-3L is a common PRO tool 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).

[0489] The EQ-5D has two components: one is a Health Utility Index score derived from five items dealing with mobility, personal care, daily activities, pain / discomfort, and anxiety / depression "today"; and the other is a current ("just now") overall health status score derived from a single 0-100 visual analog scale (VAS). Each item contributing to the EQ-5D-3L Health Utility Index score has the same 3-point response scale (1=no problem, 2=moderate problem, 3=severe problem). The VAS is fixed on the "best health condition imaginable" and the "worst health condition imaginable."

[0490] Short form 36v2 (SF-36v2) As shown in Figures 3A-C, the Short form 36v2 (SF-36v2) is a simplified, general 36-item PRO scale that assesses eight aspects of health: physical functioning (PF; 10 items), social functioning (SF; 2 items), role limitation due to physical problems (RP; 4 items), role limitation due to emotional problems (RE; 3 items), mental health (MH; 5 items), energy / vitality (VT; 4 items), physical pain (BP; 2 items), and perception of overall health (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): pp. 473-483). For each aspect, the item scores are coded, summed, and converted to a scale from 0 (worst health condition measured by the questionnaire) to 100 (best health condition). Two standardized summary scores can also be calculated from SF-36v2, which means 0 to 10 This is a physical component summary (PCS) and mental component summary (MCS) on a scale of 0 (Maruish ME (2011), User's manual for the See "SF-36v2 Health Survey (3rd Edition)," Lincoln, RI: QualityMetric Incorporated.

[0491] HAQ-DI The HAQ-DI was developed to assess the physical functioning status of adults with arthritis, but is now commonly used for many rheumatic diseases (see Wolfe F, "A brief clinical health assessment instrument: CLINHAQ," Arthritis Rheum. 1989; Vol. 32 (Supplement): 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: pp. 463-514). It includes the following 25 items: 20 4-point Likert scale questions assessing eight physical aspects of activities of daily living (dressing and grooming, standing, eating, walking, hygiene, reaching, grasping, errands and chores), 13 supplemental questions assessing the use of assistive devices, and 8 supplemental questions assessing assistance received from others. The recall period is the most recent week. The calculation of the HAQ-DI score involves three steps: summing the eight category scores by using the highest subcategory score for each category; adjusting for the use of assistive devices / appliances and / or assistance from others, as needed; and dividing the summed category scores by the number of categories answered (which must be at least 6) to obtain an HAQ-DI score ranging from 0 to 3 (3 = worst function).

[0492] Furthermore, the HAQ-DI includes two additional questions measured on a 0-100 scale: how much pain you experienced in the past week, and how you rate your condition on a 0-100 scale (0 being "very good," 100 being "very bad"). These questions measure pain and overall assessment, respectively, and are scored independently.

[0493] Clinician-reported outcomes Physician's overall assessment of disease activity - Visual Analog Scale [MD-VAS] As shown in Figure 4, those responsible for efficacy evaluation were asked to assess patients' disease activity using a fixed 100mm horizontal VAS, where 0 was considered to indicate no activity and 100 was considered to indicate the highest level of activity (see Huskisson et al., "Vertical or Horizontal Visual Analogue Scales," Ann Rheum Dis. December 1979; 38(6): p. 560).

[0494] Other reviews PMR Activity Score (PMR-AS) PMR-AS is calculated as the sum of CRP (mg / dL), visual analog score (VAS) for pain (0-10), VAS as assessed by a physician (0-10), duration of morning stiffness (MST [minutes] × 0.1), and upper limb elevation ability (EUL [3-0]).

[0495] Glucocorticoid toxicity indicators The Glucocorticoid Toxicity Index (GTI) is a composite scale designed to assess glucocorticoid-related morbidity. The GTI-Cumulative Worsening Score (CWS) captures cumulative glucocorticoid toxicity, whether it is permanent or transient. The GTI-CWS may only increase over time or remain unchanged. A lower score indicates lower glucocorticoid toxicity. The GTI Overall Improvement Score (AIS) captures both worsening and improving glucocorticoid toxicity. New or worsening toxicity contributes to a positive score, while improvement in existing toxicity contributes to a negative score. A lower score indicates lower glucocorticoid toxicity.

[0496] Cumulative dose of corticosteroids The cumulative dose of corticosteroids is a measure of a patient's exposure to corticosteroids over a period of time, for example, 14 weeks or 52 weeks.

[0497] Pharmacodynamics, pharmacokinetics, and antidrug antibodies Determined pharmacodynamic variables Changes in ESR and CRP from baseline to week 52.

[0498] Changes in IL-6 levels and soluble IL-6 receptor (sIL-6R) up to week 52.

[0499] The following describes the temporal changes in inflammatory and disease activity markers, assessed by changes in circulating immune cell types, circulating proteins, and gene expression: For inflammatory markers, immunocytophenotyping was performed at V2 (baseline), V4 (week 4), and V9 (week 24) in a subset of the patient population during the study period. Approximately 80 patients (40 patients from each treatment arm) were selected for this analysis. Disease activity in PMR patients was assessed through the 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), and V12 (week 52 EOT) to measure circulating proteins. DNA samples were collected at V2 (baseline) or at any treatment or follow-up visit, and RNA samples were collected before administration at V2 (baseline) and / or V3 (week 2) to measure gene expression.

[0500] Pharmacokinetics and antidrug antibodies Blood samples were collected before administration at each trial visit, and serum sarilumab concentration (functional) and antibodies against sarilumab were measured and analyzed according to the bioanalytical methods shown in Table 6. Pre-administration serum sarilumab concentration at week 0, and trough levels of sarilumab at weeks 2, 4, 12, 16, 24, 32, 52, and 58 were collected. In addition, post-administration samples were collected 4 to 7 days after week 24 (9th visit).

[0501] [Table 6]

[0502] Adverse events An adverse event (AE) is defined as any undesirable medical event that occurs in a patient receiving a drug or in a patient participating in a clinical trial, and does not necessarily have to be causally related to the treatment. Matching AEs between the GTI and the clinical safety database is done through standard data review and surveys. This was part of the IANS activities. All AEs were recorded from the time informed consent was signed until the end of the trial, regardless of their severity or relationship to IMP.

[0503] result Demographic characteristics and other baseline characteristics Baseline demographic and subject characteristics were generally similar between the treatment groups. Compared to the sarilumab 200 mg q2w + 14-week tapering group, the placebo + 52-week tapering group had a slightly higher number of subjects aged 75 to under 85 and a slightly lower number of subjects aged 65 to under 75.

[0504] Baseline disease characteristics were generally balanced between treatment groups, however, the sarilumab 200 mg q2w + 14-week tapering group had a higher number of subjects with other affected joints compared to the placebo + 52-week tapering group (12 [20.0%] vs. 6 [10.3%]). The mean (SD) duration of PMR for all subjects was 631.3 (752.0) days. Subjects in the placebo + 52-week tapering group had a longer duration of morning stiffness (minutes); however, the number of subjects with morning stiffness lasting more than 45 minutes was similar between treatment groups. A detailed breakdown of patient demographic characteristics and baseline disease characteristics is shown in Table 7 below.

[0505] [Table 7]

[0506] exposure The cumulative exposure and median duration of treatment for the investigational drug in the double-blind treatment were similar between the sarilumab 200 mg q2w + 14-week tapering group and the placebo + 52-week tapering group. The cumulative exposure was 47.37 person-years in the sarilumab 200 mg q2w + 14-week tapering group and 45.36 person-years in the placebo + 52-week tapering group.

[0507] Overall overview of efficacy evaluation items Table 8 provides an overall summary of the efficacy endpoints. The results of this study demonstrated that treatment with sarilumab 200 mg q2w + 14 weeks tapering provided a greater benefit to subjects with PMR than treatment with 52 weeks of CS tapering alone. The proportion of subjects achieving sustained remission at week 52 was higher in the sarilumab 200 mg q2w + 14 weeks tapering group compared to the placebo + 52 weeks tapering group, and this difference was statistically significant, thus the study achieved its primary endpoint. Furthermore, the study showed that the proportion of patients achieving sustained remission was higher in the sarilumab arm compared to the control arm when evaluated at weeks 12, 16, and from week 24 to 52. The majority of patients achieving sustained remission experienced rapid remission by week 12, with some additional response observed between weeks 16 and 24.

[0508] Regarding the primary efficacy endpoint, the results of the sensitivity analysis excluding CRP were consistent with the results of the primary analysis. Most of the secondary endpoints were also achieved.

[0509] [Table 8-1] [Table 8-2] [Table 8-3]

[0510] Primary efficacy evaluation criteria The proportion of subjects achieving sustained remission at week 52 was higher in the sarilumab 200 mg q2w + 14-week tapering group compared to the placebo + 52-week tapering group. At week 52, 17 subjects (28.3%) achieved sustained remission in the sarilumab 200 mg q2w + 14-week tapering group, compared to 6 subjects (10.3%) in the placebo + 52-week tapering group, representing a difference of 18.0% (95% confidence interval: 4.15, 31.82). (See Table 9). Thus, the difference was statistically significant, with a p-value of 0.0193.

[0511] [Table 9]

[0512] Figure 23 also shows that the proportion of patients achieving sustained remission was higher in the sarilumab arm compared to the control group from week 16 to week 52 (30.0% vs. 8.6%; difference [95% confidence interval]: 21.4 [7.7, 35.0]; p=0.0047) and from week 24 to week 52 (31.7% vs. 10.3%; difference [95% confidence interval]: 21.3 [7.2, 35.5], p=0.0063). This improvement in sustained remission rates in the sarilumab arm was due to additional responses observed between week 12 and week 24.

[0513] Similarly, in each evaluation period, the proportion of patients who achieved all independent components of sustained remission was higher in the sarilumab arm compared to the control arm. As shown in Figure 24, in both the sarilumab and control arms, disease remission rates decreased slightly from the evaluation period of weeks 12 to 52 (46.7% vs. 37.9%) to weeks 16 to 52 (40.0% vs. 31.0%) and weeks 24 to 52 (41.7% vs. 20.7%). Although disease remission decreased, this was likely due to CRP deficiency or abnormality, and the proportion of patients who did not show signs and symptoms of PMR increased over time.

[0514] In the salilumab arm, the proportion of patients without disease flare increased from the assessment period of weeks 12 to 52, to weeks 16 to 52, and to weeks 24 to 52. On the other hand, the proportion of patients with sustained normalization of CRP or adherence to the protocol-specified GC tapering remained the same throughout the three assessment periods, as shown in Figure 25. Sensitivity analyses were performed for the primary endpoint. These analyses also included additional analyses excluding the acute-phase reactant CRP from the definition of sustained remission and excluding subjects who discontinued the study treatment due to a misdiagnosis of PMR.

[0515] As shown in Table 10, excluding the acute-phase reactant CRP, the proportion of subjects achieving sustained remission at week 52 remained higher in the sarilumab 200 mg q2w + 14-week tapering group compared to the placebo + 52-week tapering group (19 subjects [31.7%] and 8 subjects [13.8%], respectively), with a difference of 17.9% (95% confidence interval: 3.13, 32.61). Consistent with the primary analysis, a statistically significant difference was observed between the sarilumab 200 mg q2w + 14-week tapering group and the placebo + 52-week tapering group, with a p-value of 0.0280.

[0516] [Table 10]

[0517] Four subjects were misdiagnosed with PMR (two in the sarilumab 200 mg q2w + 14-week tapering group and two in the placebo + 52-week tapering group). Excluding subjects misdiagnosed with PMR, the proportion of subjects achieving sustained remission at week 52 remained higher in the sarilumab 200 mg q2w + 14-week tapering group compared to the placebo + 52-week tapering group (17 subjects [29.3%] and 6 subjects [10.9%], respectively), with a difference of 18.4% (95% confidence interval: 4.08, 32.72). As shown in Table 11, a statistically significant difference was observed between the sarilumab 200 mg q2w + 14-week tapering group and the placebo + 52-week tapering group, similar to the primary analysis, with a p-value of 0.0193.

[0518] [Table 11]

[0519] To assess the robustness of the results of the primary endpoint analysis, a transition analysis was also performed. Subjects who did not achieve remission or who received rescue treatment were considered non-responders. Subjects who discontinued the trial before week 52 and did not experience a disease flare before discontinuation were considered "missing data" and were sequentially supplemented for the transition analysis. As shown in Table 12, 13 subjects were considered missing in the sarilumab 200 mg q2w + 14-week tapering group, and 9 subjects were considered missing in the placebo + 52-week tapering group.

[0520] [Table 12]

[0521] The results of the turning point analysis are shown in Table 13.

[0522] [Table 13]

[0523] As shown in Table 14, a post-hoc analysis was performed to evaluate the effect of methotrexate on the primary efficacy endpoint. No trend was observed suggesting that methotrexate use affected the primary endpoint.

[0524] [Table 14]

[0525] As shown in Figure 5, subgroup analyses were performed on the primary endpoint to assess the consistency of treatment effects. Subgroup analyses of the primary endpoint results showed a numerical trend indicating that the sarilumab 200 mg q2w + 14-week tapering group was better than the placebo + 52-week tapering group, except for subjects with baseline weight less than 60 kg; however, the sample size of this subgroup was very small. No statistically significant interaction effects were observed between each subgroup and the treatment group. Some subgroups had small sample sizes and few events.

[0526] Secondary endpoints of effectiveness Components of sustained remission As shown in Table 15, overall, the proportion of subjects achieving each component of sustained remission was higher in the sarilumab 200 mg q2w + 14-week tapering group than in the placebo + 52-week tapering group. The proportion of subjects achieving remission within 12 weeks was higher in the sarilumab 200 mg q2w + 14-week tapering group than in the placebo + 52-week tapering group (28 subjects [46.7%] and 22 subjects [37.9%], respectively). The proportion of subjects without disease flare from week 12 to week 52 was higher in the sarilumab 200 mg q2w + 14-week tapering group than in the placebo + 52-week tapering group (33 subjects [55.0%] and 19 subjects [32.8%], respectively). The proportion of subjects who achieved a sustained reduction in CRP between weeks 12 and 52 was higher in the sarilumab 200 mg q2w + 14-week tapering group than in the placebo + 52-week tapering group (40 subjects [66.7%] and 26 subjects [44.8%], respectively). The proportion of subjects who successfully adhered to prednisone tapering between weeks 12 and 52 was higher in the sarilumab 200 mg q2w + 14-week tapering group than in the placebo + 52-week tapering group (30 subjects [50.0%] and 14 subjects [24.1%], respectively).

[0527] [Table 15]

[0528] As shown in Table 16, the number of subjects (%) who showed no signs or symptoms of post-metabolic radiculopathy (PMR) after baseline visit (excluding subjects who received rescue therapy) was higher in the sarilumab 200 mg q2w + 14-week tapering group than in the placebo + 52-week tapering group at each visit. At the end of treatment (week 52), no signs or symptoms of PMR were observed in 27 subjects (84.4%) in the sarilumab 200 mg q2w + 14-week tapering group and 8 subjects (47.1%) in the placebo + 52-week tapering group (excluding subjects who received rescue therapy).

[0529] [Table 16]

[0530] Total cumulative corticoid dose (including prednisone) Table 17 shows the cumulative CS dose during the treatment period. The placebo + 52-week tapering group had a higher predicted cumulative CS dose compared to the sarilumab 200 mg q2w + 14-week tapering group (52-week and 14-week CS tapering, respectively). The median predicted cumulative CS dose (prednisone or corticosteroid equivalent) during the 52-week treatment period was 777 mg in the sarilumab 200 mg q2w + 14-week tapering group, compared to 2044 mg in the placebo + 52-week tapering group.

[0531] There was a difference in the CS tapering period between the placebo + 52-week tapering group and the sarilumab 200 mg q2w + 14-week tapering group, resulting in a larger actual cumulative CS dose in the placebo + 52-week tapering group. The median total cumulative prednisone dose (i.e., what subjects actually took) during the 52-week treatment period was 777 mg in the sarilumab 200 mg q2w + 14-week tapering group, compared to 20 in the placebo + 52-week tapering group. It was 44 mg.

[0532] The median difference between the actual cumulative CS dose and the predicted cumulative CS dose was significantly smaller in the sarilumab 200 mg q2w + 14-week tapering group compared to the placebo + 52-week tapering group (0.0 mg vs. 199.5 mg; p=0.0189).

[0533] [Table 17]

[0534] The majority of the difference between the actual cumulative sarilumab dose and the predicted cumulative sarilumab dose was due to rescue therapy received by subjects for post-metastatic malformation (PMR). As shown in Table 18, the cumulative number (%) of subjects receiving rescue therapy for PMR was lower in the sarilumab 200 mg q2w + 14-week tapering group compared to the placebo + 52-week tapering group. During the 52-week treatment period, 34 subjects (58.6%) in the placebo + 52-week tapering group received rescue therapy for PMR, compared to 19 subjects (32.2%) in the sarilumab 200 mg q2w + 14-week tapering group.

[0535] [Table 18]

[0536] Time until the first PMR flare Figure 6 shows the Kaplan-Meier estimates of the time to the first PMR flare after clinical remission up to week 52. The time to the first PMR flare was statistically significantly longer in subjects treated with sarilumab than in subjects treated with placebo, and the median was not reached in subjects treated with sarilumab. Of the subjects who achieved clinical remission during the 52-week treatment period, 41 (68.3%) were in the sarilumab 200 mg q2w + 14-week tapering group, and 30 (51.7%) were in the placebo + 52-week tapering group. Subjects in the sarilumab 200 mg q2w + 14-week tapering group were less likely to experience a PMR flare after achieving clinical remission (16.7% vs. 29.3%) compared to subjects in the placebo + 52-week tapering group, with a hazard ratio of 0.56 (95% confidence interval: 0.35–0.90; p=0.0153). The median was not reached in the sarilumab 200 mg q2w + 14-week tapering group. A post-hoc analysis was performed on the time to the first PMR flare after the clinical remission endpoint, analyzing the total time to the first PMR flare calculated since the first clinical remission. The results of the post-hoc analysis were consistent with the results of the analysis of the total time to the first PMR flare calculated from the date of randomization.

[0537] Glucocorticoid toxicity index - Cumulative Worsening Score (CWS) and Overall Improvement Score (AIS) As shown in Table 19, the sarilumab 200 mg q2w + 14-week tapering group showed a numerical trend of less cumulative worsening and greater overall improvement compared to the placebo + 52-week tapering group. However, no significant difference in CWS was observed between the sarilumab 200 mg q2w + 14-week tapering group and the placebo + 52-week tapering group, and the mean LS difference (SE) with placebo was -4.90 (9.375) (95% CI: -23.477, 13.669; p=0.6020).

[0538] [Table 19]

[0539] Similarly, as shown in Table 20, no significant difference in AIS was observed between the sarilumab 200 mg q2w + 14 weeks tapering group and the placebo + 52 weeks tapering group, and the mean LS difference (SE) from placebo was -6.59 (8.811) (95% confidence interval: -24.047, 10.862; p=0.4559).

[0540] [Table 20]

[0541] Outcomes and other evaluation items and evaluations PMR Activity Score As shown in Table 21, the proportion of subjects with low disease activity levels was higher over time in the sarilumab + 14-week tapering group compared to the placebo + 52-week tapering group. There were no subjects in the sarilumab + 14-week tapering group with high PMR activity levels at weeks 24 and 52, and the proportion of subjects with low disease activity levels was higher in the sarilumab + 14-week tapering group. The latter group had a higher rate compared to the placebo + 52-week tapering group.

[0542] [Table 21]

[0543] As shown in Table 22, the change from baseline in PMR-AS at week 52 was greater in the sarilumab 200 mg q2w + 14-week tapering group than in the placebo + 52-week tapering group (mean LS [SE] were -15.57 [0.94] and -10.27 [0.97], respectively). The mean difference in PMR-AS LS in the sarilumab 200 mg q2w + 14-week tapering group compared to the placebo + 52-week tapering group was statistically significant (-5.302, 95% CI: -8.006 to -2.597; p=0.0002).

[0544] [Table 22]

[0545] As shown in Figure 7, the greatest reduction in PMR activity was observed in both the sarilumab 200 mg q2w + 14-week tapering group and the placebo + 52-week tapering group, from baseline to 1 The decrease was observed by week 2, and in the group receiving sarilumab 200 mg q2w + 14 weeks of tapering, the decrease continued until week 52.

[0546] MD-VAS As shown in Table 23, the sarilumab 200 mg q2w + 14-week tapering group showed a greater decrease in MD-VAS from baseline at week 52 compared to the placebo + 52-week tapering group (mean LS [SE] were -40.58 [3.40] and -30.49 [3.46], respectively). The mean difference in MD-VAS LS between the sarilumab 200 mg q2w + 14-week tapering group and the placebo + 52-week tapering group was statistically significant (-10.097, 95% CI: -19.775, -0.419; p=0.0411).

[0547] [Table 23]

[0548] FACIT-Fatigue As shown in Table 24, the change from baseline in the FACIT-Fatigue scale at week 52 was numerically greater in the sarilumab 200 mg q2w + 14-week tapering group than in the placebo + 52-week tapering group (mean LS [SE] were 7.91 [1.33] and 4.17 [1.42], respectively). The mean difference in FACIT-Fatigue scale LS in the sarilumab 200 mg q2w + 14-week tapering group compared to the placebo + 52-week tapering group was 3.740 (95% CI: -0.108, 7.588; p=0.0567).

[0549] [Table 24]

[0550] Figure 12 shows the proportion of patients treated with sarilumab and placebo who reported an improvement of MCID or higher in their FACIT-F score at week 52. An MCID improvement of 4.0 or higher in FACIT-F was observed. These results indicate that sarilumab treatment led to a greater numerical improvement in the FACIT-F score than placebo treatment (higher scores indicate better function or less fatigue).

[0551] Figure 13 shows the percentage of patients who reported a FACIT-F score above the normal range at baseline and at week 52. The normal range threshold was 43.5 or higher. These results indicate that sarilumab treatment led to a greater numerical improvement in FACIT-F scores compared to placebo treatment.

[0552] EQ-5D-3L As shown in Table 25, subjects in the sarilumab 200 mg q2w + 14-week tapering group showed a greater increase from baseline in the EQ-5D-3L single-index utility score at week 52 than subjects in the placebo + 52-week tapering group (mean LS [SE] were 0.11 [0.04] and -0.02 [0.04], respectively). The mean difference in EQ-5D-3L single-index utility score between the sarilumab 200 mg q2w + 14-week tapering group and the placebo + 52-week tapering group was statistically significant (0.130, 95% CI: 0.010, 0.250; p=0.0336).

[0553] [Table 25]

[0554] As shown in Table 26, subjects in the sarilumab 200 mg q2w + 14-week tapering group showed a greater increase from baseline in EQ-5D-3L VAS scores at week 52 compared to the placebo + 52-week tapering group (mean LS [SE] were 8.37 [3.46] and -0.46 (3.68), respectively). The mean LS difference in EQ-5D-3L VAS scores between the sarilumab 200 mg q2w + 14-week tapering group and the placebo + 52-week tapering group was 8.830 (95% CI: -1.191, 18.850; p=0.0835).

[0555] [Table 26]

[0556] Figure 19 shows the long-term minimum score (LSM) changes from baseline at week 52 for EQ-5D utility scores and EQ VAS scores in patients treated with sarilumab and placebo. These results indicate that sarilumab treatment led to a statistically greater improvement in EQ-5D utility scores from baseline, with an LSM difference of 0.13 compared to placebo (P=0.0336). These results also indicate that sarilumab treatment led to a numerically greater improvement in EQ VAS scores from baseline (higher scores indicate better health status).

[0557] SF-36 As shown in Table 27, subjects in the sarilumab 200 mg q2w + 14-week tapering group showed a greater increase from baseline in PCS at week 52 compared to the placebo + 52-week tapering group (mean LS [SE] were 7.65 [1.34] and 2.87 [1.45], respectively). As shown in Figure 8, the mean difference in PCS LS between the sarilumab 200 mg q2w + 14-week tapering group and the placebo + 52-week tapering group was statistically significant (4.784, 95% CI: 0.865, 8.703; p=0.0172).

[0558] [Table 27]

[0559] As shown in Table 28, subjects in the sarilumab 200 mg q2w + 14-week tapering group showed a greater increase from baseline in MCS at week 52 compared to the placebo + 52-week tapering group (mean LS [SE] were 3.04 [1.47] and -1.71 [1.57], respectively). As shown in Figure 8, the mean difference in MCS scores between the sarilumab 200 mg q2w + 14-week tapering group and the placebo + 52-week tapering group was statistically significant (4.748, 95% CI: 0.484, 9.013; p=0.0295).

[0560] [Table 28]

[0561] Table 29 shows the LSM changes from baseline at week 52 in each domain of SF-36, including physical function (PF), physical role (RP), physical pain (BP), overall health (GH), vitality (VT), social functioning (SF), emotional role (RE), and mental health (MH), compared with placebo. As shown in Figure 9, five of the eight domains of SF-36 (MH, RP, BP, SF, and VT) showed statistically significantly greater improvement with sarilumab compared with placebo.

[0562] [Table 29]

[0563] Figure 10 shows the percentage of patients treated with sarilumab and placebo who reported improvement of MCID or higher at week 52 for various SF-36 metrics, including PCS, MCS, PF, RP, BP, GH, VT, SF, RE, and MH. For PCS (P=0.0161), patients who reported improvement of MCID or higher at a statistically significant level were... A larger proportion of patients received sarilumab, and this was the case for scores in 5 of the 8 domains of SF-36. The MCID (improvement from baseline) was 2.5 for PCS and MCS. The MCID for individual SF-36 domains was 5.0.

[0564] Figure 11 shows the percentage of patients treated with sarilumab and placebo who reported above-normal scores at baseline and at week 52 for various SF-36 metrics, including PCS, MCS, PF, RP, BP, GH, VT, SF, RE, and MH. 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 a numerically higher percentage of patients treated with sarilumab reported above-normal scores for the SF-36 MCS and the four SF-36 domain scores.

[0565] HAQ-DI As shown in Table 30, subjects in the sarilumab 200 mg q2w + 14-week tapering group showed a numerically greater decrease from baseline in the HAQ-DI standardized score at week 52 compared to the placebo + 52-week tapering group (mean LS [SE] were -0.39 [0.09] and -0.15 [0.09], respectively). The mean LS difference in the HAQ-DI standardized score between the sarilumab 200 mg q2w + 14-week tapering group and the placebo + 52-week tapering group was -0.246 (95% CI: -0.496, 0.005; p=0.0543).

[0566] [Table 30]

[0567] Figure 14 shows the percentage of patients treated with sarilumab and placebo who reported improvement of 0.22 or higher in their HAQ-DI score at week 52. The above improvements were observed. These results indicate that sarilumab treatment led to a greater numerical improvement in the HAQ-DI score compared to placebo treatment (a lower HAQ-DI score indicates greater improvement).

[0568] Figure 15 shows the proportion of patients treated with sarilumab and placebo who reported having HAQ-DI scores above the normal range at baseline and at week 52. The normal range threshold was ≤0.25. These results indicate that sarilumab treatment led to a greater numerical improvement in HAQ-DI scores than placebo treatment.

[0569] Patient-to-Patient Global Assessment (PtGA) Figure 16 shows the change in LSM (Long-Sized Statistical Mass) from baseline in the Patient Global Assessment of Disease Activity (PtGA) score at week 52 for patients treated with sarilumab and placebo. These results indicate that sarilumab treatment led to a significantly greater numerical improvement in the PtGA score compared to placebo treatment (higher scores indicate a higher level of disease activity or poorer overall health).

[0570] Figure 17 shows the percentage of patients treated with sarilumab and placebo who reported an improvement in their PtGA score exceeding MCID at week 52. An MCID improvement of 10.0 or greater was observed. These results indicate that sarilumab treatment led to a greater numerical improvement in PtGA score compared to placebo treatment.

[0571] Pain Visual Analog Scale (VAS) Figure 18 shows the change from baseline to long-term minimum pain score (LSM) of the Visual Analog Scale (VAS) at week 52 for patients treated with sarilumab and placebo. These results indicate that treatment with sarilumab resulted in a significantly greater numerical improvement in pain VAS scores compared to treatment with placebo (higher scores indicate greater pain intensity).

[0572] Resolving the signs and symptoms of PMR Figure 20 shows the proportion of patients who did not show signs and symptoms of post-metastatic regurgitation (PMR) at each visit after receiving sarilumab (200 mg Q2W + 14 weeks of GC tapering) or placebo (52 weeks of GC treatment). The proportion of patients who did not show signs and symptoms of PMR increased in the sarilumab treatment group compared to the placebo group at week 2 and continued to increase over time until week 52. The proportion of patients who did not show signs and symptoms of PMR at each visit after baseline was higher in the sarilumab treatment group. Furthermore, the difference between the two treatment groups was observed to be larger in Figure 21 than in Figure 20, because patients who received rescue therapy were excluded from the analysis in Figure 21.

[0573] Rescue therapy Figure 22 shows the cumulative proportion of patients who received rescue therapy after being treated with sarilumab (200 mg Q2W + 14 weeks of GC tapering) and placebo (52 weeks of GC treatment). These results indicate that the cumulative proportion of patients requiring rescue therapy was higher in the placebo group at each time point from baseline to week 52. The proportion of patients requiring additional GC during the study period was higher in the placebo group compared to the sarilumab group (58.6% vs. 32.2%; p=0.0053 [Fisher's exact test]). In the subgroup of patients requiring rescue GC, the median cumulative dose of rescue GC over 52 weeks was lower in the sarilumab arm (1076.1 mg [range, 8–2108]) compared to the placebo group (1326.5 mg [range, 20–2484]; p=0.5078).

[0574] Pharmacodynamics, pharmacokinetics, and antidrug antibodies Pharmacokinetic study results After multiple SC administrations of sarilumab 200 mg over q2w, the observed trough concentration of functional sarilumab increased over time, reaching a steady state by week 24, with an accumulation ratio of approximately 5-fold.

[0575] Results of pharmacodynamic tests In the group receiving sarilumab 200 mg q2w + 14 weeks of tapering, the mean serum IL-6 concentration after subcutaneous administration peaked at week 12 and then decreased after further treatment. The mean total serum sIL-6Rα concentration increased rapidly by week 2 and reached a steady state at week 24.

[0576] At week 52, the mean CRP level decreased by 6.9 mg / dL from baseline in the sarilumab 200 mg q2w + 14-week tapering group, compared to 1.7 mg / dL in the placebo + 52-week tapering group. This decrease was greater in the sarilumab 200 mg q2w + 14-week tapering group compared to the placebo + 52-week tapering group at all time points.

[0577] immunogenicity One subject in the placebo + 52-week tapering group and two subjects in the sarilumab 200 mg q2w + 14-week group developed a positive ADA reaction under treatment.

[0578] Adverse events Safety results The overall incidence of SAEs was low in both treatment groups (sarilumab 200 mg + 14-week tapering group: 8 subjects [13.6%], placebo + 52-week tapering group: 12 subjects [20.7%]). The most frequently reported SAEs occurred in SOCs of infectious and parasitic diseases (3 subjects [5.1%] in the sarilumab 200 mg + 14-week tapering group, 3 subjects [5.2%] in the placebo + 52-week tapering group).

[0579] The overall incidence of TEAEs leading to permanent discontinuation of treatment was low in both treatment groups (sarilumab 200 mg q2w + 14-week tapering group: 7 subjects [11.9%], placebo + 52-week tapering group: 4 subjects [6.9%]). The most frequently reported TEAEs leading to treatment discontinuation occurred in SOCs of infection and parasitic diseases (COVID-19, discitis, and pneumonia, 1 each [1.7%]) and hematological and lymphatic disorders (neutropenia, 3 in 5.1% [5.1%]).

[0580] Overall, mean changes in clinical laboratory values ​​and vital signs were similar across the treatment groups, except for neutropenia, with a higher incidence observed in the sarilumab 200 mg q2w + 14-week tapering group.

[0581] conclusion Enrollment for the EFC15160 trial was halted by the sponsor in July 2020 due to a prolonged recruitment schedule and the impact of the COVID-19 pandemic on the number of participants. To terminate the trial early, 118 out of the planned 280 participants were enrolled (117 received treatment). All enrolled participants were permitted to complete the trial as originally planned. As a result of the lower-than-expected enrollment, a protocol modification was implemented before database closure to change the probability of a Type I error from less than 0.01 to less than 0.05.

[0582] Overall, the results of this study demonstrated that treatment with sarilumab 200 mg q2w + 14 weeks tapering provided a greater benefit than treatment with 52 weeks of corticosteroid tapering alone in subjects with PMR. A significantly higher proportion of subjects treated with sarilumab achieved sustained remission at week 52, despite earlier corticosteroid tapering (28.3% in the sarilumab 200 mg q2w + 14 weeks tapering group compared to 10.3% in the placebo + 52 weeks tapering group; p=0.0193). This effect was consistent across pre-specified subgroups of age, sex, race, region, and BMI, all of which favored the sarilumab 200 mg q2w + 14 weeks tapering group. To further confirm the robustness of this effect, a pre-specified sensitivity analysis was performed by excluding acute-phase reactants from the definition of sustained remission. In this analysis, the proportion of subjects who achieved complete remission at week 52 was consistently statistically significantly increased in subjects treated with sarilumab (13.8% in the placebo + 52-week tapering group vs. 31.7% in the sarilumab 200 mg q2w + 14-week tapering group; p=0.0280).

[0583] The objective of the key secondary endpoint was to reduce cumulative steroid use in PMR subjects treated with sarilumab, who are known to be vulnerable to undesirable side effects of corticosteroid treatment. In this study, subjects treated with sarilumab had significantly lower median steroid use compared to placebo (2044.0 mg in the placebo + 52-week tapering group vs. 777.0 mg in the sarilumab 200 mg q2w + 14-week tapering group; p<0.0001). Furthermore, the median difference between actual cumulative CS dose and predicted cumulative CS dose was significantly lower in the sarilumab group compared to the placebo group (median: 0.0 mg vs. 199.5 mg; p=0.0189). This is a clinically significant difference, and a favorable reduction in steroid use was observed with sarilumab, as the flare rate increased in the placebo + 52-week tapering group when comparing actual and predicted steroid use in this study.

[0584] Most secondary endpoints were met. The proportion of subjects achieving disease remission by week 12 was higher in the sarilumab 200 mg q2w + 14-week tapering group (46.7% and 37.9% in the placebo + 52-week tapering group). Furthermore, the percentage of subjects who did not experience a PMR flare after clinical remission was higher in the sarilumab-treated group compared to the placebo group (55.0% vs. 32.8%). The time to the first PMR flare was statistically significantly longer in the sarilumab-treated group and did not reach the median. In addition, the sarilumab + 14-week tapering group showed higher adherence to prednisone tapering compared to the placebo + 52-week tapering group.

[0585] The number of subjects who did not show signs or symptoms of post-metastatic mitral remission (excluding those who received rescue therapy) was higher at each visit in the sarilumab 200 mg q2w + 14-week tapering group.

[0586] In the group receiving sarilumab 200 mg tapering for 2 weeks plus 14 weeks, the risk of PMR flare after achieving clinical remission was 56% lower.

[0587] In the group receiving sarilumab 200 mg q2w + 14 weeks of tapering, a numerical trend of decreasing steroid toxicity in GTI was observed, but it did not reach statistical significance.

[0588] For exploratory efficacy endpoints, the combination of rapid 14-week corticosteroid tapering and sarilumab treatment demonstrated favorable functional and symptomatic benefits compared to 52-week corticosteroid tapering with placebo.

[0589] The change from baseline in the PMR activity score at week 52 was better with sarilumab. Yes, and the mean difference between left and right was -5.302 (p=0.0002).

[0590] At week 52, the change from baseline in MD-VAS scores was better with sarilumab, with a mean difference in LS of -10.097 (p=0.0411).

[0591] At week 52, the change from baseline in the FACIT-Fatigue score showed a favorable trend with sarilumab, with a mean LS difference of 3.740 (p=0.0567).

[0592] At week 52, the change from baseline in the EQ-5D score was better with sarilumab, with a mean difference in LS of 0.130 (p=0.0336).

[0593] At week 52, the change from baseline in EQ5D-VAS scores was better with sarilumab, with a mean difference in LS of 8.830 (p=0.0835).

[0594] At week 52, the change from baseline in the SF-36 physical element score was better with sarilumab, with a mean difference of 4.487 (p=0.0172).

[0595] At week 52, the change from baseline in the SF-36 mental component score was better with sarilumab, with a mean difference of 4.748 (p=0.0295).

[0596] At week 52, the change from baseline in the HAQ-DI score showed a favorable trend with sarilumab, with a mean difference in LS of -0.246 (p=0.0543).

[0597] In this study, the combination of sarilumab 200 mg administered every two weeks to PMR subjects with rapid tapering of corticosteroids over 14 weeks demonstrated clinically significant and statistically significant differences compared to placebo plus 52 weeks of corticosteroid tapering in the primary endpoint, most secondary endpoints, and many exploratory endpoints.

[0598] In this study, sarilumab demonstrated efficacy in patients with GC-resistant PMR. The proportion of patients free from signs or symptoms of PMR was higher in the sarilumab-treated arm compared to the placebo arm at each time point after baseline, confirming that sarilumab resulted in a more rapid and sustained reduction of PMR activity compared to GC alone. Despite using less GC in the sarilumab-treated group than in the placebo arm, the need for rescue GC therapy was lower in the sarilumab-treated group than in the placebo arm.

[0599] The combination of sarilumab 200 mg q2w in patients with post-metabolic malformation (PMR) and rapid tapering of CS over 14 weeks did not reveal any new safety signals and was consistent with the known safety profile of sarilumab. No deaths were reported. The safety findings from this study, when considered together with the observed clinical benefits, support the favorable risk-benefit and clinical utility of sarilumab for the treatment of PMR.

[0600] Sarilumab is used to treat polymyalgia rheumatica (PMR) in adult patients who have an inadequate response to corticosteroids or who cannot tolerate corticosteroid tapering. [Examples]

[0601] Resolution of signs and symptoms of polymyalgia rheumatica (PMR) without glucocorticoids (GC) in patients with a history of flare and treated with sarilumab: Analysis from SAPHYR (NCT03600818, EFC15160, Phase III). In the SAPHYR trial (NCT03600818), patients with polymyalgia rheumatica (PMR) who received sarilumab plus tapering glucocorticoids (GCs) had a significantly higher rate of achieving sustained remission at week 52 (W) compared with placebo plus tapering GCs. Post-hoc data on resolution of signs and symptoms (S&S) of PMR and resolution of PMR S&S without GCs are shown over time.

[0602] method Patients enrolled between October 2018 and July 2020 received either sarilumab 200 mg Q2W + 14-W GC tapering (sarilumab arm) or placebo Q2W + 52-W GC tapering (control arm) for 52 weeks. All patients received prednisone 15 mg / day for 2 weeks, followed by blinded prednisone tapering. Patients who experienced disease flare or who failed to adhere to the pre-protocol GC tapering received open-label rescue GC.

[0603] result A total of 118 patients were enrolled (sarilumab, n=60 [1 untreated]; control, n=58). The proportion of patients free from signs and symptoms of post-morbidity regurgitation (PMR) at each visit after baseline was higher in the sarilumab arm compared to the control arm (W52, observed cases [OC]: 81.3% vs. 56.5%, intended treatment [ITT]: 65% vs. 45.8%). At W52, the proportion of patients whose signs and symptoms of PMR resolved without rescue GC was 64.3% and 45% in the sarilumab arm, respectively, compared to 22.2% and 13.8% in the control arm (Figure 26). The proportion of patients requiring rescue GC at W52 was lower in the sarilumab arm than in the control arm (31.7% vs. 58.6%).

[0604] From week 4 to week 52, the proportion of patients who did not show signs or symptoms of post-metastatic regurgitation (PMR) was higher in the sarilumab arm compared to the control arm (OC: 92.9% vs. 72.2% at week 52, ITT: 65% vs. 44.8% (Figure 27)).

[0605] Patients in the sarilumab arm were less likely to experience flare after achieving clinical remission compared to the control arm (16% vs. 29.3%; HR 0.56; 95% CI 0.35-090; p=0.0158). Flare was rare after W16 in the sarilumab arm, but persisted until W52 in the control arm (Figure 28).

[0606] conclusion Adding sarilumab to a short-term 14-week GC tapering regimen resulted in a more rapid resolution of PMR signs and symptoms from week 4 compared to a 52-week GC tapering regimen. In patients treated with sarilumab, resolution of PMR signs and symptoms without GC was maintained from week 16 to week 52. [Examples]

[0607] Efficacy of interleukin-6 receptor inhibitors for polymyalgia rheumatica Exam Overview Interleukin-6 receptor (IL-6R) inhibition has been shown to be effective in giant cell arteritis, but data on polymyalgia rheumatica (PMR) are limited. A retrospective trial was conducted to evaluate the efficacy of IL-6R inhibitors (IL-6Ri; sarilumab or tocilizumab) as third-line and second-line treatments for glucocorticoid (GC)-refractory PMR patients compared to conventional immunomodulatory (cIM) therapy.

[0608] material and method Purpose of the exam To evaluate the efficacy of IL-6R inhibitor therapy (IL-6Ri) (tocilizumab, sarilumab) as a third-line and second-line treatment for GC-refractory PMR, compared to conventional disease-modifying antirheumatic drug (cDMARD) therapy (methotrexate, azathioprine, leflunomide).

[0609] Test design This study used an observational retrospective comparative cohort design. Adults with PMR, defined as a claim for PMR diagnosis based on one hospitalization or two outpatient visits at least 30 days apart, were identified from individual-pay Medicare and Part D prescription claims from March 29, 2016, to June 30, 2020. Participants were those who initiated IL-6Ri or cIM as second-line or third-line therapy for PMR and were enrolled for 180 days prior to therapy initiation (baseline). For the third-line treatment cohort, the index date was the date of switching from cIM to IL-6Ri in the IL-6Ri group, and the index date was the date of switching from one cIM to another in the cIM group. For the second-line treatment cohort, the index date was the date of initiation of IL-6Ri in the IL-6Ri group (no prior cIM use) and the index date was the date of new cIM use in the cIM group. A 180-day washout period for the index drug was applied to all cohorts. Patients were required to be receiving GC (≤25 mg / day) on the index day and were excluded if there was evidence of serologically positive 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 confounding factors.

[0610] Outcomes assessed using an adjusted Cox proportional hazards model included: GC discontinuation; GC discontinuation or low-dose GC (<2.5 mg / day); and non-continuation in the second-line treatment cohort (discontinuation or switching of IL-6Ri or cIM), adjusted for residual imbalance factors after matching. Censoring occurred at 1 year, death, 60 days before the end of enrollment (missing ≤30 days), or at the addition of control PMR therapy, and additional censoring was applied in sensitivity analyses for drug discontinuation and / or switching.

[0611] Inclusion Criteria Second-line treatment and third-line treatment In all past data, there must be either one PMR diagnosis made during hospitalization or the first of two PMR diagnoses made during outpatient visits.

[0612] Use of oral GC on indicator days.

[0613] Continuous registration from 180 days before the indicator date (baseline period) to 1 day after.

[0614] Third-line treatment only Occurrence of cDMARD therapy at baseline prior to the benchmark date.

[0615] Occurrence of cDMARD therapy on the benchmark day.

[0616] Exclusion criteria Second-line treatment and third-line treatment The age on the indicator date is under 18 years old.

[0617] On the benchmark day, both IL-6Ri and cDMARD therapy were initiated (it is possible to use multiple drugs within the cDMARD group simultaneously, but more than two drugs should be initiated on the same day). This is not permitted. Similarly, past use of cDMARD and new use of IL-6Ri are permitted, but both cannot be started on the same day.

[0618] On the benchmark day, the GC dose exceeded 25 mg in prednisone equivalent.

[0619] Seropositive rheumatoid arthritis.

[0620] Diagnosis of other inflammatory arthritis, connective tissue disease, multiple sclerosis, and organ transplantation.

[0621] Aggressive treatment for malignant tumors.

[0622] Second-line treatment only Patients who have previously used either an IL-6Ri or a cDMARD based on available records (at least 180 days) will be excluded.

[0623] Outcome Primary Outcomes Discontinuation of oral GC therapy, defined as a lack of oral GC drug supply for more than 60 days.

[0624] Discontinuation of oral GC therapy, or achievement of the minimum daily oral GC dose (prednisone equivalent of 2.5 mg / day or less).

[0625] Secondary outcomes The cumulative oral GC dose during the follow-up period, evaluated as a cumulative total and assessed as prednisone equivalent mg ​​per patient per week for the contributing follow-up period.

[0626] Time until discontinuation of indicator therapy (missing more than 60 days) (second-line treatment cohort only).

[0627] result After matching, 409 patients in the third-line treatment and 251 patients in the second-line treatment were included in the analysis. As shown in Table 31, patient characteristics after matching were generally balanced across cohorts, with only slight differences between exposure groups. The median time from initial PMR diagnosis to the start of follow-up was approximately 1.75 years (third-line treatment) and 0.90 years (second-line treatment), which was similar in both groups. As shown in Table 32, despite matching by GC category, IL-6Ri patients initiated higher-dose GC. As shown in Table 33, after matching and adjustment, patients treated with IL-6Ri were more likely to discontinue GC or achieve low-dose GC compared to cIM patients. Unadjusted outcomes are shown in Table 34 for the second-line treatment and in Table 35 for the third-line treatment. As shown in Figure 29, the time to discontinuation or switching (non-continuation) of IL-6Ri or cIM was significantly longer in IL-6Ri patients compared to cIM patients (p=0.029).

[0628] [Table 31]

[0629] [Table 32]

[0630] [Table 33]

[0631] [Table 34]

[0632] [Table 35]

[0633] conclusion IL-6Ri therapy was more effective than cIM therapy as a steroid-saving agent in adult PMR patients. [Examples]

[0634] Efficacy of interleukin-6 receptor inhibitors for polymyalgia rheumatica Purpose of the exam To evaluate the efficacy of IL-6R inhibitor (IL-6Ri) therapy (tocilizumab, sarilumab) as a third-line (3L) and second-line (2L) treatment option for GC-refractory PMR, compared to cIM therapy (methotrexate, azathioprine, leflunomide).

[0635] material and method Test design This retrospective observational cohort study included adult patients (aged 50 and over) with PMR identified from individual-pay Medicare medical bills and Part D prescription claims in the country from January 1, 2006 to December 31, 2020.

[0636] Patients who were initiated with IL-6Ri or cIM as 2L or 3L therapy (as a substitute for GC-refractory) for PMR and who remained enrolled for more than 180 days prior to treatment initiation (baseline) were enrolled in two separate cohorts.

[0637] In the 3L cohort, patients who had previously received cIM and initiated a new IL-6Ri therapy for PMR treatment (exposed) were compared with patients who initiated a new cIM therapy different from their previous cIM (control).

[0638] For the 3L cohort, the index day was defined as the day IL-6Ri therapy was initiated after previous cIM therapy, or the day a different cIM therapy was initiated if IL-6Ri had not been used prior to the previous cIM therapy, using all available data.

[0639] In the 2L cohort, PMR patients (exposed) who received new IL-6Ri therapy and had not previously used either IL-6Ri or CIM therapy, and PM patients who received new cIM therapy. Patients with R (control) were compared to other patients. For the 2L cohort, the index date was defined as the start date of the first IL-6Ri or CIM, prior to the use of either IL-6Ri or cIM, using all available data.

[0640] Patients who initiated IL-6Ri and patients who initiated new CIM for the first time were matched 1:3 for age, sex, and GC dose category (for the 3L cohort, the recency of previous CIM therapy), and then 1:1 matching was performed using propensity scores (PS) to control for potential confounding factors.

[0641] Inclusion / Exclusion Criteria Patients diagnosed with PMR by one hospitalization or two outpatient visits at least 30 days apart, either from a clinical specialty or billing perspective, who received oral gastrocnemios (GCs) at the benchmark, and who were continuously enrolled from 180 days before to 1 day after the benchmark (baseline period) were included in this study. Patients who had received CIM therapy at any point prior to the benchmark were only eligible for the 3L cohort.

[0642] Patients were excluded if there was evidence of serologically positive rheumatoid arthritis (RA), adult-onset Still's disease, other arthritis or connective tissue disease, organ transplantation, or aggressive treatment for malignancy.

[0643] Evaluation items The primary efficacy endpoint was discontinuation of oral GC therapy, or a composite endpoint of discontinuation of GC and a minimum GC dose (less than 2 mg / day).

[0644] Secondary endpoints included the cumulative GC dose received during the follow-up period, and, for the 2L comparison cohort only, the continuation of the benchmark PMR therapy (i.e., either IL-6Ri or cIM therapy).

[0645] statistical analysis The time to GC discontinuation and the time to reaching the composite endpoint (GC discontinuation or minimum GC dose) were compared in each comparison cohort using a Cox proportional hazards model.

[0646] We compared the IL-6Ri group with the CIM-exposed group using a Cox proportional hazards model, estimated hazard ratios (HRs) with 95% confidence intervals (CIs), estimated pooled HRs, and stratified individual HRs from the 3L and 2L cohorts.

[0647] For covariates where balance was not achieved by PS matching based on a standardized mean difference (SMD) greater than 0.10 after matching, the model was further adjusted.

[0648] Three types of sensitivity analyses were performed using various censoring rules for discontinuation of indicator therapy, switching of treatments, and 12 months later.

[0649] result Patient characteristics Following direct matching and PS matching, 409 and 251 patients were assigned to the treatment arms of the 3L and 2L cohorts, respectively.

[0650] Patient characteristics were generally well-balanced, but there were slight differences between exposure groups. In the 3L cohort, IL-6Ri patients were in a category with higher GC doses at the benchmark compared to CIM patients. They were slightly more likely to be classified as RA, less likely to have claims with codes for seronegative RA, and more likely to have claims with codes for concomitant giant cell arteritis (GCA) (Table 36). All other characteristics examined were well-balanced (data not shown). In the 2L cohort, IL-6Ri patients were somewhat younger, less likely to be enrolled in Medicare due to disability, and more likely to have claims with codes for seronegative RA and GCA (Table 36).

[0651] The median time from the first PMR diagnosis observed in the claim to the start of follow-up was approximately 1.75 years (3L cohort) and 0.90 years (2L cohort), which was similar in both groups.

[0652] [Table 36]

[0653] Discontinuation of glucocorticoids or the minimum glucocorticoid dose. Based on the HRs shown in Table 37, patients treated with IL-6Ri were more likely to discontinue GC (HR [95% CI]: 1.32 [1.09~1.58]) and more likely to achieve minimal or no GC use (1.30 [1.90~1.54]) compared to the cIM group, and the results remained statistically significant regardless of the censoring rules applied to the sensitivity analysis.

[0654] Patients initiated with IL-R6i were more likely to discontinue GC use (3L cohort: 45.0% vs. 30.1%, 2L cohort: 49.0% vs. 32.7%) and more likely to discontinue or achieve minimal GC doses (3L cohort: 49.6% vs. 34.7%, 2L cohort: 55.4% vs. 39.4%) compared to patients initiated with CIM (mean follow-up period for IL-6Ri initiated patients: 147 days and 163 days for 3L and 2L, respectively; 138 days and 148 days for CIM initiated patients for 3L and 2L, respectively).

[0655] There was no significant difference between the two groups in cumulative prednisone equivalent dose during the follow-up period.

[0656] Similar results were obtained in sensitivity analyses using various censoring rules. Separate hazard ratios (HRs) comparing IL-6Ri and CIM therapy were similar in both the 3L and 2L cohorts.

[0657] [Table 37]

[0658] Treatment continuity, continuation, and switching After PS matching, the continuation of 2L treatment tended to be more favorable with IL-6Ri therapy compared with cIM therapy (p=0.055; Figure 30). Patients who started IL-6Ri were less likely to switch treatments compared with those on cIM therapy (p=0.0011; Figure 31).

[0659] conclusion In older patients with PMR, IL-6Ri therapy was effective as a steroid-saving agent compared to cIM therapy when used as either a 3L or 2L regimen. These results are consistent with the efficacy of IL-6Ri therapy in PMR. [Examples]

[0660] Long-term safety of conventional and biological IL-6Ri immunomodulators as second-line or tertiary-line treatment for polymyalgia rheumatica. We present safety data on IL-6Ri and conventional immunomodulatory (CIM) therapy over up to two years (Y) in patients with PMR.

[0661] the purpose To evaluate the safety of IL-6Ri and CIM therapy as second-line (2L) or third-line (3L) treatment for PMR.

[0662] method This was a retrospective study of US adults aged 50 years or older diagnosed with PMR (Progressive Membrane Rheumatism) based on individual Medicare data from March 29, 2016 to June 30, 2020, using one hospitalization or two outpatient visits at least 30 days apart. Patients were receiving prednisone (PS) equivalent of 25 mg or less and were initiated with IL-6Ri (tocilizumab / sarilumab) or CIM (methotrexate / leflunomide / azathioprine) as 2L / 3L therapy, and had been continuously enrolled for at least 180 days prior to the benchmark. For 2L, the benchmark date was the initiation of IL-6Ri / CIM in the absence of prior IL-6Ri / CIM use. For 3L, the benchmark date was the initiation of IL-6Ri after a previous CIM (with or without background CIM) or a new CIM. Follow-up was conducted until the end of enrollment, death, change of treatment, or 2 years, whichever came first. Patients with serologically positive rheumatoid arthritis, other arthritis or connective tissue disease, giant cell arteritis, organ transplantation, or ongoing malignancy were excluded. After stratifying by therapy selection order, IL-6Ri patients were directly matched using 1:3 variable ratio matching for age, sex, index day, baseline PS-equivalent dose category (<2.5 mg, 2.5 mg to <5 mg, 5 mg to <10 mg, 10 mg to <15 mg, 15 mg to <20 mg, 20 mg to 25 mg), and recentness of previous CIM (3L only; 1-60 days, 61-180 days, >180 days). Then, 1:1 propensity score matching was performed using multivariate logistic regression to identify variables with an SMD greater than 0.1. The inventors examined hospitalization-related infections (all and primary diagnosis), gastrointestinal perforation, major cardiac adverse events, malignancies, and drug-induced liver injury. Except for infections, patients with a history of events were excluded from each outcome-specific analysis. Outcomes were identified using validated or previously used claims-based algorithms. Incidence was reported per 100 person-years with a 2-year follow-up, using a direct Poisson test for 95% confidence intervals if there were fewer than 5 events. Adjusted hazard ratios (aHRs) for infections were estimated using a Cox proportional hazards model (assuming fewer other events).In the sensitivity analysis, the Y1 and Y2 events were examined separately and stratified into 2L vs. 3L.

[0663] result In the final cohort, covariate balance was good for the 451 patients matched in each arm. Residual imbalances were small for disability status, steroid dose category, and chronic lung disease. Event rates and aHRs are shown in Table 38; aHRs were not significant when comparing IL-6Ri versus CIM. Sensitivity analyses were consistent with the primary results, generally showing that for most outcomes, the incidence of IL-6Ri at Y2 was similar to or numerically lower than CIM, and the incidence of IL-6Ri at Y1 was lower than CIM.

[0664] [Table 38]

[0665] conclusion When comparing the incidence of serious adverse events between IL-6Ri therapy and CIM therapy, the incidence was similar for PMR (Post-Morphological Risk) up to 2 years of exposure.

Claims

1. An antibody or antigen-binding fragment thereof that specifically binds to the IL-6 receptor, for use in a method for treating polymyalgia rheumatica (PMR) in subjects requiring treatment for PMR.

2. The subject is an antibody or antigen-binding fragment thereof for use according to claim 1, having a PMR that is refractory to steroids or refractory to steroid tapering.

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

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

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

6. The subject is an antibody or antigen-binding fragment for use according to claim 5, which has been previously treated with prednisone at a dose of 7.5 mg / day or more, and / or 25 mg / day or less, or 20 mg / day or less.

7. An antibody or its antigen-binding fragment for use according to any one of claims 1 to 6, administered in combination with another therapeutic agent.

8. The therapeutic agent comprises a corticosteroid, wherein the antibody or an antigen-binding fragment thereof for use according to claim 7.

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

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

11. The antibody or its antigen-binding fragment for use according to claim 10, wherein administration of prednisone is discontinued or, if applicable, gradually reduced to less than 2.5 mg or less than 2.0 mg / day of prednisone.

12. The antibody or its antigen-binding fragment for use according to claim 11, wherein prednisone is discontinued approximately 10 to 20 weeks after the administration of the initial dose of the antibody, and in some cases, prednisone is discontinued approximately 14 weeks after the administration of the initial dose of the antibody.

13. The subject is an antibody or antigen-binding fragment thereof for use according to any one of claims 1 to 12, which has been previously treated with a disease-modifying antirheumatic drug (cDMAD).

14. The subject is an antibody or antigen-binding fragment thereof for use according to any one of claims 1 to 13, which is simultaneously treated with cDMAD.

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

16. cDMARD is methotrexate, an antibody or antigen-binding fragment for use according to claim 14 or 15.

17. An antibody or antigen-binding fragment thereof for use according to any one of claims 1 to 16, administered in a dose between approximately 150 mg and approximately 200 mg.

18. An antibody or antigen-binding fragment thereof for use according to claim 17, administered in a dose of approximately 150 mg.

19. An antibody or antigen-binding fragment thereof for use according to claim 17, administered in a dose of approximately 200 mg.

20. An antibody or its antigen-binding fragment for use according to any one of claims 1 to 17 and 19, administered as an initial dose of approximately 200 mg, with one or more secondary doses of approximately 200 mg administered every other week (q2w).

21. An antibody or antigen-binding fragment for use according to any one of claims 1 to 20, comprising 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. An antibody or its antigen-binding fragment for use according to any one of claims 1 to 21, comprising the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO:

2.

23. An antibody or its antigen-binding fragment for use according to any one of claims 1 to 22, comprising a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO:

10.

24. The antibody for use according to any one of claims 1 to 23, wherein the antibody is sarilumab.

25. An antibody or antigen-binding fragment thereof that specifically binds to the IL-6 receptor, for use in a method to reduce or eliminate the dependence of a subject having polymyalgia rheumatica (PMR) on basic therapy including corticosteroids for the treatment of PMR, said use is (a) Select patients with PMR that is partially controlled or uncontrolled with basic therapy including corticosteroids; (b) During the initial treatment period, while maintaining the patient's basal PMR therapy, administer a prescribed dose of an effective amount of an antibody or antigen-binding fragment that specifically binds to the IL-6 receptor at a prescribed frequency over the initial treatment period; and (c) While continuing to administer the antibody or its antigen-binding fragment to the target at the prescribed frequency and dose used during the initial treatment period, gradually reduce or eliminate the dose of corticosteroids administered to the target throughout the subsequent treatment period. An antibody or its antigen-binding fragment, including an antibody.

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

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

28. The subsequent treatment period is at least 14 weeks, as described in any one of claims 25 to 27. Antibodies or antigen-binding fragments thereof for use in the field.

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

30. An antibody or its antigen-binding fragment for use according to any one of claims 25 to 29, administered in a dose of approximately 200 mg.

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

32. An antibody or antigen-binding fragment for use according to any one of claims 25 to 31, comprising 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 subject is an antibody or antigen-binding fragment thereof for use according to any one of claims 1 to 32, which is seronegative to rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP).

34. The subject is an antibody or antigen-binding fragment for use according to any one of claims 1 to 33, which does not have a disorder or disease selected from the group consisting of giant cell arteritis, rheumatoid arthritis, inflammatory arthritis, connective tissue disease, rhabdomyolysis, neuropathic muscle disease, and active fibromyalgia.

35. The antibody or antigen-binding fragment 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. An antibody or antigen-binding fragment for use according to any one of claims 1 to 35, wherein at least one symptom of polymyalgia rheumatica in a subject is improved after administration of the antibody or antigen-binding fragment.

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

38. An antibody or antigen-binding fragment for use according to any one of claims 1 to 37, wherein treatment with the antibody or its antigen-binding fragment 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 Disease Therapy and Fatigue Scale (FACIT-Fatigue), the EuroQol 5-Item 3-Level Questionnaire (EQ-5D-3L), and Short Form-36v2 (SF-36v2), the Health Assessment Questionnaire Disability Index (HAQ-DI), and the Physician's Global Assessment of Disease Activity-Visual Analog Scale (MD-VAS).

39. An antibody or its antigen-binding fragment for use according to any one of claims 1 to 38, wherein treatment with the antibody or its antigen-binding fragment results in a reduction of the glucocorticoid toxicity index (GTI) score.

40. Treatment with the antibody or its antigen-binding fragment results in a decrease in the PMR activity score (PMR-AS), the antibody or its antigen for use according to any one of claims 1 to 39. Combined fragments.

41. An antibody or its antigen-binding fragment for use according to any one of claims 1 to 40, wherein treatment with the antibody or its antigen-binding fragment results in an increase in the time to the first PMR flare.

42. An antibody or antigen-binding fragment for use according to any one of claims 1 to 41, wherein treatment with the antibody or antigen-binding fragment results in remission of PMR in a subject.

43. The subject is an antibody or antigen-binding fragment thereof for use according to claim 42, having the absence of disease flare during remission.

44. An antibody or its antigen-binding fragment for use according to any one of claims 1 to 43, wherein treatment with the antibody or its antigen-binding fragment results in an increased resolution of the signs and symptoms of PMR, or resolution of the signs and symptoms of PMR without GC, in a subject.

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

46. The antibody or its antigen-binding fragment for use according to claim 44, wherein the cessation of signs and symptoms of PMR without GC is maintained from week 16 to week 52 after the initiation of treatment with the antibody or its antigen-binding fragment.

47. An antibody or its antigen-binding fragment for use according to any one of claims 1 to 46, administered subcutaneously.

48. The pharmaceutical composition is administered subcutaneously using a needle and syringe, a pen-type delivery device, or an autoinjector, and is an antibody or antigen-conjugated fragment thereof for use according to any one of claims 1 to 47.

49. An antibody or its antigen-binding fragment for use according to any one of claims 1 to 48, administered using a pre-filled syringe containing approximately 175 mg / mL of sarilumab.

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