Treatment of subjects with rheumatic polymyalgia who have received steroids

Abstract

The present disclosure provides methods and compositions for treating polymyalgia rheumatica (PMR) in a subject previously treated with a steroid. Also provided are methods of treating the subject with an interleukin-6 inhibiting therapy.

Description

Cross-references to related applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 620,601, filed January 12, 2024, which is incorporated herein by reference in its entirety. sequence list

[0002] The contents of the XML-formatted sequence list submitted electronically (name: 760702_SA9-496PC_ST26.xml; size: 18,523 bytes; creation date: January 7, 2025) are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to therapeutic treatment of polymyalgia rheumatica (PMR). In some embodiments, this disclosure relates to the use of interleukin-6 receptor (IL-6R) antagonists, such as anti-IL-6R antibodies, for the treatment of polymyalgia. Background Technology

[0004] Polymyalgia rheumatica (PMR) is a common inflammatory rheumatic disease in people over 50 years of age, with an increased prevalence between 70 and 80 years of age. PMR is primarily treated with glucocorticoids (GC), with guidelines recommending 36–48 weeks of treatment without flare-ups, or 40–52 weeks with a single flare-up. However, it is estimated that 77% of PMR patients are still receiving GC one year (52 weeks) after their initial GC treatment, and an estimated 51% and 25% of PMR patients will continue receiving GC for up to 2 years (104 weeks) and 5 years (260 weeks), respectively. Summary of the Invention

[0005] This disclosure is based on the finding that administration of IL-6 receptor inhibitors (IL-6Ri) including IL-6 antibodies and conventional synthetic immunomodulatory drugs (csIM) to subjects who have received steroids for 6 months has a GC-sparing effect in PMR patients.

[0006] On the one hand, methods are provided for reducing steroid-related toxicity in subjects with polymyalgia rheumatica (PMR) or for treating PMR in subjects in need, methods comprising: (1) Administering IL-6 inhibitory therapy to a subject with PMR who is receiving PMR therapy that includes at least a steroid and does not include IL-6 inhibitory therapy, wherein approximately six months after the start of steroid therapy, the dose of steroid administered to the subject is greater than or equal to approximately 5 mg / day; and (2) Gradually reduce the dose of steroids or discontinue steroid treatment.

[0007] In some exemplary embodiments, approximately six months after initiating steroid treatment, the steroid dose is greater than approximately 5 mg per day. In some exemplary embodiments, approximately six months after initiating steroid treatment, the steroid dose is greater than or equal to approximately 7.5 mg / day.

[0008] In some exemplary embodiments, the subject develops a new-onset PMR when steroid treatment is initiated. In some exemplary embodiments, the subject does not have giant cell arteritis or rheumatoid arthritis.

[0009] In some exemplary embodiments, steroid tapering or discontinuation begins approximately 26 weeks after the initiation of steroid treatment. In some exemplary embodiments, steroid tapering is performed in a manner that allows steroids to be discontinued after at least approximately 50 days of IL-6 inhibitory therapy. In some exemplary embodiments, steroid tapering is performed in a manner that allows steroids to be discontinued after approximately 50 to approximately 250 days of IL-6 inhibitory therapy. In some exemplary embodiments, steroids are discontinued after approximately 50 to approximately 250 days of IL-6 inhibitory therapy.

[0010] In some exemplary embodiments, the steroid comprises a corticosteroid. In some exemplary embodiments, the steroid comprises prednisone.

[0011] In some exemplary embodiments, a PMR therapy that comprises at least a steroid and does not contain an IL-6 inhibitory therapy is substantially composed of or consists of a steroid. In some exemplary embodiments, a PMR therapy that comprises at least a steroid and does not contain an IL-6 inhibitory therapy is substantially composed of or consists of a steroid and a conventional synthetic immunomodulatory drug (csIM) therapy.

[0012] In some exemplary embodiments, csIM therapy is administered within approximately six months of starting steroid treatment. In some exemplary embodiments, csIM therapy comprises methotrexate (MTX), imidazothiopurine, sulfasalazine, hydroxychloroquine, or leflunomide.

[0013] In some exemplary embodiments, IL-6 inhibition therapy is administered to a subject in combination with csIM therapy. In some exemplary embodiments, csIM therapy is selected from methotrexate, imidazothiopurine, sulfasalazine, hydroxychloroquine, and leflunomide.

[0014] In some exemplary embodiments, the IL-6 inhibition therapy comprises an anti-IL6R antibody or its antigen-binding fragment. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered at a dose of about 150 mg to about 200 mg. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered at a dose of about 150 mg. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered at a dose of about 200 mg. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered every other week (q2w).

[0015] In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) sequences of SEQ ID NO: 3, 4, and 5, and the light chain complementarity-determining region (LCDR) sequences of SEQ ID NO: 6, 7, and 8. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10. In some exemplary embodiments, the anti-IL6R antibody is sarerudumab.

[0016] In some exemplary embodiments, the subjects are 50 years of age or older. In some exemplary embodiments, a further characteristic of the subjects is a Charlson comorbidity index score, and... Figure 4 Rheumatoid arthritis is seronegative, or the patient has diabetes, myocardial infection, stroke, percutaneous coronary intervention and coronary artery bypass surgery, hypertension, unstable angina, arrhythmia, heart failure, osteoporosis or osteopenia, osteonecrosis, glaucoma, steroid myopathy, mental illness or a combination thereof.

[0017] In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously as a pharmaceutical composition using a needle and syringe, a pen delivery device, or an autoinjector. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered using a pre-filled syringe containing approximately 175 mg / mL of salperumab.

[0018] In some exemplary embodiments, administration of IL-6 inhibitory therapy improved at least one symptom of PMR in the subject. In some exemplary embodiments, administration of IL-6 inhibitory therapy reduced the subject's glucocorticoid toxicity index (GTI) score.

[0019] On the one hand, methods for treating polymyalgia rheumatica (PMR) in subjects in need are provided, including administration of a therapeutically effective dose of IL-6 inhibitory therapy, conventional synthetic immunomodulatory therapy (csIM), or IL-6 inhibitory therapy and csIM therapy, and gradual reduction of steroid dose or discontinuation of steroid therapy. The PMR subjects were receiving PMR therapy that included at least steroids and did not include IL-6 inhibitory therapy, with the steroid dose administered to the subjects being greater than or equal to about 5 mg / day approximately six months after the start of steroid therapy.

[0020] In some exemplary embodiments, approximately six months after the start of steroid treatment, the steroid dose is greater than or equal to approximately 7.5 mg / day.

[0021] In some exemplary embodiments, the subject develops a new-onset PMR when steroid treatment is initiated. In some exemplary embodiments, the subject does not have giant cell arteritis or rheumatoid arthritis.

[0022] In some exemplary embodiments, the steroid is gradually tapered off or discontinued. In some exemplary embodiments, the tapering off or discontinuation of the steroid begins approximately 26 weeks after the initiation of steroid treatment. In some exemplary embodiments, the steroid is tapered off in a manner that discontinues the steroid after at least approximately 50 days of IL-6 inhibitory therapy. In some exemplary embodiments, the steroid is tapered off in a manner that discontinues the steroid after approximately 50 to approximately 250 days of IL-6 inhibitory therapy. In some exemplary embodiments, the steroid is discontinued after at least approximately 50 days of IL-6 inhibitory therapy. In some exemplary embodiments, steroids are discontinued approximately 50 to approximately 250 days after administration of IL-6 inhibitory therapy.

[0023] In some exemplary embodiments, the steroid comprises a corticosteroid. In some exemplary embodiments, the steroid comprises prednisone.

[0024] In some exemplary embodiments, approximately six months after the initiation of steroid treatment, the csIM therapy already administered is methotrexate (MTX), imidazothiopurine, sulfasalazine, hydroxychloroquine, or leflunomide.

[0025] In some exemplary embodiments, a PMR therapy that comprises at least a steroid and does not contain an IL-6 inhibitory therapy is substantially composed of or consists of a steroid. In some exemplary embodiments, a PMR therapy that comprises at least a steroid and does not contain an IL-6 inhibitory therapy is substantially composed of or consists of a steroid and a csIM therapy.

[0026] In some exemplary embodiments, the IL-6 inhibition therapy comprises an anti-IL6R antibody or an antigen-binding fragment thereof. In some exemplary embodiments, the anti-IL6R antibody or an antigen-binding fragment thereof is administered at a dose of about 150 mg to about 200 mg. In some exemplary embodiments, the anti-IL6R antibody or an antigen-binding fragment thereof is administered at a dose of about 150 mg. In some exemplary embodiments, the anti-IL6R antibody or an antigen-binding fragment thereof is administered at a dose of about 200 mg. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered every other week (q2w).

[0027] In some exemplary embodiments, the csIM therapy comprises methotrexate, imidazothiopurine, sulfasalazine, hydroxychloroquine, or leflunomide.

[0028] In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) sequences of SEQ ID NO: 3, 4, and 5, and the light chain complementarity-determining region (LCDR) sequences of SEQ ID NO: 6, 7, and 8. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10. In some exemplary embodiments, the anti-IL6R antibody is sarerudumab.

[0029] In some exemplary embodiments, the subjects are 50 years of age or older. In some exemplary embodiments, a further characteristic of the subjects is a Charson Comorbidity Index score, and... Figure 4 Rheumatoid arthritis presents with a negative seronegative result, or has... Figure 5 Diabetes mellitus, myocardial infection, stroke, percutaneous coronary intervention and coronary artery bypass surgery, hypertension, unstable angina, arrhythmia, heart failure, osteoporosis or osteopenia, osteonecrosis, glaucoma, steroid myopathy, mental illness or a combination thereof.

[0030] In some exemplary embodiments, the IL-6R antibody or its antigen-binding fragment is administered subcutaneously. In the method of any one of claims 35-62, the anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously as a pharmaceutical composition using a needle and syringe, a pen delivery device, or an autoinjector. In the method of any one of claims 35-63, the anti-IL6R antibody or its antigen-binding fragment is administered using a pre-filled syringe containing about 175 mg / mL sarrelumab.

[0031] In some exemplary embodiments, administration of IL-6 inhibitory therapy improved at least one symptom of PMR in the subject. The method of any one of claims 35-65, wherein administration of the IL-6 inhibitory therapy reduced the subject's glucocorticoid toxicity index (GTI) score.

[0032] In another aspect, a method for treating PMR in subjects in need is provided, the method comprising: Steroid use in subjects diagnosed with PMR who are receiving PMR therapy that includes at least steroids and does not include IL-6 inhibitory therapy, wherein if the steroid dose is greater than or equal to about 5 mg daily at about six months after the start of steroid therapy, the subject is advised to undergo a different PMR therapy that includes: (a) administration of IL-6 inhibitory therapy and (b) gradual reduction of the steroid dose or discontinuation of steroid therapy.

[0033] In some exemplary embodiments, a PMR therapy that includes at least a steroid and does not include an IL-6 inhibitory therapy includes at least a steroid and a conventional synthetic immunomodulatory agent (csIM).

[0034] In some exemplary embodiments, the determination is made approximately six months after the initiation of steroid treatment.

[0035] In some exemplary embodiments, the determination is made approximately six months after the initiation of steroid treatment.

[0036] In some exemplary embodiments, approximately six months after the start of steroid treatment, the steroid dose is greater than or equal to approximately 7.5 mg / day.

[0037] In some exemplary embodiments, the subject develops a new-onset PMR when steroid treatment is initiated.

[0038] In some exemplary embodiments, the subject did not have giant cell arteritis or rheumatoid arthritis.

[0039] In some exemplary embodiments, steroids are gradually tapered off or discontinued approximately 26 weeks after the start of steroid treatment.

[0040] In some exemplary embodiments, steroids are gradually reduced in such a way that they are discontinued at least about 50 days after administration of IL-6 inhibitory therapy.

[0041] In some exemplary embodiments, steroids are gradually reduced in such a way that they are discontinued after about 50 to about 250 days of IL-6 inhibitory therapy.

[0042] In some exemplary embodiments, steroids are discontinued at least about 50 days after administration of IL-6 inhibitory therapy.

[0043] In some exemplary embodiments, steroids are discontinued approximately 50 to approximately 250 days after administration of IL-6 inhibitory therapy.

[0044] In some exemplary embodiments, the steroid comprises a corticosteroid.

[0045] In some exemplary embodiments, the steroid comprises prednisone.

[0046] In some exemplary embodiments, a PMR therapy that includes at least a steroid and does not include an IL-6 inhibitory therapy is substantially composed of or consists of a steroid.

[0047] In some exemplary embodiments, a PMR therapy that includes at least a steroid and does not include an IL-6 inhibitor therapy is essentially composed of or consists of a steroid and a conventional synthetic immunomodulatory drug (csIM) therapy.

[0048] In some exemplary embodiments, csIM therapy is administered within approximately six months of starting steroid treatment.

[0049] In some exemplary embodiments, the csIM therapy comprises methotrexate (MTX), imidazothiopurine, sulfasalazine, hydroxychloroquine, or leflunomide.

[0050] In some exemplary embodiments, the IL-6 inhibition therapy comprises an IL-6R antibody.

[0051] In some exemplary embodiments, IL-6 inhibition therapy is further combined with csIM therapy.

[0052] In some exemplary embodiments, the csIM therapy comprises MTX, imidazothiopurine, sulfasalazine, hydroxychloroquine, or leflunomide.

[0053] In some exemplary embodiments, the IL-6 inhibition therapy comprises an anti-IL6R antibody or an antigen-binding fragment thereof.

[0054] In some exemplary embodiments, the dose of the anti-IL6R antibody or its antigen-binding fragment is about 150 mg.

[0055] In some exemplary embodiments, the dose of the anti-IL6R antibody or its antigen-binding fragment is about 200 mg.

[0056] In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered every other week (q2w).

[0057] In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) sequence of SEQ ID NO: 3, 4 and 5, and the light chain complementarity-determining region (LCDR) sequence of SEQ ID NO: 6, 7 and 8.

[0058] In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2.

[0059] In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10.

[0060] In some exemplary embodiments, the anti-IL6R antibody is sarirodus antibody.

[0061] In some exemplary implementations, the subjects are 50 years of age or older.

[0062] In some exemplary embodiments, the subject is further characterized by a Charson Comorbidity Index score, and... Figure 4 Rheumatoid arthritis is seronegative, or the patient has diabetes, myocardial infection, stroke, percutaneous coronary intervention and coronary artery bypass surgery, hypertension, unstable angina, arrhythmia, heart failure, osteoporosis or osteopenia, osteonecrosis, glaucoma, steroid myopathy, mental illness or a combination thereof.

[0063] In some exemplary embodiments, an anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously.

[0064] In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously as a pharmaceutical composition using a needle and syringe, a pen delivery device, or an autoinjector.

[0065] In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered using a pre-filled syringe containing approximately 175 mg / mL of salirumab.

[0066] In some exemplary embodiments, administration of IL-6 inhibitory therapy improved at least one symptom of PMR in the subject.

[0067] In some exemplary embodiments, administration of IL-6 inhibitory therapy reduces the subject's glucocorticoid toxicity index (GTI) score.

[0068] In one aspect, the use of IL-6 inhibitory therapy in the preparation of a medicament for treating polymyalgia rheumatica (PMR) in subjects in need is provided, wherein the subject to be given IL-6 inhibitory therapy is a PMR subject receiving PMR therapy that contains at least a steroid and does not contain IL-6 inhibitory therapy, wherein approximately six months after the start of steroid therapy, the dose of steroid administered to the subject is greater than or equal to approximately 5 mg per day; and the dose of steroid is gradually reduced or steroid therapy is discontinued.

[0069] In some exemplary embodiments, approximately six months after initiating steroid treatment, the steroid dose is greater than approximately 5 mg per day. In some exemplary embodiments, approximately six months after initiating steroid treatment, the steroid dose is greater than or equal to approximately 7.5 mg / day.

[0070] In some exemplary embodiments, the subject develops a new-onset PMR when steroid treatment is initiated. In some exemplary embodiments, the subject does not have giant cell arteritis or rheumatoid arthritis.

[0071] In some exemplary embodiments, steroid tapering or discontinuation begins approximately 26 weeks after the initiation of steroid treatment. In some exemplary embodiments, steroid tapering is performed in a manner that allows steroids to be discontinued after at least approximately 50 days of IL-6 inhibitory therapy. In some exemplary embodiments, steroid tapering is performed in a manner that allows steroids to be discontinued after approximately 50 to approximately 250 days of IL-6 inhibitory therapy. In some exemplary embodiments, steroids are discontinued after approximately 50 to approximately 250 days of IL-6 inhibitory therapy.

[0072] In some exemplary embodiments, the steroid comprises a corticosteroid. In some exemplary embodiments, the steroid comprises prednisone.

[0073] In some exemplary embodiments, a PMR therapy that comprises at least a steroid and does not contain an IL-6 inhibitory therapy is substantially composed of or consists of a steroid. In some exemplary embodiments, a PMR therapy that comprises at least a steroid and does not contain an IL-6 inhibitory therapy is substantially composed of or consists of a steroid and a conventional synthetic immunomodulatory drug (csIM) therapy.

[0074] In some exemplary embodiments, csIM therapy is administered within approximately six months of starting steroid treatment. In some exemplary embodiments, csIM therapy comprises methotrexate (MTX), imidazothiopurine, sulfasalazine, hydroxychloroquine, or leflunomide.

[0075] In some exemplary embodiments, IL-6 inhibition therapy is administered to a subject in combination with csIM therapy. In some exemplary embodiments, csIM therapy is selected from methotrexate, imidazothiopurine, sulfasalazine, hydroxychloroquine, and leflunomide.

[0076] In some exemplary embodiments, the IL-6 inhibition therapy comprises an anti-IL6R antibody or an antigen-binding fragment thereof. In some exemplary embodiments, the anti-IL6R antibody or an antigen-binding fragment thereof is administered at a dose of about 150 mg to about 200 mg. In some exemplary embodiments, the anti-IL6R antibody or an antigen-binding fragment thereof is administered at a dose of about 150 mg. In some exemplary embodiments, the anti-IL6R antibody or an antigen-binding fragment thereof is administered at a dose of about 200 mg. In some exemplary embodiments, the anti-IL6R antibody or an antigen-binding fragment thereof is administered every other week (q2w).

[0077] In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) sequences of SEQ ID NO: 3, 4, and 5, and the light chain complementarity-determining region (LCDR) sequences of SEQ ID NO: 6, 7, and 8. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10. In some exemplary embodiments, the anti-IL6R antibody is sarerudumab.

[0078] In some exemplary embodiments, the subjects are 50 years of age or older. In some exemplary embodiments, a further characteristic of the subjects is a Charson Comorbidity Index score, and... Figure 4 Rheumatoid arthritis is seronegative, or the patient has diabetes, myocardial infection, stroke, percutaneous coronary intervention and coronary artery bypass surgery, hypertension, unstable angina, arrhythmia, heart failure, osteoporosis or osteopenia, osteonecrosis, glaucoma, steroid myopathy, mental illness or a combination thereof.

[0079] In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously as a pharmaceutical composition using a needle and syringe, a pen delivery device, or an autoinjector. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered using a pre-filled syringe containing approximately 175 mg / mL of salperumab.

[0080] In some exemplary embodiments, administration of IL-6 inhibitory therapy improved at least one symptom of PMR in the subject. In some exemplary embodiments, administration of IL-6 inhibitory therapy reduced the subject's glucocorticoid toxicity index (GTI) score.

[0081] On the other hand, a method for reducing steroid-related toxicity in subjects with polymyalgia rheumatica (PMR) is provided, the method comprising: (i) IL-6 inhibitory therapy is administered to subjects selected at least in part based on the following criteria: (i) having PMR and receiving PMR therapy that includes at least a steroid and does not include IL-6 inhibitory therapy; and (ii) having a daily dose of steroid greater than or equal to about 5 mg per day approximately six months after starting steroid therapy; and (ii) gradually reducing the dose of steroid or discontinuing steroid therapy.

[0082] In some exemplary embodiments, subject selection is performed. In some exemplary embodiments, selection is performed approximately six months after the start of steroid treatment. In some exemplary embodiments, selection is performed approximately six months after the start of steroid treatment.

[0083] In some exemplary embodiments, approximately six months after initiating steroid treatment, the steroid dose is greater than approximately 5 mg per day. In some exemplary embodiments, approximately six months after initiating steroid treatment, the steroid dose is greater than or equal to approximately 7.5 mg / day.

[0084] In some exemplary embodiments, the subject develops a new-onset PMR when steroid treatment is initiated. In some exemplary embodiments, the subject does not have giant cell arteritis or rheumatoid arthritis.

[0085] In some exemplary embodiments, steroid tapering or discontinuation begins approximately 26 weeks after the initiation of steroid treatment. In some exemplary embodiments, steroid tapering is performed in a manner that allows steroids to be discontinued after at least approximately 50 days of IL-6 inhibitory therapy. In some exemplary embodiments, steroid tapering is performed in a manner that allows steroids to be discontinued after approximately 50 to approximately 250 days of IL-6 inhibitory therapy. In some exemplary embodiments, steroids are discontinued after approximately 50 to approximately 250 days of IL-6 inhibitory therapy.

[0086] In some exemplary embodiments, the steroid comprises a corticosteroid. In some exemplary embodiments, the steroid comprises prednisone.

[0087] In some exemplary embodiments, a PMR therapy that comprises at least a steroid and does not contain an IL-6 inhibitory therapy is substantially composed of or consists of a steroid. In some exemplary embodiments, a PMR therapy that comprises at least a steroid and does not contain an IL-6 inhibitory therapy is substantially composed of or consists of a steroid and a conventional synthetic immunomodulatory drug (csIM) therapy.

[0088] In some exemplary embodiments, csIM therapy is administered within approximately six months of starting steroid treatment. In some exemplary embodiments, csIM therapy comprises methotrexate (MTX), imidazothiopurine, sulfasalazine, hydroxychloroquine, or leflunomide.

[0089] In some exemplary embodiments, IL-6 inhibition therapy is administered to a subject in combination with csIM therapy. In some exemplary embodiments, csIM therapy is selected from methotrexate, imidazothiopurine, sulfasalazine, hydroxychloroquine, and leflunomide.

[0090] In some exemplary embodiments, the IL-6 inhibition therapy comprises an anti-IL6R antibody or an antigen-binding fragment thereof. In some exemplary embodiments, the anti-IL6R antibody or an antigen-binding fragment thereof is administered at a dose of about 150 mg to about 200 mg. In some exemplary embodiments, the anti-IL6R antibody or an antigen-binding fragment thereof is administered at a dose of about 150 mg. In some exemplary embodiments, the anti-IL6R antibody or an antigen-binding fragment thereof is administered at a dose of about 200 mg. In some exemplary embodiments, the anti-IL6R antibody or an antigen-binding fragment thereof is administered every other week (q2w).

[0091] In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) sequences of SEQ ID NO: 3, 4, and 5, and the light chain complementarity-determining region (LCDR) sequences of SEQ ID NO: 6, 7, and 8. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO: 2. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO: 10. In some exemplary embodiments, the anti-IL6R antibody is sarerudumab.

[0092] In some exemplary embodiments, the subjects are 50 years of age or older. In some exemplary embodiments, a further characteristic of the subjects is a Charson Comorbidity Index score, and... Figure 4 Rheumatoid arthritis is seronegative, or the patient has diabetes, myocardial infection, stroke, percutaneous coronary intervention and coronary artery bypass surgery, hypertension, unstable angina, arrhythmia, heart failure, osteoporosis or osteopenia, osteonecrosis, glaucoma, steroid myopathy, mental illness or a combination thereof.

[0093] In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously as a pharmaceutical composition using a needle and syringe, a pen delivery device, or an autoinjector. In some exemplary embodiments, the anti-IL6R antibody or its antigen-binding fragment is administered using a pre-filled syringe containing approximately 175 mg / mL of salperumab.

[0094] In some exemplary embodiments, administration of IL-6 inhibitory therapy improved at least one symptom of PMR in the subject. In some exemplary embodiments, administration of IL-6 inhibitory therapy reduced the subject's glucocorticoid toxicity index (GTI) score. Attached Figure Description

[0095] The foregoing and other features and advantages of this disclosure will be more fully understood from the following detailed description of illustrative embodiments, taken in conjunction with the accompanying drawings.

[0096] Figure 1A-Figure 1BThe mean and median glucocorticoid doses at 6 months are presented graphically, based on the glucocorticoid status at one year. The mean daily dose of glucocorticoids was obtained from months 5 to 7, with p-values ​​determined using t-tests, Wilcoxon signed-rank tests, Chi-squared tests, and Fisher's exact test.

[0097] Figures 2A-2B The proportion of subjects receiving ≥ 5 mg or ≥ 7.5 mg of glucocorticoids at 6 months is presented graphically, based on their glucocorticoid status at one year. P-values ​​were determined using t-tests, Wilcoxon signed-rank tests, chi-square tests, and Fisher's correct probability tests.

[0098] Figure 3 A- Figure 3 B presents the average cumulative glucocorticoid dose at 6 months, based on the glucocorticoid status at one year. The p-value was determined using the t-test, Wilcoxon signed-rank test, chi-square test, and Fisher's correctness test.

[0099] Figure 4 A table describing key demographic and clinical characteristics at six months of age, based on glucocorticoid status at one year of age. a The study also analyzed the baseline diagnosis of asthma, atopic dermatitis, COPD, Crohn's disease, psoriasis, and ulcerative colitis, as well as the baseline HCRU (days of hospital stay, emergency room visits, outpatient visits, and unique prescriptions), but these were not significant. b The T-test is used to compare normally distributed continuous variables, the Wilcoxon signed-rank test is used to compare non-normally distributed continuous variables, the chi-square test is used to compare categorical variables, and the Fisher right probability test is used to compare categorical variables with small sample sizes. c To protect patient privacy and avoid potential patient identification, only results from studies with more than 11 patients will be published. If the number of patients is greater than 11, but the data could lead to an estimated number of patients of less than 11, the data will be edited. COPD, Chronic Obstructive Pulmonary Disease; csIM, Conventional Synthetic Immunomodulatory Agent; GC, Glucocorticoids; IQR, Interquartile Range; RA, Rheumatoid Arthritis; SD, Standard Deviation.

[0100] Figure 5 To describe the baseline comorbidities and weakness at 6 months, based on different glucocorticoid status at one year. a This includes myocardial infarction, stroke, percutaneous coronary intervention, and coronary artery bypass surgery.b The T-test is used to compare normally distributed continuous variables, the Wilcoxon signed-rank test is used to compare non-normally distributed continuous variables, the chi-square test is used to compare categorical variables, and the Fisher right probability test is used to compare categorical variables with small sample sizes. c To protect patient privacy and avoid potential patient identification, only results from studies with more than 11 patients will be published. If the number of patients is greater than 11, but the data could lead to an estimated number of less than 11 patients, the data will be edited. CFI, Claims-Based Weakness Index; GC, Glucocorticoids; MACE, Major Adverse Cardiovascular Events; PMR, Polymyalgia Rheumatoid; SD, Standard Deviation. Detailed Implementation

[0101] Before describing this disclosure, it should be understood that this disclosure is not limited to the specific methods and experimental conditions described, as such methods and conditions are variable. Although any methods and materials similar to or equivalent to those described herein may be used in practice with respect to this disclosure, typical methods and materials are described here. It should also be understood that because the scope of this disclosure will be limited only by the appended claims, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. All publications mentioned herein are incorporated herein by reference in their entirety.

[0102] This disclosure provides methods and compositions for treating polymyalgia rheumatica (PMR). Polymyalgia rheumatica is a chronic inflammatory disorder that occurs almost exclusively in people over 50 years of age. (Guggino et al. Pathogenesis of Polymyalgia Rheumatica. Reumatismo 2018 70(1):10-17) and Chatzigeorgiou C et al. Comorbidity in polymyalgia rheumatica. Reumatismo. 27 Mar 2018; 70(1):35-43, which are incorporated herein by reference in their entirety). Polymyalgia rheumatica is characterized by pain and stiffness in the shoulder and possibly the hip, elevated inflammatory factors (although occasionally normal), and a characteristic severe response to corticosteroids.

[0103] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0104] When used to refer to a specific reference value, the term "approximately" means a value similar to the referenced value. Generally, those skilled in the art will understand the extent of variation covered by "approximately" or "approximately" in that context. For example, in some embodiments, the terms "approximately" or "approximately" may cover a range of values ​​within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less of the referenced value.

[0105] The term "administering" or "administration" generally refers to administering a composition to a subject to achieve delivery of a pharmaceutical agent, either as a composition or contained in a composition, to a target or site of treatment. Those skilled in the art will recognize various routes of administration that may be used appropriately to administer to a subject (e.g., 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 applying a fixed number of doses. In some embodiments, administration may involve intermittent administration (e.g., multiple doses spaced apart in time) and / or periodic administration (e.g., a single dose spaced apart by a common period). In some embodiments, administration may involve continuous administration over at least a selected time period (e.g., infusion).

[0106] The terms “conventional synthetic immunomodulatory drugs,” “csIM,” and “synthetic disease-modifying antirheumatic drugs (sDMARDs)” are used interchangeably in this document and refer to drugs used to treat immune system disorders such as rheumatoid arthritis. Suitable csIMs or sDMARDs include, but are not limited to, methotrexate, leflunomide, imidazothiopurine, sulfasalazine, and hydroxychloroquine.

[0107] The terms “IL-6 inhibitor therapy,” “IL-6 inhibitor therapy,” and “IL-6R antagonist” are used interchangeably herein. In some embodiments, IL-6 inhibitor therapy is a therapy that partially or completely blocks the IL-6-related pathway. In some embodiments, IL-6 inhibitor therapy is an antibody. Suitable IL-6 antibodies include, but are not limited to, sarreluzumab, tocilizumab, sartiliuzumab, olozazumab, staxicumab, clazazumab, cilucalumab, wabalizumab, jejuzumab, clazazumab, zevichizumab, olozazumab, and lividilumab.

[0108] When used in the context of PMR, the term “new onset” refers to a new development or recent appearance or onset of one or more signs and symptoms of PMR. For example, in some implementations, the subject has no prior history of PMR prior to treatment.

[0109] As used in this article, the term “PMR outbreak” refers to an increase in one or more PMR symptoms.

[0110] Signs and symptoms include (i) shoulder pain associated with inflammatory stiffness, (ii) hip girdle pain associated with inflammatory stiffness, (iii) morning stiffness lasting more than 45 minutes, (iv) elevated C-reactive protein (CRP) levels, (v) elevated erythrocyte sedimentation rate (ESR), and any combination thereof.

[0111] As used herein, the terms “treat and treating” mean: (1) partially or completely relieving one or more symptoms or features of a disease, disorder and / or condition; or (2) temporarily or permanently improving, relieving, suppressing, preventing, delaying the onset, reducing the severity and / or decreasing the incidence of one or more symptoms or features of a disease, disorder and / or condition (such as PMR).

[0112] This article provides techniques (methods, uses, and compositions) for administering IL-6 inhibitory therapy to subjects identified as potentially benefiting from gradual tapering or discontinuation of steroids (e.g., glucocorticoids), thereby potentially avoiding associated steroid toxicity.

[0113] Subjects diagnosed with PMR were based on the PMR diagnostic classification criteria 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 herein by reference in its entirety). Classification criteria included patients aged 50 years or older presenting with bilateral shoulder pain (which could not be better explained by alternative diagnoses) and elevated C-reactive protein (CRP) levels and / or elevated erythrocyte sedimentation rate (ESR). Additional criteria included morning stiffness lasting longer than 45 minutes and the appearance of new symptoms involving the hip (e.g., pain, tenderness, and limited range of motion). Other classification criteria may include the absence of peripheral synovitis, the absence of positive rheumatoid arthritis (RA) serology (rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), or both), and the absence of peripheral joint pain. Additional classification criteria may include musculoskeletal ultrasound findings of bilateral shoulder abnormalities (subacromial bursitis / biceps tenosynovitis / glenohumeral effusion) or one shoulder and hip abnormality (hip effusion, trochanteric bursitis).

[0114] Diagnostic classification criteria for polymyalgia rheumatica are also described in the European League Against Rheumatism and the American College of Rheumatology (Dasgupta B et al. 2012 provisional classification criteria for polymyalgiarheumatica: a European League Against Rheumatism / American College of Rheumatology collaborative initiative Annals of the Rheumatic Diseases 2012;71:484-492, incorporated herein by reference in its entirety). Classification criteria may include patients aged 50 years or older presenting with bilateral shoulder pain (which cannot be better explained by alternative diagnoses) and elevated C-reactive protein (CRP) levels and / or elevated erythrocyte sedimentation rate (ESR). Additional criteria may include morning stiffness lasting longer than 45 minutes and the appearance of new symptoms involving the hip (e.g., pain, tenderness, and limited range of motion). (The American College of Rheumatology’s criteria for rheumatic diseases, including polymyalgia rheumatica, can be found at www.rheumatology.org / Practice-Quality / Clinical-Support / Criteria / ACR-Endorsed-Criteria, and are incorporated herein by reference in their entirety.)

[0115] IL-6 interacts directly with the IL-6Rα subunit, and the IL-6 / IL-6Rα pair forms a high-affinity complex with the glycoprotein 130 (gp130) subunit, initiating intracellular signaling via the Janus kinase (JAK)-signaling and transcriptional activating protein (STAT) (JAK / STAT) and Ras / Raf / mitogen-activated protein kinase (MAPK) pathways. IL-6Rα also exists in a soluble form, participating in trans signaling and influencing cells that do not express IL-6Rα, including synovial cells. Sarrelumarab (SAR153191), also known as REGN88, is a fully human recombinant IgG1κ monoclonal antibody targeting the α subunit of the IL-6 receptor complex (IL-6Rα). Sarrelumarab blocks IL-6 binding and disrupts the cytokine-mediated signaling cascade. Sarrelumarab is also known by the trade name KEVZARA. ® .

[0116] Tocilizumab (TCZ) is a humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody that binds to both membrane-bound and soluble IL-6 receptors, thereby inhibiting IL-6 signaling. Tocilizumab is also known by the trade name ACTEMRA. ® .

[0117] Satellizumab is a recombinant humanized monoclonal antibody that targets the human interleukin-6 (IL-6) receptor. Satellizumab is also known by the trade name ENSPRYNG®.

[0118] Lividimab is a fully human monoclonal antibody that binds to the interleukin-6 receptor. Lividimab is also known by the new trade name ILSIRA®.

[0119] Zobalizumab is a bispecific nanobody that binds to the interleukin-6 receptor. Zobalizumab is also known as ALX-0061.

[0120] Setuximab is a chimeric monoclonal antibody against human and mouse immunoglobulins that directly binds to and neutralizes human IL-6, thereby reducing the level of unbound IL-6 and preventing it from binding to its receptor. Setuximab is also known as SYLVANT®.

[0121] Cilucalumab is a fully human monoclonal IgG1κ antibody that selectively blocks circulating IL-6. Cilucalumab is also known by its development code CNTO-136 and the provisional trade name PLIVENSIA. TM .

[0122] Jeremab is a recombinant humanized IgG1λ monoclonal antibody targeting interleukin-6. Jeremab is also known as RYI-008, ARGX-109, and GB224.

[0123] Clarizumab is a humanized monoclonal antibody that binds to interleukin-6.

[0124] Zevezimab is a monoclonal antibody that binds to interleukin-6. Zevezimab is also known as MEDI5117, CAT6001, and WBP216.

[0125] Oluzumab is a humanized monoclonal antibody that binds to interleukin-6. Oluzumab is also known as CDP6038.

[0126] In some exemplary embodiments, suitable IL-6R antagonists or IL-6 inhibitory antibodies are selected from the group consisting of sarrizumab, tocilizumab, sartilizumab, lividilumab, and vobalizumab, and any of their antigen-binding fragments.

[0127] Persistent malignant toxicity (PMR) is primarily treated with steroids such as glucocorticoids (GCs). Several guidelines for managing PMR recommend 36–48 weeks of treatment in subjects without a flare-up, or 40–52 weeks in subjects with a single flare-up. However, steroid treatment for PMR often exceeds these guidelines. Prolonged steroid use raises concerns about steroid use-related adverse events and toxicities, especially in older adults (e.g., 50 years and older). Therefore, identifying factors or criteria that may predict which individuals will benefit from steroid discontinuation would be beneficial for managing PMR. Early identification of patients who may require GC treatment for more than a year may be helpful, as these patients may be able to receive other non-GC therapies (also known as GC-conserving therapy) and potentially avoid GC toxicity. Therefore, identifying variables that predict a lack of response in patients with PMR may allow these patients to benefit from GC-conserving therapy.

[0128] This disclosure identifies characteristics such as the steroid dosage of subjects at six months, and finds that said characteristics can predict their steroid use for at least one year. Therefore, such subjects using a 6-month steroid dosage are treated with GC-modification therapy.

[0129] The data provided in this disclosure suggest that certain subject populations are more likely to benefit from gradual tapering or discontinuation of steroid use in favor of non-steroidal interventions (GC-modification therapy), such as IL-6 inhibitory therapy or conventional synthetic immunomodulatory therapy (csIM). In various embodiments, a therapeutically effective dose of IL-6 inhibitory therapy may be administered to PMR subjects who have previously received steroids at a dose greater than or equal to about 5 mg / day for at least six months after initiating steroid therapy or conventional synthetic immunomodulatory (csIM) therapy. In some embodiments, IL-6 inhibitory therapy is an antibody that specifically binds to the IL-6 receptor or an antigen-binding fragment thereof.

[0130] In some implementations, a method is provided for treating polymyalgia rheumatica (PMR) in a subject of need, comprising administering a therapeutically effective amount of IL-6 inhibitory therapy (e.g., an IL-6R antibody that specifically binds to the IL-6 receptor or an antigen-binding fragment thereof), conventional synthetic immunomodulatory (csIM) therapy, or IL-6 inhibitory therapy (e.g., an IL-6R antibody or an antigen-binding fragment thereof) and csIM therapy (e.g., MTX), and gradually tapering off or discontinuing steroid use, wherein the subject of need is given steroid at a dose greater than or equal to about 5 mg / day approximately six months after initiation of steroid therapy, or a dose of steroid and csIM therapy greater than or equal to about 5 mg / day approximately six months after initiation of steroid therapy.

[0131] In some embodiments, administration of IL-6 inhibitory therapy (e.g., anti-IL-6R antibody or its antigen-binding fragment) reduces the cumulative amount of steroids received by the subject (as measured over a period of time following administration of IL-6 inhibitory therapy). In some embodiments, such a period of time may be approximately 2 months, approximately 4 months, approximately 5 months, or approximately 6 months after administration of IL-6 inhibitory therapy. In some embodiments, such a period of time may be approximately 2 to 6 months or approximately 2 to 4 months.

[0132] In some embodiments, the cumulative amount of steroids is reduced by 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 compared to the cumulative amount of steroids measured over a period of time prior to the administration of IL-6 inhibitory therapy. In some embodiments, such a period of time may be about 2 months, about 4 months, about 5 months, or about 6 months, or about 2 to 6 months, or about 2 to 4 months prior to the administration of IL-6 inhibitory therapy. therapy.

[0133] In some embodiments, the determination of the administration of different PMR therapies (e.g., IL-6 inhibitory therapy) is based on a daily steroid dose (e.g., greater than or equal to about 5 mg / day) or a cumulative steroid dose. In some embodiments, the steroid dose can be assessed by either the daily steroid dose or the cumulative steroid dose at 6 months after the initiation of steroid treatment. The disclosures related to the daily dose of steroid treatment also apply to the cumulative steroid dose.

[0134] In some implementations, if the cumulative dose of steroids at 6 months after the start of 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, greater than or equal to about 2000 mg, or 1250 mg to 3000 mg, then it is recommended that at least the subject currently receiving steroid treatment undergo different PMR therapies, including: (a) administration of IL-6 inhibitory therapy and (b) gradual reduction of the steroid dose or discontinuation of steroid treatment.

[0135] In some embodiments, the steroid doses (whether daily or cumulative) provided in this disclosure are prednisone equivalent doses. Methods for improving PMR-related patient-reported outcome (PRO) and clinician-reported outcome (ClinRO) measures.

[0136] Methods are provided for improving one or more PMR-related patient-reported outcome (PRO) measures in subjects in need, wherein the method includes administering a pharmaceutical composition comprising an IL-6R antagonist to the subject. Methods are also provided for improving one or more PMR-related clinical-reported outcome (ClinRO) measures in subjects in need, wherein the method includes administering a pharmaceutical composition comprising an IL-6R antagonist to the subject.

[0137] The implementation plan for PMR-related PRO measures includes: (1) Fatigue Assessment Scale for Treatment of Chronic Diseases (FACIT-Fatigue), (2) EuroQol Five Dimensions Three Levels Questionnaire (EQ-5D-3L), (3) Short Form-36v2 (SF-36v2), (4) Health Assessment Questionnaire Disability Index (HAQ-DI), (5) Patient Total Assessment of Disease Activity (PtGA), and (6) Visual Analogue Scale for Pain (VAS).

[0138] "Improvement in PMR-related PRO measures" means an increase in one or more of the FACIT-Fatigue Score, EQ-5D-3L Score, or SF-36v2 Score relative to baseline; and / or a decrease in one or more of the HAQ-DI Score, PtGA Score, or Pain-VAS Score relative to baseline. As used herein, the term "baseline" in relation to PMR-related PRO measures means the value of the patient's PRO measure before or at the time of administration of the pharmaceutical composition containing an IL-6R antagonist.

[0139] The implementation plan for PMR-related ClinRO measures includes physician-based overall assessment of disease activity – the Visual Analogue Scale (MD-VAS).

[0140] "Improvement in PMR-related ClinRO measure" means a decrease in MD-VAS score relative to baseline. As used herein, the term "baseline" in relation to PMR-related ClinRO measure refers to the patient's ClinRO measure value before or at the time of administration of a pharmaceutical composition containing an IL-6R antagonist.

[0141] To determine whether PMR-related parameters have “improved,” these parameters are quantified at baseline and at time points following administration of the pharmaceutical composition described herein. For example, PMR-related parameters may be measured at days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, or weeks 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 32, 40, 52, or longer after initial treatment with the pharmaceutical composition. The difference between the value of a parameter at a specific time point after the start of treatment and the value of the parameter at baseline is used to determine whether the PMR-related parameter has been "improved" (e.g., increased or decreased, depending on the specific parameter being measured).

[0142] As used herein, the term “acquire” or “acquiring” refers to the possession of a physical entity or value (e.g., a numerical value) through “direct acquisition” or “indirect acquisition” of a physical entity or value (such as a PMR-related parameter). “Direct acquisition” means obtaining a physical entity or value by performing a process (e.g., conducting a synthetic or analytical method). “Indirect acquisition” means receiving a physical entity or value from another party or source (e.g., a third-party laboratory that directly acquires the physical entity or value). Direct acquisition of a physical entity includes performing a process involving a physical change in a physical substance (e.g., a starting material). Exemplary changes include: creating a physical entity from two or more starting materials, shearing or crushing a substance, separating or purifying a substance, combining two or more separated entities into a mixture, or conducting a chemical reaction involving the breaking or formation of covalent or non-covalent bonds. Direct acquisition of a value includes performing a process involving a physical change in a sample or another substance; for example, performing an analytical process (sometimes referred to herein as “physical analysis”) that involves a physical change in a substance (e.g., a sample, analyte, or reagent).

[0143] Information obtained indirectly may be provided in the form of a report, for example, in paper or electronic form, such as from an online database or application (“App”). This report or information may be provided by, for example, a healthcare institution (such as a hospital or clinic); or a healthcare provider (such as a doctor or nurse). Functional Assessment Fatigue Scale for Chronic Disease Therapy

[0144] According to some implementations, administration of IL-6R antagonists to patients resulted in an increase in the Functional Assessment of Chronic Disease Fatigue Scale (FACIT Fatigue) score relative to baseline. FACIT-Fatigue is a general PRO tool that includes 13 items measuring fatigue. Patients rated each item on a scale of 0 to 4 (0 = not at all, 1 = a little, 2 = somewhat, 3 = quite a lot, 4 = very a lot). The scores were summarized to give a total score between 0 and 52. The recall phase was the most recent 7 days.

[0145] Treatments that lead to an increase in FACIT-fatigue scores relative to baseline are provided. For example, administration of an IL-6R antagonist to subjects in need results in an increase in FACIT-fatigue scores relative to baseline of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50. EuroQol-5 Dimension 3 Level Version (EQ-5D-3L)

[0146] According to some implementations, administration of an IL-6R antagonist to a patient resulted in an increase in EQ-5D-3L relative to baseline. EQ-5D-3L is a general PRO tool for measuring health status (EuroQol Group, EuroQol-a newfacility for the measurement of health-related quality of life, Health Policy 1990; 16(3):199-208). EQ-5D has two components: a “today” health utility index score derived from five items (involving mobility, self-care, daily activities, pain / discomfort, and anxiety / depression), and a current (“moment”) overall health status score derived from a single 0-100 Visual Analogue Scale (VAS). The EQ-5D utility score for death is set to 0, and perfect health is set to 1. The VAS is anchored to “ideal state of health” and “ideal state of health”.

[0147] Treatments leading to an increase in EQ VAS scores relative to baseline were provided. For example, administration of an IL-6R antagonist to subjects in need resulted in an increase in EQ VAS scores relative to baseline of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50. 51, 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.

[0148] Treatments that resulted in an increase in the EQ-5D utility score relative to baseline were provided. For example, administration of an IL-6R antagonist to subjects in need resulted in an increase in the EQ-5D utility score relative to baseline of approximately 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, or 0.95 points. Summary Table 36v2 (SF-36v2)

[0149] According to certain implementations, administration of IL-6R antagonists to patients resulted in an increase in Short Form 36v2 (SF-36v2) scores relative to baseline. Short Form 36v2 (SF-36v2) is a short form of the Universal 36-Item PRO tool that assesses health across eight multi-item dimensions: physical functioning (PF; 10 items), social functioning (SF; 2 items), role limitation due to physical problems (RP; 4 items), role limitation due to emotional problems (RE; 3 items), mental health (MH; 5 items), energy / vitality (VT; 4 items), physical pain (BP; 2 items), and overall perceived health (GH; 5 items) (Ware et al. The MOS 36-Item Short-Form Health Survey (SF-36): I. Conceptual Framework and Item Selection, Medical Care 1992; 30(6):473-483). For each dimension, the item scores are coded, summed, and converted into a scale from 0 (the worst possible health status as measured by the questionnaire) to 100 (the best possible health status). Two standardized summary scores can also be calculated using the SF-36v2; Physical Summary (PCS) and Mental Summary (MCS) (a 0-100 scale) (see Maruish ME (2011) User's manual for the SF-36v2 Health Survey (3rd edition). Lincoln, RI: QualityMetric).

[0150] Treatments leading to an increase in SF-36v2 scores relative to baseline were provided. For example, administration of an IL-6R antagonist to subjects in need resulted in an increase in SF-36v2 scores relative to baseline of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45. 46, 47, 48, 49, 50, 51, 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)

[0151] The HAQ-DI was developed to assess the physical functioning of adults with arthritis, but it is now commonly used in many rheumatic conditions (see Wolfe F, “A brief clinical health assessment instrument: CLINHAQ,” Arthritis Rheum. 1989; 32 (Supplement): S9, and Wolfe F, “Data collection and utilization: a methodology for clinical practice and clinical research,” Rheumatoid arthritis: pathogenesis, assessment, outcome and treatment, New York: Marcel Dekker, 1994: 463-514). It contains 25 items: 20 four-point Likert scale questions assessing eight physical dimensions of daily living activities (dressing and grooming, getting up, eating, walking, washing, reaching, grasping, and chores), 13 additional questions assessing the use of assistive devices, and 8 additional questions assessing assistance received from another person. The recall phase is the most recent week. To calculate the HAQ-DI score, there are three steps: sum the scores of the eight categories using the highest subcategory score in each category; adjust the use of assistive devices and / or assistance from another person at the time of instruction; and divide the summed category scores by the number of categories answered (must be at least 6) to obtain an HAQ-DI score of 0-3 (3 = worst function). In addition, the HAQ-DI has two additional questions measured on a 0-100 scale: How much pain have you experienced in the past week? Please rate your expression on a scale of 0 to 100 (0 represents “very good” health, 100 represents “very poor” health). Rate the questions independently (measure pain and overall assessment separately).

[0152] Treatments that resulted in a reduction in HAQ-DI scores relative to baseline were provided. For example, administration of an IL-6R antagonist to subjects in need resulted in a reduction in HAQ-DI scores relative to baseline of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 4 6, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points. Patient overall assessment of disease activity (PtGA)

[0153] PtGA is a single question scored from 0 to 100, focusing on overall health or disease activity from the patient's perspective. A higher score indicates a higher level of disease activity or a worse overall health.

[0154] Treatments that resulted in a reduction in PtGA scores relative to baseline were provided. For example, administration of an IL-6R antagonist to subjects in need resulted in a reduction in PtGA scores relative to baseline of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46. 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points. Visual Analogue Scale (VAS) for Pain

[0155] The pain VAS is a one-dimensional patient-reported measure of pain intensity (see Delgado et al., “Validation of digital visual analog scale pain scoring with a traditional paper-based visual analog scale in adults”, Journal of the American Academy of Orthopaedic Surgeons, March; 2(3)). The pain VAS score ranges from 0 to 100, with higher scores indicating greater pain intensity.

[0156] Treatment methods that resulted in a reduction in pain VAS scores relative to baseline were provided. For example, administration of an IL-6R antagonist to subjects in need resulted in a reduction in pain VAS scores relative to baseline of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 4 6, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points. Physician's overall assessment of disease activity - Visual Simulation Scale [MD-VAS]

[0157] In MD-VAS, physicians score patients’ disease activity on a VAS anchored at a 100 mm level, where 0 is considered inactive and 100 is considered most active (see Huskisson et al., “Vertical or Horizontal Visual Analogue Scales”, Ann Rheum Dis. Dec. 1979; 38(6):560).

[0158] Treatments leading to a reduction in MD-VAS scores relative to baseline were provided. For example, administration of an IL-6R antagonist to subjects in need resulted in a reduction in HAQ-DI scores relative to baseline of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 4 6, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points.

[0159] The methods described herein can further improve one or more other PMR-related outcomes, including but not limited to the PMR activity score (PMR-AS), glucocorticoid toxicity index (GTI), cumulative corticosteroid dose, and time to PMR outbreak. PMR Activity Rating (PMR-AS)

[0160] PMR-AS was calculated as the sum of CRP (mg / dL), visual analog scale (VAS) score for pain (0 to 10), VAS score for physician assessment (0 to 10), duration of morning stiffness (MST [min] x 0.1), and ability to lift the upper limb (EUL [3-0]).

[0161] Treatments leading to a reduction in PMR-AS scores relative to baseline were provided. For example, administration of an IL-6R antagonist to subjects in need resulted in a reduction in PMR-AS scores relative to baseline of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 4 6, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points. Glucocorticoid toxicity index

[0162] The Glucocorticoid Toxicity Index (GTI) is a composite scale designed to assess the incidence of glucocorticoid-related toxicity. The GTI Cumulative Worsening Score (CWS) reflects cumulative glucocorticoid toxicity, whether permanent or transient. The GTI-CWS can only increase or remain constant over time. A lower score indicates lower glucocorticoid toxicity. The GTI Overall Improvement Score (AIS) reflects both the worsening and improvement of glucocorticoid toxicity. New or worsening toxicity contributes a positive score, while improvement in existing toxicity contributes a negative score. A lower score indicates lower glucocorticoid toxicity.

[0163] Treatments that resulted in a reduction in GTI-CWS or GTI-AIS scores relative to baseline were provided. For example, administration of an IL-6R antagonist to subjects in need resulted in a reduction in GTI-CWS or GTI-AIS scores relative to baseline of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44. 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 points. Cumulative corticosteroid dose

[0164] The cumulative dose of corticosteroids is the dose taken over a period of time (e.g., approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 5). The amount of corticosteroids exposed to patients within 2, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 weeks.

[0165] Treatment methods are provided that result in a reduction in the cumulative dose of corticosteroids over a period of time compared to treatment without an IL-6R antagonist. For example, in various embodiments, administration of an IL-6R antagonist to a subject in need results in a reduction in the cumulative dose of corticosteroids of approximately 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or 3000 mg. In various embodiments, after six months of prior treatment with corticosteroids, an IL-6R antagonist or csIM or a combination thereof is administered to the subject in need, resulting in a reduction in the cumulative corticosteroid dose of approximately 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or 3000 mg. Time until the PMR outbreak

[0166] Treatments that result in an increased amount of time until a patient experiences a PMR outbreak are provided. For example, administration of an IL-6R antagonist to a patient in need results in an increased amount of time until the patient experiences a PMR outbreak, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45. 46, 47, 48, 49, 50, 51, 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. Application method and preparation

[0167] The methods described herein include administering a therapeutically effective amount of anti-IL-6R antibody to a subject. As used herein, the phrase “therapeutically effective amount” means the dose of the therapeutic agent that results in treatment of polymyalgia rheumatica. As used herein, “treatment” means causing a detectable improvement in one or more symptoms associated with polymyalgia rheumatica, or causing a biological effect (e.g., a decrease in the level of a specific biomarker) associated with one or more underlying pathological mechanisms that produce the condition or one or more symptoms. For example, the following symptoms or conditions are associated with polymyalgia rheumatica: bilateral shoulder pain, hip pain or tenderness and limited hip mobility, elevated C-reactive protein (CRP) levels, elevated erythrocyte sedimentation rate (ESR), and morning stiffness lasting for several minutes or more (e.g., 30 or 45 minutes).

[0168] In various implementations, “improvement” in PMR-related symptoms refers to a reduction in the incidence of PMR symptoms, which may be associated with improvement in one or more P-related tests, scores, or measures (as described herein). For example, improvement may be associated with an increase over time relative to baseline in one or more markers of C-reactive protein (CRP), ESR, IL-6, soluble IL-6R, and / or inflammation, as well as markers of disease activity (as assessed in changes in circulating immune cell type, circulating proteins, and gene expression). As used herein, the term “baseline” for PMR-related parameters means the value of a patient’s PMR-related parameter prior to or at the time of administration of the antibody described herein.

[0169] Detectable “improvement” can also be detected using at least one of the tests, ratings, or measures described herein. In various implementations, improvement is detected by a reduction in PMR symptoms selected from the following groups: morning stiffness, neck pain, shoulder pain, hip girdle pain, limited shoulder range of motion, limited hip girdle range of motion, systemic symptoms (e.g., fatigue, weight loss, and low-grade fever), and other features consistent with a PMR outbreak as determined by a clinician-investigator. In various implementations, improvement is detected by using at least one of the following groups: Patient-Reported Outcomes (PRO) questionnaire, the Functional Assessment of Treatment of Chronic Disease Fatigue Scale (FACIT-Fatigue), EQ-5D-3L, Short Form 36v2, HAQ-DI, PMR-AS, ​​and physician’s overall assessment of disease activity (e.g., the Visual Analogue Scale [MD-VAS]).

[0170] In various implementations, detectable improvement is defined as sustained remission of the disease. As used herein, “sustained remission” of a subject’s PMR is defined as one or more of the following: (i) disease remission, particularly at week 12 after initiation of treatment with a therapeutically effective dose of anti-IL-6R antibody (i.e., absence of signs and symptoms of PMR in the subject); (ii) absence of disease flare-ups; (iii) normalization of C-reactive protein, particularly between week 12 and week 52; or (iv) adherence to a steroid tapering regimen, particularly a glucocorticoid tapering regimen (e.g., prednisone tapering), particularly between week 12 and week 52.

[0171] In another implementation, treatment is ineffective when a dose of anti-IL-6R antibody does not cause a detectable improvement in one or more parameters or symptoms associated with PMR, or does not cause a biological effect associated with one or more underlying pathological mechanisms that produce PMR or one or more symptoms.

[0172] In various embodiments, the IL-6R antibody is administered subcutaneously. In various embodiments, the IL-6R antibody is salperumab. In various embodiments, csIM (e.g., MTX) or a combination of IL-6R antibody and csIM is administered.

[0173] In various implementations, the therapeutically effective amount of anti-IL-6R antibody administered to the subject will vary depending on the subject's age and size (e.g., weight or body surface area), the route of administration, and other factors well known to those skilled in the art.

[0174] In various embodiments, the dose is a fixed dose independent of the subject's weight or surface area. In various embodiments, the subject is at least 50 years old. In various embodiments, the subject is older than 50 years old. In various embodiments, the subject is 50-60 years old, 55-70 years old, 65-80 years old, 70-90 years old, or 50-90 years old.

[0175] This disclosure provides a method of using a therapeutic composition comprising an anti-IL-6R antibody or an antigen-binding fragment thereof, and, if desired, one or more additional therapeutic agents. The therapeutic compositions of this disclosure will be administered together with suitable carriers, excipients, and / or other agents incorporated into the formulation to provide improved delivery, tolerability, etc. Many suitable formulations can be found in formulations known to all medicinal chemists: Remington's PharmaceuticalSciences, Mack Publishing Company, Easton, Pennsylvania. These formulations include, for example, powders, pastes, ointments, gels, waxes, oils, lipids, and lipid-containing vesicles (such as LIPOFECTIN). ® DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, carbowax emulsions (polyethylene glycol with different molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax.

[0176] Various delivery systems are known and can be used to administer the pharmaceutical compositions provided herein, such as encapsulation in liposomes, microparticles, microcapsules, and receptor-mediated endocytosis. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The compositions can be administered via any convenient route, such as by infusion or bolus, absorption through the epithelial or mucosal lining of the skin (e.g., oral mucosa, rectal and intestinal mucosa), and can be administered together with other bioactive agents. Administration can be systemic or local. IL-6R antibodies can be administered subcutaneously.

[0177] The drug composition can also be delivered in vesicles (such as liposomes). In some embodiments, the drug composition can be delivered in a controlled release system, for example, using a pump or polymeric material. In some embodiments, the controlled release system can be positioned close to the target of the composition, so that only a portion of the systemic dose is needed.

[0178] Injectable formulations may include dosage forms such as intravenous, subcutaneous, intradermal, and intramuscular injections, local injections, and intravenous infusions. These injectable formulations can be prepared using publicly known methods. For example, they can be prepared by dissolving, suspending, or emulsifying the aforementioned antibodies or their salts in a sterile aqueous or oily medium conventionally used for injection. As an aqueous medium for injection, such as physiological saline, isotonic solutions containing glucose and other adjuvants, it can be used in combination with suitable solubilizers such as alcohols (e.g., ethanol), polyols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants [e.g., polysorbate 80, HCO-50 (a polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. As an oily medium, such as sesame oil or soybean oil, it can be used in combination with solubilizers such as benzyl benzoate, benzyl alcohol, etc. The resulting injection solution can be filled into suitable ampoules.

[0179] The antibody is typically formulated as described in this article and International Publication No. WO 2011 / 085158 (which is incorporated herein by reference in its entirety).

[0180] In various embodiments, the antibody is administered as an aqueous buffer solution of approximately pH 6.0, which contains: - Approximately 21 mM histidine, - Approximately 45 mM arginine, - Approximately 0.2% (w / v) polysorbate 20, - Approximately 5% (w / v) sucrose, and The antibody concentration is between approximately 100 mg / mL and approximately 200 mg / mL.

[0181] In another embodiment, the antibody is administered as an aqueous buffer solution of approximately pH 6.0, which contains: - Approximately 21 mM histidine, - Approximately 45 mM arginine, - Approximately 0.2% (w / v) polysorbate 20, - Approximately 5% (w / v) sucrose, and - At least approximately 130 mg / mL of this antibody.

[0182] In another embodiment, the antibody is administered as an aqueous buffer solution of approximately pH 6.0, which contains: - Approximately 21 mM histidine, - Approximately 45 mM arginine, - Approximately 0.2% (w / v) polysorbate 20, - Approximately 5% (w / v) sucrose, and - Approximately 131.6 mg / mL of this antibody.

[0183] In another embodiment, the antibody is administered as an aqueous buffer solution of approximately pH 6.0, which contains: - Approximately 21 mM histidine, - Approximately 45 mM arginine, - Approximately 0.2% (w / v) polysorbate 20, - Approximately 5% (w / v) sucrose; and - Approximately 175 mg / mL of this antibody.

[0184] In other embodiments, the antibody is administered as an aqueous buffer solution at pH 6.0, comprising: -21 mM histidine, -45 mM arginine, -0.2% (w / v) polysorbate 20, -5% (w / v) sucrose, and The antibody concentration is between -100 mg / mL and 200 mg / mL.

[0185] In another embodiment, the antibody is administered as an aqueous buffer solution at pH 6.0, which contains: -21 mM histidine, -45 mM arginine, -0.2% (w / v) polysorbate 20, -5% (w / v) sucrose, and - At least 130 mg / mL of this antibody.

[0186] In another embodiment, the antibody is administered as an aqueous buffer solution at pH 6.0, which contains: -21 mM histidine, -45 mM arginine, -0.2% (w / v) polysorbate 20, -5% (w / v) sucrose, and The antibody was -131.6 mg / mL.

[0187] In another embodiment, the antibody is administered as an aqueous buffer solution at pH 6.0, which contains: -21 mM histidine, -45 mM arginine, -0.2% (w / v) polysorbate 20, -5% (w / v) sucrose; and The antibody is at a concentration of -175 mg / mL.

[0188] In various embodiments, the antibody is administered in a stable pharmaceutical formulation comprising: (i) 25 mM to 100 mM histidine; (ii) 25 mM to 50 mM arginine; (iii) 3% to 10% w / v sucrose; and (iv) 0.1% to 0.2% polysorbate 20, wherein the formulation has a pH of about 5.8, about 6.0, or about 6.2, and, as determined by size exclusion chromatography, at least 90% of the antibody in its natural form is recovered after storage at 45°C for one month. In various embodiments, about 200 mg of the antibody (e.g., sarrelumbab) is administered to the subject. In various embodiments, about 150 mg of the antibody (e.g., sarrelumbab) is administered to the subject.

[0189] In various embodiments, the antibody is administered in a stable pharmaceutical formulation comprising: (i) histidine at a concentration of about 10 mM to about 25 mM; (ii) arginine at a concentration of about 25 mM to about 50 mM; (iii) sucrose at a concentration of about 5% to about 10% w / v; and (iv) polysorbate at a concentration of about 0.1% to about 0.2% w / v, wherein the formulation has a pH of about 5.8, about 6.0, or about 6.2, and, as determined by size exclusion chromatography, at least 90% of the antibody in its natural form is recovered after storage at 45°C for one month. In various embodiments, about 200 mg of the antibody (e.g., sarerutumab) is administered to the subject. In various embodiments, about 150 mg of the antibody (e.g., sarerutumab) is administered to the subject.

[0190] Advantageously, the above-described pharmaceutical compositions for oral or parenteral use are prepared into dosage forms suitable for matching the dosage of the active ingredient. Such dosage forms for unit doses include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0191] In various embodiments, the anti-IL-6R antibody (or a pharmaceutical formulation containing the antibody) can be administered to a patient using any acceptable device or mechanism. For example, the administration can be performed using a syringe and needle or a reusable pen and / or auto-injector delivery device. The methods disclosed herein include administering the anti-IL-6R antibody (or a pharmaceutical formulation containing the antibody) using a number of reusable pen and / or auto-injector delivery devices. Implementations 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®, OPTIPENSTARLET®, and OPTICLIK® (Sanofi-Aventis, Frankfurt, Germany).Embodiments of disposable pen-type and / or auto-injector delivery devices for subcutaneous delivery of the pharmaceutical compositions disclosed herein include, but are not limited to, the SOLOSTAR® pen (Sanofi-Aventis), FLEXPEN® (Sanofi) and KWIKPEN® (Eli Lilly), SURECLICK® auto-injector (Amgen, Thousand Oaks, CA), PENLET® (Haselmeier, Stuttgart, Germany), EPIPEN® (Dey, LP), and HUMIRA® pen (AbbVie Inc., North Chicago, IL), to name just a few.

[0192] In various embodiments, the antibody is administered using a pre-filled syringe. In various embodiments, the antibody is administered using a pre-filled syringe containing a safety system. For example, the safety system prevents accidental needlestick injuries. In various embodiments, the antibody is administered using a pre-filled syringe containing the ERIS safety system (West Pharmaceutical Services Inc.).

[0193] In various embodiments, the antibody is administered using an autoinjector. In various embodiments, the antibody is administered using an autoinjector (SHL Group) characterized by PUSHCLICK® technology. In various embodiments, the autoinjector is a device including a syringe that allows administration of a dose of the composition and / or antibody to the subject.

[0194] This article also considers the use of microinfusion devices to deliver anti-IL-6R antibodies (or pharmaceutical formulations containing such antibodies) to patients. As used herein, the term "microinfusion device" refers to a subcutaneous delivery device designed to slowly administer large volumes (e.g., up to about 2.5 mL or more) of therapeutic formulations over an extended period of time (e.g., about 10, 15, 20, 25, 30 or more minutes). Microinfusion devices are particularly suitable for delivering large doses of therapeutic proteins contained in high concentrations (e.g., about 100, 125, 150, 175, 200 mg / mL or higher) and / or viscous solutions.

[0195] In various embodiments, an inadequate response to prior treatment means that the subject's pain is not well controlled after receiving prior treatment at the maximum tolerated typical dose. In one embodiment, an inadequate response to prior treatment means that, despite prior treatment, the subject still has moderate or high disease activity and poor prognostic characteristics. In various embodiments, an inadequate response to prior treatment means that, despite prior treatment, the subject still has unimproved or worsened pain symptoms (e.g., any of the symptoms listed herein). dose

[0196] The amount of IL-6R antagonist (e.g., anti-IL-6R antibody) administered to a subject according to the methods described herein is typically a therapeutically effective amount. As used herein, the phrase "therapeutically effective amount" means the amount of IL-6R antagonist that results in improvement in one or more PMR-related PRO or ClinRO measures (as defined elsewhere herein). "Therapeutically effective amount" also includes the amount of IL-6R antagonist that inhibits, prevents, mitigates, 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 the subject. In the case of anti-IL-6R antibodies, the effective therapeutic dose can be from approximately 0.05 mg to approximately 700 mg, for example, approximately 0.05 mg, approximately 0.1 mg, approximately 1.0 mg, approximately 1.5 mg, approximately 2.0 mg, approximately 3.0 mg, approximately 5.0 mg, approximately 7.0 mg, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg, approximately 240 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, etc. mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, or approximately 700 mg In some embodiments, 200 mg of anti-IL-6R antibody is administered. In some embodiments, 150 mg of anti-IL-6R antibody is administered. In some embodiments, 300 mg of anti-IL-6R antibody is administered. In some embodiments, 150 mg to 200 mg of anti-IL-6R antibody is administered.

[0197] The amount of IL-6R antagonist contained in a single dose can be expressed as milligrams of antibody per kilogram of subject body weight (i.e., mg / kg). For example, the IL-6R antagonist can be administered to a patient at a dose of about 0.0001 to about 10 mg / kg of subject body weight. For example, the IL-6R antagonist can be administered at doses of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, or 6 mg / kg.

[0198] In some embodiments, the initial dose is substantially the same as the loading dose. In some embodiments, the initial dose is about 1.1 times, about 1.2 times, about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times, about 1.7 times, about 1.8 times, about 1.9 times, about 2.0 times, about 2.5 times, about 3.0 times, or more times the loading dose.

[0199] In some implementations, two or more doses (e.g., 2, 3, 4, or 5 or more) are administered at the start of the treatment regimen as an “initial dose” or “loading dose,” followed by subsequent doses (e.g., a “maintenance dose”) administered at a lower frequency. In one implementation, the maintenance dose may be lower than the loading or initial dose.

[0200] In some exemplary embodiments, the IL-6R antagonist is administered at a dose of about 150 mg or about 200 mg. In a particular exemplary embodiment, the IL-6R antagonist is administered at an initial dose of about 200 mg and one or more second doses or maintenance doses of about 200 mg, with the second dose administered every other week (q2w).

[0201] In some exemplary embodiments, the subject is an adult, and the IL-6R antagonist is administered at a dose of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg. In another exemplary embodiment, the subject is an adult, and the IL-6R antagonist is administered at an initial dose of about 600 mg and one or more second or maintenance doses of about 300 mg, with the second dose administered every other week (q2w). In yet another exemplary embodiment, the subject is an adult, and the IL-6R antagonist is administered at an initial dose of about 400 mg and one or more second or maintenance doses of about 200 mg, with the second dose administered every other week (q2w). In some implementations, the subjects are adults, the initial dose contains about 300 mg of an IL-6R antagonist, and one or more subsequent doses contain about 300 mg of an IL-6R antagonist administered every other week.

[0202] In some exemplary embodiments, the IL-6R antagonist is administered at a concentration of 150 mg / mL using a pre-filled device. In some embodiments, the 150 mg / mL IL-6R antagonist solution in the pre-filled device is used to deliver approximately 300 mg of IL-6R antagonist in a 2 mL injection. In some exemplary embodiments, the IL-6R antagonist is administered at a concentration of 175 mg / mL using a pre-filled device. In some embodiments, the 175 mg / mL IL-6R antagonist solution in the pre-filled device is used to deliver approximately 200 mg of IL-6R antagonist in a 1.14 mL injection. In some exemplary embodiments, the IL-6R antagonist is administered at a concentration of 131 mg / mL using a pre-filled device. In some embodiments, the 131 mg / mL IL-6R antagonist solution in the pre-filled device is used to deliver approximately 150 mg of IL-6R antagonist in a 1.14 mL injection. Combination therapy

[0203] Some embodiments of the methods described herein involve administering one or more additional therapeutic agents in combination with an IL-6R antagonist to a subject. As used herein, the expression "in combination with" means administering an additional therapeutic agent before, after, or simultaneously with a pharmaceutical composition comprising an IL-6R antagonist. In some embodiments, the term "in combination with" includes administering an IL-6R antagonist sequentially or concurrently with a second therapeutic agent. Methods for treating PMR or related conditions or complications are provided, comprising administering an IL-6R antagonist in combination with a second therapeutic agent to achieve additive or synergistic activity.

[0204] For example, when administered "before" a pharmaceutical composition containing an IL-6R antagonist, an additional therapeutic agent may be administered approximately 72 hours, approximately 60 hours, approximately 48 hours, approximately 36 hours, approximately 24 hours, approximately 12 hours, approximately 10 hours, approximately 8 hours, approximately 6 hours, approximately 4 hours, approximately 2 hours, approximately 1 hour, approximately 30 minutes, approximately 15 minutes, or approximately 10 minutes before administration of the pharmaceutical composition containing an IL-6R antagonist. When administered "after" a pharmaceutical composition containing an IL-6R antagonist, an additional therapeutic agent may be administered approximately 10 minutes, approximately 15 minutes, approximately 30 minutes, approximately 1 hour, approximately 2 hours, approximately 4 hours, approximately 6 hours, approximately 8 hours, approximately 10 hours, approximately 12 hours, approximately 24 hours, approximately 36 hours, approximately 48 hours, approximately 60 hours, or approximately 72 hours after administration of the pharmaceutical composition containing an IL-6R antagonist. "Simultaneous" administration with a pharmaceutical composition containing an IL-6R antagonist means that the additional therapeutic agent is administered to the subject in a separate dosage form within 5 minutes (before, after, or simultaneously) of administration of the pharmaceutical composition containing an IL-6R antagonist, or as a single combined dose formulation containing both the additional therapeutic agent and the IL-6R antagonist.

[0205] In exemplary embodiments, the additional therapeutic agent administered in combination with the IL-6R antagonist is a background therapy. In some embodiments, the background therapy includes steroids. In exemplary embodiments, the background therapy is a corticosteroid. Corticosteroids are steroid hormones produced in the adrenal cortex of vertebrates, and synthetic analogs of said hormones. Corticosteroids include prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, tecortisone valerate, prednisolone, and methylprednisolone. In some embodiments, the corticosteroid is prednisone. According to other embodiments, the corticosteroid may also be selected from triamcinolone, triamcinolone acetonide, mometasone, ansine, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluclocolone, hydrocortisone-17-valerate, halometasone, aclomethasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednisone ester, clobetasone-17-butyrate, clobetasone-17-propionate, fluclocolone hexanoate, fluclocolone neovalerate, fluprednisolone acetate, hydrocortisone-17-butyrate, hydrocortisone-17-acetylpropionate, hydrocortisone-17-butyropropionate, cyclosporine, and prednisone ester.

[0206] In some embodiments, the method results in a reduction in the need for background therapy. Reducing the dose of background therapy may also be referred to as "gradual tapering." For example, in some embodiments, the method results in a reduction in the dose and / or frequency of background therapy. In an exemplary embodiment, the method results in a reduction in the dose and / or frequency of corticosteroid background therapy.

[0207] In some implementations, the method results in the discontinuation of background therapy. In an exemplary implementation, the method results in the discontinuation of background corticosteroid therapy.

[0208] In some embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in subjects who have had an inadequate response to background therapy, particularly steroids such as corticosteroids. In exemplary embodiments, the method results in treatment of PMR (or one or more symptoms of PMR) in cases where there is a reduced or no need for background corticosteroid therapy.

[0209] In some embodiments, the method is used to treat PMR (or one or more symptoms of PMR) in subjects who cannot tolerate gradual tapering of background therapy (particularly gradual tapering of steroids such as corticosteroids). In exemplary embodiments, the method results in treatment of PMR (or one or more symptoms of PMR) in cases where there is a reduced need for or no need for background corticosteroid therapy.

[0210] In some embodiments, the method is used to treat patients with poor response to background therapy (particularly steroids such as corticosteroids) and / or intolerance to gradual tapering of background therapy, particularly steroid tapering, such as corticosteroid tapering, in patients with poor response to background therapy (particularly steroids such as corticosteroids). In exemplary embodiments, the method results in treatment of patients with poor response to background corticosteroid therapy (particularly steroids such as corticosteroids) or no need for it. In some embodiments, the method is used to treat patients with poor response to or intolerance to gradual tapering of corticosteroids in adult subjects with poor response to or intolerance to corticosteroids.

[0211] In some embodiments, background corticosteroid therapy may be administered at a dose of about 5 mg / day or more to about 80 mg / day. In some embodiments, background corticosteroid therapy may be administered at a dose of about 5 mg / day or more, or at a dose of about 7.5 mg / day, greater than 5 mg / day to 7 mg / day, 7 mg / day to 15 mg / day, 15 mg / day to 20 mg / day, about 20 mg / day to about 50 mg / day, and about 35 mg / day to about 80 mg / day. In some embodiments, the background corticosteroid therapy is administered at doses of approximately greater than 5.0 mg / day, 7.5 mg / day, approximately 10 mg / day, approximately 12.5 mg / day, approximately 15 mg / day, approximately 20 mg / day, approximately 25 mg / day, approximately 30 mg / day, approximately 35 mg / day, approximately 40 mg / day, approximately 45 mg / day, approximately 50 mg / day, approximately 55 mg / day, approximately 60 mg / day, approximately 65 mg / day, approximately 70 mg / day, approximately 75 mg / day, or approximately 80 mg / day. In one exemplary embodiment, the background corticosteroid therapy is administered at a dose of approximately greater than 5 mg / day.

[0212] In some implementations, the dose of background therapy is gradually reduced along with treatment with IL-6R inhibitory therapy or csIM. Patients with polymyalgia rheumatica attempting to gradually reduce their daily dose of corticosteroid therapy to a lower dose of corticosteroid may experience at least one episode of flare, for example, when the dose reduction results in the patient no longer experiencing shoulder pain, hip girdle pain, or both, or morning inflammatory stiffness lasting longer than a certain period of time (e.g., 45 minutes). As described herein, treatment with an IL-6R antibody or antibody fragment can reduce the frequency of flare episodes because the subject's daily dose of corticosteroid therapy is gradually reduced or decreased over time.

[0213] In some embodiments, background corticosteroid therapy may be gradually reduced from about 7.5 mg / day or greater to about 1 mg / day. In some embodiments, background corticosteroid therapy may be gradually reduced from about less than 7.5 mg / day, less than 6.0 mg / day, less than 5 mg / day, less than 4 mg / day, 3 mg / day, 2 mg / day, or 1 mg / day. In some embodiments, the gradual reduction is from 7.5 mg / day to 5.0 mg / day, from 6 mg / day to 3 mg / day, from 4 mg / day to 2 mg / day, from 3 mg / day to 1 mg / day, or from 1 mg / day to 5 mg / day.

[0214] In some implementations, steroid tapering or discontinuation begins at approximately 24 weeks, approximately 25 weeks, approximately 26 weeks, 30 weeks, 40 weeks, or up to one year. In some implementations, tapering begins at approximately 24 weeks to approximately 30 weeks, approximately 26 weeks to approximately 36 weeks, approximately 30 weeks to approximately 40 weeks, or 40 weeks to approximately 52 weeks.

[0215] In some implementations, steroids are gradually tapered off in such a manner that they are discontinued after 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, or at least about 150 days of administration of IL-6 inhibitory therapy (e.g., anti-IL-6R antibody or its antigen-binding fragment).

[0216] In some embodiments, steroids are gradually tapered off in such a manner that they are discontinued after approximately 25 to approximately 300 days of administration of IL-6 inhibitory therapy (e.g., anti-IL-6R antibody or its antigen-binding fragment). In some embodiments, steroids are gradually tapered off in such a manner that they are discontinued after approximately 50 to approximately 250 days, approximately 50 to approximately 300 days, approximately 50 to approximately 350 days, at least approximately 50 to 150 days, at least approximately 50 to 100 days, at least approximately 50 to 80 days, at least approximately 50 to 70 days, or at least approximately 50 to 60 days of administration of IL-6 inhibitory therapy (e.g., anti-IL-6R antibody or its antigen-binding fragment).

[0217] In some implementations, steroids are discontinued after administration of IL-6 inhibitory therapy (e.g., anti-IL-6R antibody or its antigen-binding fragment) for 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, or at least about 150 days.

[0218] In some embodiments, steroids are discontinued after approximately 25 to approximately 300 days of administration of IL-6 inhibitory therapy (e.g., anti-IL-6R antibody or its antigen-binding fragment). In some embodiments, steroids are gradually tapered off in such a manner that they are discontinued after approximately 50 to approximately 250 days, approximately 50 to approximately 300 days, approximately 50 to approximately 350 days, at least approximately 50 to 150 days, at least approximately 50 to 100 days, at least approximately 50 to 80 days, at least approximately 50 to 70 days, or at least approximately 50 to 60 days of administration of IL-6 inhibitory therapy (e.g., anti-IL-6R antibody or its antigen-binding fragment).

[0219] In some implementations, after a period of administration of IL-6 inhibitory therapy (e.g., anti-IL-6R antibody or its antigen-binding fragment), the steroid dose administered to the desired PMR subject is gradually reduced to less than or equal to about 2.5 mg / day (prednisone equivalent), less than or equal to about 2 mg / day (prednisone equivalent), less than or equal to about 1.5 mg / day (prednisone equivalent), less than or equal to about 1 mg / day (prednisone equivalent), or less than or equal to about 0.5 mg / day (prednisone equivalent). In some implementations, 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, or at least about 250 days. In some implementations, such time periods can be approximately 25 days to approximately 1 year, approximately 50 days to approximately 1 year, approximately 50 days to approximately 300 days, or approximately 50 days to approximately 250 days.

[0220] Other therapeutic agents may be, for example, another IL-6R antagonist, an IL-6 antagonist, a steroid, etc. In one exemplary embodiment, the additional therapeutic agent is a corticosteroid. In another exemplary embodiment, the additional therapeutic agent is prednisone.

[0221] In some embodiments, the additional therapeutic agent administered in combination with the IL-6R antagonist is a vaccine. In some exemplary embodiments, the vaccine is a viral vaccine or a bacterial vaccine. In some exemplary embodiments, the vaccine is a live (e.g., live-attenuated) viral vaccine or a live (e.g., live-attenuated) bacterial vaccine.

[0222] 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, Universal), DT (Universal), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), hepatitis A (e.g., HepA (Havrix, Vaqta), HepA-HepB (Twinrix)), and hepatitis B (e.g., HepB (Engerix-B, Recombivax)). HB, Heplisav-B), DTaP-HepB-IPV (Pediarix), HepA-HepB (Twinrix)), Haemophilus influenzae type b (Hib) (e.g., Hib (ActHIB, PedvaxHIB, Hiberix), DTaP-IPV / Hib (Pentacel)), Human papillomavirus (HPV) (e.g., HPV9 (Gardasil 9)), Influenza (flu) (e.g., IIV (also known as IIV3, IIV4, RIV3, RIV4 and ccIIV4) (Afluria, Fluad, Flublok, Flucelvax, FluLaval, Fluarix, Fluvirin, Fluzone, Fluzone High-Dose, Fluzone Intradermal), LAIV (FluMist)), Japanese encephalitis (e.g., JE (Ixiaro)), Measles (e.g., MMR (MMR) Mumps (MMR II, MMRV (ProQuad)), meningococci (e.g., MenACWY (Menactra, Menveo), MenB (Bexsero, Trumenba)), mumps (e.g., MMR (MMR II), MMRV (ProQuad)), pertussis (e.g., DTaP (Daptacel, Infanrix), Tdap (Adacel, Boostrix), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel)), pneumococci (e.g., PCV13 (Prevnar13), PPSV23 (Pneumovax 23)), poliomyelitis (e.g.,Polio (Ipol), DTaP-IPV (Kinrix, Quadracel), DTaP-HepB-IPV (Pediarix), DTaP-IPV / Hib (Pentacel), rabies (e.g., Rabies (Imovax Rabies, RabAvert)), rotavirus (e.g., RV1 (Rotarix), RV5 (RotaTeq)), rubella (e.g., MMR (MMR II), MMRV (ProQuad)), herpes zoster (e.g., ZVL (Zostavax), RZV (Shingrix)), smallpox (e.g., Vaccinia (ACAM2000)), tetanus (e.g., DTaP (Daptacel, Infanrix), Td (Tenivac, General), DT (General), 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)), chickenpox (e.g., VAR (Varivax), MMRV (ProQuad)), yellow fever (e.g., YF (YF-Vax)), etc. For all purposes, the CDC Vaccine List (cdc.gov / vaccines / vpd / vaccines-list.html), which is incorporated herein by reference in its entirety, also lists suitable vaccines. In some implementations, the vaccine is a tetanus, diphtheria, pertussis, and / or seasonal trivalent / quadrivalent influenza vaccine.

[0223] In some implementations, the vaccine is an inactivated vaccine, recombinant vaccine, conjugated vaccine, subunit vaccine, polysaccharide vaccine, or toxoid vaccine. In some implementations, the vaccine is a yellow fever vaccine. In some implementations, subjects treated with the vaccine are simultaneously treated with an IL-6R antagonist against PMR.

[0224] In some embodiments, treatment with the IL-6R antagonist is stopped or terminated prior to vaccine treatment. In some embodiments, treatment with the IL-6R antagonist is stopped approximately 1 to 9 weeks prior to vaccine administration (e.g., approximately 1, approximately 1½, approximately 2, approximately 2½, approximately 3, approximately 3½, approximately 4, approximately 4½, approximately 5, approximately 5½, approximately 6, approximately 6½, approximately 7, approximately 7½, approximately 8, approximately 8½, approximately 9 weeks or longer). In some embodiments, treatment with the IL-6R antagonist is stopped approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 11, approximately 12, approximately 13, approximately 14, approximately 15, approximately 16, approximately 17, approximately 18, approximately 19, approximately 20, approximately 21, approximately 22, approximately 23, approximately 24, approximately 25, approximately 26, approximately 27, approximately 28, approximately 29, approximately 30, approximately 31 weeks prior to vaccine administration. Discontinue IL-6R antagonist treatment after approximately 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 days.

[0225] In some implementations, treatment with an IL-6R antagonist is resumed after vaccination. In some implementations, treatment with an IL-6R antagonist is resumed approximately 1 to approximately 14 weeks after vaccination (e.g., approximately 1, approximately 1½, approximately 2, approximately 2½, approximately 3, approximately 3½, approximately 4, approximately 4½, approximately 5, approximately 5½, approximately 6, approximately 6½, approximately 7, approximately 7½, approximately 8, approximately 8½, approximately 9, approximately 9½, approximately 10, approximately 10½, approximately 11, approximately 11½, approximately 12, approximately 12½, approximately 13, approximately 13½, approximately 14, approximately 14½ weeks or longer). In some implementation schemes, approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, and 46 after vaccination. Recovery with IL-6R antagonist treatment occurred approximately 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or approximately 90 days after treatment.

[0226] In some implementations, the effectiveness of the IL-6R antagonist is not reduced by combination with a vaccine or by subsequent administration of a vaccine.

[0227] In some implementations, the effectiveness of the vaccine is not reduced by administration in combination with an IL-6R antagonist or by administration of an IL-6R antagonist first and / or subsequently. In some implementations, when the vaccine is co-administered with an IL-6R antagonist, subjects exhibit a protective neutralizing titer.

[0228] In some exemplary embodiments, the vaccine described herein is administered to the subject, wherein at least one dose of an IL-6R antagonist is administered to the subject before, during, or after the administration of the vaccine. Application plan

[0229] According to certain implementations, multiple doses of an IL-6R antagonist can be administered to a subject over a defined time period. Such methods involve sequentially administering multiple doses of an IL-6R antagonist to a subject. As used herein, “sequentially administering” means administering each dose of the IL-6R antagonist to the subject at different time points, for example, on different dates spaced apart by predetermined intervals (e.g., hours, days, weeks, or months). Methods are provided that include sequentially administering a single initial dose of an IL-6R antagonist to a patient, followed by one or more second doses of the IL-6R antagonist, and, if necessary, one or more third doses of the IL-6R antagonist.

[0230] A method is provided that includes administering a pharmaceutical composition containing an IL-6R antagonist to a subject at the following frequencies: approximately four times a week, twice a week, once a week (q1w), once every two weeks (q2w is interchangeable with once every two weeks, once every two weeks, or once every two weeks), once every three weeks (q3w), once every four weeks (q4w), once every five weeks (q5w), once every six weeks (q6w), once every seven weeks (q7w), once every eight weeks (q8w), once every nine weeks (q9w), once every ten weeks (q10w), once every eleven weeks (q11w), once every twelve weeks (q12w), or lower frequencies, as long as a therapeutic response is achieved.

[0231] In some embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, a dose of about 150 mg or about 200 mg may be administered once weekly. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, a dose of about 150 mg or about 200 mg may be administered once every two weeks (every two weeks is interchangeable with every other week, every two weeks, or q2w). In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, a dose of about 150 mg or about 200 mg may be administered once every three weeks. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, a dose of about 150 mg or about 200 mg may be administered once every four weeks (monthly). In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, a dose of about 150 mg or about 200 mg may be administered once every five weeks. In other embodiments involving the administration of a pharmaceutical composition comprising an anti-IL-6R antibody, a dose of about 150 mg or about 200 mg may be administered once every six weeks. In some exemplary embodiments, the route of administration is subcutaneous.

[0232] The term "week" refers to a period of time of (n x 7 days) ± 3 days, such as (n x 7 days) ± 2 days, (n x 7 days) ± 1 day, or (n x 7 days), where "n" indicates the number of weeks, such as 1, 2, 3, 4, 5, 6, 8, 12 or more weeks.

[0233] The terms “initial dose,” “second dose,” and “third dose” refer to the temporal sequence of administration of the IL-6R antagonist. Therefore, the “initial dose” is the dose administered at the start of the treatment regimen (also known as the “baseline dose” or “loading dose”); the “second dose” is the dose administered after the initial dose; and the “third dose” is the dose administered after the second dose. The initial, second, and third doses may all contain the same amount of IL-6R antagonist, or they may differ from each other in terms of administration frequency. However, in some embodiments, the amount of IL-6R antagonist contained in the initial, second, and / or third doses may differ from each other during treatment (e.g., adjusted up or down as appropriate). In some embodiments, two or more (e.g., 2, 3, 4, or 5) doses are administered at the start of the treatment regimen as a “loading dose,” followed by subsequent doses administered at a lower frequency (e.g., a “maintenance dose”). In one embodiment, the maintenance dose may be lower than the loading dose. In one embodiment, the second dose / maintenance dose may be equal to the initial dose / loading dose. For example, one or more initial doses / loading doses of 150 mg or 200 mg of an IL-6R antagonist may be administered, followed by a second dose / maintenance dose of about 150 mg or about 200 mg. In one embodiment, the loading dose may be separate, such as two or more doses administered at different time points, for example, two loading doses, wherein a second loading dose is administered two weeks after the first loading dose.

[0234] In some embodiments, the initial dose comprises 200 mg of antibody or antigen-binding fragment thereof, and one or more second doses comprise 200 mg of antibody or antigen-binding fragment thereof administered every other week (every other week is interchangeable with every two weeks, once every two weeks, or q2w).

[0235] In various implementations, the initial dose or loading dose is administered 6 months after treatment with background therapy (such as corticosteroids).

[0236] In one exemplary implementation, each second and / or third dose is administered 1 to 14 weeks immediately following the previous dose (e.g., 1, 1½, 2, 2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½, 12, 12½, 13, 13½, 14, 14½ weeks or longer). The phrase “immediately following the previous dose” means that in a multiple-dose sequence, the patient is given a dose of the IL-6R antagonist before the dose immediately following the one in the sequence, without any intervening doses.

[0237] This method may include administering any number of second and / or third doses of an IL-6R antagonist to a patient. For example, in some embodiments, only a single second dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) second doses are administered to the patient. Similarly, in some embodiments, only a single third dose is administered to the patient. In other embodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) third doses are administered to the patient.

[0238] In embodiments involving multiple second doses, each second dose may be administered at the same frequency as the other second doses. For example, each second dose may be administered to the patient 1 to 2 weeks immediately following the previous dose. Similarly, in embodiments involving multiple third doses, each third dose may be administered at the same frequency as the other third doses. For example, each third dose may be administered to the patient 2 to 4 weeks immediately following the previous dose. Alternatively, the frequency of administration of the second and / or third doses to the patient may vary throughout the treatment regimen. The physician may also adjust the administration frequency during the treatment process based on the individual patient's needs following clinical examination.

[0239] A method is provided that includes sequentially administering an IL-6R antagonist and a second therapeutic agent to a patient to treat PMR or related conditions. In some embodiments, the method includes administering one or more doses of an IL-6R antagonist, followed by administering one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) doses of a second therapeutic agent. For example, one or more doses of about 150 mg to about 200 mg of an IL-6R antagonist may be administered, followed by administering one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) doses of a second therapeutic agent (e.g., corticosteroids) to treat, alleviate, reduce, or improve one or more PMR symptoms. In some embodiments, administering one or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) doses of an IL-6R antagonist results in an improvement in one or more PMR-related parameters, followed by administration of a second therapeutic agent to prevent recurrence of at least one PMR symptom. Alternative embodiments relate to the co-administration of an IL-6R antagonist with a second therapeutic agent. For example, one or more (e.g., 2, 3, 4, 5, 6, 7, 8 or more) doses of an IL-6R antagonist are administered, and a second therapeutic agent is administered at separate doses and at frequencies similar to or different from those of the IL-6R antagonist. In some embodiments, the second therapeutic agent is administered before, after, or simultaneously with the IL-6R antagonist.

[0240] In some embodiments, the IL-6R antagonist is administered every other week for 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48 weeks or longer. In a particular embodiment, the IL-6R antagonist is administered for at least 14 weeks. In an exemplary embodiment, the IL-6R antagonist is administered for at least 52 weeks. Treatment group

[0241] The methods described herein include administering a therapeutic composition containing an IL-6R antagonist to subjects in need. The term "subject in need" means a person or non-human animal that exhibits one or more symptoms or indications of PMR, or has been diagnosed with PMR.

[0242] In relevant embodiments, a “subject in need” may be a subject who has been prescribed or is currently taking steroids prior to receiving an IL-6R antagonist, csIM, or a combination thereof. In some embodiments, a subject may be a subject who has been prescribed or is currently taking corticosteroids prior to receiving an IL-6R antagonist, csIM, or a combination thereof. In some embodiments, the subject is currently taking prednisone or a prednisone equivalent. For example, a method is provided that includes administering an IL-6R antagonist to a subject who has received a regular course of prednisone for eight weeks or more immediately prior to receiving the IL-6R antagonist (such prior treatment is referred to herein as “background treatment”). In an exemplary embodiment, the subject has been taking a regular course of prednisone at a dose at least greater than or equal to 5.0 mg / day or 7.5 mg / day and not exceeding 20 mg / day or a prednisone equivalent.

[0243] In yet another embodiment, the amount of corticosteroid (e.g., prednisone) is gradually reduced before or after the initiation of the IL-6R antagonist, csIM, or a combination thereof.

[0244] In another exemplary embodiment, the “subject in need” is diagnosed with steroid-resistant PMR before receiving the IL-6R antagonist. In some embodiments, the subject’s signs and symptoms of PMR persist despite steroid treatment. In yet another exemplary embodiment, the “subject in need” is diagnosed with corticosteroid (e.g., prednisone)-resistant PMR before receiving the IL-6R antagonist. In some embodiments, the subject’s symptoms of PMR persist despite corticosteroid (e.g., prednisone) treatment.

[0245] In another exemplary embodiment, prior to receiving the IL-6R antagonist, the “subject in need” was diagnosed with steroid-tapered refractory PMR. In some embodiments, the subject experiences a PMR outbreak when attempting steroid tapering. In an exemplary embodiment, the subject is steroid-tapered refractory (e.g., prednisone) and experiences a PMR outbreak when attempting steroid tapering (e.g., prednisone).

[0246] In another embodiment, "subject in need" refers to a subject whose PMR is not adequately controlled by steroids or csIM. In other embodiments, "subject in need" refers to a subject whose PMR is not adequately controlled by corticosteroids (e.g., prednisone) or csIM or a combination thereof (e.g., MTX). In some embodiments, "subject in need" refers to a subject for whom steroid use is not recommended (i.e., the subject experiences steroid-related adverse reactions or is currently undergoing treatment with one or more drugs that cannot be combined with steroid therapy). In some embodiments, "subject in need" refers to a subject for whom corticosteroids (e.g., prednisone) are not recommended (i.e., the subject experiences adverse reactions related to corticosteroids (e.g., prednisone) or is currently undergoing treatment with one or more drugs that cannot be combined with corticosteroids (e.g., prednisone).

[0247] In another exemplary embodiment, the “subject in need” is a subject for whom steroid use is medically not recommended (i.e., the subject has a history of allergic reactions, adverse reactions, or other medical history in which steroid use is not recommended). In another exemplary embodiment, the subject is a subject for whom corticosteroids (e.g., prednisone) are medically not recommended (i.e., the subject has a history of allergic reactions, adverse reactions, or other medical history in which corticosteroids (e.g., prednisone) are not recommended).

[0248] In another exemplary embodiment, the “subject in need” is a subject who has previously had an inadequate response to one or more steroids. In an exemplary embodiment, the subject is a subject who has previously had an inadequate response to corticosteroids (e.g., prednisone).

[0249] In another exemplary embodiment, the “subject in need” is a subject who cannot tolerate gradual tapering of steroids. In an exemplary embodiment, the subject is a subject who cannot tolerate gradual tapering of corticosteroids (e.g., gradual tapering of prednisone).

[0250] In another exemplary embodiment, the “subject in need” is a subject who has previously responded poorly to steroids and / or is intolerant of steroid tapering. In an exemplary embodiment, the subject is a subject who has previously responded poorly to corticosteroids (e.g., prednisone) and / or is intolerant of corticosteroid tapering (e.g., prednisone tapering).

[0251] In some embodiments, the “subject in need” is at least 50 years old. In an exemplary embodiment, the subject is older than 50 years old. In other exemplary embodiments, the subject suffers from bilateral shoulder pain. In still other exemplary embodiments, the subject has a C-reactive protein (CRP) level > 10 mg / L and / or an erythrocyte sedimentation rate (ESR) > 30 mm / hr. In some exemplary embodiments, the subject suffers from morning stiffness. In other exemplary embodiments, the subject does not have joint involvement other than the shoulder joint. In still other exemplary embodiments, the subject suffers from hip pain or limited range of motion. In some exemplary embodiments, the subject is seronegative for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP). In other exemplary embodiments, the subject has at least one subdeltoid bursitis and / or biceps tenosynovitis and / or posterior or axillary glenohumeral synovitis in the shoulder, and at least one hip synovitis and / or trochanteric bursitis.

[0252] In some implementation schemes, subjects have a Charlson Comorbidity Index score and are seronegative for rheumatoid arthritis, such as... Figure 4 As shown. In some implementations, subjects also include those with diabetes, myocardial infection, stroke, percutaneous coronary intervention and coronary artery bypass surgery, hypertension, unstable angina, arrhythmia, heart failure, osteoporosis or osteopenia, osteonecrosis, glaucoma, steroid myopathy, mental illness, or a combination thereof. Methods for evaluating pharmacodynamic PMR-related parameters

[0253] Methods are provided for assessing one or more pharmacodynamic PMR-related parameters induced by administration of a pharmaceutical composition containing an IL-6R antagonist in subjects of need. A decrease in the incidence of PMR symptoms or an improvement in PMR-related PRO or ClinRO measures may be associated with an improvement in one or more pharmacodynamic PMR-related parameters; however, such an association is not necessarily observed in all cases.

[0254] The implementation of “pharmacodynamic PMR-related parameters” includes, for example, the following: (a) biomarker expression levels and (b) serum protein and RNA analysis. “Improvement in pharmacodynamic PMR-related parameters” means, for example, a decrease in one or more of the levels of IL-6, IL6R, and C-reactive protein (CRP) relative to baseline, or a decrease in erythrocyte sedimentation rate (ESR). As used herein, the term “baseline” for pharmacodynamic PMR-related parameters means the value of the pharmacodynamic PMR-related parameter in a patient before or at the time of administration of the pharmaceutical composition described herein.

[0255] To assess pharmacodynamic PMR-related parameters, these parameters are quantified at baseline and at time points following administration of the drug composition. For example, pharmacodynamic PMR-related parameters can be measured approximately on day 1, day 2, day 3, day 4, day 5, day 6, day 7, day 8, day 9, day 10, day 11, day 12, day 14, or approximately 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, or longer after treatment with the drug composition. The difference between parameter values ​​at a specific time point after the start of treatment and parameter values ​​at baseline is used to determine whether pharmacodynamic PMR-related parameters have changed, such as “improvement” (e.g., increase or decrease, depending on the specific parameter measured).

[0256] In some implementations, administration of an IL-6R antagonist to a patient results in a change in the expression of a specific biomarker, such as a decrease or increase. PMR-related 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 may lead to a decrease in IL-6, IL6R, or CRP levels. This decrease can be detected approximately at week 1, week 2, week 3, week 4, week 5, or longer after administration of the IL-6R antagonist. Biomarker expression can be determined using methods known in the art. For example, protein levels can be measured using an ELISA (enzyme-linked immunosorbent assay). RNA levels can be measured using reverse transcription-coupled polymerase chain reaction (RT-PCR).

[0257] Biomarker expression (as discussed above) can be measured by detecting proteins or RNA in serum. Serum samples can also be used to monitor additional protein or RNA biomarkers associated with response to treatment with IL-6R antagonists or IL-6 signaling. In some embodiments, RNA samples are used to determine RNA levels (non-genetic analysis), such as the RNA levels of biomarkers; and in other embodiments, RNA samples are used for transcriptome sequencing (e.g., genetic analysis). Interleukin-6 receptor antagonists

[0258] This disclosure includes a method comprising administering to a subject an antibody or antigen-binding fragment thereof that specifically binds to hIL-6R. As used herein, the term "hIL-6R" refers to a human cytokine receptor that specifically binds to human interleukin-6 (IL-6). In some embodiments, the antibody administered to the patient specifically binds to the extracellular domain of hIL-6R.

[0259] As used herein, the term "antibody" refers to an immunoglobulin molecule comprising four polypeptide chains linked together by disulfide bonds—two heavy (H) chains and two light (L) chains—as well as its polymers (e.g., IgM). Each heavy chain contains a heavy chain variable region (abbreviated herein as HCVR or V). H The heavy-chain constant region contains three structural domains, C H 1. C H 2 and C H 3. Each light chain contains a light chain variable region (abbreviated as LCVR or V in this article). L ) and the light chain constant region. The light chain constant region contains a structural domain (C L 1). V H District and V L The region can be further subdivided into highly variable regions called complementary determinant regions (CDRs), interspersed with more conservative regions called framing regions (FRs). Each V H and V L It consists of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the antibody (or its antigen-binding portion) may be identical to the human germline sequence, or may be natural or artificially modified. The common amino acid sequence can be defined based on the side-by-side analysis of two or more CDRs.

[0260] As used herein, the term "antibody" also includes the antigen-binding fragment of a complete antibody molecule. As used herein, the terms "antigen-binding portion" and "antigen-binding fragment" of an antibody include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. Antigen-binding fragments of antibodies can be derived from complete antibody molecules, for example, using any suitable standard technique, such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding variable domains and, if desired, constant domains. This DNA is known and / or readily available from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. DNA can be sequenced and manipulated chemically or using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into suitable conformations or to introduce codons, generate cysteine ​​residues, modify, add, or delete amino acids, etc.

[0261] Non-limiting embodiments 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) the smallest recognition unit consisting of amino acid residues mimicking the hypervariable region of an antibody (e.g., a separated complementarity-determining region (CDR), such as a CDR3 peptide), or a restricted FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single-domain antibodies, domain-deficient antibodies, chimeric antibodies, CDR-grafted antibodies, biantibodies, triantibodies, tetraantibodies, microantibodies, nanobodies (e.g., monovalent and bivalent nanobodies), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the term "antigen-binding fragments" as used herein.

[0262] Antibody antigen-binding fragments typically contain at least one variable domain. Variable domains can have any size or amino acid composition and will generally contain at least one CDR adjacent to or in frame one or more frames. L V of domain association H In the antigen-binding fragment of the domain, V H Domain and V L Domains can be positioned relative to each other in any suitable arrangement. For example, variable regions can be dimers and contain V. H -V H V H -V L or V L -V L Dimer. Alternatively, the antigen-binding fragment of the antibody may contain monomer V.H or V L Structural domain.

[0263] In some embodiments, the antigen-binding fragment of the 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 can be found in the antigen-binding fragment of the antibody include: (i) V H -C H 1; (ii) V H -C H 2; (iii) V H -C H 3; (iv) V H -C H 1-C H 2; (v)V H -C H 1-C H 2-C H 3; (vi) V H -C H 2-C H 3; (vii) V H -C L (viii) V L -C H 1; (ix) V L -C H 2; (x) V L -C H 3;(xi) V L -C H 1-C H 2;(xii) V L -C H 1-C H 2-C H 3; (xiii) V L -C H 2-C H 3; and (xiv) V L -C L In any configuration of the variable and constant domains (including any of the exemplary configurations listed above), the variable and constant domains can be directly connected to each other or connected via full or partial hinge or linker regions. In various embodiments, the hinge region can consist of at least two (e.g., 5, 10, 15, 20, 40, 60, or more) amino acids that create flexible or semi-flexible connections between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, in various embodiments, the antigen-binding fragment of the antibody can comprise the domains listed above and / or one or more monomers V.H or V L Homodimers or heterodimers (or other polymers) of any variable and constant domain configurations of non-covalently associated domains (e.g., via one or more disulfide bonds).

[0264] In some embodiments, the antibody or antibody fragment used in the methods disclosed herein may be a monospecific antibody. In some embodiments, the antibody or antibody fragment used in the methods disclosed herein may be a multispecific antibody, which may be specific to different epitopes of a single target polypeptide, or may contain antigen-binding domains specific to epitopes of more than one target polypeptide. Exemplary forms of bispecific antibodies that may be used in the context of certain embodiments involve the use of a first immunoglobulin (Ig) C. H 3 structural domains and second Ig C H 3 structural domains, where the first Ig C H 3 structural domains and second Ig C H The three domains differ from each other by at least one amino acid, and this at least one amino acid difference reduces the binding of the bispecific antibody to protein A compared to a bispecific antibody lacking this amino acid difference. In one embodiment, the first IgC H 3-domain binding to protein A and second IgC H Domain 3 contains mutations that reduce or eliminate protein A binding, such as the H95R modification (based on IMGT exon numbering; based on EU numbering, it is H435R). Second C H 3 may further include Y96F modification (according to IMGT; Y436F according to EU). In the case of IgG1 antibody, it may be included in the second C H Other modifications found in section 3 include: D16E, L18M, N44S, K52N, V57M, and V82I (according to IMGT; according to EU, D356E, L358M, N384S, K392N, V397M, and V422I); in the case of IgG2 antibody, N44S, K52N, and V82I (according to IMGT; according to EU, N384S, K392N, and V422I); and in the case of IgG4 antibody, Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (according to IMGT; according to EU, Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I). Variations of the above-described bispecific antibody forms are considered within the scope of certain embodiments. In various implementations, any multispecific antibody form, including the exemplary bispecific antibody forms disclosed herein, can be adapted using conventional techniques available in the art to suit the context of the antigen-binding fragment of the anti-IL-6R antibody.

[0265] Compared to corresponding germline sequences, the fully human anti-IL-6R antibodies disclosed herein may contain one or more amino acid substitutions, insertions, and / or deletions in the architecture and / or CDR regions of the heavy and light chain variable domains. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with germline sequences available from, for example, public antibody sequence databases. This disclosure includes antibodies and antigen-binding fragments derived from any amino acid sequence disclosed herein, wherein one or more amino acids in one or more architecture and / or CDR regions are reverted to one or more corresponding germline residues or to conserved amino acid substitutions (natural or non-natural) of one or more corresponding germline residues (such sequence changes are referred to herein as “germline reversion mutations”). Those skilled in the art can readily generate numerous antibody and antigen-binding fragments comprising one or more individual germline reversion mutations or combinations thereof, starting from the heavy and light chain variable region sequences disclosed herein. In some embodiments, V H and / or V L All structural residues and / or CDR residues within the domain are reverted to the germline sequence. In other embodiments, only certain residues are mutated back to the germline sequence, for example, mutated residues found only in the first 8 amino acids of FR1 or in the last 8 amino acids of FR4, or mutated residues found only in CDR1, CDR2, or CDR3. Furthermore, this document includes antibodies that may contain any combination of two or more germline reversion mutations within the structural and / or CDR regions, i.e., certain individual residues are reverted to the germline sequence while retaining certain other residues different from the germline sequence. Once obtained, antibody-antigen binding fragments containing one or more germline reversion mutations can be readily tested for one or more desired properties, such as increased binding specificity, increased binding affinity, increased or enhanced antagonistic or agonistic biological properties (optionally), reduced immunogenicity, etc. Antibody-antigen binding fragments obtained in this general manner are covered in this disclosure.

[0266] The constant region of an antibody is important in its ability to fix complement and mediate cell-dependent cytotoxicity. Therefore, antibody isotypes can be selected based on whether they are ideal for mediating cytotoxicity.

[0267] As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Nevertheless, in various embodiments, the human antibodies characterized in this disclosure (e.g., in CDRs, and in some embodiments, in CDR3) include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutations in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which a germline CDR sequence derived from another mammalian species (such as a mouse) has been grafted onto a human structural sequence.

[0268] As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, generated, or isolated in a recombinant manner, such as antibodies expressed using a recombinant expression vector transfected into host cells (further described below), antibodies isolated from a recombinant combined human antibody library (further described below), antibodies isolated from animals (e.g., mice) that are transgenic for the human immunoglobulin gene, or antibodies prepared, expressed, generated, or isolated by any other method involving splicing a human immunoglobulin gene sequence to another DNA sequence. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies are mutagenized in vitro (or, when using animals transgenic for the human Ig sequence, in vivo somatic cell mutagenesis) and thus the V of the recombinant antibody... H and V L The amino acid sequence of the region is as follows, derived from human lineage V. H and V L When a sequence is associated with another sequence, that sequence may not be naturally present in the human antibody germline library.

[0269] Human antibodies can exist in two forms associated with hinge heterogeneity. In one embodiment, the immunoglobulin molecule comprises a stable four-chain construct of approximately 150-160 kDa, wherein the dimers are held together by interchain heavy chain disulfide bonds. In another embodiment, the dimers are not linked by interchain disulfide bonds and form a molecule of approximately 75-80 kDa, which consists of covalently coupled light and heavy chains (half-antibodies). In some embodiments, the forms are extremely difficult to separate, even after affinity purification.

[0270] The frequency of the second form in each intact IgG isotype is attributable 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 occurrence rate of the second form to levels typically observed using the human IgG1 hinge. In various embodiments, this disclosure covers the hinge, C... H 2 or CH Region 3 contains one or more mutated antibodies, which may be desirable, for example, in production, to improve the yield of the desired antibody form.

[0271] As used herein, "isolated antibody" means an antibody that has been identified and isolated and / or recovered from at least one component of its natural environment. For example, an antibody that has been isolated or removed from at least one component of an organism or from tissues or cells in which antibodies are naturally present or naturally produced is a "isolated antibody." In various embodiments, isolated antibodies also include in situ antibodies within recombinant cells. In other embodiments, isolated antibodies are antibodies that have undergone at least one purification or isolation step. In various embodiments, isolated antibodies may be substantially free of other cellular material and / or chemicals.

[0272] The term "specific binding" refers to the formation of a relatively stable complex between an antibody or its antigen-binding fragment and the antigen under physiological conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis and surface plasmon resonance. For example, as used herein, antibodies that "specifically bind" IL-6R include those with the following K... D (As measured in a surface plasmon resonance assay) Antibodies or portions thereof that bind IL-6R (e.g., human IL-6R): 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. In some embodiments, the antibody is expressed as a K+ of about 0.1 nM to about 1000 nM or about 1 nM to about 100 nM. D It binds to IL-6R (e.g., human IL-6Rα). In some embodiments, the antibody is in the form of about 1 pM to about 100 pM or about 40 pM to about 60 pM of K. D It binds to IL-6R (e.g., human IL-6Rα). Specific binding can also be characterized by a dissociation constant of at least about 1 × 10⁻⁶. -6 M or less. In other embodiments, the dissociation constant is at least about 1 × 10⁻⁶. -7 M, 1×10 -8 M or 1×10 -9 M. However, isolated antibodies that specifically bind to human IL-6R may be cross-reactive to other antigens, such as IL-6R molecules from other (non-human) species.

[0273] As used herein, the term “surface plasmon resonance” refers to an optical phenomenon that allows for the analysis of real-time interactions by detecting changes in protein concentration within a biosensor matrix, for example, using a BIACORE® system (Biacore Life Sciences division of GE Healthcare, Piscataway, New Jersey).

[0274] As used in this article, the term "K" D "The purpose is to refer to the equilibrium dissociation constant of antibody-antigen interaction."

[0275] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site called a paratope in the variable region of an antibody molecule. A single antigen can have more than one epitope. Therefore, different antibodies can bind to different regions of the antigen and can have different biological effects. Epitopes can be conformational or linear. Conformational epitopes are generated by spatially juxtaposed amino acids from different segments of a linear polypeptide chain. Linear epitopes are epitopes generated from adjacent amino acid residues in a polypeptide chain. In some cases, epitopes may include sugar, phosphoryl, or sulfonyl groups on the antigen.

[0276] In various embodiments, anti-IL-6R antibodies usable in the methods described herein may contain one or more amino acid substitutions, insertions, and / or deletions in the architecture and / or CDR regions of the variable domains of the heavy and light chains, compared to the corresponding germline sequence from which the antibody is derived. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with germline sequences available from, for example, public antibody sequence databases. In various embodiments, this disclosure includes methods for using antibodies and antigen-binding fragments derived from any amino acid sequence disclosed herein, wherein one or more amino acid mutations within one or more architecture and / or CDR regions are mutated to one or more corresponding residues of the germline sequence from which the antibody is derived, or one or more corresponding residues of another human germline sequence, or conserved amino acid substitutions of such one or more corresponding germline residues (such sequence changes are collectively referred to herein as “germline mutations”). Numerous antibodies and antigen-binding fragments can be constructed containing one or more individual germline mutations or combinations thereof. In some embodiments, all architecture residues and / or CDR residues within the VH and / or VL domains are reverted to residues found in the original germline sequence from which the antibody is derived. In other embodiments, only certain residues (e.g., mutated residues found only in the first 8 amino acids of FR1 or the last 8 amino acids of FR4, or mutated residues found only in CDR1, CDR2, or CDR3) are reverted to the original germline sequence. In other embodiments, one or more frame and / or CDR residues are mutated to one or more corresponding residues of a different germline sequence (i.e., a germline sequence different from the one from which the antibody was originally derived). Furthermore, the antibody may contain any combination of two or more germline mutations within the frame and / or CDR regions, for example, where certain individual residues are mutated to corresponding residues of a germline sequence, while certain other residues different from the original germline sequence are maintained, or mutated to corresponding residues of a different germline sequence. Once obtained, one or more desired properties of the antibody and antigen-binding fragment containing one or more germline mutations can be readily tested, such as increased binding specificity, increased binding affinity, increased or enhanced antagonistic or agonistic biological properties (optionally), reduced immunogenicity, etc. Uses of antibody and antigen-binding fragments obtained in this general manner are covered in this disclosure.

[0277] This disclosure also includes methods for using anti-IL-6R antibodies comprising variants of any HCVR, LCVR, and / or CDR amino acid sequences disclosed herein with one or more conserved substitutions. For example, this disclosure includes using anti-IL-6R antibodies having HCVR, LCVR, and / or CDR amino acid sequences having, for example, 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, or other conserved amino acid substitutions relative to any HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0278] According to this disclosure, in various embodiments, an anti-IL-6R antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR), wherein the HCVR, LCVR, and / or CDR comprises any amino acid sequence of the anti-IL-6R antibody described in U.S. Patent No. 7,582,298 (which is incorporated herein by reference in its entirety). In some embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (HCDR) of an HCVR containing the amino acid sequence of SEQ ID NO: 1 and a light chain complementarity-determining region (LCDR) of an LCVR containing the amino acid sequence of SEQ ID NO: 2. According to some embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In yet other embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises an HCVR containing the amino acid sequence of SEQ ID NO: 1 and an LCVR containing the amino acid sequence of SEQ ID NO: 2.

[0279] In another embodiment, the anti-IL-6R antibody or its antigen-binding fragment comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10. In some embodiments, the extracellular domain of hIL-6R comprises the amino acid sequence of SEQ ID NO: 11. According to certain exemplary embodiments, the method of this disclosure includes using an anti-IL-6R antibody or its bioequivalence, which is known in the art as sarelumab. In some embodiments, sarelumab comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 3; HCDR2 comprises the amino acid sequence of SEQ ID NO: 4; HCDR3 comprises the amino acid sequence of SEQ ID NO: 5; LCDR1 comprises the amino acid sequence of SEQ ID NO: 6; LCDR2 comprises the amino acid sequence of SEQ ID NO: 7; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments, sarritumarab comprises an HCVR containing the amino acid sequence of SEQ ID NO: 1 and an LCVR containing the amino acid sequence of SEQ ID NO: 2. In some embodiments, sarritumarab comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 9 and a light chain containing the amino acid sequence of SEQ ID NO: 10.

[0280] The amino acid sequence of SEQ ID NO: 1 is as follows: (CDR sequence highlighted: IMGT number in bold; Kabat number underlined; Chothia number in italics). The amino acid sequence of SEQ ID NO: 2 is as follows: (CDR sequence highlighted: IMGT number in bold; Kabat number underlined; Chothia number in italics). The amino acid sequence of SEQ ID NO: 3 is RFTDDYA (according to the IMGT number CDR-H1). The amino acid sequence of SEQ ID NO: 4 is ISWNSGRI (CDR-H2 according to the IMGT number). The amino acid sequence of SEQ ID NO: 5 is AKGRDSFDI (CDR-H3 according to IMGT number). The amino acid sequence of SEQ ID NO: 6 is QGISSW (CDR-L1 according to IMGT number). The amino acid sequence of SEQ ID NO: 7 is GAS (according to the IMGT number CDR-L2). The amino acid sequence of SEQ ID NO: 8 is QQANSFPYT (CDR-L3 according to IMGT number). The amino acid sequence of SEQ ID NO: 9 is (CDR sequence highlighted: IMGT number in bold; Kabat number underlined; Chothia number in italics). The amino acid sequence of SEQ ID NO: 10 is as follows: (CDR sequence highlighted: IMGT number in bold; Kabat number underlined; Chothia number in italics). The amino acid sequence of SEQ ID NO: 11 is as follows: .

[0281] In some embodiments, the sequence identity of the sequences 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%. A certain percentage of "sequence identity" between one polynucleotide or polypeptide and another polynucleotide or polypeptide means that, when aligned, that percentage of bases or amino acids are identical and in the same relative positions when comparing the two sequences. Sequence identity can be determined in a variety of different ways. To determine sequence identity, sequence alignment can be performed using various methods and computer programs (e.g., BLAST, T-COFFEE, MUSCLE, MAFFT, etc.), which are available on websites on the World Wide Web, including ncbi.nlm.nili.gov / BLAST, ebi.ac.uk / Tools / msa / tcoffee / , ebi.ac.uk / Tools / msa / muscle / , and mafft.cbrc.jp / alignment / software / . See, for example, Altschul et al. (1990), J. Mol. Bioi. [Journal of Molecular Biology] 215:403-10. Sequence analysis software is commonly used to measure the sequence similarity of peptides, also known as sequence identity. Protein analysis software uses similarity measures assigned to various substitutions, deletions, and other modifications, including conserved amino acid substitutions, to match similar sequences. For example, 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 peptides, such as between homologous peptides from different biological species or between wild-type proteins and their mutant counterparts. See, for example, GCG version 6.1. FASTA (a program in GCG version 6.1) can also be used to compare peptide sequences using default or recommended parameters. FASTA (e.g., FASTA2 and FASTA3) provides alignment of the best overlapping regions between the query sequence and the search sequence and a percentage of sequence identity (Pearson (2000), ibid.). When comparing the sequences of this invention with databases containing numerous sequences from different organisms, another preferred algorithm is the computer program BLAST, particularly blastp or tblastn, using preset parameters. See, for example, Altschul et al. (1990) J. MoI. Biol. [Journal of Molecular Biology] 215: 403 410 and Altschul et al. (1997) Nucleic Acids Res. [Nucleic Acid Research] 25:3389 402.

[0282] In some embodiments, the sequence identity with 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, and SEQ ID NO:8 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%. According to this disclosure, in various embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises a heavy chain variable region (HCVR), a light chain variable region (LCVR), and / or a complementarity-determining region (CDR), which comprises any amino acid sequence of the anti-IL-6R antibody described in U.S. Patent No. 7,521,052 (which is incorporated herein by reference in its entirety). The hybridoma cell line producing tocilizumab (TCZ) was internationally deposited on July 12, 1989, under the Budapest Treaty as FERM BP-2998 at the International Patent Organism Depository (AIST Tsukuba Central 6, 1-1, Higashi 1-chome, Tsukuba City, Ibaraki Prefecture). In some embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises a heavy chain complementarity-determining region (HCDR) and / or a light chain complementarity-determining region (LCDR) of an HCVR containing the amino acid sequence of SEQ ID NO: 13, and a light chain complementarity-determining region (LCDR) of an LCVR containing the amino acid sequence of SEQ ID NO: 12. According to some embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises three HCDRs (i.e., HCDR1, HCDR2, and HCDR3) and three LCDRs (i.e., LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises the amino acid sequence of SEQ ID NO: 17; HCDR2 comprises the amino acid sequence of SEQ ID NO: 18; HCDR3 comprises the amino acid sequence of SEQ ID NO: 19; LCDR1 comprises the amino acid sequence of SEQ ID NO: 14; LCDR2 comprises the amino acid sequence of SEQ ID NO: 15; and LCDR3 comprises the amino acid sequence of SEQ ID NO: 16. In various embodiments, the anti-IL-6R antibody or its antigen-binding fragment comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 13 and a light chain containing the amino acid sequence of SEQ ID NO: 12.

[0283] In another embodiment, the anti-IL-6R antibody or its antigen-binding fragment comprises a heavy chain containing the TCZ heavy chain amino acid sequence and a light chain containing the TCZ light chain amino acid sequence. 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 this disclosure include using an anti-IL-6R antibody, known in the art as tocilizumab, or a bioequivalence thereof.

[0284] The amino acid sequence of SEQ ID NO: 12 is as follows: DIQMTQSPSSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC The amino acid sequence of SEQ ID NO: 13 is as follows: VQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGS LVTVSSASTKGPSVFPLAPSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG. The amino acid sequence of SEQ ID NO: 14 is RASQDISSYLN. The amino acid sequence of SEQ ID NO: 15 is YTSRLHS. The amino acid sequence of SEQ ID NO: 16 is QQGNTLPYT. The amino acid sequence of SEQ ID NO: 17 is SDHAWS. The amino acid sequence of SEQ ID NO: 18 is YISYSGITTYNPSLK. The amino acid sequence of SEQ ID NO: 19 is SLARTTAMDY.

[0285] As used herein, the term "bioequivalent" refers to a molecule that, when administered at the same molar dose and under similar conditions (e.g., the same route of administration), has similar bioavailability (rate and extent of utilization), such that its effects in both efficacy and safety can be expected to be substantially the same as those of the comparative molecule. Two pharmaceutical compositions containing an anti-IL-6R antibody are pharmaceutically equivalent, meaning they contain the same amount of the active ingredient (e.g., the IL-6R antibody), in the same dosage form, via the same route of administration, and meet the same or comparable criteria. Bioequivalence can be determined, for example, by comparing the pharmacokinetic parameters of the two compositions in in vivo studies. Commonly used parameters in bioequivalence studies include peak plasma concentration (Cmax) and area under the plasma drug concentration-time curve (AUC).

[0286] In some embodiments, this disclosure relates to a method of administering an antibody to a subject, the antibody comprising a heavy chain variable region containing sequence SEQ ID NO: 1 and a light chain variable region containing sequence SEQ ID NO: 2.

[0287] This disclosure provides pharmaceutical compositions comprising such antibodies, and methods of using said compositions.

[0288] The antibody in various embodiments comprises a heavy chain variable region containing the sequence SEQ ID NO: 1 and a light chain variable region containing the sequence SEQ ID NO: 2, and is an antibody that specifically binds to the human interleukin-6 receptor (hIL-6R). See International Publication No. WO 2007 / 143168, which is incorporated herein by reference in its entirety. In one embodiment, the antibody comprises a heavy chain variable region containing the sequence SEQ ID NO: 9 and a light chain variable region containing the sequence SEQ ID NO: 10. In various embodiments, the antibody is sarerucitabine. Salrerucitabine is also known by the trade name KEVZARA. ® . Example

[0289] To identify characteristics associated with glucocorticoid (GC) use in newly diagnosed PMR patients at one year, this was part of a multicenter, randomized, double-blind, placebo-controlled 52-week phase 3 study to evaluate the efficacy and safety of sarrerucizumab in patients with active PMR.

[0290] This is an exploratory analysis of the initial cohort of PMR patients identified from fee-for-service Medicare claims between October 1, 2016, and December 31, 2020. Patients were included if they had no prior history of PMR, were ≥ 50 years old, had ≥ 1 hospitalization or ≥ 2 outpatient PMR claims within ≥ 30 days and < 365 days (ICD-10-CM M35.3). They had to start GC (prednisone equivalent) 7.5–25 mg / day and receive ≥ 200 mg within the first 30 days, and use GC for ≥ 4 months. Continuous enrollment for ≥ 1 year prior to the date of diagnosis was required. Patients with a history of giant cell arteritis (with / without PMR) were excluded based on all available data. Patients with other systemic rheumatic diseases, active malignant tumor treatment, multiple sclerosis (MS), organ transplantation, or those who had been on medication as prescribed with conventional synthetic immunomodulatory drugs [csIM (methotrexate [MTX], leflunomide, imidazothiopurine)] or interleukin-6 receptor inhibitors for ≤ 1 year prior to diagnosis to 6 months after GC initiation were also excluded (GC cohort). Patients meeting other criteria who received csIM ≤ 6 months after GC initiation were analyzed separately (csIM cohort). The primary outcome was a comparison of the characteristics (demographic, clinical, and healthcare resource utilization) of patients who received GC at 1 year versus those who stopped GC (> 60-day interval) at 6 months. Relative contraindications for GC were defined using diagnostic, procedural, or drug codes. Weakness was assessed using a validated claims-based weakness index and defined using published thresholds.

[0291] Results: The GC cohort included a total of 4748 patients, and the csIM cohort included 318 patients. MTX was the most common type of csIM [200 / 318 (62.9%)]. Among patients in the GC and csIM cohorts, 3038 (64.0%) and 183 (57.5%) underwent GC at 1 year, respectively.

[0292] In both cohorts, patients who received GC at 1 year showed significantly higher daily GC doses at 6 months (Figure 1). In both cohorts, significantly more patients who received GC at 1 year than those who stopped GC received GC doses ≥ 5 or ≥ 7.5 mg at 6 months (Figure 2). In both cohorts, patients who received GC at 1 year also had significantly higher cumulative GC usage at 6 months compared to those who stopped GC. Figure 3 and Figure 4 ).

[0293] In the GC cohort, demographic characteristics, the presence of comorbidities, and frailty were not associated with GC use at 1 year, while in the csIM cohort, age, year of GC initiation, initial GC dose, and glaucoma were significantly associated with GC use at 1 year. Figure 4 and Figure 5 ).

[0294] Sensitivity analysis, including patients who started MTX within 6 months (N = 200), found that MTX use within 6 months was also significantly associated with GC use at 1 year. Significantly fewer patients who received GC received MTX within 6 months compared to patients who stopped GC at 1 year [111 / 3149 (3.5%) vs. 89 / 1799 (4.9%); p = 0.015].

[0295] Conclusion: Assessing GC dosage at 6 months may be a practical and useful tool to identify patients who may benefit from GC-restricted therapy. References / Publications 1.Dejaco C et al. Arthritis Rheumatol 2015, 67:2569–80 2. Floris A et al. Clin Rheumatol 2022, 41:19–31 3.Perricone C et al. Clin and Exp Med 2023, 23:3391–7 4.Birra D et al. Clin Exp Rheum 2020, 38:436–41 5.Curtis J, et al. Arthritis Rheumatol 2023, 75 6.Kim DH et al. J Gerontol A Biol Sci Med Sci 2018, 73:980–7 7.Halawa OA, et al, Ophthalmol 2023, 130: 646-54

Claims

1. A method for reducing steroid-related toxicity in subjects suffering from polymyalgia rheumatica (PMR) or for treating PMR in subjects in need, comprising: (1) Administering IL-6 inhibitory therapy to a PMR subject receiving a PMR therapy that includes at least a steroid and does not include IL-6 inhibitory therapy, wherein approximately six months after the start of steroid therapy, the steroid dose administered to the subject is greater than or equal to approximately 5 mg / day; and (2) Gradually reduce the dose of the steroid or discontinue the treatment with the steroid.

2. The method of any one of claims 1-2, wherein the dose of the steroid is greater than about 5 mg / day approximately six months after the start of the steroid treatment.

3. The method of claim 1, wherein approximately six months after the start of steroid treatment, the dose of the steroid is greater than or equal to approximately 7.5 mg / day.

4. The method of any one of claims 1-3, wherein the subject develops new-onset PMR when the steroid treatment is initiated.

5. The method of any one of claims 1-4, wherein the subject does not have giant cell arteritis or rheumatoid arthritis.

6. The method of any one of claims 1-5, wherein the steroid is gradually tapered off or discontinued approximately 26 weeks after the start of steroid treatment.

7. The method of any one of claims 1-6, wherein the steroid is gradually reduced in such a manner that the steroid is discontinued after at least about 50 days of administration of the IL-6 inhibitory therapy.

8. The method of claim 7, wherein the steroid is gradually reduced in such a manner that the steroid is discontinued after about 50 days to about 250 days of administration of the IL-6 inhibitory therapy.

9. The method of any one of claims 1-8, wherein the steroid is discontinued at least about 50 days after administration of the IL-6 inhibitory therapy.

10. The method of claim 9, wherein the steroid is discontinued after about 50 days to about 250 days of administration of the IL-6 inhibitory therapy.

11. The method of any one of claims 1-10, wherein the steroid comprises a corticosteroid.

12. The method of any one of claims 1-11, wherein the steroid comprises prednisone.

13. The method of any one of claims 1-12, wherein the PMR therapy, which comprises at least a steroid and does not contain an IL-6 inhibitory therapy, is substantially composed of or consists of a steroid.

14. The method of any one of claims 1-12, wherein the PMR therapy comprising at least a steroid and not an IL-6 inhibitor therapy is substantially composed of or comprised of a steroid and a conventional synthetic immunomodulatory drug (csIM) therapy.

15. The method of claim 14, wherein the csIM therapy is received within approximately six months of starting the steroid.

16. The method of claim 14 or 15, wherein the csIM therapy comprises methotrexate (MTX), imidazothiopurine, sulfasalazine, hydroxychloroquine, or leflunomide.

17. The method of any one of claims 14-16, wherein the IL-6 inhibitory therapy is administered in combination with the csIM therapy to the subject.

18. The method of claim 17, wherein the csIM therapy is selected from methotrexate, imidazothiopurine, sulfasalazine, hydroxychloroquine, and leflunomide.

19. The method of any one of claims 1-18, wherein the IL-6 inhibition therapy comprises an anti-IL6R antibody or an antigen-binding fragment thereof.

20. The method of claim 19, wherein the anti-IL6R antibody or its antigen-binding fragment is administered at a dose of about 150 mg to about 200 mg.

21. The method of any one of claims 19-20, wherein the anti-IL6R antibody or its antigen-binding fragment is administered at a dose of about 150 mg.

22. The method of any one of claims 19-20, wherein the anti-IL6R antibody or its antigen-binding fragment is administered at a dose of about 200 mg.

23. The method of any one of claims 19-22, wherein the anti-IL6R antibody or its antigen-binding fragment is administered every other week (q2w).

24. The method of any one of claims 19-23, wherein the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) sequences of SEQ ID NO: 3, 4 and 5, and comprises the light chain complementarity-determining region (LCDR) sequences of SEQ ID NO: 6, 7 and 8.

25. The method of any one of claims 19-24, wherein the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO:

2.

26. The method of any one of claims 19-25, wherein the anti-IL6R antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO:

10.

27. The method of any one of claims 19-26, wherein the anti-IL6R antibody is sarriromumab.

28. The method of any one of claims 1-27, wherein the subject is 50 years of age or older.

29. The method of any one of claims 1-28, wherein the subject is further characterized by a Charson Comorbidity Index score and is seronegative for rheumatoid arthritis as shown in Figure 4, or has diabetes, myocardial infection, stroke, percutaneous coronary intervention and coronary artery bypass surgery, hypertension, unstable angina, arrhythmia, heart failure, osteoporosis or osteopenia, osteonecrosis, glaucoma, steroid myopathy, mental illness, or a combination thereof.

30. The method of any one of claims 19-29, wherein the anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously.

31. The method of any one of claims 19-30, wherein the anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously as a pharmaceutical composition using a needle and syringe, a pen delivery device or an autoinjector.

32. The method of any one of claims 19-31, wherein the anti-IL6R antibody or its antigen-binding fragment is administered using a pre-filled syringe containing about 175 mg / mL sarrlumab.

33. The method of any one of claims 1-32, wherein administration of the IL-6 inhibitory therapy improves at least one symptom of the subject's PMR.

34. The method of any one of claims 1-33, wherein administration of the IL-6 inhibitory therapy reduces the subject's glucocorticoid toxicity index (GTI) score.

35. A method for treating polymyalgia rheumatica (PMR) in a subject of need, the method comprising administering a therapeutically effective dose of IL-6 inhibitory therapy, conventional synthetic immunomodulatory therapy (csIM), or IL-6 inhibitory therapy and csIM therapy, and gradually tapering off a steroid dose or discontinuing steroid therapy. The PMR subjects were receiving PMR therapy that included at least a steroid and did not include IL-6 inhibitory therapy, and the steroid dose administered to the subjects was greater than or equal to about 5 mg / day approximately six months after the start of the steroid therapy.

36. The method of claim 35, wherein approximately six months after the initiation of the steroid treatment, the dose of the steroid is greater than or equal to approximately 7.5 mg / day.

37. The method of any one of claims 35-36, wherein the subject develops new-onset PMR when the steroid treatment is initiated.

38. The method of any one of claims 35-37, wherein the subject does not have giant cell arteritis or rheumatoid arthritis.

39. The method of any one of claims 35-38, wherein the steroid is gradually reduced or discontinued.

40. The method of any one of claims 35-39, wherein the steroid is gradually tapered off or discontinued approximately 26 weeks after the start of steroid treatment.

41. The method of any one of claims 35-40, wherein the steroid is gradually reduced in such a manner that the steroid is discontinued at least 50 days after administration of the IL-6 inhibitory therapy.

42. The method of claim 41, wherein the steroid is gradually reduced in such a manner that the steroid is discontinued after about 50 days to about 250 days of administration of the IL-6 inhibitory therapy.

43. The method of any one of claims 35-42, wherein the steroid is discontinued at least about 50 days after administration of the IL-6 inhibitory therapy.

44. The method of claim 43, wherein the steroid is discontinued after about 50 days to about 250 days of administration of the IL-6 inhibitory therapy.

45. The method of any one of claims 35-44, wherein the steroid comprises a corticosteroid.

46. ​​The method of any one of claims 35-45, wherein the steroid comprises prednisone.

47. The method of any one of claims 35-46, wherein the csIM therapy administered approximately six months after the initiation of the steroid treatment is methotrexate (MTX), imidazothiopurine, sulfasalazine, hydroxychloroquine, or leflunomide.

48. The method of any one of claims 35-47, wherein the PMR therapy, which comprises at least a steroid and does not contain an IL-6 inhibitory therapy, is substantially composed of or consists of a steroid.

49. The method of any one of claims 35-47, wherein the PMR therapy, which comprises at least a steroid and does not contain an IL-6 inhibitory therapy, is substantially composed of or consists of a steroid and a csIM therapy.

50. The method of any one of claims 35-49, wherein the IL-6 inhibition therapy comprises an anti-IL6R antibody or an antigen-binding fragment thereof.

51. The method of claim 50, wherein the anti-IL6R antibody or its antigen-binding fragment is administered at a dose of about 150 mg to about 200 mg.

52. The method of claim 50 or 51, wherein the anti-IL6R antibody or its antigen-binding fragment is administered at a dose of about 150 mg.

53. The method of any one of claims 50-51, wherein the anti-IL6R antibody or its antigen-binding fragment is administered at a dose of about 200 mg.

54. The method of any one of claims 50-53, wherein the anti-IL6R antibody or its antigen-binding fragment is administered every other week (q2w).

55. The method of any one of claims 35-54, wherein the csIM therapy comprises methotrexate, imidazoline, sulfasalazine, hydroxychloroquine, or leflunomide.

56. The method of any one of claims 50-55, wherein the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) sequences of SEQ ID NO: 3, 4 and 5, and comprises the light chain complementarity-determining region (LCDR) sequences of SEQ ID NO: 6, 7 and 8.

57. The method of any one of claims 50-56, wherein the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO:

2.

58. The method of any one of claims 50-57, wherein the anti-IL6R antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO:

10.

59. The method of any one of claims 50-58, wherein the anti-IL6R antibody is sarriromumab.

60. The method of any one of claims 35-59, wherein the subject is 50 years of age or older.

61. The method of any one of claims 35-60, wherein the subject is further characterized by a Charson Comorbidity Index score and is seronegative for rheumatoid arthritis (Figure 4), or has diabetes, myocardial infection, stroke, percutaneous coronary intervention and coronary artery bypass surgery, hypertension, unstable angina, arrhythmia, heart failure, osteoporosis or osteopenia, osteonecrosis, glaucoma, steroid myopathy, mental illness, or a combination thereof (Figure 5).

62. The method of any one of claims 50-61, wherein the IL-6R antibody or its antigen-binding fragment is administered subcutaneously.

63. The method of any one of claims 50-62, wherein the anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously as a pharmaceutical composition using a needle and syringe, a pen delivery device or an autoinjector.

64. The method of any one of claims 50-63, wherein the anti-IL6R antibody or its antigen-binding fragment is administered using a pre-filled syringe containing about 175 mg / mL sarrlumab.

65. The method of any one of claims 35-64, wherein administration of the IL-6 inhibitory therapy improves at least one symptom of the subject's PMR.

66. The method of any one of claims 35-65, wherein administration of the IL-6 inhibitory therapy reduces the subject's glucocorticoid toxicity index (GTI) score.

67. A method for treating a subject with PMR, the method comprising: Steroid use in subjects diagnosed with PMR who are receiving PMR therapy that includes at least a steroid and does not include IL-6 inhibitory therapy, wherein if the dose of the steroid is greater than or equal to about 5 mg per day about six months after the start of steroid therapy, the subject is advised to undergo a different PMR therapy that includes: (a) administration of IL-6 inhibitory therapy and (b) gradual reduction of the dose of the steroid or discontinuation of the steroid therapy.

68. The method of claim 67, wherein the PMR therapy comprising at least a steroid and not an IL-6 inhibitory therapy comprises at least a steroid and a conventional synthetic immunomodulatory agent (csIM).

69. The method of claim 67 or 68, wherein the determination is made approximately six months after the initiation of the steroid treatment.

70. The method of any one of claims 67-69, wherein the determination is made approximately six months after the initiation of the steroid treatment.

71. The method of any one of claims 67-70, wherein, approximately six months after the initiation of the steroid treatment, the dose of the steroid is greater than or equal to approximately 7.5 mg / day.

72. The method of any one of claims 67-71, wherein the subject develops new-onset PMR when steroid treatment is initiated.

73. The method of any one of claims 67-72, wherein the subject does not have giant cell arteritis or rheumatoid arthritis.

74. The method of any one of claims 67-73, wherein the steroid is gradually tapered off or discontinued approximately 26 weeks after the start of steroid treatment.

75. The method of any one of claims 67-74, wherein the steroid is gradually reduced in such a manner that the steroid is discontinued at least 50 days after administration of the IL-6 inhibitory therapy.

76. The method of claim 75, wherein the steroid is gradually reduced in such a manner that the steroid is discontinued after about 50 days to about 250 days of administration of the IL-6 inhibitory therapy.

77. The method of any one of claims 67-76, wherein the steroid is discontinued at least about 50 days after administration of the IL-6 inhibitory therapy.

78. The method of claim 77, wherein the steroid is discontinued after about 50 days to about 250 days of administration of the IL-6 inhibitory therapy.

79. The method of any one of claims 67-78, wherein the steroid comprises a corticosteroid.

80. The method of any one of claims 67-79, wherein the steroid comprises prednisone.

81. The method of any one of claims 67-81, wherein the PMR therapy, which comprises at least a steroid and does not contain an IL-6 inhibitory therapy, is substantially composed of or consists of a steroid.

82. The method of any one of claims 67-81, wherein the PMR therapy comprising at least a steroid and not an IL-6 inhibitor therapy is substantially composed of or comprised of a steroid and a conventional synthetic immunomodulatory agent (csIM) therapy. 83.

85. The method of any one of claims 67-82, wherein the csIM therapy is received within approximately six months of starting the steroid.

84. The method of any one of claims 67-83, wherein the csIM therapy comprises methotrexate (MTX), imidazothiopurine, sulfasalazine, hydroxychloroquine, or leflunomide.

85. The method of any one of claims 67-84, wherein the IL-6 inhibition therapy comprises an IL-6R antibody.

86. The method of any one of claims 67-85, wherein the IL-6 inhibition therapy is further combined with csIM therapy.

87. The method of claim 86, wherein the csIM therapy comprises MTX, imidazothiopurine, sulfasalazine, hydroxychloroquine, or leflunomide.

88. The method of any one of claims 67-87, wherein the IL-6 inhibition therapy comprises an anti-IL6R antibody or an antigen-binding fragment thereof.

89. The method of claim 88, wherein the dose of the anti-IL6R antibody or its antigen-binding fragment is about 150 mg.

90. The method of claim 88, wherein the dose of the anti-IL6R antibody or its antigen-binding fragment is about 200 mg.

91. The method of any one of claims 88-90, wherein the anti-IL6R antibody or its antigen-binding fragment is administered every two weeks (q2w).

92. The method of any one of claims 88-91, wherein the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain complementarity-determining region (HCDR) sequence of SEQ ID NO: 3, 4 and 5, and comprises the light chain complementarity-determining region (LCDR) sequence of SEQ ID NO: 6, 7 and 8.

93. The method of any one of claims 88-92, wherein the anti-IL6R antibody or its antigen-binding fragment comprises the heavy chain variable region sequence of SEQ ID NO: 1 and the light chain variable region sequence of SEQ ID NO:

2.

94. The method of any one of claims 88-93, wherein the anti-IL6R antibody or its antigen-binding fragment comprises a heavy chain containing SEQ ID NO: 9 and a light chain containing SEQ ID NO:

10.

95. The method of any one of claims 88-94, wherein the anti-IL6R antibody is sareruciclovir.

96. The method of any one of claims 67-95, wherein the subject is 50 years of age or older.

97. The method of any one of claims 67-96, wherein the subject is further characterized by a Charson Comorbidity Index score and is seronegative for rheumatoid arthritis as shown in Figure 4, or has diabetes, myocardial infection, stroke, percutaneous coronary intervention and coronary artery bypass surgery, hypertension, unstable angina, arrhythmia, heart failure, osteoporosis or osteopenia, osteonecrosis, glaucoma, steroid myopathy, mental illness, or a combination thereof.

98. The method of any one of claims 88-97, wherein the anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously.

99. The method of any one of claims 88-98, wherein the anti-IL6R antibody or its antigen-binding fragment is administered subcutaneously as a pharmaceutical composition using a needle and syringe, a pen delivery device or an autoinjector.

100. The method of any one of claims 88-99, wherein the anti-IL6R antibody or its antigen-binding fragment is administered using a pre-filled syringe containing about 175 mg / mL sarrlumab.

101. The method of any one of claims 67-100, wherein administration of the IL-6 inhibitory therapy improves at least one symptom of the subject's PMR.

102. The method of any one of claims 67-101, wherein administration of the IL-6 inhibitory therapy reduces the subject's glucocorticoid toxicity index (GTI) score.

103. Use of IL-6 inhibition therapy in the preparation of a medicament for treating a subject with polymyalgia rheumatica (PMR) according to any one of claims 1-102.

Images