Compositions and methods for treating frail subjects with polymyalgia rheumatica by administering an il-6r antagonist

Abstract

The present disclosure relates to the use of an anti-IL6 receptor inhibitor for treating polymyalgia rheumatica (PMR) in a frail subject. Methods of reducing or eliminating dependence of a frail subject with PMR on a background therapy comprising a corticosteroid for the treatment of PMR are provided. Methods of reducing or eliminating dependence of a frail subject with PMR on a background therapy comprising a corticosteroid for the treatment of PMR, wherein the subject has a Claims-Based Frailty Index (CFI) value of greater than or equal to about 0.2 or a CFI value of greater than or equal to about 0.25, are provided.

Description

COMPOSITIONS AND METHODS FOR TREATING FRAIL SUBJECTS WITH POLYMYALGIA RHEUMATICA BY ADMINISTERING AN IL-6R ANTAGONISTRELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 620,471, filed January 12, 2024, the entire disclosure of which is hereby incorporated by reference in its entirety for all purposes.SEQUENCE LISTING

[0002] This application contains a Sequence Listing which has been submitted herewith and is hereby incorporated by reference in its entirety. Said .xml copy, created on January 07, 2025, is named 760704-SA9-495PC, and is 18,788 bytes in size.FIELD

[0003] The present disclosure relates to the field of therapeutic treatment of polymyalgia rheumatica (PMR). In certain aspects, the disclosure relates to the use of interleukin-6 receptor (IL-6R) antagonists, such as anti-IL-6R antibodies, to treat PMR in a frail subject.BACKGROUND

[0004] Polymyalgia rheumatica (PMR) is a chronic, inflammatory disease of unknown etiology characterized by pain and morning stiffness of the shoulder, neck and pelvic girdle, and is frequently associated with low-grade fever, fatigue, malaise, and weight loss. The debilitating effect of the disease can significantly affect the quality of life of PMR patients. It typically affects individuals older than 50 years, with prevalence varying by age and population (Gonzalez, G. et al., 2009 Arthritis Rheum. 61(10): 1454-61). In 2008, the number of PMR cases in the US was estimated to be 711,000 (Lawrence, R.C. et al., 2008 Arthritis Rheum. 58( 1 ):26-35). The prevalence is higher in women than in men and increases dramatically with age. Based on the only population-based study of PMR in the US, the prevalence ranged from 21 per 100,000 among persons ages 50-54 years to 4,070 per 100,000 among those age ≥90 years (Lawrence, et al. Estimates of the prevalence of arthritis and other rheumatic conditionsin the United States, Part II. Arthritis Rheum. 2008;58(l):26-35). In Europe, higher rates have been noted in Northern European compared with Southern European populations. In patients who are ≥50 years of age, annual incidence rates of 50 / 100,000 were noted in Sweden and 68 / 100,000 in Denmark compared to 13 / 100,000 in Italy and 14-19 / 100,000 in Spain (Gonzalez, G. et al., 2009 Arthritis Rheum. 61(10): 1454-61).

[0005] Although the cause is unknown, both genetic and the environmental factors are thought to be involved. Research suggests that inflammation of the joints and the bursae around these joints leads to the symptoms of pain and stiffness associated with PMR. Although there are no definitive tests, there are guidelines to help in the clinical diagnosis of PMR (Dasgupta, B. et al. 2010 Rheumatology. 49(1): 186-90).

[0006] Although PMR is typically treated with low doses of glucocorticoids (GC), there is a subset of patients who are steroid-dependent or are unable to taper off prednisone or equivalent below 10 mg / day without relapse of symptoms and are therefore at risk of complications of long-term steroid therapy. In the 2015 American College of Rheumatology / European League against Rheumatism (ACR / EULAR) guidelines, the recommended minimum effective starting dose is within the range of 12.5-25 mg of prednisone (or equivalent) daily (Dejaco, C. et al. 2017 Rheumatology. 56(4):506-15). Mean treatment duration is approximately 2 to 3 years. GC use with a slow taper will reduce symptoms rapidly for most patients. However, nearly half of the patients with PMR treated with GC do not respond adequately based on laboratory and clinical markers of disease activity in one report (Dasgupta, B. et al. 2010 Rheumatology. 49(1): 186-90). In another report, among patients with baseline prednisone doses >10 mg / day, only 30% had remission at 1 year (Caporali, R. et al. 2004 Ann Intern Med. 141 (7):493 -500).SUMMARY

[0007] The current treatment protocol for PMR includes long-term oral glucocorticoid therapy. One drawback of long-term oral glucocorticoid therapy is the potential link to comorbidity. (Chatzigeorgiou C, et al. Comorbidity in polymyalgia rheumatica. Reumatismo. 2018 Mar 27;70( 1 ):35-43). There remains a need for an effective treatment for PMR with fewer adverse side effects.

[0008] Treatment of PMR is hindered by a paucity of GC -sparing therapies with proven efficacy. A retrospective study showed treatment with IL-6 receptor inhibitors (IL-6Ri) vs. conventional synthetic immunomodulatory drugs (csIM [methotrexate, leflunomide, and azathioprine]) was associated with greater likelihood of GC discontinuation (HR [95% CI]: 1.32 [1.09-1.58]) at 1 year (Curtis JR et al. Academy of Managed Care Pharmacy Annual Meeting 2023. Poster No. Ml 8). Frailty, characterized by increased vulnerability to stressors related to aging and poor health outcomes may be accelerated and more prevalent in patients with PMR vs. the general population (Sattui SE et al. Rheumatology (Oxford) 2022;61 :4455- 64). Prolonged GC treatment may exacerbate frailty (Motta F et al. Front Immunol 2020; 11 :576134.). Thus there is an unmet need for reducing GC use in frail patients.

[0009] The disclosure is based in part on the discovery that IE-6 receptor inhibitor (IE-6Ri) therapy had a greater GC-sparing effect than conventional synthetic immunomodulatory drugs (csIM) in frail patients with PMR.

[0010] In one aspect, a method for treating polymyalgia rheumatica (PMR) in a frail subject, comprising administering to a frail subject having PMR an effective amount of an interleukin- 6 (IE 6) receptor inhibitor is provided.

[0011] In certain exemplary embodiments, the IL-6 receptor inhibitor is an antibody or antigenbinding fragment thereof that specifically binds IL-6 receptor.

[0012] In certain exemplary embodiments, the subject has PMR that is refractory to a steroid or is refractory to a steroid taper. In certain exemplary embodiments, the subject has had an inadequate response to a steroid or cannot tolerate a steroid taper.

[0013] In certain exemplary embodiments, the steroid comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0014] In certain exemplary embodiments, the subject was previously treated with the at least one steroid (e.g., a corticosteroid such as prednisone) at: (i) a dose (e.g., a prednisone equivalent dose) of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day (a prednisone equivalent dose); or (ii) a dose of about 5 mg / day (a prednisone equivalent dose). In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of greater than or equal to about 2.5 mg / day, greater than or equal to about 5 mg / day, greater than or equal to about 10 mg / day, greater than or equal to about 15 mg / day, or greaterthan or equal to about 20 mg / day. In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of less than or equal to about 25 mg / day, less than or equal to about 20 day, mg / day, less than or equal to about 15 mg / day, less than or equal to about 10 mg / day, or less than or equal to about 25 mg / day.

[0015] In certain exemplary embodiments, the IL-6 receptor inhibitor is administered in combination with a second therapeutic agent. In certain exemplary embodiments, the second therapeutic agent comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0016] In certain exemplary embodiments, the corticosteroid is administered: (i) at a dose (e.g., a prednisone equivalent dose) of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day (a prednisone equivalent dose); or (ii) about 5 mg / day (a prednisone equivalent dose). In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of greater than or equal to about 2.5 mg / day, greater than or equal to about 5 mg / day, greater than or equal to about 10 mg / day, greater than or equal to about 15 mg / day, or greater than or equal to about 20 mg / day. In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of less than or equal to about 25 mg / day, less than or equal to about 20 day, mg / day, less than or equal to about 15 mg / day, less than or equal to about 10 mg / day, or less than or equal to about 25 mg / day.

[0017] In certain exemplary embodiments, the dose of corticosteroid is discontinued or tapered, optionally to less than or equal to about 2.5 mg / day or less than or equal to about 2.0 mg / day.

[0018] In certain exemplary embodiments, the dose of corticosteroid is discontinued or tapered to a dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose), after the IL-6 inhibitor (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of time. In certain exemplary embodiments, such a period of time may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time may be about 25days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0019] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at about 10 weeks, at about 12 weeks, at about 14 weeks, at about 16 weeks, at about 18 weeks, at about 20 weeks, at about 25 weeks, or at about 30 weeks, or later, after administering a first dose of the IL-6 receptor inhibitor.

[0020] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at between about 10 weeks and about 20 weeks after administering a first dose of the IL-6 receptor inhibitor, optionally wherein the corticosteroid is discontinued beginning at about 14 weeks after administering a first dose of the IL-6 receptor inhibitor.

[0021] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days.

[0022] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning about 25 days to about 300 days, about 50 days to about 250 days, about 50 days to about 300 days, about 50 days to about 350 days.

[0023] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days.

[0024] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0025] In certain exemplary embodiments, the subject was previously treated with a conventional synthetic immunomodulatory drug (csIM). In certain exemplary embodiments, the subject is concomitantly treated with a csIM in addition to the IL-6 receptor inhibitor. In certain exemplary embodiments, the csIM is selected from: methotrexate, azathioprine,sulfasalazine, hydroxychloroquine, and leflunomide. In certain exemplary embodiments, the csIM is or comprises methotrexate.

[0026] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

[0027] In certain exemplary embodiments, the subject has a Claims-Based Frailty Index (CFI) value of greater than or equal to about 0.25, or greater than or equal to about 0.35. In certain exemplary embodiments, the subject has a CFI value of about 0.25 to about 0.34 or ≥ about 0.35. In certain exemplary embodiments, the subject has a CFI value of ≥ about 0.25.

[0028] In certain exemplary embodiments, the subject is mildly frail. In certain exemplary embodiments, the subject is moderate -to-severely frail.

[0029] In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0030] In certain exemplary embodiments, the subject 50 years old or older. In certain exemplary embodiments, the subject is 65 years old or older.

[0031] In certain exemplary embodiments, the subject was previously administered both a glucocorticoid and a csIM.

[0032] In certain exemplary embodiments, the subject has one or more comorbidities selected from: asthma, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, giant cell arteritis, psoriasis and seronegative rheumatoid arthritis.

[0033] In certain exemplary embodiments, the IL-6 receptor inhibitor is used as a second line (2L) treatment. In certain exemplary embodiments, the IL-6 receptor inhibitor is used as a third line (3L) treatment.

[0034] In certain exemplary embodiments, the subject has bilateral shoulder pain.

[0035] In certain exemplary embodiments, the subject has a C-reactive protein (CRP) level of >10 mg / L and / or an erythrocyte sedimentation rate (ESR) >30 mm / hr.

[0036] In certain exemplary embodiments, the subject has morning stiffness .

[0037] In certain exemplary embodiments, the subject has an absence of joint involvement other than the shoulder joint.

[0038] In certain exemplary embodiments, the subject has hip pain or limited range of motion.

[0039] In certain exemplary embodiments, the subject is seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP).

[0040] In certain exemplary embodiments, the subject does not have a disorder or disease selected from: giant cell arteritis, rheumatoid arthritis, inflammatory arthritis, connective tissue disease, rhabdomyolysis, neuropathic muscular disease, and active fibromyalgia. In certain exemplary embodiments, the connective tissue disease is selected from: systemic lupus erythematosus, systemic sclerosis, vasculitis, myositis, mixed connective tissue disease, and ankylosing spondylitis.

[0041] In certain exemplary embodiments, the subject has at least one shoulder with subdeltoid bursitis and / or biceps tenosynovitis and / or posterior or axillary glenohumeral synovitis, and at least one hip with synovitis and / or trochanteric bursitis.

[0042] In certain exemplary embodiments, at least one symptom of PMR in the subject is improved after administering the IL-6 receptor inhibitor.

[0043] In certain exemplary embodiments, the at least one symptom is selected from: shoulder pain associated with inflammatory stiffness; hip pain associated with inflammatory stiffness; elevated C reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR); and any combinations thereof.

[0044] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in the improvement of least one patient reported outcome measure or clinician reported outcome measure selected from the group consisting of: functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue), EuroQol five-dimensional three-level questionnaire (EQ-5D-3L), and Short form-36v2 (SF-36v2), health assessment questionnaire disability index (HAQ-DI), and physician global assessment of disease activity- Visual Analog Scale (MD-VAS).

[0045] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in a decrease in glucocorticoid toxicity index (GTI) score.

[0046] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in a decrease in PMR activity score (PMR-AS).

[0047] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in an increase in time to first PMR flare. In certain exemplary embodiments, the first PMR flare includes a symptom selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0048] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in remission of PMR in the subject.

[0049] In certain exemplary embodiments, the subject has an absence of disease flare in remission. In certain exemplary embodiments, a symptom of PMR flare is selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0050] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in increased resolution of PMR signs and symptoms or GC-free resolution of PMR signs and symptoms in the subject. In certain exemplary embodiments, the resolution of PMR signs and symptoms is achieved from week 4 after starting treatment with the IL-6 receptor inhibitor. In certain exemplary embodiments, the GC-free resolution of PMR signs and symptoms is maintained from week 16 after starting treatment with the IL-6 receptor inhibitor to week 52.

[0051] In certain exemplary embodiments, the antibody is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

[0052] In certain exemplary embodiments, the IL-6 inhibitory therapy comprises an anti-anti- IL6R antibody or an antigen-binding fragment thereof. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg to about 200 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered every other week (q2w).

[0053] In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4 and 5, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7 and 8. In certain exemplary embodiments, the anti- IL6R antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL6R antibody is sarilumab.

[0054] In certain exemplary embodiments, the antibody is sarilumab or a variant thereof (e.g., a variant with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to the sarilumab sequence, or a biosimilar thereof.

[0055] In certain exemplary embodiments, the IL-6 receptor inhibitor is administered subcutaneously. In certain exemplary embodiments, the IL-6 receptor inhibitor is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0056] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, discontinues corticosteroid use.

[0057] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, achieves a minimal corticosteroid dose of less than or equal to about 2 mg / day.

[0058] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, achieves a minimal corticosteroid dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose). In certain exemplary embodiments, such a period of time for administration of an IL-6R inhibitor may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time for administration of an IL-6R inhibitor may beabout 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0059] In another aspect, a method of reducing or eliminating dependence of a frail subject with polymyalgia rheumatica (PMR) on a background therapy comprising a corticosteroid for the treatment of PMR is provided, comprising: (a) selecting a frail patient who has PMR that is partially controlled or uncontrolled with a background therapy comprising a corticosteroid; administering to the frail patient an effective amount of an interleukin-6 (IL 6) receptor inhibitor at a defined frequency for an initial treatment period while maintaining the subject’s background PMR therapy for the initial treatment period; and gradually reducing or eliminating the dosage of the corticosteroid administered to the subject over the course of a subsequent treatment period while continuing to administer the IL-6 receptor inhibitor to the subject at the defined frequency and dose used during the initial treatment period.

[0060] In certain exemplary embodiments, the IL-6 receptor inhibitor is an antibody or antigenbinding fragment thereof that specifically binds IL-6 receptor.

[0061] In certain exemplary embodiments, the subject has PMR that is refractory to a steroid or is refractory to a steroid taper. In certain exemplary embodiments, the subject has had an inadequate response to a steroid or cannot tolerate a steroid taper.

[0062] In certain exemplary embodiments, the steroid comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0063] In certain exemplary embodiments, the subject was previously treated with the at least one steroid (e.g., a corticosteroid such as prednisone) at: (i) a dose (e.g., a prednisone equivalent dose) of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day (a prednisone equivalent dose); or (ii) a dose of about 5 mg / day (a prednisone equivalent dose). In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of greater than or equal to about 2.5 mg / day, greater than or equal to about 5 mg / day, greater than or equal to about 10 mg / day, greater than or equal to about 15 mg / day, or greater than or equal to about 20 mg / day. In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of less than or equal to about 25 mg / day, less than or equal to about 20 day, mg / day, less than or equal to about 15 mg / day, less than or equal to about 10 mg / day, or less than or equal to about 25 mg / day.

[0064] In certain exemplary embodiments, the IL-6 receptor inhibitor is administered in combination with a second therapeutic agent. In certain exemplary embodiments, the second therapeutic agent comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0065] In certain exemplary embodiments, the corticosteroid is administered: (i) at a dose (e.g., a prednisone equivalent dose) of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day (a prednisone equivalent dose); or (ii) about 5 mg / day (a prednisone equivalent dose). In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of greater than or equal to about 2.5 mg / day, greater than or equal to about 5 mg / day, greater than or equal to about 10 mg / day, greater than or equal to about 15 mg / day, or greater than or equal to about 20 mg / day. In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of less than or equal to about 25 mg / day, less than or equal to about 20 day, mg / day, less than or equal to about 15 mg / day, less than or equal to about 10 mg / day, or less than or equal to about 25 mg / day.

[0066] In certain exemplary embodiments, the dose of corticosteroid is discontinued or tapered, optionally to less than or equal to about 2.5 mg / day or less than or equal to about 2.0 mg / day.

[0067] In certain exemplary embodiments, the dose of corticosteroid is discontinued or tapered to a dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose), after the IL-6 inhibitor (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of time. In certain exemplary embodiments, such a period of time may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time may be about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0068] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at about 10 weeks, at about 12 weeks, at about 14 weeks, at about 16 weeks, at about18 weeks, at about 20 weeks, at about 25 weeks, or at about 30 weeks, or later, after administering a first dose of the IL-6 receptor inhibitor.

[0069] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at between about 10 weeks and about 20 weeks after administering a first dose of the IL-6 receptor inhibitor, optionally wherein the corticosteroid is discontinued beginning at about 14 weeks after administering a first dose of the IL-6 receptor inhibitor.

[0070] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days.

[0071] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning about 25 days to about 300 days, about 50 days to about 250 days, about 50 days to about 300 days, about 50 days to about 350 days.

[0072] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days.

[0073] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0074] In certain exemplary embodiments, the subject was previously treated with a conventional synthetic immunomodulatory drug (csIM). In certain exemplary embodiments, the subject is concomitantly treated with a csIM in addition to the IL-6 receptor inhibitor. In certain exemplary embodiments, the csIM is selected from: methotrexate, azathioprine, sulfasalazine, hydroxychloroquine, and leflunomide. In certain exemplary embodiments, the csIM is or comprises methotrexate.

[0075] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

[0076] In certain exemplary embodiments, the subject has a Claims-Based Frailty Index (CFI) value of greater than or equal to about 0.25, or greater than or equal to about 0.35. In certain exemplary embodiments, the subject has a CFI value of about 0.25 to about 0.34 or ≥ about 0.35. In certain exemplary embodiments, the subject has a CFI value of ≥ about 0.25.

[0077] In certain exemplary embodiments, the subject is mildly frail. In certain exemplary embodiments, the subject is moderate -to-severely frail.

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

[0079] In certain exemplary embodiments, the subject 50 years old or older. In certain exemplary embodiments, the subject is 65 years old or older.

[0080] In certain exemplary embodiments, the subject was previously administered both a glucocorticoid and a csIM.

[0081] In certain exemplary embodiments, the subject has one or more comorbidities selected from: asthma, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, giant cell arteritis, psoriasis and seronegative rheumatoid arthritis.

[0082] In certain exemplary embodiments, the IL-6 receptor inhibitor is used as a second line (2L) treatment. In certain exemplary embodiments, the IL-6 receptor inhibitor is used as a third line (3L) treatment.

[0083] In certain exemplary embodiments, the subject has bilateral shoulder pain.

[0084] In certain exemplary embodiments, the subject has a C-reactive protein (CRP) level of >10 mg / L and / or an erythrocyte sedimentation rate (ESR) >30 mm / hr.

[0085] In certain exemplary embodiments, the subject has morning stiffness.

[0086] In certain exemplary embodiments, the subject has an absence of joint involvement other than the shoulder joint.

[0087] In certain exemplary embodiments, the subject has hip pain or limited range of motion.

[0088] In certain exemplary embodiments, the subject is seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP).

[0089] In certain exemplary embodiments, the subject does not have a disorder or disease selected from: giant cell arteritis, rheumatoid arthritis, inflammatory arthritis, connective tissue disease, rhabdomyolysis, neuropathic muscular disease, and active fibromyalgia. In certain exemplary embodiments, the connective tissue disease is selected from: systemic lupus erythematosus, systemic sclerosis, vasculitis, myositis, mixed connective tissue disease, and ankylosing spondylitis.

[0090] In certain exemplary embodiments, the subject has at least one shoulder with subdeltoid bursitis and / or biceps tenosynovitis and / or posterior or axillary glenohumeral synovitis, and at least one hip with synovitis and / or trochanteric bursitis.

[0091] In certain exemplary embodiments, at least one symptom of PMR in the subject is improved after administering the IL-6 receptor inhibitor.

[0092] In certain exemplary embodiments, the at least one symptom is selected from: shoulder pain associated with inflammatory stiffness; hip pain associated with inflammatory stiffness; elevated C reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR); and any combinations thereof.

[0093] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in the improvement of least one patient reported outcome measure or clinician reported outcome measure selected from the group consisting of: functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue), EuroQol five-dimensional three-level questionnaire (EQ-5D-3L), and Short form-36v2 (SF-36v2), health assessment questionnaire disability index (HAQ-DI), and physician global assessment of disease activity- Visual Analog Scale (MD-VAS).

[0094] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in a decrease in glucocorticoid toxicity index (GTI) score.

[0095] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in a decrease in PMR activity score (PMR-AS).

[0096] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in an increase in time to first PMR flare. In certain exemplary embodiments, the first PMR flareincludes a symptom selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0097] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in remission of PMR in the subject.

[0098] In certain exemplary embodiments, the subject has an absence of disease flare in remission. In certain exemplary embodiments, a symptom of PMR flare is selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0099] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in increased resolution of PMR signs and symptoms or GC-free resolution of PMR signs and symptoms in the subject. In certain exemplary embodiments, the resolution of PMR signs and symptoms is achieved from week 4 after starting treatment with the IL-6 receptor inhibitor. In certain exemplary embodiments, the GC-free resolution of PMR signs and symptoms is maintained from week 16 after starting treatment with the IL-6 receptor inhibitor to week 52.

[0100] In certain exemplary embodiments, the antibody is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

[0101] In certain exemplary embodiments, the IL-6 inhibitory therapy comprises an anti-anti - IL6R antibody or an antigen-binding fragment thereof. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg to about 200 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered every other week (q2w).

[0102] In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4 and 5, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7 and 8. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain variableregion sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL6R antibody is sarilumab.

[0103] In certain exemplary embodiments, the antibody is sarilumab or a variant thereof (e.g., a variant with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to the sarilumab sequence, or a biosimilar thereof

[0104] In certain exemplary embodiments, the IL-6 receptor inhibitor is administered subcutaneously. In certain exemplary embodiments, the IL-6 receptor inhibitor is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0105] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, discontinues corticosteroid use.

[0106] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, achieves a minimal corticosteroid dose of less than or equal to about 2 mg / day.

[0107] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, achieves a minimal corticosteroid dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose). In certain exemplary embodiments, such a period of time for administration of an IL-6R inhibitor may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time for administration of an IL-6R inhibitor may be about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0108] In another aspect, a method of reducing or eliminating dependence of a subject with polymyalgia rheumatica (PMR) on a background therapy comprising a corticosteroid for the treatment of PMR, wherein the subject has a Claims-Based Frailty Index (CFI) value of greaterthan or equal to about 0.15 is provided, comprising: (a) selecting a patient having a CFI value of greater than or equal to about 0.15 who has PMR that is partially controlled or uncontrolled with a background therapy comprising a corticosteroid; (b) administering to the frail patient an effective amount of an interleukin-6 (IL 6) receptor inhibitor at a defined frequency for an initial treatment period while maintaining the subject’s background PMR therapy for the initial treatment period; and (c) gradually reducing or eliminating the dosage of the corticosteroid administered to the subject over the course of a subsequent treatment period while continuing to administer the IL-6 receptor inhibitor to the subject at the defined frequency and dose used during the initial treatment period.

[0109] In certain exemplary embodiments, the IL-6 receptor inhibitor is an antibody or antigen-binding fragment thereof that specifically binds IL-6 receptor.

[0110] In certain exemplary embodiments, the subject has PMR that is refractory to a steroid or is refractory to a steroid taper. In certain exemplary embodiments, the subject has had an inadequate response to a steroid or cannot tolerate a steroid taper.

[0111] In certain exemplary embodiments, the steroid comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0112] In certain exemplary embodiments, the subject was previously treated with the at least one steroid (e.g., a corticosteroid such as prednisone) at: (i) a dose (e.g., a prednisone equivalent dose) of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day (a prednisone equivalent dose); or (ii) a dose of about 5 mg / day (a prednisone equivalent dose). In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of greater than or equal to about 2.5 mg / day, greater than or equal to about 5 mg / day, greater than or equal to about 10 mg / day, greater than or equal to about 15 mg / day, or greater than or equal to about 20 mg / day. In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of less than or equal to about 25 mg / day, less than or equal to about 20 day, mg / day, less than or equal to about 15 mg / day, less than or equal to about 10 mg / day, or less than or equal to about 25 mg / day.

[0113] In certain exemplary embodiments, the IL-6 receptor inhibitor is administered in combination with a second therapeutic agent. In certain exemplary embodiments, the second therapeutic agent comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0114] In certain exemplary embodiments, the corticosteroid is administered: (i) at a dose (e.g., a prednisone equivalent dose) of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day (a prednisone equivalent dose); or (ii) about 5 mg / day (a prednisone equivalent dose). In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of greater than or equal to about 2.5 mg / day, greater than or equal to about 5 mg / day, greater than or equal to about 10 mg / day, greater than or equal to about 15 mg / day, or greater than or equal to about 20 mg / day. In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of less than or equal to about 25 mg / day, less than or equal to about 20 day, mg / day, less than or equal to about 15 mg / day, less than or equal to about 10 mg / day, or less than or equal to about 25 mg / day.

[0115] In certain exemplary embodiments, the dose of corticosteroid is discontinued or tapered, optionally to less than or equal to about 2.5 mg / day or less than or equal to about 2.0 mg / day.

[0116] In certain exemplary embodiments, the dose of corticosteroid is discontinued or tapered to a dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose), after the IL-6 inhibitor (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of time. In certain exemplary embodiments, such a period of time may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time may be about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0117] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at about 10 weeks, at about 12 weeks, at about 14 weeks, at about 16 weeks, at about 18 weeks, at about 20 weeks, at about 25 weeks, or at about 30 weeks, or later, after administering a first dose of the IL-6 receptor inhibitor.

[0118] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at between about 10 weeks and about 20 weeks after administering a first dose of the IL-6 receptor inhibitor, optionally wherein the corticosteroid is discontinued beginning at about 14 weeks after administering a first dose of the IL-6 receptor inhibitor.

[0119] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days.

[0120] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning about 25 days to about 300 days, about 50 days to about 250 days, about 50 days to about 300 days, about 50 days to about 350 days.

[0121] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days.

[0122] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0123] In certain exemplary embodiments, the subject was previously treated with a conventional synthetic immunomodulatory drug (csIM). In certain exemplary embodiments, the subject is concomitantly treated with a csIM in addition to the IL-6 receptor inhibitor. In certain exemplary embodiments, the csIM is selected from: methotrexate, azathioprine, sulfasalazine, hydroxychloroquine, and leflunomide. In certain exemplary embodiments, the csIM is or comprises methotrexate.

[0124] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

[0125] In certain exemplary embodiments, the subject has a Claims-Based Frailty Index (CFI) value of greater than or equal to about 0.25, or greater than or equal to about 0.35. In certainexemplary embodiments, the subject has a CFI value of about 0.25 to about 0.34 or ≥ about 0.35. In certain exemplary embodiments, the subject has a CFI value of ≥ about 0.25.

[0126] In certain exemplary embodiments, the subject is mildly frail. In certain exemplary embodiments, the subject is moderate -to-severely frail.

[0127] In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0128] In certain exemplary embodiments, the subject 50 years old or older. In certain exemplary embodiments, the subject is 65 years old or older.

[0129] In certain exemplary embodiments, the subject was previously administered both a glucocorticoid and a csIM.

[0130] In certain exemplary embodiments, the subject has one or more comorbidities selected from: asthma, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, giant cell arteritis, psoriasis and seronegative rheumatoid arthritis.

[0131] In certain exemplary embodiments, the IL-6 receptor inhibitor is used as a second line (2L) treatment. In certain exemplary embodiments, the IL-6 receptor inhibitor is used as a third line (3L) treatment.

[0132] In certain exemplary embodiments, the subject has bilateral shoulder pain.

[0133] In certain exemplary embodiments, the subject has a C-reactive protein (CRP) level of >10 mg / L and / or an erythrocyte sedimentation rate (ESR) >30 mm / hr.

[0134] In certain exemplary embodiments, the subject has morning stiffness .

[0135] In certain exemplary embodiments, the subject has an absence of joint involvement other than the shoulder joint.

[0136] In certain exemplary embodiments, the subject has hip pain or limited range of motion.

[0137] In certain exemplary embodiments, the subject is seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP).

[0138] In certain exemplary embodiments, the subject does not have a disorder or disease selected from: giant cell arteritis, rheumatoid arthritis, inflammatory arthritis, connective tissuedisease, rhabdomyolysis, neuropathic muscular disease, and active fibromyalgia. In certain exemplary embodiments, the connective tissue disease is selected from: systemic lupus erythematosus, systemic sclerosis, vasculitis, myositis, mixed connective tissue disease, and ankylosing spondylitis.

[0139] In certain exemplary embodiments, the subject has at least one shoulder with subdeltoid bursitis and / or biceps tenosynovitis and / or posterior or axillary glenohumeral synovitis, and at least one hip with synovitis and / or trochanteric bursitis.

[0140] In certain exemplary embodiments, at least one symptom of PMR in the subject is improved after administering the IL-6 receptor inhibitor.

[0141] In certain exemplary embodiments, the at least one symptom is selected from: shoulder pain associated with inflammatory stiffness; hip pain associated with inflammatory stiffness; elevated C reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR); and any combinations thereof.

[0142] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in the improvement of least one patient reported outcome measure or clinician reported outcome measure selected from the group consisting of: functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue), EuroQol five-dimensional three-level questionnaire (EQ-5D-3L), and Short form-36v2 (SF-36v2), health assessment questionnaire disability index (HAQ-DI), and physician global assessment of disease activity- Visual Analog Scale (MD-VAS).

[0143] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in a decrease in glucocorticoid toxicity index (GTI) score.

[0144] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in a decrease in PMR activity score (PMR- AS).

[0145] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in an increase in time to first PMR flare. In certain exemplary embodiments, the first PMR flare includes a symptom selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0146] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in remission of PMR in the subject.

[0147] In certain exemplary embodiments, the subject has an absence of disease flare in remission. In certain exemplary embodiments, a symptom of PMR flare is selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0148] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in increased resolution of PMR signs and symptoms or GC-free resolution of PMR signs and symptoms in the subject. In certain exemplary embodiments, the resolution of PMR signs and symptoms is achieved from week 4 after starting treatment with the IL-6 receptor inhibitor. In certain exemplary embodiments, the GC-free resolution of PMR signs and symptoms is maintained from week 16 after starting treatment with the IL-6 receptor inhibitor to week 52.

[0149] In certain exemplary embodiments, the antibody is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

[0150] In certain exemplary embodiments, the IL-6 inhibitory therapy comprises an anti-anti - IL6R antibody or an antigen-binding fragment thereof. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg to about 200 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered every other week (q2w).

[0151] In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4 and 5, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7 and 8. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragmentthereof comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL6R antibody is sarilumab.

[0152] In certain exemplary embodiments, the antibody is sarilumab or a variant thereof (e.g., a variant with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to the sarilumab sequence, or a biosimilar thereof

[0153] In certain exemplary embodiments, the IL-6 receptor inhibitor is administered subcutaneously. In certain exemplary embodiments, the IL-6 receptor inhibitor is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0154] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, discontinues corticosteroid use.

[0155] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, achieves a minimal corticosteroid dose of less than or equal to about 2 mg / day.

[0156] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, achieves a minimal corticosteroid dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose). In certain exemplary embodiments, such a period of time for administration of an IL-6R inhibitor may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time for administration of an IL-6R inhibitor may be about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0157] In another aspect, a method of reducing or eliminating dependence of a frail subject with polymyalgia rheumatica (PMR) on a background therapy comprising a corticosteroid for the treatment of PMR, wherein the subject has a Claims-Based Frailty Index (CFI) value of between about 0.25 and about 0.34 is provided, comprising: (a) selecting a fail patient who has PMR and a CFI value of between about 0.25 and about 0.34 that is partially controlled oruncontrolled with a background therapy comprising a corticosteroid; (b) administering to the frail patient an effective amount of an interleukin-6 (IL 6) receptor inhibitor at a defined frequency for an initial treatment period while maintaining the subject’s background PMR therapy for the initial treatment period; and (c) gradually reducing or eliminating the dosage of the corticosteroid administered to the subject over the course of a subsequent treatment period while continuing to administer the IL-6 receptor inhibitor to the subject at the defined frequency and dose used during the initial treatment period.

[0158] In certain exemplary embodiments, the IL-6 receptor inhibitor is an antibody or antigen-binding fragment thereof that specifically binds IL-6 receptor.

[0159] In certain exemplary embodiments, the subject has PMR that is refractory to a steroid or is refractory to a steroid taper. In certain exemplary embodiments, the subject has had an inadequate response to a steroid or cannot tolerate a steroid taper.

[0160] In certain exemplary embodiments, the steroid comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0161] In certain exemplary embodiments, the subject was previously treated with the at least one steroid (e.g., a corticosteroid such as prednisone) at: (i) a dose (e.g., a prednisone equivalent dose) of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day (a prednisone equivalent dose); or (ii) a dose of about 5 mg / day (a prednisone equivalent dose). In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of greater than or equal to about 2.5 mg / day, greater than or equal to about 5 mg / day, greater than or equal to about 10 mg / day, greater than or equal to about 15 mg / day, or greater than or equal to about 20 mg / day. In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of less than or equal to about 25 mg / day, less than or equal to about 20 day, mg / day, less than or equal to about 15 mg / day, less than or equal to about 10 mg / day, or less than or equal to about 25 mg / day.

[0162] In certain exemplary embodiments, the IL-6 receptor inhibitor is administered in combination with a second therapeutic agent. In certain exemplary embodiments, the second therapeutic agent comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0163] In certain exemplary embodiments, the corticosteroid is administered: (i) at a dose (e.g., a prednisone equivalent dose) of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day (a prednisone equivalent dose); or (ii) about 5 mg / day (a prednisone equivalent dose). In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of greater than or equal to about 2.5 mg / day, greater than or equal to about 5 mg / day, greater than or equal to about 10 mg / day, greater than or equal to about 15 mg / day, or greater than or equal to about 20 mg / day. In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of less than or equal to about 25 mg / day, less than or equal to about 20 day, mg / day, less than or equal to about 15 mg / day, less than or equal to about 10 mg / day, or less than or equal to about 25 mg / day.

[0164] In certain exemplary embodiments, the dose of corticosteroid is discontinued or tapered, optionally to less than or equal to about 2.5 mg / day or less than or equal to about 2.0 mg / day.

[0165] In certain exemplary embodiments, the dose of corticosteroid is discontinued or tapered to a dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose), after the IL-6 inhibitor (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of time. In certain exemplary embodiments, such a period of time may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time may be about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0166] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at about 10 weeks, at about 12 weeks, at about 14 weeks, at about 16 weeks, at about 18 weeks, at about 20 weeks, at about 25 weeks, or at about 30 weeks, or later, after administering a first dose of the IL-6 receptor inhibitor.

[0167] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at between about 10 weeks and about 20 weeks after administering a first dose of the IL-6 receptor inhibitor, optionally wherein the corticosteroid is discontinued beginning at about 14 weeks after administering a first dose of the IL-6 receptor inhibitor.

[0168] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days.

[0169] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning about 25 days to about 300 days, about 50 days to about 250 days, about 50 days to about 300 days, about 50 days to about 350 days.

[0170] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days.

[0171] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0172] In certain exemplary embodiments, the subject was previously treated with a conventional synthetic immunomodulatory drug (csIM). In certain exemplary embodiments, the subject is concomitantly treated with a csIM in addition to the IL-6 receptor inhibitor. In certain exemplary embodiments, the csIM is selected from: methotrexate, azathioprine, sulfasalazine, hydroxychloroquine, and leflunomide. In certain exemplary embodiments, the csIM is or comprises methotrexate.

[0173] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

[0174] In certain exemplary embodiments, the subject has a Claims-Based Frailty Index (CFI) value of greater than or equal to about 0.25, or greater than or equal to about 0.35. In certainexemplary embodiments, the subject has a CFI value of about 0.25 to about 0.34 or ≥ about 0.35. In certain exemplary embodiments, the subject has a CFI value of ≥ about 0.25.

[0175] In certain exemplary embodiments, the subject is mildly frail. In certain exemplary embodiments, the subject is moderate -to-severely frail.

[0176] In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0177] In certain exemplary embodiments, the subject 50 years old or older. In certain exemplary embodiments, the subject is 65 years old or older.

[0178] In certain exemplary embodiments, the subject was previously administered both a glucocorticoid and a csIM.

[0179] In certain exemplary embodiments, the subject has one or more comorbidities selected from: asthma, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, giant cell arteritis, psoriasis and seronegative rheumatoid arthritis.

[0180] In certain exemplary embodiments, the IL-6 receptor inhibitor is used as a second line (2L) treatment. In certain exemplary embodiments, the IL-6 receptor inhibitor is used as a third line (3L) treatment.

[0181] In certain exemplary embodiments, the subject has bilateral shoulder pain.

[0182] In certain exemplary embodiments, the subject has a C-reactive protein (CRP) level of >10 mg / L and / or an erythrocyte sedimentation rate (ESR) >30 mm / hr.

[0183] In certain exemplary embodiments, the subject has morning stiffness .

[0184] In certain exemplary embodiments, the subject has an absence of joint involvement other than the shoulder joint.

[0185] In certain exemplary embodiments, the subject has hip pain or limited range of motion.

[0186] In certain exemplary embodiments, the subject is seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP).

[0187] In certain exemplary embodiments, the subject does not have a disorder or disease selected from: giant cell arteritis, rheumatoid arthritis, inflammatory arthritis, connective tissuedisease, rhabdomyolysis, neuropathic muscular disease, and active fibromyalgia. In certain exemplary embodiments, the connective tissue disease is selected from: systemic lupus erythematosus, systemic sclerosis, vasculitis, myositis, mixed connective tissue disease, and ankylosing spondylitis.

[0188] In certain exemplary embodiments, the subject has at least one shoulder with subdeltoid bursitis and / or biceps tenosynovitis and / or posterior or axillary glenohumeral synovitis, and at least one hip with synovitis and / or trochanteric bursitis.

[0189] In certain exemplary embodiments, at least one symptom of PMR in the subject is improved after administering the IL-6 receptor inhibitor.

[0190] In certain exemplary embodiments, the at least one symptom is selected from: shoulder pain associated with inflammatory stiffness; hip pain associated with inflammatory stiffness; elevated C reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR); and any combinations thereof.

[0191] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in the improvement of least one patient reported outcome measure or clinician reported outcome measure selected from the group consisting of: functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue), EuroQol five-dimensional three-level questionnaire (EQ-5D-3L), and Short form-36v2 (SF-36v2), health assessment questionnaire disability index (HAQ-DI), and physician global assessment of disease activity- Visual Analog Scale (MD-VAS).

[0192] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in a decrease in glucocorticoid toxicity index (GTI) score.

[0193] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in a decrease in PMR activity score (PMR- AS).

[0194] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in an increase in time to first PMR flare. In certain exemplary embodiments, the first PMR flare includes a symptom selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0195] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in remission of PMR in the subject.

[0196] In certain exemplary embodiments, the subject has an absence of disease flare in remission. In certain exemplary embodiments, a symptom of PMR flare is selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0197] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in increased resolution of PMR signs and symptoms or GC-free resolution of PMR signs and symptoms in the subject. In certain exemplary embodiments, the resolution of PMR signs and symptoms is achieved from week 4 after starting treatment with the IL-6 receptor inhibitor. In certain exemplary embodiments, the GC-free resolution of PMR signs and symptoms is maintained from week 16 after starting treatment with the IL-6 receptor inhibitor to week 52.

[0198] In certain exemplary embodiments, the antibody is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

[0199] In certain exemplary embodiments, the IL-6 inhibitory therapy comprises an anti-anti - IL6R antibody or an antigen-binding fragment thereof. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg to about 200 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered every other week (q2w).

[0200] In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4 and 5, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7 and 8. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragmentthereof comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL6R antibody is sarilumab.

[0201] In certain exemplary embodiments, the antibody is sarilumab or a variant thereof (e.g., a variant with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to the sarilumab sequence, or a biosimilar thereof

[0202] In certain exemplary embodiments, the IL-6 receptor inhibitor is administered subcutaneously. In certain exemplary embodiments, the IL-6 receptor inhibitor is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0203] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, discontinues corticosteroid use.

[0204] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, achieves a minimal corticosteroid dose of less than or equal to about 2 mg / day.

[0205] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, achieves a minimal corticosteroid dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose). In certain exemplary embodiments, such a period of time for administration of an IL-6R inhibitor may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time for administration of an IL-6R inhibitor may be about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0206] In another aspect, a method of reducing or eliminating dependence of a frail subject with polymyalgia rheumatica (PMR) on a background therapy comprising a corticosteroid for the treatment of PMR, wherein the subject has a Claims-Based Frailty Index (CFI) value of ≥0.35 is provided, comprising: (a) selecting a fail patient who has PMR and a CFI value of ≥0.35 that is partially controlled or uncontrolled with a background therapy comprising acorticosteroid; (b) administering to the frail patient an effective amount of an interleukin-6 (IL 6) receptor inhibitor at a defined frequency for an initial treatment period while maintaining the subject’s background PMR therapy for the initial treatment period; and (c) gradually reducing or eliminating the dosage of the corticosteroid administered to the subject over the course of a subsequent treatment period while continuing to administer the IL-6 receptor inhibitor to the subject at the defined frequency and dose used during the initial treatment period.

[0207] In certain exemplary embodiments, the IL-6 receptor inhibitor is an antibody or antigen-binding fragment thereof that specifically binds IL-6 receptor.

[0208] In certain exemplary embodiments, the subject has PMR that is refractory to a steroid or is refractory to a steroid taper. In certain exemplary embodiments, the subject has had an inadequate response to a steroid or cannot tolerate a steroid taper.

[0209] In certain exemplary embodiments, the steroid comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0210] In certain exemplary embodiments, the subject was previously treated with the at least one steroid (e.g., a corticosteroid such as prednisone) at: (i) a dose (e.g., a prednisone equivalent dose) of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day (a prednisone equivalent dose); or (ii) a dose of about 5 mg / day (a prednisone equivalent dose). In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of greater than or equal to about 2.5 mg / day, greater than or equal to about 5 mg / day, greater than or equal to about 10 mg / day, greater than or equal to about 15 mg / day, or greater than or equal to about 20 mg / day. In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of less than or equal to about 25 mg / day, less than or equal to about 20 day, mg / day, less than or equal to about 15 mg / day, less than or equal to about 10 mg / day, or less than or equal to about 25 mg / day.

[0211] In certain exemplary embodiments, the IL-6 receptor inhibitor is administered in combination with a second therapeutic agent. In certain exemplary embodiments, the second therapeutic agent comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0212] In certain exemplary embodiments, the corticosteroid is administered: (i) at a dose (e.g., a prednisone equivalent dose) of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day (a prednisone equivalent dose); or (ii) about 5 mg / day (a prednisone equivalent dose). In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of greater than or equal to about 2.5 mg / day, greater than or equal to about 5 mg / day, greater than or equal to about 10 mg / day, greater than or equal to about 15 mg / day, or greater than or equal to about 20 mg / day. In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of less than or equal to about 25 mg / day, less than or equal to about 20 day, mg / day, less than or equal to about 15 mg / day, less than or equal to about 10 mg / day, or less than or equal to about 25 mg / day.

[0213] In certain exemplary embodiments, the dose of corticosteroid is discontinued or tapered, optionally to less than or equal to about 2.5 mg / day or less than or equal to about 2.0 mg / day.

[0214] In certain exemplary embodiments, the dose of corticosteroid is discontinued or tapered to a dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose), after the IL-6 inhibitor (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of time. In certain exemplary embodiments, such a period of time may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time may be about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0215] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at about 10 weeks, at about 12 weeks, at about 14 weeks, at about 16 weeks, at about 18 weeks, at about 20 weeks, at about 25 weeks, or at about 30 weeks, or later, after administering a first dose of the IL-6 receptor inhibitor.

[0216] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at between about 10 weeks and about 20 weeks after administering a first dose of the IL-6 receptor inhibitor, optionally wherein the corticosteroid is discontinued beginning at about 14 weeks after administering a first dose of the IL-6 receptor inhibitor.

[0217] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days.

[0218] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning about 25 days to about 300 days, about 50 days to about 250 days, about 50 days to about 300 days, about 50 days to about 350 days.

[0219] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days.

[0220] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0221] In certain exemplary embodiments, the subject was previously treated with a conventional synthetic immunomodulatory drug (csIM). In certain exemplary embodiments, the subject is concomitantly treated with a csIM in addition to the IL-6 receptor inhibitor. In certain exemplary embodiments, the csIM is selected from: methotrexate, azathioprine, sulfasalazine, hydroxychloroquine, and leflunomide. In certain exemplary embodiments, the csIM is or comprises methotrexate.

[0222] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

[0223] In certain exemplary embodiments, the subject has a Claims-Based Frailty Index (CFI) value of greater than or equal to about 0.25, or greater than or equal to about 0.35. In certainexemplary embodiments, the subject has a CFI value of about 0.25 to about 0.34 or ≥ about 0.35. In certain exemplary embodiments, the subject has a CFI value of ≥ about 0.25.

[0224] In certain exemplary embodiments, the subject is moderate-to-severely frail.

[0225] In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0226] In certain exemplary embodiments, the subject 50 years old or older. In certain exemplary embodiments, the subject is 65 years old or older.

[0227] In certain exemplary embodiments, the subject was previously administered both a glucocorticoid and a csIM.

[0228] In certain exemplary embodiments, the subject has one or more comorbidities selected from: asthma, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, giant cell arteritis, psoriasis and seronegative rheumatoid arthritis.

[0229] In certain exemplary embodiments, the IL-6 receptor inhibitor is used as a second line (2L) treatment. In certain exemplary embodiments, the IL-6 receptor inhibitor is used as a third line (3L) treatment.

[0230] In certain exemplary embodiments, the subject has bilateral shoulder pain.

[0231] In certain exemplary embodiments, the subject has a C-reactive protein (CRP) level of >10 mg / L and / or an erythrocyte sedimentation rate (ESR) >30 mm / hr.

[0232] In certain exemplary embodiments, the subject has morning stiffness.

[0233] In certain exemplary embodiments, the subject has an absence of joint involvement other than the shoulder joint.

[0234] In certain exemplary embodiments, the subject has hip pain or limited range of motion.

[0235] In certain exemplary embodiments, the subject is seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP).

[0236] In certain exemplary embodiments, the subject does not have a disorder or disease selected from: giant cell arteritis, rheumatoid arthritis, inflammatory arthritis, connective tissue disease, rhabdomyolysis, neuropathic muscular disease, and active fibromyalgia. In certainexemplary embodiments, the connective tissue disease is selected from: systemic lupus erythematosus, systemic sclerosis, vasculitis, myositis, mixed connective tissue disease, and ankylosing spondylitis.

[0237] In certain exemplary embodiments, the subject has at least one shoulder with subdeltoid bursitis and / or biceps tenosynovitis and / or posterior or axillary glenohumeral synovitis, and at least one hip with synovitis and / or trochanteric bursitis.

[0238] In certain exemplary embodiments, at least one symptom of PMR in the subject is improved after administering the IL-6 receptor inhibitor.

[0239] In certain exemplary embodiments, the at least one symptom is selected from: shoulder pain associated with inflammatory stiffness; hip pain associated with inflammatory stiffness; elevated C reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR); and any combinations thereof.

[0240] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in the improvement of least one patient reported outcome measure or clinician reported outcome measure selected from the group consisting of: functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue), EuroQol five-dimensional three-level questionnaire (EQ-5D-3L), and Short form-36v2 (SF-36v2), health assessment questionnaire disability index (HAQ-DI), and physician global assessment of disease activity- Visual Analog Scale (MD-VAS).

[0241] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in a decrease in glucocorticoid toxicity index (GTI) score.

[0242] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in a decrease in PMR activity score (PMR- AS).

[0243] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in an increase in time to first PMR flare. In certain exemplary embodiments, the first PMR flare includes a symptom selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0244] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in remission of PMR in the subject.

[0245] In certain exemplary embodiments, the subject has an absence of disease flare in remission. In certain exemplary embodiments, a symptom of PMR flare is selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0246] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in increased resolution of PMR signs and symptoms or GC-free resolution of PMR signs and symptoms in the subject. In certain exemplary embodiments, the resolution of PMR signs and symptoms is achieved from week 4 after starting treatment with the IL-6 receptor inhibitor. In certain exemplary embodiments, the GC-free resolution of PMR signs and symptoms is maintained from week 16 after starting treatment with the IL-6 receptor inhibitor to week 52.

[0247] In certain exemplary embodiments, the antibody is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

[0248] In certain exemplary embodiments, the IL-6 inhibitory therapy comprises an anti-anti - IL6R antibody or an antigen-binding fragment thereof. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg to about 200 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered every other week (q2w).

[0249] In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4 and 5, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7 and 8. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL6R antibody is sarilumab.

[0250] In certain exemplary embodiments, the antibody is sarilumab or a variant thereof (e.g., a variant with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to the sarilumab sequence, or a biosimilar thereof.

[0251] In certain exemplary embodiments, the IL-6 receptor inhibitor is administered subcutaneously. In certain exemplary embodiments, the IL-6 receptor inhibitor is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0252] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, discontinues corticosteroid use.

[0253] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, achieves a minimal corticosteroid dose of less than or equal to about 2 mg / day.

[0254] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, achieves a minimal corticosteroid dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose). In certain exemplary embodiments, such a period of time for administration of an IL-6R inhibitor may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time for administration of an IL-6R inhibitor may be about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0255] In another aspect, a method for treating polymyalgia rheumatica (PMR) in a frail subject is provided, comprising: selecting a frail subject having PMR; and administering to the subject an effective amount of an interleukin-6 (IL 6) receptor inhibitor.

[0256] In certain exemplary embodiments, the IL-6 receptor inhibitor is an antibody or antigen-binding fragment thereof that specifically binds IL-6 receptor.

[0257] In certain exemplary embodiments, the subject has PMR that is refractory to a steroid or is refractory to a steroid taper. In certain exemplary embodiments, the subject has had an inadequate response to a steroid or cannot tolerate a steroid taper.

[0258] In certain exemplary embodiments, the steroid comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0259] In certain exemplary embodiments, the subject was previously treated with the at least one steroid (e.g., a corticosteroid such as prednisone) at: (i) a dose (e.g., a prednisone equivalent dose) of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day (a prednisone equivalent dose); or (ii) a dose of about 5 mg / day (a prednisone equivalent dose). In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of greater than or equal to about 2.5 mg / day, greater than or equal to about 5 mg / day, greater than or equal to about 10 mg / day, greater than or equal to about 15 mg / day, or greater than or equal to about 20 mg / day. In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of less than or equal to about 25 mg / day, less than or equal to about 20 day, mg / day, less than or equal to about 15 mg / day, less than or equal to about 10 mg / day, or less than or equal to about 25 mg / day.

[0260] In certain exemplary embodiments, the IL-6 receptor inhibitor is administered in combination with a second therapeutic agent. In certain exemplary embodiments, the second therapeutic agent comprises a corticosteroid. In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0261] In certain exemplary embodiments, the corticosteroid is administered: (i) at a dose (e.g., a prednisone equivalent dose) of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day (a prednisone equivalent dose); or (ii) about 5 mg / day (a prednisone equivalent dose). In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of greater than or equal to about 2.5 mg / day, greater than or equal to about 5 mg / day, greater than or equal to about 10 mg / day, greater than or equal to about 15 mg / day, or greater than or equal to about 20 mg / day. In certain exemplary embodiments, the subject was previously treated with the at least one steroid at a dose of less than or equal to about 25 mg / day, less than or equal to about 20 day, mg / day, less than or equal to about 15 mg / day, less than or equal to about 10 mg / day, or less than or equal to about 25 mg / day.

[0262] In certain exemplary embodiments, the dose of corticosteroid is discontinued or tapered, optionally to less than or equal to about 2.5 mg / day or less than or equal to about 2.0 mg / day.

[0263] In certain exemplary embodiments, the dose of corticosteroid is discontinued or tapered to a dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose), after the IL-6 inhibitor (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of time. In certain exemplary embodiments, such a period of time may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time may be about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0264] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at about 10 weeks, at about 12 weeks, at about 14 weeks, at about 16 weeks, at about 18 weeks, at about 20 weeks, at about 25 weeks, or at about 30 weeks, or later, after administering a first dose of the IL-6 receptor inhibitor.

[0265] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at between about 10 weeks and about 20 weeks after administering a first dose of the IL-6 receptor inhibitor, optionally wherein the corticosteroid is discontinued beginning at about 14 weeks after administering a first dose of the IL-6 receptor inhibitor.

[0266] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days.

[0267] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning about 25 days to about 300 days, about 50 days to about 250 days, about 50 days to about 300 days, about 50 days to about 350 days.

[0268] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days.

[0269] In certain exemplary embodiments, the corticosteroid is tapered or discontinued beginning about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0270] In certain exemplary embodiments, the subject was previously treated with a conventional synthetic immunomodulatory drug (csIM). In certain exemplary embodiments, the subject is concomitantly treated with a csIM in addition to the IL-6 receptor inhibitor. In certain exemplary embodiments, the csIM is selected from: methotrexate, azathioprine, sulfasalazine, hydroxychloroquine, and leflunomide. In certain exemplary embodiments, the csIM is or comprises methotrexate.

[0271] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

[0272] In certain exemplary embodiments, the subject has a Claims-Based Frailty Index (CFI) value of greater than or equal to about 0.25, or greater than or equal to about 0.35. In certain exemplary embodiments, the subject has a CFI value of about 0.25 to about 0.34 or ≥ about 0.35. In certain exemplary embodiments, the subject has a CFI value of ≥ about 0.25.

[0273] In certain exemplary embodiments, the subject is mildly frail. In certain exemplary embodiments, the subject is moderate -to-severely frail.

[0274] In certain exemplary embodiments, the corticosteroid comprises prednisone.

[0275] In certain exemplary embodiments, the subject 50 years old or older. In certain exemplary embodiments, the subject is 65 years old or older.

[0276] In certain exemplary embodiments, the subject was previously administered both a glucocorticoid and a csIM.

[0277] In certain exemplary embodiments, the subject has one or more comorbidities selected from: asthma, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, giant cell arteritis, psoriasis and seronegative rheumatoid arthritis.

[0278] In certain exemplary embodiments, the IL-6 receptor inhibitor is used as a second line (2L) treatment. In certain exemplary embodiments, the IL-6 receptor inhibitor is used as a third line (3L) treatment.

[0279] In certain exemplary embodiments, the subject has bilateral shoulder pain.

[0280] In certain exemplary embodiments, the subject has a C-reactive protein (CRP) level of >10 mg / L and / or an erythrocyte sedimentation rate (ESR) >30 mm / hr.

[0281] In certain exemplary embodiments, the subject has morning stiffness.

[0282] In certain exemplary embodiments, the subject has an absence of joint involvement other than the shoulder joint.

[0283] In certain exemplary embodiments, the subject has hip pain or limited range of motion.

[0284] In certain exemplary embodiments, the subject is seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP).

[0285] In certain exemplary embodiments, the subject does not have a disorder or disease selected from: giant cell arteritis, rheumatoid arthritis, inflammatory arthritis, connective tissue disease, rhabdomyolysis, neuropathic muscular disease, and active fibromyalgia. In certain exemplary embodiments, the connective tissue disease is selected from: systemic lupus erythematosus, systemic sclerosis, vasculitis, myositis, mixed connective tissue disease, and ankylosing spondylitis.

[0286] In certain exemplary embodiments, the subject has at least one shoulder with subdeltoid bursitis and / or biceps tenosynovitis and / or posterior or axillary glenohumeral synovitis, and at least one hip with synovitis and / or trochanteric bursitis.

[0287] In certain exemplary embodiments, at least one symptom of PMR in the subject is improved after administering the IL-6 receptor inhibitor.

[0288] In certain exemplary embodiments, the at least one symptom is selected from: shoulder pain associated with inflammatory stiffness; hip pain associated with inflammatory stiffness; elevated C reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR); and any combinations thereof.

[0289] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in the improvement of least one patient reported outcome measure or clinician reported outcome measure selected from the group consisting of: functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue), EuroQol five-dimensional three-level questionnaire (EQ-5D-3L), and Short form-36v2 (SF-36v2), health assessment questionnaire disability index (HAQ-DI), and physician global assessment of disease activity- Visual Analog Scale (MD-VAS).

[0290] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in a decrease in glucocorticoid toxicity index (GTI) score.

[0291] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in a decrease in PMR activity score (PMR- AS).

[0292] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in an increase in time to first PMR flare. In certain exemplary embodiments, the first PMR flare includes a symptom selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0293] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in remission of PMR in the subject.

[0294] In certain exemplary embodiments, the subject has an absence of disease flare in remission. In certain exemplary embodiments, a symptom of PMR flare is selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

[0295] In certain exemplary embodiments, treatment with the IL-6 receptor inhibitor results in increased resolution of PMR signs and symptoms or GC-free resolution of PMR signs and symptoms in the subject. In certain exemplary embodiments, the resolution of PMR signs and symptoms is achieved from week 4 after starting treatment with the IL-6 receptor inhibitor. Incertain exemplary embodiments, the GC-free resolution of PMR signs and symptoms is maintained from week 16 after starting treatment with the IL-6 receptor inhibitor to week 52.

[0296] In certain exemplary embodiments, the antibody is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof

[0297] In certain exemplary embodiments, the IL-6 inhibitory therapy comprises an anti-anti - IL6R antibody or an antigen-binding fragment thereof In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg to about 200 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 150 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered at a dose of about 200 mg. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof is administered every other week (q2w).

[0298] In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) sequences of SEQ ID NOs: 3, 4 and 5, and comprises light chain complementarity determining region (LCDR) sequences of SEQ ID NOs: 6, 7 and 8. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence of SEQ ID NO: 1 and a light chain variable region sequence of SEQ ID NO: 2. In certain exemplary embodiments, the anti-IL6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO: 9 and a light chain comprising SEQ ID NO: 10. In certain exemplary embodiments, the anti-IL6R antibody is sarilumab.

[0299] In certain exemplary embodiments, the antibody is sarilumab or a variant thereof (e.g., a variant with at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to the sarilumab sequence, or a biosimilar thereof.

[0300] In certain exemplary embodiments, the IL-6 receptor inhibitor is administered subcutaneously. In certain exemplary embodiments, the IL-6 receptor inhibitor is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

[0301] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, discontinues corticosteroid use.

[0302] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, achieves a minimal corticosteroid dose of less than or equal to about 2 mg / day.

[0303] In certain exemplary embodiments, the subject, upon administration of the IL-6R inhibitor, achieves a minimal corticosteroid dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose). In certain exemplary embodiments, such a period of time for administration of an IL-6R inhibitor may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time for administration of an IL-6R inhibitor may be about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.BRIEF DESCRIPTION OF THE DRAWINGS

[0304] The accompanying drawings, which are incorporated herein and constitute part of this specification, illustrate exemplary embodiments of the disclosure, and, together with the general description given above and the detailed description given below, serve to explain the features of the disclosure.

[0305] FIG. 1 is a table depicting the distribution of patient’s characteristics by exposure group for a combined cohort. ^Unless otherwise stated, continuous variables are reported as mean (SD) and categorical as n (5). 'To protect patient privacy and avoid potential identification of patients, only results with >11 patients are reported and data are redacted when there are >11 patents when such results would allow derivation of the number of patients when <11 are reported.#Prednisone equivalents.aCovariates used as direct match criterion.bCovariates in PS model.cCovariates not included in direct match or PS model. Index date was the date IL-6Ri or csIM was initiated. Baseline was defined as the 180 days prior to index date.csIM, conventional synthetic immunomodulators; GC, glucocorticoids; IL-6Ri, interleukin-6 receptor inhibitors; IQR, interquartile range; PMR, polymyalgia rheumatica; PS, propensity score; SD, standard deviation.

[0306] FIG. 2 is a table depicting GC discontinuation and GC discontinuation or minimal GC at one year from index in propensity score (PS)-matched IL-6Ri and csIM in frail patients with PMR. Patients were direct matched on age, gender, baseline daily GC dose category, index day daily GC category, history of GCA, and recency of csIM (3L only) and then PS matched for both 2L and 3L on region, calendar year, baseline GC dose, COPD, seronegative rheumatoid arthritis, and outpatient office visits. For 2L only on Crohn’s disease, psoriasis, ulcerative colitis, and baseline inpatient days. For 3L only on age, index day GC dose category, and asthma. ^Pearson’s Chi-squared test.#Prednisone equivalents. CI, confidence interval; COPD, chronic obstructive pulmonary disease; csIM, conventional synthetic immunomodulators; GC, glucocorticoids; GCA, giant cell arteritis; HR, hazard ratio; IL-6Ri, interleukin-6 receptor inhibitors; IQR, interquartile range; PS, propensity score; SD, standard deviation; 2L, second line; 3L, third line.

[0307] FIG. 3A - FIG. 3B depict the questionnaire for the EuroQol 5 dimensions 3 level version (EQ-5D-3L) assessment, a generic PRO instrument which measures health status.

[0308] FIG. 4A - FIG. 4C depict the questionnaire for the Short Form 36v2 (SF-36v2), a short form generic, 36 item PRO instrument that evaluates 8 multi-item dimensions of health: physical functioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, energy / vitality, bodily pain, and general health perception.

[0309] FIG. 5 depicts the questionnaire for the physician global assessment of disease activity Visual Analog Scale [MD-VAS] used to rate the patient’s disease activity on an anchored 100 mm horizontal VAS where 0 is considered not active and 100 is considered the most active.

[0310] FIG. 6 is a table depicting common frailty scales (from Motta F et al. Front Immunol 2020; 11 :576134). (18) Porta C, et al. Tumor-derived prostaglandin E2 promotes p50 NF-icB- dependent differentiation of monocytic MDSC. Cancer Res (2020) 80(13):2874-88. doi: 10.1158 / 0008-5472. can-19-2843; (19) Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol (2009) 9(3): 162-74. doi: 10.1038 / nri2506; (20) Ostuni R et al. Latent Enhancers Activated by Stimulation in Differentiated Cells.Cell (2013) 152(1):157— 71. doi: 10.1016 / j.cell.2012.12.018; (21) Quinn SR. O’Neill LA. A trio of microRNAs that control Toll-like receptor signalling. Int Immunol (2011) 23(7):421-5. doi: 10.1093 / intimm / dxr034; (22) Takeuch O, Akira S. Epigenetic control of macrophage polarization. Eur J Immunol (2011) 41(9):2490-3. doi: 10.1002 / eji.201141792; (23) Gomes Ana P et al. Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear- Mitochondrial Communication during Aging. Cell (2013) 155(7): 1624-38. doi: 10.1016 / j .cell.2013.11.037; (24) Yoshino J et al. Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice. Cell Metab (2011) 14(4):528-36. doi: 10.1016 / j.cmet.2011.08.014; (25) Imai S-I, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol (2014) 24(8):464-71. doi: 10.1016 / j.tcb.2014.04.002.

[0311] FIG. 7 is a table showing prevalent health outcomes and functional status according to the Claims-Based Frailty Index (CFI).

[0312] FIG. 8 depicts a table showing the association of CFI and Charlson Comorbidity Index (CCI) with adverse health outcomes in two years.

[0313] FIG. 9 graphically depicts cumulative GC dose at 1 year from index date in PS matched frail patients with PMR. *Total mg prednisone equivalents dispensed over follow- up / days of follow-up observation x 7.#Pearson’s Chi-squared test, Wilcoxon rank sum test.

[0314] FIG. 10 depicts a table summarizing hazard ratios in frail patients with PMR after PS match stratified by second (2E) and third (3E) therapy. *Cox models were used to estimate hazard ratios with 95% confidence intervals. **60 days prior to end of enrollment. ^Adjusted for age, region, original reason for Medicare, baseline weekly prednisone-equivalent dose, chronic obstructive pulmonary disease, seronegative rheumatoid arthritis, and giant cell arteritis. Adjustment of hazard ratios was not required as the difference between groups for all PS match covariates was not statistically significant (P ≥ 0.05).

[0315] FIG. 11 is a schematic depicting the study design set forth in Example 1.aSarilumab, tocilizumab.bMethotrexate, leflunomide, azathioprine. *Direct match criteria amended to address potential residual confounders. **PS matched on: region, calendar year, baseline GC dose, COPD, seronegative rheumatoid arthritis, and outpatient office visits (2E and 3E); Crohn’s disease, psoriasis, ulcerative colitis, and baseline inpatient days (2E only); and age,index day GC dose category, and asthma (3L only). ^Treatment gap > 60 days. 2 mg / day prednisone equivalent.

[0316] FIG. 12 graphically depicts a Kaplan Meier survival curve of time to GC discontinuation up to 1 year. CI, confidence interval; GC, glucocorticoids; HR, hazard ratio; IL-6, interleukin-6; IL-6Ri, IL-6 receptor inhibitors; MTX, methotrexate.

[0317] FIG. 13 graphically depicts a Kaplan Meier survival curve of time to minimal / no GC up to 1 year. CI, confidence interval; GC, glucocorticoids; HR, hazard ratio; IL-6, interleukin- 6; IL-6Ri, IL-6 receptor inhibitors; MTX, methotrexate.DETAILED DESCRIPTION

[0318] Before the disclosure is described, it is to be understood that the disclosure is not limited to particular methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, because the scope of the disclosure will be limited only by the appended claims.

[0319] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0320] The term “about,” when used in reference to a particular recited numerical value, means that a value that is similar to the recited value. In general, those skilled in the art, familiar within the context, will appreciate the relevant degree of variance encompassed by “about” or “approximately” in that context. For example, in some embodiments, the term “approximately” or “about” may encompass a range of values that are within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the recited value.

[0321] The term “administering” or “administration” typically refers to the administration of a composition to a subject to achieve delivery of an agent that is, or is included in, a composition to a target site or a site to be treated. Those of ordinary skill in the art will be aware of a variety of routes that may, in appropriate circumstances, be utilized for administration to a subject, for example a human. For example, in some embodiments, administration may be parenteral or subcutaneous. In some embodiments, administration may involve only a single dose. In some embodiments, administration may involve application of a fixed number ofdoses. In some embodiments, administration may involve dosing that is intermittent (e.g., a plurality of doses separated in time) and / or periodic (e.g., individual doses separated by a common period) dosing. In some embodiments, administration may involve continuous dosing (e.g., perfusion) for at least a selected period.

[0322] The terms “conventional synthetic immunomodulatory drug,” “csIM,” “synthetic disease-modifying antirheumatic drug (sDMARD),” can be used interchangeably herein and refer to drugs used to treat immune system conditions such as rheumatoid arthritis. Suitable csIMs or sDMARDs include, but are not limited to, methotrexate, leflunomide, azathioprine, sulfasalazine, hydroxychloroquine and the like.

[0323] Although any methods and materials similar or equivalent to those described herein can be used in the practice of the disclosures herein, the typical methods and materials are now described. All publications mentioned herein are incorporated herein by reference in their entirety.

[0324] The present disclosure provides methods and compositions for treating polymyalgia rheumatica (PMR) in a frail subject.

[0325] Polymyalgia rheumatica is a chronic, inflammatory disorder almost exclusively occurring in people over 50 years old. (Guggino et al. Pathogenesis of Polymyalgia Rheumatica. Reumatismo 2018 70(l):10-17) and Chatzigeorgiou C, et al. Comorbidity in polymyalgia rheumatica. Reumatismo. 2018 Mar 27;70(l):35-43, incorporated by reference herein in their entireties). Polymyalgia rheumatica presents with pain and stiffness of the shoulders and possibly the hip, elevated inflammatory makers (although occasionally normal), and a characteristic dramatic response to corticosteroids. Classification criteria for the diagnosis of polymyalgia rheumatica are described in the European League Against Rheumatism and the American College of Rheumatology (Dasgupta B, et al. 2012 provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism / American College of Rheumatology collaborative initiative. Annals of the Rheumatic Diseases 2012; 71 :484-492, incorporated by reference herein in its entirety). Criteria for classification include a patient who is 50 years old or older presenting with bilateral shoulder pain (not better explained by an alternative diagnosis) and elevated C-reactive protein (CRP) levels and / or elevated erythrocyte sedimentation rate (ESR). Additional criteria include the presence of morning stiffness for more than 45 minutes, and the presentation of new symptoms involving the hip (e.g., pain, tenderness, and limited movement). Additionalclassification criteria can include the lack of peripheral synovitis, lack of positive rheumatoid arthritis (RA) serology (rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), or both), and absence of peripheral joint pain. Additional classification criteria can include musculoskeletal ultrasound findings of bilateral shoulder abnormalities (subacromial bursitis / bicipital tenosynovitis / glenohumeral effusion) or abnormalities in one shoulder and hip (hip effusion, trochanteric bursitis).

[0326] Classification criteria for the diagnosis of polymyalgia rheumatica are described herein. See also the European League Against Rheumatism and the American College of Rheumatology, Dasgupta B, et al. 2012 provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism / American College of Rheumatology collaborative initiative. Annals of the Rheumatic Diseases 2012; 71 :484-492, incorporated herein in their entireties). Criteria for classification may include a patient who is 50 years old or older presenting with bilateral shoulder pain (not better explained by an alternative diagnosis) and elevated C-reactive protein (CRP) levels and / or elevated erythrocyte sedimentation rate (ESR). Additional criteria may include the presence of morning stiffness for more than 45 minutes, and the presentation of new symptoms involving the hip (e.g., pain, tenderness, and limited movement). (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, incorporated herein in its entirety).

[0327] As used herein, the terms “frail” and “frailty” refer to a syndrome characterized by a decline in physiologic reserve and homeostasis, leading to increased vulnerability to stressors and poor outcomes, including disability, falls, hospitalization and mortality. Frailty in an individual may be measured by one or more scales including, but not limited to, Claims-Based Frailty Index (CFI), Fried’s Frailty Phenotype, Frailty Index of Accumulated Deficits (FI-CD), Gill Frailty Measure, Frailty / Vigor Assessment, Canadian Study of Health and Aging Clinical Frailty Scale (CSHA-CFS), Brief Frailty Instrument, Vulnerable Elders Survey, Fatigue, Resistance, Ambulation, Illness and Loss of Weight Index (FRAIL) and the like (See FIGs. 6 and 7).

[0328] For CFI, relevant ICD codes, CPT codes, and HCPCS codes from Medicare data sets were extracted during the 12-month period prior to patients’ Health and Retirement Study (HRS) interviews (Kim et al. The Journals of Gerontology: Series A, Volume 74, Issue 8,August 2019, Pages 1271-1276; doi.org / 10.1093 / gerona / glyl97). Each claims-based variable was weighted by the coefficients derived from a regression model that related variables to a standard survey-based frailty index and summed to generate a CFI (See FIG. 7). This CFI can range from 0 to 1 , with higher values indicating greater frailty. Although CFI is a continuous measure, with a cut-point of more than or equal to 0.25 used to define frailty, median CFI can also be used as a threshold to identify frail patients (See Example 1).

[0329] For CFI, subjects are asked about self-rated health (excellent, very good, good, fair, poor); the frequency and intensity of mild, moderate, and vigorous activity (physical inactivity is defined as the bottom 20% for each sex); falls in the past 2 years; and ability to perform 6 activities of daily living (ADE; dressing, walking across a room, bathing, eating, transferring, toileting), 6 instrumental activities of daily living (IADE; cooking, shopping, using telephone, taking medications, doing housework, managing money), and physical tasks (walking several blocks, climbing 1 flight of stairs, lifting 10 pounds). Weight loss is defined as loss of more than 10-pound loss in measured weight over 2 years. Gait speed (m / s) is calculated from the average of 2 timed 8-feet walks at usual pace. Grip strength (kg) is measured as the average of two measurements in the dominant hand. A Charlson comorbidity index (CCI) is computed using the 12-month Medicare data prior to the HRS interview (See FIG. 8). In certain exemplary embodiments, CFI values are classified as robust: <0.15; pre-frail: 0.15-0.24; mildly frail: 0.25-0.34; and moderate-to-severely frail: ≥0.35. (See Kim DH, et al. J Gerontol A Biol Sci Med Sci. 2019;74(8): 1271— 6.) In certain exemplary embodiments, a frail individual has a CFI of ≥0.2. In certain exemplary embodiments, a frail individual has a CFI of ≥0.25. Individuals with higher values CFI typically have more functional limitations, lower physical performance, and greater risks of death, institutionalization, disabilities, hospitalization, and prolonged skilled nursing facility stay, independently of age, sex, and CCI. Subjects with higher CFI typically have lower mean gait speed and weaker grip strength. Higher CFI is associated with death, institutionalization, activity of daily living disability, instrumental activity of daily living disability, hospitalization, and prolonged skilled nursing facility stay.

[0330] The terms “IE-6 inhibitory therapy,” “IE-6 inhibitor therapy,” “IE-6R antagonist” are used herein interchangeably. In some embodiments, an IE-6 inhibitory therapy is a therapy that partially or completely blocks an IE-6-associated pathway. In some embodiments an IE-6 inhibitory therapy is an antibody. Suitable IE-6 antibodies, include, but are not limited to, sariluniab, tocilizumab, satralizumab, olokizumab, siltuximab, clazakizumab, sirukumab, vobarilizumab, gerilimzumab, clazakizumab, ziltivekimab, olokizumab, and levilimab.

[0331] The term “new onset,” when used in the context of PMR, means a newly developed or recent appearance or beginning of one or more signs and symptoms of PMR. For example, in some embodiments, a subject does not have a prior history of PMR before the treatment of the subject.

[0332] As used herein, the term “PMR flare” refers to an increase in one or more PMR symptoms.

[0333] The signs and symptoms include (i) shoulder pain associated with inflammatory stiffness, (ii) hip girdle pain associated with inflammatory stiffness, (iii) morning stiffness for more than 45 minutes, (iv) elevated C-reactive protein (CRP) levels, (v) elevated erythrocyte sedimentation rate (ESR), and any combination thereof.

[0334] As used herein, the terms “treat,” and “treating,” mean to: (1) partially or completely alleviate one or more symptoms or features of a disease, disorder, and / or condition; or (2) ameliorate, relieve, inhibit, prevent, delay onset of, reduce the severity of, and / or reduce the incidence of one or more symptoms or features of a disease, disorder, and / or condition, e.g., PMR, either on a temporary or permanent basis.

[0335] IL-6 interacts directly with the IL-6Ra subunit and the IL-6 / IL-6Ra pair forms a high affinity complex with the glycoprotein 130 (gp 130) subunit and initiates intracellular signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) (JAK / STAT) and Ras / Raf / mitogen-activated protein kinase (MAPK) pathways. IL-6Ra also exists in a soluble form, which is involved in trans-signaling and allows IL-6 to affect cells that do not express IL-6Ra including synovial cells in the joint.

[0336] Sarilumab (SAR153191), also designated as REGN88, is a recombinant IgGl kappa monoclonal antibody of fully human sequence directed against the alpha subunit of the IL-6 receptor complex (IL-6Ra). Sarilumab blocks the binding of IL-6 and interrupts the cytokine -mediated signaling cascade. Sarilumab is also known by the tradename KEVZARA®.

[0337] Tocilizumab (TCZ) is a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody that binds to the membrane -bound and soluble IL-6 receptors, inhibiting IL-6 signaling. Tocilizumab is also known by the tradename ACTEMRA®.

[0338] Satralizumab is a recombinant humanized monoclonal antibody targeted against human interleukin-6 (IL-6) receptors. Satralizumab is also known by the tradename ENSPRYNG®.

[0339] Levilimab is a fully human monoclonal antibody that binds to interleukin-6 receptor. Levilimab is also known by the tradename ILSIRA®.

[0340] Vobarilizumab is a bispecific nanobody that binds to interleukin-6 receptor. Vobarilizumab is also known as ALX-0061.

[0341] Siltuximab is a chimeric, human-murine immunoglobulin monoclonal antibody that binds to and neutralizes human IL-6 directly, thereby decreasing levels of unbound IL-6 and preventing binding to its receptor. Siltuximab is also known as SYLVANT®.

[0342] Sirukumab is a fully human monoclonal IgGl kappa antibody that selectively blocks circulating IL-6. Sirukumab is also known by its developmental code name CNTO-136, and tentative brand name PLIVENSIA™.

[0343] Gerilimzumab is a recombinant humanized IgGIX monoclonal antibody against interleukin-6. Gerilimzumab is also known as RYI-008, ARGX-109 and GB224.

[0344] Clazakizumab is a humanized monoclonal antibody that binds interleukin-6.

[0345] Ziltivekimab is a monoclonal antibody that binds interleukin-6. Ziltivekimab is also known as MEDI5117, CAT6001 and WBP216

[0346] Olokizumab is humanized monoclonal antibody that binds interleukin-6. Olokizumab is also known as CDP6038.

[0347] In certain exemplary embodiments, a suitable IL 6R antagonist is selected from the group consisting of sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

[0348] Conventional synthetic immunomodulatory drugs (csIMs or synthetic diseasemodifying antirheumatic drugs (DMARDS)) include, but are not limited to, methotrexate, leflunomide, azathioprine, sulfasalazine, hydroxychloroquine and the like.

[0349] In some embodiments, the subject had an inadequate response to current treatment for PMR. In some embodiments, the subject's current treatment includes a suitable corticosteroid selected from the group consisting of prednisone, prednisolone, methyl-prednisolone and the like.Methods for Improving PMR-associated Patient-Reported Outcome (PRO) Measures and Clinician-Reported Outcome (ClinRO) Measures

[0350] Methods for improving one or more PMR-associated patient-reported outcome (PRO) measures in a subject in need thereof, wherein the methods comprise administering a pharmaceutical composition comprising an IL-6R antagonist to the subject, are provided. Methods for improving one or more PMR-associated clinician-reported outcome (ClinRO) measures in a subject in need thereof, wherein the methods comprise administering a pharmaceutical composition comprising an IL-6R antagonist to the subject, are provided.

[0351] Examples of PMR-associated PRO measures include: (1) functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue), (2) EuroQol five-dimensional three-level questionnaire (EQ-5D-3E), (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).

[0352] An “improvement in a PMR-associated PRO measure” means an increase from baseline of one or more of FACIT-Fatigue score, EQ-5D-3E score, or SF-36v2 score; and / or a decrease from baseline of one or more of HAQ-DI score, PtGA score, or Pain-VAS score. As used herein, the term “baseline,” with regard to a PMR-associated PRO measure, means the numerical value of the PRO measure for a patient prior to or at the time of administration of a pharmaceutical composition comprising an IE-6R antagonist.

[0353] An example of a PMR-associated ClinRO measure includes physician global assessment of disease activity-visual analog scale (MD-VAS).

[0354] An “improvement in a PMR-associated ClinRO measure” means a decrease from baseline of MD-VAS score. As used herein, the term “baseline,” with regard to a PMR-associated ClinRO measure, means the numerical value of the ClinRO measure for a patient prior to or at the time of administration of a pharmaceutical composition comprising an IE-6R antagonist.

[0355] To determine whether a PMR-associated parameter has “improved,” the parameter is quantified at baseline and at a time point after administration of the pharmaceutical composition described herein. For example, a PMR-associated parameter may be measured at day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, orat week 3, week 4, week 5, week 6, week 7, week 8, week 9, week 10, week 11, week 12, week 13, week 14, week 15, week 16, week 17, week 18, week 19, week 20, week 21, week 22, week 23, week 24, week 32, week 40, week 52, or longer, after the initial treatment with the pharmaceutical composition. The difference between the value of the parameter at a particular time point following initiation of treatment and the value of the parameter at baseline is used to establish whether there has been an “improvement” in the PMR-associated parameter (e.g., an increase or decrease, as the case may be, depending on the specific parameter being measured).

[0356] The terms “acquire” or “acquiring” as used herein, refer to obtaining possession of a physical entity, or a value, e.g., a numerical value, by “directly acquiring” or “indirectly acquiring” the physical entity or value, such as a PMR-associated parameter. “Directly acquiring” means performing a process (e.g., performing a synthetic or analytical method) to obtain the physical entity or value. “Indirectly acquiring” refers to receiving the physical entity or value from another party or source (e.g., a third-party laboratory that directly acquired the physical entity or value). Directly acquiring a physical entity includes performing a process that includes a physical change in a physical substance, e.g., a starting material. Exemplary changes include making a physical entity from two or more starting materials, shearing or fragmenting a substance, separating or purifying a substance, combining two or more separate entities into a mixture, performing a chemical reaction that includes breaking or forming a covalent or non-covalent bond. Directly acquiring a value includes performing a process that includes a physical change in a sample or another substance, e.g., performing an analytical process which includes a physical change in a substance, e.g., a sample, analyte, or reagent (sometimes referred to herein as “physical analysis”).

[0357] Information that is acquired indirectly can be provided in the form of a report, e.g., supplied in paper or electronic form, such as from an online database or application (an “App”). The report or information can be provided by, for example, a healthcare institution, such as a hospital or clinic; or a healthcare provider, such as a doctor or nurse.The Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-Fatigue)

[0358] According to certain embodiments, administration of an IL-6R antagonist to a patient results in an increase from baseline of the functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue) score (Table 1). FACIT-Fatigue is a generic PRO instrumentwhich includes 13 items to measure fatigue. Each item is rated by patients on a 0 to 4 scale (0 = not at all, 1 = a little bit, 2 = somewhat, 3 = quite a bit, 4 = very much). Scores are summarized to give a total score between 0 and 52. The recall period is the last 7 days.

[0359] Therapeutic methods are provided that result in an increase in FACIT -Fatigue score from baseline. For example, administration of an IE-6R antagonist to a subject in need thereof causes an increase in FACIT-Fatigue score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0360] Table 1: FACIT-Fatigue scaleEuroQol-5 dimensions, 3 level version (EQ-5D-3L)

[0361] According to certain embodiments, administration of an IE-6R antagonist to a patient results in an increase from baseline of EQ-5D-3E. The EQ-5D-3E is a generic PRO instrument which measures health status (EuroQol Group, EuroQol-a new facility for the measurement of health-related quality of life, Health Policy 1990; 16(3): 199-208). There are two components to the EQ-5D; a health utility index score derived from 5 items addressing mobility, self-care, usual activities, pain / discomfort, and anxiety / depression “today”, and a current (“right now”)general health status score derived from a single 0-100 Visual Analog Scale (VAS). EQ-5D index utility scores are anchored at 0 for death and 1 for perfect health. The items contributing to the EQ-5D-3L health utility index score each have the same 3 -point response scale (1 = no problem, 2 = moderate problems, 3 = severe problems). The VAS is anchored with “best imaginable health state” and “worst imaginable health state.”

[0362] Therapeutic methods are provided that result in an increase in EQ VAS score from baseline. For example, administration of an IL-6R antagonist to a subject in need thereof causes an increase in EQ VAS score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 points.

[0363] Therapeutic methods are provided that result in an increase in EQ-5D index utility score from baseline. For example, administration of an IL-6R antagonist to a subject in need thereof causes an increase in EQ-5D index utility score from baseline of about 0.05, 0.1, 0.15, 0.2. 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, or 0.95 points.Short form 36v2 (SF-36v2)

[0364] According to certain embodiments, administration of an IL-6R antagonist to a patient results in an increase from baseline of Short form 36v2 (SF-36v2). The Short Form 36v2 (SF-36v2) is a short-form generic, 36-item PRO instrument that evaluates 8 multi-item dimensions of health: physical functioning (PF; 10 items), social functioning (SF; 2 items), role limitations due to physical problems (RP; 4 items), role limitations due to emotional problems (RE; 3 items), mental health (MH; 5 items), energy / vitality (VT; 4 items), bodily pain (BP; 2 items), and general health perception (GH; 5 items) (Ware, et al. The MOS 36-Item Short-Form Health Survey (SF-36): I. Conceptual Framework and Item Selection, Medical Care 1992;30(6):473-483). For each dimension, item scores are coded, summed, and transformed on to a scale from 0 (worst possible health state measured by the questionnaire) to 100 (best possible health state). Two standardized summary scores can also be calculated from the SF-36v2; the physical component summary (PCS) and the mental health component summary (MCS) on a scale from 0-100 (See Maruish ME (2011) User’s manual for the SF-36v2 Health Survey (3rd ed).. Eincoln, RI: QualityMetric Incorporated).

[0365] Therapeutic methods are provided that result in an increase in SF-36v2 score from baseline. For example, administration of an IL-6R antagonist to a subject in need thereof causes an increase in SF-36v2 score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 points.Health assessment questionnaire disability index (HAQ-DI)

[0366] The HAQ-DI was developed to assess physical functional status in adults with arthritis but is now commonly used among many rheumatologic conditions (See Wolfe F “A brief clinical health assessment instrument: CLINHAQ” Arthritis Rheum. 1989; 32 (suppl): S9 and Wolfe F. “Data collection and utilization: a methodology for clinical practice and clinical research” Rheumatoid arthritis: pathogenesis, assessment, outcome and treatment, New York: Marcel Dekker, 1994: 463-514). It contains 25 items: 20 4-point Likert-scale questions assessing 8 physical dimensions of activities of daily living (dressing and grooming, arising, eating, walking, hygiene, reaching, gripping, and errands and chores), 13 additional questions assessing use of assistive devices, and 8 additional questions assessing help received from another. The recall period is the last week. To calculate the HAQ-DI Score, there are 3 steps: sum the 8 category scores by using the highest sub-category score from each category; adjust for use of aids / devices and / or help from another person when indicated; and divide the summed category scores by the number of categories answered (must be a minimum of 6) to obtain a HAQ-DI score of 0-3 (3=worst functioning). In addition, the HAQ-DI has two additional questions, measured on 0-100 scales: How much pain have you had in the past week? Please rate how well you are doing on a scale of 0 to 100 (0 represents “very well” and 100 represents “very poor” health). These questions, measuring pain and global assessment respectively, are independently scored.

[0367] Therapeutic methods are provided that result in a decrease in HAQ-DI score from baseline. For example, administration of an IL-6R antagonist to a subject in need thereof causes a decrease in HAQ-DI score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 points.Patient Global Assessment of Disease Activity (PtGA)

[0368] PtGA is a single question with a score of 0 to 100 that focuses on overall health or disease activity from the patient perspective. A higher score represents a higher level of disease activity or a worse global health.

[0369] Therapeutic methods are provided that result in a decrease in PtGA score from baseline. For example, administration of an IL-6R antagonist to a subject in need thereof causes a decrease in PtGA score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 points.Pain Visual Analog Scale (VAS)

[0370] Pain VAS is a unidimensional, patient reported measure of pain intensity (See Delgado et al. “Validation of digital visual analog scale pain scoring with a traditional paper-based visual analog scale in adults” Journal of the American Academy of Orthopaedic Surgeons, Mar;2(3)). Pain VAS score ranges from 0 to 100 and a higher score indicates greater pain intensity.

[0371] Therapeutic methods are provided that result in a decrease in Pain VAS score from baseline. For example, administration of an IL-6R antagonist to a subject in need thereof causes a decrease in Pain VAS score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 points.Physician global assessment of disease activity- Visual Analog Scale [MD-VAS]

[0372] In the MD-VAS, a physician rates the patient’s disease activity on an anchored 100 mm horizontal VAS where 0 is considered not active and 100 is considered the most active(See Huskisson et al. “Vertical or Horizontal Visual Analogue Scales” Ann Rheum Dis. 1979 Dec; 38(6):560).

[0373] Therapeutic methods are provided that result in a decrease in MD-VAS score from baseline. For example, administration of an IL-6R antagonist to a subject in need thereof causes a decrease in HAQ-DI score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 points.

[0374] The methods described herein may further improve one or more other PMR-associated outcomes, including, without limitation, PMR activity score (PMR-AS), glucocorticoid toxicity index (GTI), cumulative corticosteroid dose and time to PMR flare.PMR Activity Score (PMR-AS)

[0375] PMR-AS is calculated as the sum of CRP (mg / dL), visual analog score (VAS) for pain (0 to 10), VAS for physician’s assessment (0 to 10), duration of morning stiffness (MST [min] X 0.1), and the ability to elevate the upper limbs (EUL [3-0]).

[0376] Therapeutic methods are provided that result in a decrease in PMR-AS score from baseline. For example, administration of an IL-6R antagonist to a subject in need thereof causes a decrease in PMR-AS score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 points.Glucocorticoid Toxicity Index and Components

[0377] Glucocorticoid Toxicity Index (GTI) is a composite scale designed to assess glucocorticoid-related morbidity and potential steroid- sparing effect of treatment alternatives. GTI-cumulative worsening score (CWS) captures cumulative glucocorticoid toxicity regardless of whether it is permanent or transient. The GTI-CWS can only increase or remain the same over time. A lower score indicates lower glucocorticoid toxicity. The GTI-aggregateimprovement score (AIS) captures both worsening and improvement in glucocorticoid toxicity. New or worsening toxicities contribute a positive score and improvements in existing toxicities contribute a negative score. A lower score indicates lower glucocorticoid toxicity.

[0378] In some embodiments, the administration of an IL-6R inhibitor (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) decreases the cumulative amount of the steroid received by the subject as measured over a period of time after the administration of the IL-6R inhibitor. In some embodiments, such a period of time may be about 2 months, about 4 months, about 5 months, or about 6 months after the administration of the IL-6R inhibitor.

[0379] In some embodiments, the decrease in the cumulative amount of the steroid is at least 30%, at least 40%, at least 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95% or more, as compared to the cumulative amount of the steroid as measured over a period of time before the administration of the IL-6R inhibitor therapy. In some embodiments, such a period of time may be about 2 months, about 4 months, about 5 months, or about 6 months before the administration of the IL-6R inhibitor.

[0380] The Composite GTI and the GTI Specific List constitute the overall GTI. The Composite GTI consists of nine domains and 31 items that assess the potential side effects of glucocorticoid, and include evaluation of body mass index (BMI), glucose tolerance, blood pressure, lipid metabolism, bone mineral density, glucocorticoid-induced myopathy, skin toxicity, neuropsychiatric toxicity and infection. These were the potential CS toxicities that were likely to occur during the course of a clinical trial and could vary depending on the extent of CS exposure, and that are weighted and scored.

[0381] Therapeutic methods are provided that result in a decrease in GTI-CWS or GTI-AIS score from baseline. For example, administration of an IL-6R antagonist to a subject in need thereof causes a decrease in GTI-CWS or GTI-AIS score from baseline of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 points.

[0382] The GTI Specific List consists of 11 domains and 23 items that are not weighted, and captures other CS related toxicities not found in the Composite GTI (see Table 2, below). Information related to the domains / items of the Specific List were collected if available at thescheduled time points (baseline, week 12, week 24, week 40 and week 52), but no pre-specified assessments related to the domains in the Specific List, unless for cause, were required within the conduct of this study.

[0383] Table 2: Specific list for glucocorticoid toxicity indexCumulative Corticosteroid Dose

[0384] The cumulative corticosteroid dose is a measure of a patient’s exposure to corticosteroids over a period of time, such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 weeks.

[0385] Therapeutic methods are provided that result in a decrease cumulative corticosteroid dose over a period of time with treatment with the IL-6R antagonist compared to treatment without the IL-6R antagonist. For example, administration of an IL-6R antagonist to a subject in need thereof causes a decrease in cumulative corticosteroid dose of about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or 3000 mg.Time to PMR Flare

[0386] Therapeutic methods are provided that result in an increase in the amount of time until a patient experiences a PMR flare. For example, administration of an IL-6R antagonist to a subject in need thereof causes an increase in the amount of time until a patient experiences a PMR flare of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,99, or 100 weeks.Methods of Administration and Formulations

[0387] The methods described herein comprise administering a therapeutically effective amount of an anti-IL-6R antibody to a subject. As used herein, the phrase “therapeutically effective amount” means a dose of the therapeutic that results in treatment of PMR. As used herein, “treating” refers to causing a detectable improvement in one or more symptoms associated with polymyalgia rheumatica or causing a biological effect (e.g., a decrease in the level of a particular biomarker) that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s). For example, the following symptoms or conditions are associated with polymyalgia rheumatica: bilateral shoulder pain, pain or tenderness in the hip and limited hip movement, elevated C-reactive protein (CRP) levels, elevated erythrocyte sedimentation rate (ESR), and the presence of morning stiffness for more than a number of minutes (e.g., 30 or 45 minutes).

[0388] An “improvement” in an PMR-associated symptom in various embodiments refers reduction in the incidence of the PMR symptom which may correlate with an improvement in one or more P-associated test, score or metric (as described here). For example, the improvement may correlate an increase from baseline of one or more of C-reactive protein (CRP), ESR, IL-6, soluble IL-6R, and / or markers of inflammation and disease activity over time as assessed in circulating immune cell types, circulating proteins, and gene expression changes. As used herein, the term “baseline,” with regard to a PMR-associated parameter, means the numerical value of the PMR-associated parameter for a patient prior to or at the time of administration of the antibody described herein.

[0389] A detectable “improvement” can also be detected using at least one test, score or metric described herein. In various embodiments, the improvement is detected by a reduction in a symptom of PMR selected from the group consisting of: morning stiffness, pain in the neck, pain in the shoulder, pain in the hip girdles, limited range of motion of the shoulders, limited range of motion in the hip girdles, constitutional symptoms (e.g., fatigue, weight loss and low grade fever), and other features judged by the clinician-investigator to be consistent with a PMR flare. In various embodiments, the improvement is detected by using at least one selected from the group consisting of: a patient-reported outcome (PRO) questionnaire, a functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue), EQ-5D-3L, Short Form 36v2, HAQ-DI, PMR-AS, and physician global assessment of disease activity (e.g., Visual Analog Scale (MD-VAS)).

[0390] In various embodiments, a detectable improvement is defined as a sustained remission of the disease. As used herein, a “sustained remission” of PMR in a subject is defined as being one or several of the following: (i) disease remission, in particular by week 12 after initiation of the treatment with a therapeutically effective amount of an anti-IL-6R antibody (i.e., absence of signs and symptoms of PMR in the subject); (ii) absence of disease flare; (iii) C-reactive protein normalization, in particular from weeks 12 to 52; or (iv) adherence to a steroid taper protocol, in particular a glucocorticoid taper (e.g., prednisone taper) protocol, in particular from weeks 12 to 52.

[0391] In another example, a treatment has not been effective when a dose of anti-IL-6R antibody does not result in a detectable improvement in one or more parameters or symptoms associated with PMR or which does not cause a biological effect that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s) of PMR.

[0392] In various embodiments, an IL-6R antibody is administered subcutaneously. In various embodiments, the IL-6R antibody is sarilumab, tocilizumab, satralizumab, levilimab, or vobarilizumab or any antigen-binding fragments thereof.

[0393] In various embodiments, a therapeutically effective amount of anti-IL-6R antibody that is administered to the subject will vary depending upon the age and the size (e.g., body weight or body surface area) of the subject as well as the route of administration and other factors well known to those of ordinary skill in the art.

[0394] In various embodiments, the dose is a fixed dose regardless of the body weight or surface area of the subject. In various embodiments, the subject is at least 50 years old. In various embodiments, the subject is older than 50 years old.

[0395] The disclosure provides methods of using therapeutic compositions comprising anti-IL-6R antibodies or antigen-binding fragments thereof and, optionally, one or more additional therapeutic agents. The therapeutic compositions of the present disclosure will be administered with suitable carriers, excipients, and / or other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary 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, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN®), DNA conjugates, anhydrousabsorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbo wax.

[0396] Various delivery systems are known and can be used to administer pharmaceutical compositions provided herein, e.g., encapsulation in liposomes, microparticles, microcapsules, receptor mediated endocytosis. Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc), and may be administered together with other biologically active agents. Administration can be systemic or local. The IL-6R antibody can be administered subcutaneously.

[0397] The pharmaceutical composition can also be delivered in a vesicle, such as a liposome. In certain embodiments, the pharmaceutical composition can be delivered in a controlled release system, for example, with the use of a pump or polymeric materials. In certain embodiments, a controlled release system can be placed in proximity of the composition’s target, thus requiring only a fraction of the systemic dose.

[0398] The injectable preparations may include dosage forms for intravenous, subcutaneous, intracutaneous and intramuscular injections, local injection, drip infusions, etc. These injectable preparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc). As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared can be filled in an appropriate ampoule.

[0399] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0400] In various embodiments, the anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) can be administered to the patient using any acceptable device or mechanism. For example, the administration can be accomplished using a syringe and needle or with 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 to administer an anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody). Examples of such devices include, but are not limited to 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®, OPTIPEN STARLET®, and OPTICLIK® (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen and / or autoinjector delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present disclosure include, but are not limited to the SOLOSTAR® pen (Sanofi-Aventis), the FLEXPEN® (Novo Nordisk), and the KWIKPEN® (Eli Lilly), the SURECLICK® Autoinjector (Amgen, Thousand Oaks, CA), the PENLET® (Haselmeier, Stuttgart, Germany), the EPIPEN® (Dey, L.P.)., and the HUMIRA® Pen (AbbVie Inc., North Chicago, IL), to name only a few.

[0401] In various embodiments, the antibody is administered with a prefilled syringe. In various embodiments, the antibody is administered with a prefilled syringe containing a safety system. For example, the safety system prevents an accidental needle-stick injury. In various embodiments, the antibody is administered with a prefilled syringe containing an ERIS safety system (West Pharmaceutical Services Inc)..

[0402] In various embodiments, the antibody is administered with an auto -injector. In various embodiments, the antibody is administered with an auto-injector featuring the PUSHCLICK® technology (SHL Group). In various embodiments, the auto-injector is a device comprising a syringe that allows for administration of a dose of the composition and / or antibody to a subject.

[0403] The use of a microinfusor to deliver an anti-IL-6R antibody (or pharmaceutical formulation comprising the antibody) to a patient is also contemplated herein. As used herein, the term “microinfusor” means a subcutaneous delivery device designed to slowly administer large volumes (e.g., up to about 2.5 mL or more) of a therapeutic formulation over a prolonged period of time (e.g., about 10, 15, 20, 25, 30 or more minutes). Microinfusors are particularly useful for the delivery of large doses of therapeutic proteins contained within high concentration (e.g., about 100, 125, 150, 175, 200 mg / rnL or more) and / or viscous solutions.

[0404] In various embodiments, an inadequate response to prior treatment refers to subjects whose pain is not well controlled after receiving the prior treatment at the maximum tolerated typical dose. In an embodiment, an inadequate response to prior treatment refers to subjects who have moderate or high disease activity and features of poor prognosis despite prior treatment. In various embodiments, an inadequate response to prior treatment refers to subjects with a pain symptom (e.g., any symptom listed herein) that has not improved or that has worsened despite prior treatment.Dosage

[0405] 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 amount. As used herein, the phrase “therapeutically effective amount” means an amount of IL-6R antagonist that results in improvement in one or more PMR-associated PRO measures or ClinRO measures (as defined elsewhere herein). A “therapeutically effective amount” also includes an amount of IL-6R antagonist that inhibits, prevents, lessens, or delays the progression of PMR in a subject. In some embodiments, a therapeutically effective amount of anti-IL-6R antibody reduces the dose of corticosteroid (e.g., prednisone) administered to a subject. In the case of an anti-IL-6R antibody, a therapeutically effective amount can be from about 0.05 mg to about 700 mg, e.g., about 0.05 mg, about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 3.0 mg, about 5.0 mg, about 7.0 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, or about 700 mg of the anti-IL-6R antibody. In certain embodiments, 200 mg of an anti-IL-6R antibody is administered. In certain embodiments, 150 mg of an anti-IL-6R antibody is administered. In certain embodiments, 300 mg of an anti-IL-6R antibody is administered.

[0406] The amount of IL-6R antagonist contained within the individual doses may be expressed in terms of milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). For example, the IL-6R antagonist may be administered to a patient at a dose of about 0.0001 to about 10 mg / kg of subject body weight. For example, the IL-6R antagonist can be administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg or 6 mg / kg.

[0407] In certain embodiments, the initial dose is about the same as the loading dose. In certain embodiments, the initial dose is about l.lx, about 1.2x, about 1.3x, about 1.4x, about 1.5x, about 1.6x, about 1.7x, about 1.8x, about 1.9x, about 2. Ox, about 2.5x, about 3. Ox, or more of the loading dose.

[0408] In certain embodiments, two or more (e.g., 2, 3, 4, or 5 or more) doses are administered at the beginning of the treatment regimen as “initial doses” or “loading doses” followed by subsequent doses that are administered on a less frequent basis (e.g., “maintenance doses”). In one embodiment, the maintenance dose may be lower than the loading or initial dose.

[0409] In certain exemplary embodiments, the IL-6R antagonist is administered at a dose of about 150 mg or about 200 mg. In particularly exemplary embodiments, the IL-6R antagonist is administered at an initial dose of about 200 mg and one or more secondary doses or maintenance doses of about 200 mg, and the secondary doses are administered every other week (q2w).

[0410] In certain exemplary embodiments, a subject is an adult, and the IL-6R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In exemplary embodiments, a subject is an adult, and the IL-6R antagonist is administered at an initial dose of about 600 mg and one or more secondary dosesor maintenance doses of about 300 mg, and the secondary doses are administered every other week (q2w). In other exemplary embodiments, a subject is an adult, and the IL-6R antagonist is administered at an initial dose of about 400 mg and one or more secondary doses or maintenance doses of about 200 mg, and the secondary doses are administered every other week (q2w). In certain embodiments, a subject is an adult, the initial dose comprises about 300 mg of the IL-6R antagonist, and the one or more subsequent doses comprise about 300 mg of the IL-6R antagonist administered every other week.

[0411] In certain exemplary embodiments, an IL-6R antagonist is administered at a concentration of 150 mg / mL using a prefilled device. In some embodiments, a 150 mg / mL IL-6R antagonist solution in a pre-filled device is used to deliver about 300 mg IL-6R antagonist in a 2 mL injection. In certain exemplary embodiments, an IL-6R antagonist is administered at a concentration of 175 mg / mL using a prefilled device. In some embodiments, a 175 mg / mL IL-6R antagonist solution in a pre-filled device is used to deliver about 200 mg IL-6R antagonist in a 1.14 mL injection. In certain exemplary embodiments, an IL-6R antagonist is administered at a concentration of 131 mg / mL using a prefilled device. In some embodiments, a 131 mg / mL IL-6R antagonist solution in a pre-filled device is used to deliver about 150 mg IL-6R antagonist in a 1.14 mL injection.Combination Therapies

[0412] Certain embodiments of the methods described herein comprise administering to the subject 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 agents are administered before, after, or concurrent with the pharmaceutical composition comprising the IL-6R antagonist. In some embodiments, the term “in combination with” includes sequential or concomitant administration of an IL-6R antagonist and a second therapeutic agent. Methods to treat PMR or an associated condition or complication comprising administration of an IL-6R antagonist in combination with a second therapeutic agent for additive or synergistic activity, are provided.

[0413] For example, when administered “before” the pharmaceutical composition comprising the IL-6R antagonist, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes,about 15 minutes, or about 10 minutes prior to the administration of the pharmaceutical composition comprising the IL-6R antagonist. When administered “after” the pharmaceutical composition comprising the IL-6R antagonist, the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after the administration of the pharmaceutical composition comprising the IL-6R antagonist. Administration “concurrent” with the pharmaceutical composition comprising the IL-6R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within less than 5 minutes (before, after, or at the same time) of administration of the pharmaceutical composition comprising the IL-6R antagonist, or administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the IL-6R antagonist.

[0414] In exemplary embodiments, an additional therapeutic agent administered in combination with the IL-6R antagonist is a background therapy. In some embodiments, a background therapy includes a steroid. In exemplary embodiments, the background therapy is a corticosteroid. Corticosteroids are steroid hormones produced in the adrenal cortex of vertebrates, and synthetic analogues of these hormones. Corticosteroids include prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone and methylprednisolone. In some embodiments, the corticosteroid is prednisone. According to other embodiments, the corticosteroid can also be selected from triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-valerate, halometasone, alclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, hydrocortisone-17-butyrate, hydrocortisone- 17-aceponate, hydrocortisone- 17-buteprate, ciclesonide and prednicarbate.

[0415] In certain embodiments, the method leads to a reduced need of the background therapy. Reducing the dose of a background therapy may also be termed “tapering.” For example, in certain embodiments, the method leads to reduced dose and / or reduced frequency of the background therapy. In exemplary embodiments, the method leads to reduced doseand / or reduced frequency of corticosteroid background therapy.

[0416] In certain embodiments, the method leads to a discontinuation of the background therapy. In exemplary embodiments, the method leads to a discontinuation of corticosteroid background therapy.

[0417] In certain embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in a subject that has had an inadequate response to a background therapy, in particular to steroids such as corticosteroids. In exemplary embodiments, the method leads to treatment of PMR (or one or more symptoms of PMR) with a reduced need or without the need for corticosteroid background therapy.

[0418] In certain embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in a subject who cannot tolerate a background therapy taper, in particular a steroid taper such as a corticosteroid taper. In exemplary embodiments, the method leads to treatment of PMR (or one or more symptoms of PMR) with a reduced need or without the need for corticosteroid background therapy.

[0419] In certain embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in a subject that has had an inadequate response to a background therapy, in particular to steroids such as corticosteroids and / or in a subject who cannot tolerate a background therapy taper, in particular a steroid taper such as a corticosteroid taper. In exemplary embodiments, the method leads to treatment of PMR (or one or more symptoms of PMR) with a reduced need or without the need for corticosteroid background therapy. In some embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in an adult subject who has had an inadequate response to corticosteroids or who cannot tolerate corticosteroid taper.

[0420] In some embodiments, the corticosteroid background therapy can be administered from about 7.5 mg / day to about 80 mg / day. In certain embodiments, the corticosteroid background 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, the corticosteroid background therapy is administered at a dosage 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 an exemplary embodiment, the corticosteroid background therapy isadministered at a dosage of about 15 mg / day. In an exemplary embodiment, the corticosteroid background therapy is administered at a dosage of about ≥7.5 mg / day. In an exemplary embodiment, the corticosteroid background therapy is administered at a dosage of about ≥5.0 mg / day. In an exemplary embodiment, the corticosteroid background therapy is administered at a dosage of about <5.0 mg / day. In an exemplary embodiment, the corticosteroid background therapy is administered at a dosage of about ≥ 2.5 mg / day. In an exemplary embodiment, the corticosteroid background therapy is administered at a dosage of about 5 mg / day.

[0421] As used herein, a “dose of a steroid” (e.g., a daily dose or a cumulative dose) provided in the present disclosure is the same as “a prednisone equivalent dose,” and these terms can be used interchangeably.

[0422] In certain exemplary embodiments, a frail subject with PMR is or was treated with at least one steroid, e.g., a corticosteroid such as prednisone, at (i) a dose of about ≥ 2.5 mg / day (prednisone equivalent dose) and optionally less than or equal to about 25 mg / day (prednisone equivalent dose); or (ii) a dose of about 5 mg / day (of prednisone equivalent dose).

[0423] In certain exemplary embodiments, a frail subject with PMR is or was treated with a dose of greater than or equal to about 2.5 mg / day, greater than or equal to about 5 mg / day, greater than or equal to about 10 mg / day, greater than or equal to about 15 mg / day, greater than or equal to about 20 mg / day.

[0424] In certain exemplary embodiments, a frail subject with PMR is or was treated with a dose of less than or equal to about 25 mg / day, less than or equal to about 20 day, mg / day, less than or equal to about 15 mg / day, less than or equal to about 10 mg / day, less than or equal to about 25 mg / day.

[0425] In some embodiments, the dose of the background therapy is tapered with treatment with the IL-6R antagonist. PMR patients attempting to taper the daily dosage of corticosteroid treatment to lower dosages of corticosteroid can experience at least one episode of flare, e.g., reducing the dose such that the patient no longer experiences shoulder pain, hip girdle pain, or both, along with inflammatory stiffness lasting more than a certain period of time (e.g., 45 minutes) in the morning. Treatment with an IL-6R antibody or antibody fragment, as described herein, can lessen the episodes of flare as a subject’s daily dosage of corticosteroid treatment is tapered, or decreased, over time.

[0426] In certain exemplary embodiments, a steroid being administered to a frail subject with PMR is tapered to a dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose), after the IL-6 inhibitory therapy (e.g., an anti-IL-6R antibody or antigen-binding fragment thereof) is administered for a period of time. In some embodiments, such a period of time may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time may be about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days, about 50 days to about 250 days.

[0427] In some embodiments, a frail subject, upon administration of an IL-6R inhibitor described herein for a period of time, achieves a minimal corticosteroid dose of less than or equal to about 2.5 mg / day (prednisone equivalent dose), less than or equal to about 2 mg / day (prednisone equivalent dose), less than or equal to about 1.5 mg / day (prednisone equivalent dose), less than or equal to about 1 mg / day (prednisone equivalent dose), or less than or equal to about 0.5 mg / day (prednisone equivalent dose). In some embodiments, such a period of time for administration of an IL-6R inhibitor may be at least about 50 days, at least about 60 days, at least about 70 days, at least about 80 days, at least about 90 days, at least about 100 days, at least about 125 days, at least about 150 days, at least about 200 days, at least about 250 days. In some embodiments, such a period of time for administration of an IL-6R inhibitor may be about 25 days to about 1 year, about 50 days to about 1 year, about 50 days to about 300 days.

[0428] In certain embodiments, a steroid dose at 6 months from the start of the steroid treatment can be evaluated by a daily steroid dose or cumulative steroid dose, we should add some language in the spec to support the use of the cumulative steroid dose for all the methods as described in the claims reciting a daily dose. Some example language is: “if the cumulative dose of a steroid at 6 months from start of the steroid treatment is greater than or equal to about 1250 mg, greater than or equal to about 1500 mg, greater than or equal to about 1750 mg, or greater than or equal to about 2000 mg, a subject who is receiving at least the steroid treatment is recommended for a different PMR therapy comprising: (a) administering an IL-6 inhibitory therapy and (b) tapering the dose of the steroid or discontinuing the steroid treatment.” Pleaseexpand it as appropriate and make sure that this concept applies to all method claims reciting the daily dose.

[0429] The additional therapeutic agent may be, e.g., another IL-6R antagonist, an IL-6 antagonist, a steroid, etc. In an exemplary embodiment, the additional therapeutic is a corticosteroid. In a further exemplary embodiment, the additional therapeutic is prednisone.

[0430] In some embodiments, an 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., live-attenuated) viral vaccine or a live (e.g., live-attenuated) bacterial vaccine.

[0431] Suitable vaccines include, but are not limited to adenovirus, anthrax (e.g., AVA vaccine (BioThrax)), cholera (e.g., Vaxchora), diphtheria (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), hepatitis A (e.g., HepA (Havrix, Vaqta), HepA-HepB (Twinrix)), hepatitis B (e.g., HepB (Engerix-B, Recombivax HB, Heplisav-B), DTaP-HepB-IPV (Pediarix), HepA-HepB (Twinrix)), Haemophilus influenzae type b (Hib) (e.g., Hib (ActHIB, PedvaxHIB, Hiberix), DTaP-IPV / Hib (Pentacel)), human papillomavirus (HPV) (e.g., HPV9 (Gardasil 9)), influenza (flu) (e.g., IIV (also called IIV3, IIV4, RIV3, RIV4 and ccIIV4) (Afluria, Fluad, Flublok, Flucelvax, FluEaval, Fluarix, Fluvirin, Fluzone, Fluzone High-Dose, Fluzone Intradermal), EAIV (FluMist)), Japanese encephalitis (e.g., JE (Ixiaro)), measles (e.g., MMR (M-M-R II), MMRV (ProQuad)), meningococcus (e.g., MenACWY (Menactra, Menveo), MenB (Bexsero, Trumenba)), mumps (e.g., MMR (M-M-R II), 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 (Prevnarl3), PPSV23 (Pneumovax 23)), polio (e.g., Polio (Ipol), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), rabies (e.g., Rabies (Imovax Rabies, RabAvert)), rotavirus (e.g., RV1 (Rotarix), RV5 (RotaTeq)), rubella (e.g., MMR (M-M-R II), MMRV (ProQuad)), shingles (e.g., ZVE (Zostavax), RZV (Shingrix)), smallpox (e.g., Vaccinia (ACAM2000)), tetanus (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, generic), DT (generic), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), tuberculosis, typhoid fever (e.g., Typhoid Oral (Vivotif), Typhoid Polysaccharide (Typhim Vi)), varicella (e.g., VAR (Varivax), MMRV (ProQuad)), yellow fever (e.g., YF (YF-Vax)) and the like.Suitable vaccines are also listed at the US Centers for Disease Control vaccine list, 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 tri valent / quadri valent influenza vaccine.

[0432] 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 subject treated with the vaccine is concurrently treated for PMR with an IL-6R antagonist.

[0433] In certain embodiments, treatment with an IL-6R antagonist is suspended or terminated prior to treatment with the vaccine. In certain embodiments, treatment with the IL-6R antagonist is suspended about 1 to about 9 (e.g., about 1, about 1%, about 2, about 2%, about 3, about 3%, about 4, about 4%, about 5, about 5%, about 6, about 6%, about 7, about YU, about 8, about 8%, about 9, or more) weeks prior to administration of the vaccine. In some embodiments, treatment with the IL-6R antagonist is suspended about 1 , about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, or about 60 days prior to administration of the vaccine.

[0434] In certain embodiments, treatment with the IL-6R antagonist is resumed subsequent to treatment with the vaccine. In certain embodiments, treatment with the IL-6R antagonist is resumed about 1 to about 14 (e.g., about 1, about 1%, about 2, about 2%, about 3, about 3%, about 4, about 4%, about 5, about 5%, about 6, about 6%, about 7, about 7%, about 8, about 8%, about 9, about 9%, about 10, about 10%, about 11, about 11%, about 12, about 12%, about 13, about 13%, about 14, about 14%, or more) weeks subsequent to administration of the vaccine. In some embodiments, treatment with the IL-6R antagonist is resumed about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, or about 90 days subsequent to administration of the vaccine.

[0435] In certain embodiments, the effectiveness of the IL-6R antagonist is not decreased by administration in combination with the vaccine, or by subsequent administration of the vaccine.

[0436] In some embodiments, the effectiveness of the vaccine is not decreased by administration in combination with the IL-6R antagonist, or by previous and / or subsequent administration of the IL-6R antagonist. In some embodiments, the subject develops seroprotective neutralization titers to the vaccine when the vaccine is co-administered with the IL-6R antagonist.

[0437] In certain exemplary embodiments, a subject is administered a vaccine described herein, wherein before, during, or after administration of the vaccine, the subject is administered at least one dose of IL-6R antagonist.Administration Regimens

[0438] According to certain embodiments, multiple doses of an IL-6R antagonist may be administered to a subject over a defined time course. Such methods comprise sequentially administering to a subject multiple doses of an IL-6R antagonist. As used herein, “sequentially administering” means that each dose of IL-6R antagonist is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). Methods that comprise sequentially administering to the patient a single initial dose of an IL-6R antagonist, followed by one or more secondary doses of the IL-6R antagonist, and optionally followed by one or more tertiary doses of the IL-6R antagonist, are provided.

[0439] Methods comprising administering to a subject a pharmaceutical composition comprising an IL-6R antagonist at a dosing frequency of about four times a week, twice a week, once a week (ql w), once every two weeks (every two weeks is used interchangeably with every other week, bi-weekly or q2w), once every three weeks (tri-weekly or q3w), once every fourweeks (monthly or q4w), once every five weeks (q5w), once every six weeks (q6w), once every seven weeks (q7w), once every eight weeks (q8w), once every nine weeks (q9w), once every ten weeks (qlOw), once every eleven weeks (ql Iw), once every twelve weeks (ql2w), or less frequently so long as a therapeutic response is achieved, are provided.

[0440] In certain embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, once a week dosing of an amount of about 150 mg or about 200 mg can be employed. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, once every two weeks dosing (every two weeks is used interchangeably with every other week, bi-weekly or q2w) of an amount of about 150 mg, or about 200 mg can be employed. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, once every three weeks dosing of an amount of about 150 mg or about 200 mg can be employed. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, once every four weeks dosing (monthly dosing) of an amount of about 150 mg or about 200 mg can be employed. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, once every five weeks dosing of an amount of about 150 mg or about 200 mg can be employed. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, once every six weeks dosing of an amount of about 150 mg or about 200 mg can be employed. In certain exemplary embodiments, the route of administration is subcutaneous.

[0441] The term “week” or “weeks” refers to a period of (n x 7 days) ±3 days, e.g., (n x 7 days) ±2 days, (n x 7 days) ±1 day, or (n x 7 days), wherein “n” designates the number of weeks, e.g., 1, 2, 3, 4, 5, 6, 8, 12 or more.

[0442] The terms “initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of the IL-6R antagonist. Thus, the “initial dose” is the dose that is administered at the beginning of the treatment regimen (also referred to as the “baseline dose” or “loading dose”); the “secondary doses” are the doses that are administered after the initial dose; and the “tertiary doses” are the doses that are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of IL-6R antagonist, or may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of IL-6R antagonist contained in the initial, secondary and / or tertiary doses varies from one another (e.g., adjusted up or down as appropriate) during the course oftreatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the beginning of the treatment regimen as “loading doses” followed by subsequent doses that are administered on a less frequent basis (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 IL-6R antagonist may be administered followed by secondary doses / maintenance doses of about 150 mg or about 200 mg, respectively. In one embodiment, a loading dose may be split, e.g., two or more doses administered at different time points, e.g., two loading doses wherein a second loading dose is administered two weeks after a first loading dose.

[0443] In some embodiments, the initial dose comprises 200 mg of the antibody or antigen-binding fragment thereof, and the one or more secondary doses comprises 200 mg of the antibody or antigen-binding fragment thereof administered every other week (every other week is used interchangeably with every two weeks, bi-weekly or q2w).

[0444] In one exemplary embodiment, each secondary and / or tertiary dose is administered 1 to 14 (e.g., 1, 1%, 2, 2%, 3, 3%, 4, 4%, 5, 5%, 6, 6%, 7, T / i, 8, 8%, 9, 9%, 10, 10%, 11, 11%, 12, 12%, 13, 13%, 14, 14%, or more) weeks after the immediately preceding dose. The phrase “the immediately preceding dose” means, in a sequence of multiple administrations, the dose of IL-6R antagonist that is administered to a patient prior to the administration of the very next dose in the sequence with no intervening doses.

[0445] The methods may include administering to a patient any number of secondary and / or tertiary doses of an IL-6R antagonist. For example, in certain embodiments, only a single secondary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses are administered to the patient. Likewise, in certain embodiments, only a single tertiary dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiary doses are administered to the patient.

[0446] In embodiments involving 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 immediately preceding dose. Similarly, in embodiments involving multiple tertiary doses, each tertiary dose may be administered at the same frequency as the other tertiary doses. For example, each tertiary dosemay be administered to the patient 2 to 4 weeks after the immediately preceding dose. Alternatively, the frequency at which the secondary and / or tertiary doses are administered to a patient can vary over the course of the treatment regimen. The frequency of administration may also be adjusted during the course of treatment by a physician depending on the needs of the individual patient following clinical examination.

[0447] Methods comprising sequential administration of an IL-6R antagonist and a second therapeutic agent, to a patient to treat PMR or an associated condition are provided. In some embodiments, the methods comprise administering one or more doses of an IL-6R antagonist followed by one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of a second therapeutic agent. For example, one or more doses of about 150 mg to about 200 mg of the IL-6R antagonist may be administered after which one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of a second therapeutic agent (e.g., a corticosteroid) may be administered to treat, alleviate, reduce or ameliorate one or more symptoms of PMR. In some embodiments, the IL-6R antagonist is administered at one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) resulting in an improvement in one or more PMR-associated parameters followed by the administration of a second therapeutic agent to prevent recurrence of at least one symptom of PMR. Alternative embodiments pertain to concomitant administration of an IL-6R antagonist and a second therapeutic agent. For example, one or more doses (e.g., 2, 3, 4, 5, 6, 7, 8, or more) of an IL-6R antagonist are administered and a second therapeutic agent is administered at a separate dosage at a similar or different frequency relative to the IL-6R antagonist. In some embodiments, the second therapeutic agent is administered before, after or concurrently with the IL-6R antagonist.

[0448] In certain embodiments, the IL-6R antagonist is administered every other week for 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks, 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 weeks or more. In specific embodiments, the IL-6R antagonist is administered for at least 14 weeks. In an exemplary embodiment, the IL-6R antagonist is administered for at least 52 weeks.Treatment Populations

[0449] The methods provided herein include administering to a subject in need thereof a therapeutic composition comprising an IL-6R antagonist. The expression “a subject in needthereof’ means a human or non-human animal that exhibits one or more symptoms or indicia of PMR and frailty, or who has been diagnosed with PMR and frailty.

[0450] In a related embodiment, a “subject in need thereof’ may be a subject who, prior to receiving an IL-6R antagonist, has been prescribed or is currently taking a steroid. In some embodiments, the subject may be a subject who, prior to receiving an IL-6R antagonist, has been prescribed or is currently taking a corticosteroid. In some embodiments, the subject is currently taking prednisone. For example, methods that comprise administering an IL-6R antagonist to a subject who has been taking a regular course of prednisone for eight or more weeks immediately preceding the administration of the IL-6R antagonist (such prior treatments are referred to herein as “background treatments”) are provided. In exemplary embodiments, the subject has been taking a regular course of prednisone at a dose of at least 7.5 mg / day and not more than 20 mg / day. In certain exemplary embodiments, the subject has been taking a regular course of prednisone at a dose of greater than or equal to about 2.5 mg / day. In certain exemplary embodiments, the subject has been taking a regular course of prednisone about dose of 5 mg / day.

[0451] In yet other embodiments, the amount of the corticosteroid, such as the amount of prednisone, is gradually decreased prior to or after the start of IL-6R antagonist administration.

[0452] In another exemplary embodiment, a “subject in need thereof’ has a diagnosis of PMR refractory to steroids prior to receiving the IL-6R antagonist. In some embodiments, the PMR symptoms of the subject persist despite treatment with steroids. In still another exemplary embodiment, a “subject in need thereof’ has a diagnosis of PMR refractory to corticosteroids (e.g., prednisone) prior to receiving the IL-6R antagonist. In some embodiments, the PMR symptoms of the subject persist despite treatment with corticosteroids (e.g., prednisone).

[0453] In another exemplary embodiment, a “subject in need thereof’ has a diagnosis of PMR refractory to steroid taper prior to receiving the IL-6R antagonist. In some embodiments, the subject experiences PMR flare when steroid taper is attempted. In an exemplary embodiment, the subject is refractory to corticosteroid (e.g., prednisone) taper and the subject experiences PMR flare when corticosteroid (e.g., prednisone) taper is attempted.

[0454] In another embodiment, a “subject in need thereof’ is a subject whose PMR is not adequately controlled with steroids. In other embodiments, a “subject in need thereof’ is a subject whose PMR is not adequately controlled with corticosteroids (e.g., prednisone). Insome embodiments, a “subject in need thereof’ is a subject for whom steroids are not advisable (i.e., the subject experiences adverse effects associated with steroids or is on a medication(s) that cannot be combined with steroid therapies. In some embodiments, a “subject in need thereof’ is a subject for whom corticosteroids (e.g., prednisone) are not advisable (i.e., the subject experiences adverse effects associated with corticosteroids (e.g., prednisone) or is on a medication(s) that cannot be combined with corticosteroids (e.g., prednisone).

[0455] In a further exemplary embodiment, a “subject in need thereof’ is a subject for whom steroids are not medically advisable (i.e., the subject has an allergy, a history of an adverse reaction, or other medical history wherein administration of steroids is not advisable). In an exemplary embodiment, the subject is a subject for whom corticosteroids (e.g., prednisone) are not medically advisable (i.e., the subject has an allergy, a history of an adverse reaction, or other medical history wherein administration of corticosteroids (e.g., prednisone) is not advisable).

[0456] In a further exemplary embodiment, a “subject in need thereof’ is a subject who has had an inadequate response to one or more steroids. In an exemplary embodiment, the subject is a subject who has had an inadequate response to a corticosteroid (e.g., prednisone).

[0457] In a further exemplary embodiment, a “subject in need thereof’ is a subject who cannot tolerate steroid taper. In an exemplary embodiment, the subject is a subject who cannot tolerate corticosteroid taper (e.g., prednisone taper).

[0458] In a further exemplary embodiment, a “subject in need thereof’ is a subject who has had an inadequate response to steroid and / or who cannot tolerate steroid taper. In an exemplary embodiment, the subject is a subject who has had an inadequate response to corticosteroids (e.g., prednisone) and / or who cannot tolerate corticosteroid taper (e.g., prednisone taper).

[0459] In some embodiments, a “subject in need thereof’ is at least 50 years old. In exemplary embodiments, the subject is older than 50 years old. In other exemplary embodiments, the subject has bilateral shoulder pain. In still other exemplary embodiments, the subject has a C-reactive protein (CRP) level of >10 mg / L and / or an erythrocyte sedimentation rate (ESR) >30 mm / hr. In some exemplary embodiments, the subject has morning stiffness. In other exemplary embodiments, the subject has an absence of joint involvement other than the shoulder joint. In still other exemplary embodiments, the subject has hip pain or limited range of motion. In some exemplary embodiments, the subject is seronegative for rheumatoid factor(RF) and anti-cyclic citrullinated peptide (anti-CCP). In other exemplary embodiments, the subject has at least one shoulder with subdeltoid bursitis and / or biceps tenosynovitis and / or posterior or axillary glenohumeral synovitis, and at least one hip with synovitis and / or trochanteric bursitis.Methods for Assessing Pharmacodynamic PMR-Associated Parameters

[0460] Methods for assessing one or more pharmacodynamic PMR-associated parameters in a subject in need thereof, caused by administration of a pharmaceutical composition comprising an IL-6R antagonist, are provided. A reduction in the incidence of PMR symptoms or an improvement in a PMR-associated PRO or ClinRO measure may correlate with an improvement in one or more pharmacodynamic PMR-associated parameters; however, such a correlation is not necessarily observed in all cases.

[0461] Examples of “pharmacodynamic PMR-associated parameters” include, for example, the following: (a) biomarker expression levels and (b) serum protein and RNA analysis. An “improvement in a pharmacodynamic PMR-associated parameter” means, for example, a decrease from baseline of one or more of levels of IL-6, IL6R, and C-reactive protein (CRP), or a decrease in erythrocyte sedimentation rate (ESR). As used herein, the term “baseline,” with regard to a pharmacodynamic PMR-associated parameter, means the numerical value of the pharmacodynamic PMR-associated parameter for a patient prior to or at the time of administration of a pharmaceutical composition described herein.

[0462] To assess a pharmacodynamic PMR-associated parameter, the parameter is quantified at baseline and at a time point after administration of the pharmaceutical composition. For example, a pharmacodynamic PMR-associated parameter may be measured at about day 1, about day 2, about day 3, day 4, about day 5, about day 6, about day 7, about day 8, about day 9, about day 10, about day 11, about day 12, about day 14, or at about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 11, about week 12, about week 13, about week 14, about week 15, about week 16, about week 17, about week 18, about week 19, about week 20, about week 21, about week 22, about week 23, about week 24, or longer, after the initial treatment with the pharmaceutical composition. The difference between the value of the parameter at a particular time point following initiation of treatment and the value of the parameter at baseline is used to establish whether there has been change, such as an “improvement”, in the pharmacodynamicPMR-associated parameter (e.g., an increase or decrease, as the case may be, depending on the specific parameter being measured).

[0463] In certain embodiments, administration of an IL-6R antagonist to a patient causes a change, such as a decrease or increase, in expression of a particular biomarker. PMR-associated biomarkers include, but are not limited to total IL-6, IL6R, and C-reactive protein (CRP). For example, administration of an IL-6R antagonist to a PMR patient can cause a decrease in IL-6, IL6R, or C-reactive protein (CRP) levels. The decrease can be detected at about week 1, about week 2, about week 3, about week 4, about week 5, or longer following administration of the IL-6R antagonist. Biomarker expression 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 coupled to polymerase chain reaction (RT-PCR).

[0464] Biomarker expression, as discussed above, can be assayed by detection of protein or RNA in serum. The serum samples can also be used to monitor additional protein or RNA biomarkers related to response to treatment with an IL-6R antagonist or IL-6 signaling. In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), e.g., RNA levels of biomarkers; and in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis).Interleukin-6 Receptor Antagonists

[0465] The present disclosure includes methods that comprise administering to a subject an antibody, or an antigen-binding fragment thereof, that binds specifically to hIL-6R. As used herein, the term “hIL-6R” means a human cytokine receptor that specifically binds human interleukin-6 (IL-6). In certain embodiments, the antibody that is administered to the patient binds specifically to the extracellular domain of hIL-6R.

[0466] The term “antibody,” as used herein, refers to immunoglobulin molecules comprising four polypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or Vn) and a heavy chain constant region. The heavy chain constant region comprises three domains, CHI, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CLI). The VH and VLregions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino -terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the antibody (or antigen-binding portion thereof) may be identical to the human germline sequences, or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0467] The term “antibody,” as used herein, also includes antigen-binding fragments of full antibody molecules. The terms “antigen-binding portion” of an antibody, “antigen-binding fragment” of an antibody, and the like, 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 an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

[0468] 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 the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide), or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, and bivalent nanobodies), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression “antigen-binding fragment,” as used herein.

[0469] An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL domains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.

[0470] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody include: (I) VH-CHI ; (ii) VH-CH2; (iii) VH-Cn3; (iv) VH-CH1 -CH2; (V) VH-CH1 -CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1 ; (ix) VL-CH2; (X) VL-CH3 ; (xi) VL-CH1 -CH2; (xii) VL-CH1 -CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may in various embodiments consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody may in various embodiments comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and / or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)).

[0471] In certain embodiments, the antibody or antibody fragment for use in a method disclosed herein may be a monospecific antibody. In certain embodiments, the antibody or antibody fragment for use in a method disclosed herein may be a multispecific antibody, which may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for epitopes of more than one target polypeptide. An exemplary bi-specific antibody format that can be used in the context certain embodiments involves the use of a first immunoglobulin (Ig) CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least oneamino acid difference reduces binding of the bispecific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second CH3 may further comprise an Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second CH3 include: D16E, E18M, N44S, K52N, V57M, and V82I (by IMGT; D356E, E358M, N384S, K392N, V397M, and V422I by EU) in the case of IgGl antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of IgG4 antibodies. Variations on the bi-specific antibody format described above are contemplated within the scope of certain embodiments. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, may in various embodiments be adapted for use in the context of an antigen-binding fragment of an anti-IL-6R antibody using routine techniques available in the art.

[0472] The fully-human anti-IL-6R antibodies disclosed herein may comprise one or more amino acid substitutions, insertions and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present disclosure includes antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and / or CDR regions are back-mutated to the corresponding germline residue(s) or to a conservative amino acid substitution (natural or non-natural) of the corresponding germline residue(s) (such sequence changes are referred to herein as “germline back-mutations”). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline back-mutations or combinations thereof. In certain embodiments, all of the framework residues and / or CDR residues within the VH and / or VL domains are mutated back to the germline sequence. In other embodiments, only certain residues are mutated back to the germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 orCDR3. Furthermore, included herein are antibodies that may contain any combination of two or more germline back-mutations within the framework and / or CDR regions, i.e., wherein certain individual residues are mutated back to the germline sequence while certain other residues that differ from the germline sequence are maintained. Once obtained, antibodies and antigen-binding fragments that contain one or more germline back-mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present disclosure.

[0473] The constant region of an antibody is important in the ability of an antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody may be selected on the basis of whether it is desirable for the antibody to mediate cytotoxicity.

[0474] The term “human antibody,” as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies featured in the disclosure may in various embodiments nonetheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in some embodiments CDR3. However, the term “human antibody,” as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0475] The term “recombinant human antibody,” as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somaticmutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0476] Human antibodies can exist in two forms that are associated with hinge heterogeneity. In an embodiment, an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In another embodiment, the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody). In certain embodiments, these forms have been extremely difficult to separate, even after affinity purification.

[0477] The frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form to levels typically observed using a human IgGl hinge. The instant disclosure encompasses in various embodiments antibodies having one or more mutations in the hinge, CH2 or CH3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.

[0478] An “isolated antibody,” as used herein, means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an “isolated antibody”. In various embodiments, the isolated antibody also includes an antibody in situ within a recombinant cell. In other embodiments, isolated antibodies are antibodies that have been 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.

[0479] The term “specifically binds,” or the like, means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that “specifically binds” IL-6R, as usedherein, includes antibodies that bind IL-6R (e.g., human IL-6R) or portion thereof with a KD of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM or about 0.5 nM, as measured in a surface plasmon resonance assay. In some embodiments, the antibody binds IL-6R (e.g., human IL-6Ra) with a KD of from about 0.1 nM to about 1000 nM or from about 1 nM to about 100 nM. In some embodiments, the antibody binds IL-6R (e.g., human IL-6Ra) with a KD of from about 1 pM to about 100 pM or from about 40 pM to about 60 pM. Specific binding can also be characterized by a dissociation constant of at least about 1x10-6M or smaller. In other embodiments, the dissociation constant is at least about Ixl0-7M, 1 x 10’8M, or lx I0-9M. An isolated antibody that specifically binds human IL-6R may, however, have cross-reactivity to other antigens, such as IL-6R molecules from other (non-human) species.

[0480] The term “surface plasmon resonance,” as used herein, refers to an optical phenomenon that allows for the analysis of real-time interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORE® system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0481] The term “KD,” as used herein, is intended to refer to the equilibrium dissociation constant of an antibody-antigen interaction.

[0482] The term “epitope” refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstance, an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen.

[0483] The anti-IL-6R antibodies useful for 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 regions of the heavy and light chain variable domains as compared tothe corresponding germline sequences from which the antibodies were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present disclosure includes in various embodiments methods involving the use of antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and / or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as “germline mutations”). Numerous antibodies and antigen-binding fragments may be constructed which comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and / or CDR residues within the VH and / or VL domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the original germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and / or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). Furthermore, the antibodies may contain any combination of two or more germline mutations within the framework and / or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a certain germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antibodies and antigen-binding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. The use of antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present disclosure.

[0484] In some embodiments, the sequence identity of a sequence disclosed herein is at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, and up to 100% identical to a reference sequence. A polypeptide has acertain percent “sequence identity” to another polypeptide, meaning that, when aligned, that a percentage of bases or amino acids are the same, and in the same relative position, when comparing the two sequences. Sequence identity can be determined in a number of different manners. To determine sequence identity, sequences can be aligned using various methods and computer programs (e.g., BLAST, T-COFFEE, MUSCLE, MAFFT, etc.), available on the internet at sites including ncbi.nlm.nili.gov / BLAST, ebi.ac.uk / Tools / msa / tcoffee / , ebi.ac.uk / Tools / msa / muscle / , mafft.cbrc.jp / alignment / software / . See, e.g., Altschul et al. (1990), J. Mol. Biol. 215:403-10.

[0485] Sequence similarity for polypeptides, which is also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG software contains programs such as Gap and Bestfit which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1. Polypeptide sequences also can be compared using FASTA using default or recommended parameters, a program in GCG Version 6.1. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (2000) supra). Another preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially BLASTP or TBLASTN, using default parameters. See, e.g., Altschul et al. (1990) J. Mol. Biol. 215: 403 410 and Altschul et al. (1997) Nucleic Acids Res. 25:3389 402.

[0486] The present disclosure also includes methods involving the use of anti-IL-6R antibodies comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present disclosure includes the use of anti-IL-6R antibodies having HCVR, LCVR, and / or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0487] According to the present disclosure, the anti-IL-6R antibody, or antigen-binding fragment thereof, in various embodiments comprises a heavy chain variable region (HCVR),light chain variable region (LCVR), and / or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the anti-IL-6R antibodies described in U.S. Patent No. 7,582,298, incorporated herein by reference in its entirety. In certain embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDRs) of a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and the light chain complementarity determining regions (LCDRs) of a LCVR comprising the amino acid sequence of SEQ ID NO: 2. According to certain embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (i.e., HCDR1, HCDR2 and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In yet other embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises an HCVR comprising the amino acid sequence of SEQ ID NO: 1 and an LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[0488] In another embodiment, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the extracellular domain of hIL-6R comprises the amino acid sequence of SEQ ID NO: 11. According to certain exemplary embodiments, the methods of the present disclosure comprise the use of the anti-IL-6R antibody referred to and known in the art as sarilumab, or a bioequivalent thereof.

[0489] The amino acid sequence of SEQ ID NO: 1 isEVOLVESGGGLVQPGRSLRLSCAAS7?FTFDDFAMHWVROAPGKGLEWVSGI SIEVSGTflGYADSVKGRFTISRDNAENSLFLOMNGLRAEDTALYYCAKGTfDSFD / WG QGTMVTVSS(CDR sequences are highlighted: IMGT numbering in bold; Kabat numbering underlined; Chothia numbering italicized).The amino acid sequence of SEQ ID NO: 2 isDIQMTQSPSSVSASVGDRVTITCTMSflG / AAIFLzlWYOOKPGKAPKLLIYGASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFASYYC0(M7VS,FPF7FGOGTKLEIK(CDR sequences are highlighted: IMGT numbering in bold; Kabat numbering underlined; Chothia numbering italicized).The amino acid sequence of SEQ ID NO: 3 is RFTFDDYA (CDR-H1 according to IMGT numbering).The amino acid sequence of SEQ ID NO: 4 is ISWNSGRI (CDR-H2 according to IMGT numbering).The amino acid sequence of SEQ ID NO: 5 is AKGRDSFDI (CDR-H3 according to IMGT numbering).The amino acid sequence of SEQ ID NO: 6 is QGISSW (CDR-L1 according to IMGT numbering).The amino acid sequence of SEQ ID NO: 7 is GAS (CDR-L2 according to IMGT numbering).The amino acid sequence of SEQ ID NO: 8 is QQANSFPYT (CDR-L3 according to IMGT numbering).The amino acid sequence of SEQ ID NO: 9 isEVOLVESGGGLVOPGRSLRLSCAAS / eFTFDDFAMHWVROAPGKGLEWVSGISlFAAG7?IGYADSVKGRFTISRDNAENSLFLOMNGLRAEDTALYYCAKG7?D5,FD / WGOGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(CDR sequences are highlighted: IMGT numbering in bold; Kabat numbering underlined; Chothia numbering italicized).The amino acid sequence of SEQ ID NO: 10 isDIOMTOSPSSVSASVGDRVTITCEASOG / SSfFEJWYOOKPGKAPKLLIYG / lASEESGVP SRFSGSGSGTDFTLTISSLQPEDFASYYCOCMAS'E'PFTFGQGTKLEIKRTVAAPSVFIFP PSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(CDR sequences are highlighted: IMGT numbering in bold; Kabat numbering underlined; Chothia numbering italicized).The amino acid sequence of SEQ ID NO: 11 isMVAVGCALLAALLAAPGAALAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNA TVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVD VPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQ ESQKFSCQLAVPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITVTAV ARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDA WSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQALTTN KDDDNILFRDSANATSLPVQD.

[0490] In some embodiments, a sarilumab variant is provided, said variant having at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% sequence identity to one or more of SEQ ID NO:1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11.

[0491] According to the present disclosure, the anti-IL-6R antibody, or antigen-binding fragment thereof, in various embodiments comprises a heavy chain variable region (HCVR), light chain variable region (LCVR), and / or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the anti-IL-6R antibodies described in U.S. Patent No. 7,521,052, incorporated herein by reference in its entirety. The hybridoma cell line producing tocilizumab (TCZ) has been internationally deposited at International Patent Organism Depository (AIST Tsukuba Central 6, 1-1, Higashi 1-chome, Tsukuba-shi, Ibaraki Pref.) on the basis of Budapest Treaty as FERM BP-2998 on Jul. 12, 1989. In certain embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises the heavy chain complementarity determining regions (HCDRs) and or the light chain complementarity determining regions (LCDRs) of a HCVR comprising the amino acidsequence of SEQ ID NO : 13 and the light chain complementarity determining regions (LCDRs) of a LCVR comprising the amino acid sequence of SEQ ID NO: 12. According to certain embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises three HCDRs (i.e., HCDR1, HCDR2 and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2 and LCDR3), wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 17; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 18; the HCDR3 comprises the amino acid sequence of SEQ ID NO: 19; the LCDR1 comprises the amino acid sequence of SEQ ID NO: 14; the LCDR2 comprises the amino acid sequence of SEQ ID NO: 15; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 16. In various embodiments, the anti-IL-6R antibody or antigen-binding fragment thereof comprises an heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and an light chain comprising the amino acid sequence of SEQ ID NO: 12.

[0492] In another embodiment, the anti-IL-6R antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of the heavy chain of TCZ and a light chain comprising the amino acid sequence of the light chain of TCZ. In some embodiments, the extracellular domain of hIL-6R comprises the amino acid sequence of the extracellular domain of TCZ. According to certain exemplary embodiments, the methods of the present disclosure comprise the use of the anti-IL-6R antibody referred to and known in the art as tocilizumab, or a bioequivalent thereof.

[0493] The amino acid sequence of SEQ ID NO: 12 isDIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGV PSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECThe amino acid sequence of SEQ ID NO: 13 isVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITT YNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPP CPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVH NAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG.The amino acid sequence of SEQ ID NO: 14 is RASQDISSYLN.The amino acid sequence of SEQ ID NO: 15 is YTSRLHS.The amino acid sequence of SEQ ID NO: 16 is QQGNTLPYT.The amino acid sequence of SEQ ID NO: 17 is SDHAWS.The amino acid sequence of SEQ ID NO: 18 is YISYSGITTYNPSLK.The amino acid sequence of SEQ ID NO: 19 is SLARTTAMDY.

[0494] The term “bioequivalent” as used herein, refers to a molecule having similar bioavailability (rate and extent of availability) after administration at the same molar dose and under similar conditions (e.g., same route of administration), such that the effect, with respect to both efficacy and safety, can be expected to be essentially same as the comparator molecule. Two pharmaceutical compositions comprising 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 meeting the same or comparable standards. Bio equivalence can be determined, for example, by an in vivo study comparing a pharmacokinetic parameter for the two compositions. Parameters commonly used in bioequivalence studies include peak plasma concentration (Cmax) and area under the plasma drug concentration time curve (AUC).EXAMPLES

[0495] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the methods and compositions featured in the invention, and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.Example 1. Effectiveness of Interleukin-6 Receptor Inhibitors versus Conventional Synthetic Immunomodulatory Therapy for Treatment of Frail Patients with Polymyalgia RheumaticaObjectives

[0496] To compare effectiveness of IL-6R1 vs. csIM therapy as second (2L) and third (3L) line treatment for frail patients with PMR.Methods

[0497] A subgroup analysis of patients with frailty from a retrospective cohort study comparing the effectiveness of IL-6Ri to csIM in 2L and 3L treatment of patients with PMR identified from 3 / 2016-6 / 2019 using Medicare claims data was conducted. Direct match criteria were updated with 6 vs. 3 GC dose categories, baseline GC dose category, and history of giant cell arteritis and then propensity score (PS) matched. IL-6Ri and csIM matched pairs were then assessed with a validated claims-based frailty index (CFI) (Kim DH et al. J Gerontol A Biol Sci Med Sci 2019;74:1271-76). Although CFI ≥0.2 (Halawa OA et al. Ophthalmology 2023;130:646-54) and ≥0.25 (Kim et al., Supra) have been used as thresholds for mild frailty, due to sample size median CFI was used as the threshold to identify more frail patients. Matched pairs of patients with CFI ≥median, were retained for comparison. The primary outcomes were time-to-GC discontinuation (>60-day gap) and time-to-GC discontinuation or minimal GC ( ≤2 mg / day of prednisone equivalent) using Cox proportional hazards models stratified by 2L or 3L treatment. Patients were censored at 1 year, 60 days prior to the end of enrollment, death, outcome achievement, stopping csIM / IL-6Ri therapy or switching csIM / IL- 6Ri therapy. Cumulative GC dose was also compared. The study design is shown schematically at FIG. 11.Results

[0498] Of the 187 2L and 228 3L PS matched pairs from the parent cohort, 89 (35 [39.3%] 2L and 54 [60.7%] 3L) had CFI ≥0.2, the median. The most common csIM therapy in 2L and 3L was methotrexate (77.1%) and leflunomide (64.8%), respectively. Patient characteristics were generally balanced (FIG. 1) though IL-6Ri vs. csIM initiators were less likely to enroll in Medicare due to disability (19.1% vs. 31.5%) and had more inpatient days during baseline (Mean [SD] 2.1 [6.2] vs. 0.9 [2.6]) (FIG. 1). IL-6Ri vs. csIM initiators were significantly more likelyto discontinue GC (HR [95% CI] 2.32 [1.35-3.99], P=0.002) and achieve discontinuation of GC or minimal GC (HR [95% CI] 2.23 [1.34-3.71], P=0.002), and used significantly less GC (Mean [SD], mg; (3017.6 [4327.1] vs. 5764.0 [14690.3], P=0.025)) (FIG. 2). IL-6Ri vs. csIM initiators were found to have a significantly lower cumulative GC dose at 1 year in thefrailty subgroup (FIG. 9) Results of sensitivity analyses for discontinuation of GC varying the censoring rules by removing censoring for 1 year, stopping or switching csIM or IL-6Ri, and stopping csIM or IL-6Ri resulted in similar findings with HR (95% CI) of 1.88 (1.14, 3.10), P=0.013; 2.49 (1.59, 3.89), PO.OOl and 2.71 (1.71, 4.29), P<0.001, respectively (FIG. 10).Conclusion

[0499] Compared to csIM, IL-6Ri therapy had a greater GC-sparing effect in frail patients with PMR. The effect size (HR 2.23) observed in patients with frailty was larger than in the overall PMR cohort (HR 1.32), indicating patients with frailty can derive even greater benefit from IL-6Ri therapy compared to csIM therapy.Example 2. Real-World Effectiveness of Interleukin-6 Receptor Inhibitors Compared to Methotrexate in Steroid-Refractory Frail Patients with Polymyalgia RheumaticaBackground

[0500] This current study compared IL-6Ri to MTX as 2L PMR treatment, with frailty as an inclusion criteria and level of frailty as a PS match covariate. Frailty was defined as CFI ≥ 0.25, the validated threshold in the general population (see, e.g., Kim DH, et al. J Gerontol A Biol Sci Med Sci. 2019;74(8):1271-6, incorporated by reference), reducing the likelihood of inclusion of patients with pre-frailty.Objective

[0501] To compare the effectiveness of IL-6Ri to MTX in GC-reffactory frail patients with PMR.Methods

[0502] This was an observational retrospective comparative cohort study comparing the effectiveness of IL-6Ri to MTX using US Medicare claims data. Inclusion criteria were: age ≥ 50 years with ≥ 1 inpatient or ≥ 2 outpatient PMR diagnosis codes ≥ 30 days apart, on ≤ 25 mg prednisone equivalent dose (PED), a CFI ≥ 0.25, initiation of an IL-6Ri or MTX (index date) with no prior history of IL-6Ri or csIM therapy, and continuous enrollment 180 days prior (baseline) to 1 day. Patients initiating IL-6Ri and csIM therapy on the same day, and patientswith seropositive rheumatoid arthritis (RA), other systemic rheumatic disease (except giant cell arteritis (GCA)), organ transplant, multiple sclerosis, or active malignancy treatment during baseline were excluded. Due to the difficulty in differentiating PMR from seronegative RA clinically, and given patients with GCA often develop PMR, patients with seronegative RA and GCA diagnosis codes were not excluded. Additionally, diagnosis of seronegative RA and GCA may also have been used to obtain reimbursement for off-label use of IL-6Ri.

[0503] MTX initiators were direct matched to IL-6Ri initiators on age, gender, GC dose category (daily baseline and index day), and history of GCA and then PS matched on demographics, reason for qualifying for Medicare, GC dose category (daily baseline and index day), time since diagnosis, healthcare resource utilization, and comorbidities.

[0504] Primary and key secondary outcomes were time to GC discontinuation (> 60 day gap) and time to minimal ( ≤ 2 mg / day PED) or no GC, respectively. Both standardized mean difference (SMD) > 0.1 and p < 0.5 were used for determination of imbalance for PS match and adjustment of the Cox outcome model.Results

[0505] A total of 290 / 1017 (29%) and 1402 / 7645 (18.3%) patients in the IL-6Ri and MTX groups, respectively, had a CFI ≥ 0.25. Of these, 86 matched pairs were identified who were receiving 2L treatment and had no prior IL-6Ri therapy. Patient characteristics were generally balanced, though the mean time from first PMR diagnosis to index date (1025 vs. 799 days) and the occurrence of seronegative RA (32.6% vs. 22.1%) were higher in the IL-6Ri vs. MTX groups. About one-fourth of the patients were moderately-severely frail (CFI ≥0.35, 20.9% vs. 26.7%) at baseline (Table 3). Time to GC discontinuation (FIG. 12) and time to minimal or no GC (FIG. 13) up to 1 year were significantly shorter for the IE-6Ri vs. MTX-treated patients ([HR {95% CI} 1.75 {1.05, 2.93}; p=0.033]; median days until GC discontinuation: 244 vs. 332; and [HR {95% CI} 1.86 {1.15, 3.00}; p=0.011]; median days until minimal or no GC: 191 vs. 316), respectively.

[0506] Table 3. Post-Propensity Score Match Patient Characteristics.Age at index date, years Y* 79.0 (6.0) 78.4 (5.6) 0.10 0.395aGender, female Y* 71 (82.6%) 67 0.12 0.444b(77.9%)Race N 0.20 0.505cWhite 77 (89.5%) 76(88.4%)Black <11 <11Other <11 <11Region N 0.17 0.989cWest 25 (29.1 %) 25(29.1 %)Midwest Redacted RedactedNortheast 23 (26.7%) 23(26.7%)South 24 (27.9%) 23(26.7%)Unknown <11 <11Original reason eligible for Medicare Y 0.00 >0.999bAge 65 or older 72 (83.7%) 72(83.7%)Disabled 14 (16.3%) 14(16.3%)Baseline prednisone equivalent dose N 8.9 (6.1 ) 8.8 (6.1 ) 0.02 0.901a(mg / day)Baseline prednisone equivalent dose Y* 0.15 0.995ccategory (mg / day)<2.5 <11 <112.5-<5 14 (16.3%) 15(17.4%)35 (40.7%) 365— <10 (41.9%)19 (22.1 %) 2110— <15 (24.4%)15-<20 <11 <1120-25 <11 <11>25 <11 <11Index day prednisone equivalent N 12.1 (6.2) 11.5 (5.9) 0.09 0.526adose (mg)Index day prednisone equivalent Y* 0.35 0.404cdose category (mg)<2.5 <11 <112.5-<5 <11 <1127 (31.4%) 345— <10 (39.5%)17 (19.8%) 2310— <15 (26.7%)21 (24.4%)15-<20 13(15.1 %)16 (18.6%) 1320-25 (15.1%)Charlson Comorbidity Index N 4.0 (2.5) 3.6 (2.7) 0.14 0.259aTime from first PMR diagnosis to Y 1 ,024.9 799.0 0.23 0.183aindex date (1 ,047.0) (886.0)Frailty Y 0.14 0.371b68 (79.1%) 63Mildly frail (CFI: 0.25-0.34) (73.3%)Moderately - severely frail (CFI: 18 (20.9%) 23>0.35) (26.7%)Y* 43 (50.0%) 43 0.00 >0.999GCA (any history)b(50.0%)Baseline period comorbidities Y13 (15.1%) 16 -0.09 0.541Asthmab(18.6%)Atopic dermatitis <11 <11 -0.15 >0.999c21 (24.4%) 13 0.24 0.126COPDb(15.1%)Crohn disease <11 <11 0.15 >0.999cPsoriasis <11 <11 -0.15 0.621c28 (32.6%) 19 0.24 0.124Seronegative RAb(22.1%)Ulcerative colitis <11 <11 0.15 >0.999cInpatient days3.2 (7.1) 1.8 (4.1) 0.23 0.345aEmergency department visits1.0 (1.8) 1.0 (1.3) 0.03 0.450anumberOutpatient office visits number Y 13.4 (6.3) 13.3 (6.9) 0.01 0.772aCalendar year of index date Y 0.50 0.120b<11 132016(15.1%) <11 142017(16.3%) 11 (12.8%) 152018(17.4%) 21 (24.4%) 152019(17.4%) 12 (14.0%) 152020(17.4%)2021 20 (23.3%) <112022 <11 <11

[0507] Index date was the date IL-6Ri or MTX was initiated. Baseline was defined as the 180 days prior to index date. *Unless otherwise stated, continuous variables are reported as Mean (SD) and categorical as n (%); 'To protect patient privacy and avoid potential identification of patients only results with ≥11 patients are reported, and data are redacted when there are >11 patients when such results would allow derivation of the number of patients when <11 are reported; "Covariatcs used both for direct and PS match. Imbalances were assessed using a1combination of SMD and p values. When the SMD reached the threshold indicating an imbalance, p value was used to determine significance. If the p value did not show significance, the variable was not considered for further testing of matched pairs.aWilcoxon rank sum test;bPearson’s Chi-squared test;cFisher’s exact test. CFI, claims-based frailty index; COPD, chronic obstructive pulmonary disease; GCA, giant cell arteritis; IL-6Ri, IL-6 receptor inhibitors; MTX, methotrexate; PMR, polymyalgia rheumatica; PS, propensity score; RA, rheumatoid arthritis; SMD, standardized mean difference; SD, standard deviation.Conclusions

[0508] IL-6Ri therapy led to a more rapid discontinuation of GCs or to achieving a minimal GC dose of ≤2 mg / day in the 2L-treated frail patients with PMR. Thus, this vulnerable population may derive greater benefit from IL-6Ri therapy compared with MTX.References below are incorporated herein to the extent that is relevant for the purpose of the present disclosure described herein:

[0509] Sattui SE, et al. Rheumatology (Oxford). 2022;61(l l):4455-64.

[0510] Motta F, et al. Front Immunol. 2020; 11 :576134.

[0511] Halawa OA, et al. Ophthalmology. 2023;130(6):646-54.

[0512] Sattui SE, et al. EULAR 2024. Poster POS1427.

[0513] Kim DH, et al. J Gerontol A Biol Sci Med Sci. 2019;74(8): 1271-6.

Claims

CLAIMS1. A method for treating polymyalgia rheumatica (PMR) in a frail subject, comprising administering to a frail subject having PMR an effective amount of an interleukin-6 (IL-6) receptor inhibitor.

2. The method of claim 1, wherein the IL-6 receptor inhibitor is an antibody or antigenbinding fragment thereof that specifically binds IL-6 receptor.

3. The method of claim 1 or 2, wherein the subject has PMR that is refractory to a steroid or is refractory to a steroid taper.

4. The method of claim 1 , 2 or 3, wherein the subject has had an inadequate response to a steroid or cannot tolerate a steroid taper.

5. The method of claim 3 or 4, wherein the steroid comprises a corticosteroid.

6. The method of claim 5, wherein the corticosteroid comprises prednisone.

7. The method of any one of claims 3-6, wherein the subject was previously treated with the at least one steroid at: (i) a dose of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day; or (ii) a dose of about 5 mg / day.

8. The method of any one of the preceding claims, wherein the IL-6 receptor inhibitor is administered in combination with a second therapeutic agent.

9. The method of claim 8, wherein the second therapeutic agent comprises a corticosteroid.

10. The method of claim 9, wherein the corticosteroid comprises prednisone.

11. The method of claim 9 or 10, wherein the corticosteroid is administered: (i) at a dose of about ≥ 2.5 mg / day and optionally less than or equal to about 25 mg / day; or (ii) about 5 mg / day.

12. The method of claim 11, wherein the dose of corticosteroid is discontinued or tapered, optionally to less than or equal to about 2.5 mg / day or less than or equal to about 2.0 mg / day.

13. The method of claim 12, wherein the corticosteroid is tapered or discontinued beginning at about 10 weeks, at about 12 weeks, at about 14 weeks, at about 16 weeks, at about 18 weeks, at about 20 weeks, at about 25 weeks, or at about 30 weeks, or later, after administering a first dose of the IL-6 receptor inhibitor.

14. The method of claim 12, wherein the corticosteroid is tapered or discontinued beginning at between about 10 weeks and about 20 weeks after administering a first dose of the IL-6 receptor inhibitor, optionally wherein the corticosteroid is discontinued beginning at about 14 weeks after administering a first dose of the IL-6 receptor inhibitor.

15. The method of any of the preceding claims, wherein the subject was previously treated with a conventional synthetic immunomodulatory drug (csIM).

16. The method of the preceding claims, wherein the subject is concomitantly treated with a csIM in addition to the IL-6 receptor inhibitor.

17. The method of claim 16, wherein the csIM is selected from: methotrexate, azathioprine, sulfasalazine, hydroxychloroquine, and leflunomide.

18. The method of claim 17 or 17, wherein the csIM is or comprises methotrexate.

19. The method of any one of claims 2-18, wherein the antibody or antigen-binding fragment thereof is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

20. The method of any one of the preceding claims, wherein the subj ect has a Claims-Based Frailty Index (CFI) value of greater than or equal to about 0.25, or greater than or equal to about 0.35.

21. The method of any one of the preceding claims, wherein the subject has a CFI value of about 0.25 to about 0.34 or ≥ about 0.35.

22. The method of any one of claims 1-21, wherein the subject has a CFI value of ≥ about 0.25.

23. The method of any one of claims 1-21, wherein the subject is mildly frail.

24. The method of any one of claims 1-21, wherein the subject is moderate-to-severely frail.

25. A method of reducing or eliminating dependence of a frail subject with polymyalgia rheumatica (PMR) on a background therapy comprising a corticosteroid for the treatment of PMR comprising:(a) selecting a frail patient who has PMR that is partially controlled or uncontrolled with a background therapy comprising a corticosteroid;(b) administering to the frail patient an effective amount of an interleukin-6 (IL-6) receptor inhibitor at a defined frequency for an initial treatment period while maintaining the subject’s background PMR therapy for the initial treatment period; and(c) gradually reducing or eliminating the dosage of the corticosteroid administered to the subject over the course of a subsequent treatment period while continuing to administer the IL-6 receptor inhibitor to the subject at the defined frequency and dose used during the initial treatment period.

26. The method of claim 25, wherein the IL-6 receptor inhibitor is an antibody or antigenbinding fragment thereof that specifically binds IL-6 receptor.

27. The method of claim 25, wherein the subject has a CFI value of greater than or equal to about 0.25, or greater than or equal to about 0.35.

28. The method of claim 25, wherein the subject has a CFI value of between about 0.25 and about 0.34 or ≥ 0.25.

29. The method of claim 25, wherein the subject has a CFI value of ≥ 0.25.

30. The method of claim 25, wherein the subject is mildly frail.

31. The method of claim 25, wherein the subject is moderate-to-severely frail.

32. The method of claim 25, wherein the corticosteroid comprises prednisone.

33. The method of any one of the preceding claims, wherein the subject 50 years old or older.

34. The method of any one of the preceding claims, wherein the subject is 65 years old or older.

35. The method of any one of the preceding claims, wherein the subject was previously administered both a glucocorticoid and a csIM.

36. The method of any one of the preceding claims, wherein the subject has one or more comorbidities selected from: asthma, atopic dermatitis, chronic obstructive pulmonary disease, Crohn's disease, giant cell arteritis, psoriasis and seronegative rheumatoid arthritis.

37. The method of any one of the preceding claims, wherein the IL-6 receptor inhibitor is used as a second line (2L) treatment.

38. The method of any one of the preceding claims, wherein the IL-6 receptor inhibitor is used as a third line (3L) treatment.

39. The method of any one of the preceding claims, wherein the subject has bilateral shoulder pain.

40. The method of any one of the preceding claims, wherein the subject has a C-reactive protein (CRP) level of >10 mg / L and / or an erythrocyte sedimentation rate (ESR) >30 mm / hr.

41. The method of any one of the preceding claims, wherein the subject has morning stiffness.

42. The method of any one of the preceding claims, wherein the subject has an absence of joint involvement other than the shoulder joint.

43. The method of any one the preceding claims, wherein the subj ect has hip pain or limited range of motion.

44. The method of any one of the preceding claims, wherein the subject is seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP).

45. The method of any one of the preceding claims, wherein the subject does not have a disorder or disease selected from: giant cell arteritis, rheumatoid arthritis, inflammatory arthritis, connective tissue disease, rhabdomyolysis, neuropathic muscular disease, and active fibromyalgia.

46. The method of claim 45, wherein the connective tissue disease is selected from: systemic lupus erythematosus, systemic sclerosis, vasculitis, myositis, mixed connective tissue disease, and ankylosing spondylitis.

47. The method of any one of the preceding claims, wherein the subject has at least one shoulder with subdeltoid bursitis and / or biceps tenosynovitis and / or posterior or axillary glenohumeral synovitis, and at least one hip with synovitis and / or trochanteric bursitis.

48. The method of any one of the preceding claims, wherein at least one symptom of PMR in the subject is improved after administering the IL-6 receptor inhibitor.

49. The method of claim 48, wherein the at least one symptom is selected from: shoulder pain associated with inflammatory stiffness; hip pain associated with inflammatory stiffness; elevated C-reactive protein (CRP) levels; and elevated erythrocyte sedimentation rate (ESR); and any combinations thereof.

50. The method of any one of the preceding claims, wherein treatment with the IL-6 receptor inhibitor results in the improvement of least one patient reported outcome measure or clinician reported outcome measure selected from the group consisting of: functional assessment of chronic illness therapy fatigue scale (FACIT-Fatigue), EuroQol five-dimensional three-level questionnaire (EQ-5D-3L), and Short form-36v2 (SF-36v2), health assessment questionnaire disability index (HAQ-DI), and physician global assessment of disease activity- Visual Analog Scale (MD-VAS).

51. The method of any one of the preceding claims, wherein treatment with the IL-6 receptor inhibitor results in a decrease in glucocorticoid toxicity index (GTI) score.

52. The method of any one of the preceding claims, wherein treatment with the IL-6 receptor inhibitor results in a decrease in PMR activity score (PMR- AS).

53. The method of any one of the preceding claims, wherein treatment with the IL-6 receptor inhibitor results in an increase in time to first PMR flare.

54. The method of claim 53, wherein the first PMR flare includes a symptom selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

55. The method of any one of the preceding claims, wherein treatment with the IL-6 receptor inhibitor results in remission of PMR in the subject.

56. The method of claim 55, wherein the subject has an absence of disease flare in remission.

57. The method of claim 56, wherein a symptoms of PMR flare is selected from shoulder pain associated with inflammatory stiffness and hip girdle pain associated with inflammatory stiffness.

58. The method of any one of the preceding claims, wherein treatment with the IL-6 receptor inhibitor results in increased resolution of PMR signs and symptoms or GC-ffee resolution of PMR signs and symptoms in the subject.

59. The method of claim 58, wherein the resolution of PMR signs and symptoms is achieved from week 4 after starting treatment with the IL-6 receptor inhibitor.

60. The method of claim 58, wherein the GC-free resolution of PMR signs and symptoms is maintained from week 16 after starting treatment with the IL-6 receptor inhibitor to week 52.

61. The method of claim 26-60, wherein the antibody is selected from: sarilumab, tocilizumab, satralizumab, levilimab, and vobarilizumab and any antigen-binding fragments thereof.

62. A method of reducing or eliminating dependence of a subject with polymyalgia rheumatica (PMR) on a background therapy comprising a corticosteroid for the treatment of PMR, wherein the subject has a Claims-Based Frailty Index (CFI) value of greater than or equal to about 0.15, comprising:(a) selecting a patient having a CFI value of greater than or equal to about 0.15 who has PMR that is partially controlled or uncontrolled with a background therapy comprising a corticosteroid;(b) administering to the frail patient an effective amount of an interleukin- 6 (IL-6) receptor inhibitor at a defined frequency for an initial treatment period while maintaining the subject’s background PMR therapy for the initial treatment period; and(c) gradually reducing or eliminating the dosage of the corticosteroid administered to the subject over the course of a subsequent treatment period while continuing to administer the IL-6 receptor inhibitor to the subject at the defined frequency and dose used during the initial treatment period.

63. The method of claim 62, wherein the IL-6 receptor inhibitor is an antibody or antigenbinding fragment thereof that specifically binds IL-6 receptor.

64. A method of reducing or eliminating dependence of a frail subject with polymyalgia rheumatica (PMR) on a background therapy comprising a corticosteroid for the treatment of PMR, wherein the subject has a Claims-Based Frailty Index (CFI) value of between about 0.25 and about 0.34, comprising:(a) selecting a fail patient who has PMR and a CFI value of between about 0.25 and about 0.34 that is partially controlled or uncontrolled with a background therapy comprising a corticosteroid;(b) administering to the frail patient an effective amount of an interleukin- 6 (IL-6) receptor inhibitor at a defined frequency for an initial treatment period while maintaining the subject’s background PMR therapy for the initial treatment period; and(c) gradually reducing or eliminating the dosage of the corticosteroid administered to the subject over the course of a subsequent treatment period while continuing to administer the IL-6 receptor inhibitor to the subject at the defined frequency and dose used during the initial treatment period.

65. The method of claim 64, wherein the IL-6 receptor inhibitor is an antibody or antigenbinding fragment thereof that specifically binds IL-6 receptor.

66. A method of reducing or eliminating dependence of a frail subject with polymyalgia rheumatica (PMR) on a background therapy comprising a corticosteroid for the treatment of PMR, wherein the subject has a Claims-Based Frailty Index (CFI) value of ≥0.35, comprising:(a) selecting a fail patient who has PMR and a CFI value of ≥0.35 that is partially controlled or uncontrolled with a background therapy comprising a corticosteroid;(b) administering to the frail patient an effective amount of an interleukin- 6 (IL-6) receptor inhibitor at a defined frequency for an initial treatment period while maintaining the subject’s background PMR therapy for the initial treatment period; and(c) gradually reducing or eliminating the dosage of the corticosteroid administered to the subject over the course of a subsequent treatment period while continuing to administer the IL-6 receptor inhibitor to the subject at the defined frequency and dose used during the initial treatment period.

67. The method of claim 66, wherein the IL-6 receptor inhibitor is an antibody or antigenbinding fragment thereof that specifically binds IL-6 receptor.

68. A method for treating polymyalgia rheumatica (PMR) in a frail subject, comprising: selecting a frail subject having PMR; and administering to the subject an effective amount of an interleukin-6 (IL-6) receptor inhibitor.

69. The method of claim 68, wherein the IL-6 receptor inhibitor is an antibody or antigenbinding fragment thereof that specifically binds IL-6 receptor.

70. The method of any one of the preceding claims, wherein the IL-6 receptor inhibitor is administered subcutaneously.

71. The method of any one of the preceding claims, wherein the IL-6 receptor inhibitor is administered subcutaneously using a needle and syringe, a pen delivery device, or an autoinjector.

72. The method of any one of the preceding claims, wherein the subject, upon administration of the IL-6R inhibitor, discontinues corticosteroid use.

73. The method of any one of the preceding claims, wherein the subject, upon administration of the IL-6R inhibitor, achieves a minimal corticosteroid dose of less than or equal to about 2 mg / day.

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