JP2020045351A - Compositions for treatment of rheumatoid arthritis and methods of using the same - Google Patents

Abstract

To provide compositions and methods of treating and improving symptoms of rheumatoid arthritis.SOLUTION: Methods use an antibody that specifically binds human interleukin-6 receptor (hIL-6R).SELECTED DRAWING: None

Description

RELATED APPLICATIONS This application is hereby incorporated by reference herein in its entirety, US Provisional Application No. 61 / 907,796, filed November 22, 2013, and US Provisional Application filed June 6, 2014. No. 62 / 008,787 and European Patent Application No. EP 143066366.7 filed on Sep. 5, 2014.

  The present invention relates to the field of therapeutic treatment of rheumatoid arthritis. More specifically, the present invention relates to the use of an interleukin-6 receptor (IL-6R) antagonist, such as an anti-IL-6R antibody, in combination with a disease modifying antirheumatic drug to treat rheumatoid arthritis.

  In North America and Europe, it is estimated that about 0.5% to 1% of the adult population has rheumatoid arthritis (RA). RA affects women twice as many as men, and the incidence is highest in women older than 40 years.

  The causes of RA are not completely understood. RA is defined by a series of symptoms and is characterized by persistent synovitis and progressive articular cartilage and bone destruction. The hallmark of the disease is symmetric polyarthritis that characteristically involves the small joints of the hands and feet. The inflammatory process involves other organs, characteristically bone marrow (anemia), eyes (scleritis, episcleritis), lungs (interstitial pneumonia, pleurisy), heart (pericarditis) and skin ( (Nodules, leukocytic vasculitis). Systemic inflammation is a manifestation of abnormal laboratory findings such as anemia, increased erythrocyte sedimentation rate, increased fibrinogen and C-reactive protein (CRP) and clinical symptoms such as malaise, weight loss, and muscle atrophy of affected joints. It is characterized by. The presence of polyclonal high titer rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies is evidence of immune dysregulation. It has been estimated that 65% to 70% of RA patients suffer from progressive disease that causes joint destruction, disability, and premature death.

  Treatment includes both pharmacotherapy and non-drug treatments, the purpose being to control arthritis and prevent joint destruction and disability. Non-pharmacological treatments, including physical therapy, splints and fixators, occupational therapy and dietary changes, do not stop the progression of joint destruction. Analgesics and anti-inflammatory drugs, including steroids, suppress symptoms but neither stop progression. Disease modifying antirheumatic drugs (DMARDs) can slow disease progression.

  Medical treatments still important for existing therapies that improve the symptoms associated with RA (eg, inflammation), as well as those that inhibit or stop the progression of structural damage (joint damage and destruction) in subjects with RA There are needs above. There is also a need for treatments that further improve physical function (eg, clothing and grooming, standing, eating, walking, hygiene, movement, grip, and other activities).

The present disclosure provides a method of inhibiting the development of structural damage in a subject suffering from rheumatoid arthritis, comprising administering to the subject an effective amount of salilumab. Typically, inhibition of the progression of structural damage is measured by a modified Van der Heijde total Sharp score.
(MTSS) is evaluated based on a change from the baseline (BL).

  The present disclosure also provides a method of improving physical function in a subject suffering from rheumatoid arthritis, comprising administering to the subject an effective amount of salilumab. Typically, improvement in physical function is assessed by a change in the Health Assessment Questionnaire Disability Index (HAQ-DI) from baseline (BL).

  The present disclosure provides a method of treating rheumatoid arthritis in a subject in need thereof. The method comprises administering to the subject an effective amount of salilumab (SAR153191) and a member of the group consisting of leflunomide, sulfasalazine and hydroxychloroquine. In certain embodiments, the subject has previously been treated for ineffective rheumatoid arthritis by administering a TNF-α antagonist. Specifically, subjects could have been treated with a TNF-α antagonist for at least 3 months or could be intolerant to a TNF-α antagonist. The TNF-α antagonist could be etanercept, infliximab, adalimumab, golimumab or certolizumab. In other embodiments, the subject has previously been treated for ineffective rheumatoid arthritis by administering methotrexate.

  Salilumab can be administered from 50 mg to 150 mg per week, or 100 mg to 200 mg per two weeks.

  In certain specific embodiments, salilumab and leflunomide are administered to the subject. Leflunomide can be administered orally. Leflunomide can also be administered to a subject at 10 mg to 20 mg per day.

  In another specific embodiment, salilumab and sulfasalazine are administered to the subject. Sulfasalazine can be administered orally. Sulfasalazine can also be administered to a subject from 1000 mg to 3000 mg per day.

  In another specific embodiment, salilumab and hydroxychloroquine are administered to the subject. Hydroxychloroquine can be administered orally. Hydroxychloroquine can also be administered to a subject from 200 mg to 400 mg per day.

  According to any of the embodiments described herein, the subject is treated with salilumab and / or methotrexate at 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 weeks or more it can. In certain embodiments, the subject is administered salilumab and methotrexate for 12, 16, 24 or 52 weeks or more. In certain embodiments, the subject is administered salilumab and methotrexate for 52 weeks or more. Specifically, salilumab is administered at 150 mg or 200 mg every 2 weeks for at least 52 weeks. According to another embodiment, salilumab is administered from 100 mg to 250 mg every 2 weeks for at least 52 weeks. In another embodiment, salilumab is administered from 150 mg to 200 mg every two weeks. According to any of these embodiments, salilumab is administered subcutaneously.

In some embodiments, as a result of the treatment, the subject achieves a 20% or 50% improvement in the American College of Rheumatology Core Set Disease Index after 12 weeks of treatment. In another embodiment, as a result of the treatment, the subject achieves a 20%, 50% or 70% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

  In some embodiments, as a result of the treatment, the subject achieves a lower disease activity score after 12 weeks of treatment compared to the subject before the treatment. The disease activity score may be 2.6 or less at 12 weeks. The disease activity score may drop by more than 1.2 during the 12th week from the start of treatment. The disease activity score may be less than or equal to 3.2 at 12 weeks. The disease activity score may drop by more than 0.6 during the 12th week from the start of treatment. The disease activity score may be less than 5.1 at 12 weeks.

  In some embodiments, as a result of the treatment, the subject achieves a lower disease activity score after 24 weeks of treatment compared to the pre-treatment subject. The disease activity score may be 2.6 or less at 24 weeks. The disease activity score may drop by more than 1.2 during the 24 weeks from the start of treatment. The disease activity score may be 3.2 or less at 24 weeks. The disease activity score may drop by more than 0.6 during the 24 weeks from the start of treatment. The disease activity score may be 5.1 or less at 24 weeks.

  The disclosure also includes administering to the subject an effective amount of salilumab and methotrexate, wherein the subject has previously been treated for ineffective rheumatoid arthritis by administering an anti-TNF-α therapeutic. Methods for treating rheumatoid arthritis in a subject in need thereof are provided. In certain embodiments, the subject has previously been treated for ineffective rheumatoid arthritis by administering methotrexate. Methotrexate can be administered to the subject at 10 mg to 25 mg per week.

  According to the invention, the subject is a mammal. The mammal can be a human. In certain embodiments, the human is a progeny of an individual from the Asia or Pacific region. Humans, descendants of individuals from the Asia or Pacific region, can be administered 6 mg to 25 mg of methotrexate per week.

  In certain embodiments, the subject has previously been treated for ineffective rheumatoid arthritis by administering a TNF-α antagonist. Specifically, subjects could have been treated with a TNF-α antagonist for at least 3 months or could be intolerant to a TNF-α antagonist. The TNF-α antagonist could be etanercept, infliximab, adalimumab, golimumab or certolizumab. In other embodiments, the subject has previously been treated for ineffective rheumatoid arthritis by administering methotrexate.

  Salilumab can be administered from 50 mg to 150 mg per week, or 100 mg to 200 mg per two weeks.

  In some embodiments, as a result of the treatment, the subject achieves a 20% or 50% improvement in the American College of Rheumatology Core Set Disease Index after 12 weeks of treatment. In another embodiment, as a result of the treatment, the subject achieves a 20%, 50% or 70% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

  In some embodiments, as a result of the treatment, the subject achieves a lower disease activity score after 12 weeks of treatment compared to the subject before the treatment. The disease activity score may be 2.6 or less at 12 weeks. The disease activity score may drop by more than 1.2 during the 12th week from the start of treatment. The disease activity score may be less than or equal to 3.2 at 12 weeks. The disease activity score may drop by more than 0.6 during the 12th week from the start of treatment. The disease activity score may be less than 5.1 at 12 weeks.

  In some embodiments, as a result of the treatment, the subject achieves a lower disease activity score after 24 weeks of treatment compared to the pre-treatment subject. The disease activity score may be 2.6 or less at 24 weeks. The disease activity score may drop by more than 1.2 during the 24 weeks from the start of treatment. The disease activity score may be 3.2 or less at 24 weeks. The disease activity score may drop by more than 0.6 during the 24 weeks from the start of treatment. The disease activity score may be 5.1 or less at 24 weeks.

  The present disclosure also provides a pharmaceutical composition comprising an effective amount of salilumab and a member of the group consisting of leflunomide, sulfasalazine and hydroxychloroquine. Salilumab can be present at 50 mg to 150 mg per dose, or 100 mg to 200 mg per dose.

  In certain specific embodiments, the composition comprises salilumab and leflunomide. Leflunomide can be present in an oral dosage form. Leflunomide can be present in the composition at 10 to 20 mg per dose.

  In another specific embodiment, the composition comprises salilumab and sulfasalazine. Sulfasalazine can be present in an oral dosage form. Sulfasalazine can be present in the composition at 1000 mg to 3000 mg per day in a subject.

  In another specific embodiment, the composition comprises salilumab and hydroxychloroquine. Hydroxychloroquine can be present in an oral dosage form. Hydroxychloroquine can be present in the composition at 200 mg to 400 mg per day in a subject.

  In certain embodiments, the present disclosure also provides a method of treating rheumatoid arthritis in a subject previously treated by administering methotrexate, leflunomide, sulfasalazine and / or hydroxychloroquine, comprising an effective amount of salilumab Provided to a subject.

  In one embodiment, the subject has previously been treated for ineffective rheumatoid arthritis by administering methotrexate, leflunomide, sulfasalazine and / or hydroxychloroquine.

  In another embodiment, salilumab is administered as a monotherapy.

  In another embodiment, methotrexate, leflunomide, sulfasalazine and / or hydroxychloroquine are administered together with salilumab.

  In another embodiment, salilumab and methotrexate are administered together.

  In one embodiment, methotrexate is administered from 6 mg to 25 mg per week.

  In certain embodiments, salilumab is administered from 50 mg to 150 mg per week. In another embodiment, salilumab is administered from 100 mg to 200 mg every two weeks. In another embodiment, salilumab is administered at 100 mg every two weeks. In another embodiment, salilumab is administered at 150 mg every two weeks. In another embodiment, salilumab is administered at 200 mg every two weeks.

In certain embodiments, the subject achieves a 20% improvement in the American College of Rheumatology Core Set Disease Index (ACR20) after 12 weeks of treatment. In another embodiment, the subject achieves a 50% improvement (ACR50) in the American College of Rheumatology Core Set Disease Index after 12 weeks of treatment. In another embodiment, the subject achieves a 70% improvement in the American College of Rheumatology Core Set Disease Index (ACR70) after 12 weeks of treatment.

  In certain embodiments, the subject has previously been treated for ineffective rheumatoid arthritis by administering a TNF-α antagonist. In one embodiment, the subject has been treated with an anti-TNF-α antagonist for at least three months in the last two years, or the subject has been intolerant to at least one TNF-α antagonist. In another embodiment, the TNF-α antagonist is a biological anti-TNF-α. In another embodiment, the TNF-α antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and / or sertolizumab pegol.

  In another embodiment, the disclosure provides a pharmaceutical composition comprising an effective amount of salilumab and a member of the group consisting of methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine.

  In yet another embodiment, the present disclosure provides a pharmaceutical composition comprising salilumab and a pharmaceutical composition comprising methotrexate, leflunomide, sulfasalazine or hydroxychloroquine for sequential or simultaneous use as a medicament.

Examples of embodiments of the present invention are listed below.
Embodiment 1: A method of treating rheumatoid arthritis in a subject in need thereof, comprising administering to the subject an effective amount of salilumab (SAR153191) and a member of the group consisting of leflunomide, sulfasalazine and hydroxychloroquine.

  Embodiment 2: The method of Embodiment 1, wherein the subject has previously been treated for ineffective rheumatoid arthritis by administering a TNF-α antagonist.

  Embodiment 3: The method of Embodiment 2, wherein the TNF-α antagonist is a biological anti-TNF-α antagonist.

  Embodiment 4: The method of Embodiment 2 or 3, wherein the subject has been treated with a TNF-α antagonist for at least 3 months.

  Embodiment 5: The method of Embodiment 2 or 3, wherein the subject has been intolerant to the TNF-α antagonist.

  Embodiment 6: The method of Embodiment 2 or 3, wherein the TNF-α antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab and certolizumab.

  Embodiment 7: The method of Embodiment 2 or 3, wherein the subject has previously been treated for ineffective rheumatoid arthritis by administering methotrexate.

  Embodiment 8: The method of Embodiment 1, wherein salilumab is administered from 50 mg to 150 mg per week.

  Embodiment 9: The method of Embodiment 1, wherein salilumab is administered from 100 mg to 200 mg every two weeks.

  Embodiment 10: The method of Embodiment 1, wherein salilumab and leflunomide are administered to the subject.

  Embodiment 11: The method of Embodiment 10, wherein leflunomide is administered orally.

  Embodiment 12: The method of Embodiment 10, wherein leflunomide is administered to the subject at 10 mg to 20 mg per day.

  Embodiment 13: The method of Embodiment 1, wherein salilumab and sulfasalazine are administered to the subject.

  Embodiment 14: The method of Embodiment 13, wherein the sulfasalazine is administered orally.

  Embodiment 15: The method of Embodiment 13, wherein the subject is administered 1000 to 3000 mg of sulfasalazine per day.

  Embodiment 16: The method of Embodiment 1, wherein salilumab and hydroxychloroquine are administered to the subject.

  Embodiment 17: The method of Embodiment 16, wherein hydroxychloroquine is administered orally.

  Embodiment 18: The method of Embodiment 16, wherein the hydroxychloroquine is administered to the subject from 200 mg to 400 mg per day.

  Embodiment 19: The method of any of embodiments 1-18, wherein the subject achieves a 20% improvement in the American College of Rheumatology Core Set Disease Index after 12 weeks of treatment.

  Embodiment 20: The method of any of embodiments 1-18, wherein the subject achieves a 50% improvement in the American College of Rheumatology Core Set Disease Index after 12 weeks of treatment.

  Embodiment 21: The method of any of embodiments 1-18, wherein the subject achieves a 20% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

  Embodiment 22: The method of any of embodiments 1-18, wherein the subject achieves a 50% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

  Embodiment 23: The method of any of embodiments 1-18, wherein the subject achieves a 70% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

  Embodiment 24: The method of any of embodiments 1-18, wherein the subject achieves a lower disease activity score after 12 weeks of treatment compared to the pre-treatment subject.

  Embodiment 25: The method of Embodiment 24, wherein the disease activity score is 2.6 or less at 12 weeks.

  Embodiment 26: The method of Embodiment 24, wherein the disease activity score is reduced by more than 1.2 during the 12th week from the start of treatment.

  Embodiment 27: The method of Embodiment 24, wherein the disease activity score is 3.2 or less at 12 weeks.

  Embodiment 28: The method of Embodiment 24, wherein the disease activity score drops by more than 0.6 during the 12th week from the start of treatment.

  Embodiment 29: The method of Embodiment 24, wherein the disease activity score is 5.1 or less at 12 weeks.

  Embodiment 30: Embodiment 24 wherein the disease activity score decreases by more than 2.0 (eg, 2.2, 2.3, 2.4, 2.5 or more) during the 12th week from the start of treatment. the method of.

  Embodiment 31: The method of Embodiment 24, wherein the subject achieves a disease activity score (DAS) remission after 12 weeks of treatment.

  Embodiment 32: The method of any of embodiments 24-31, wherein the disease activity score (DAS) is a DAS28 score.

  Embodiment 33: The method of Embodiment 32, wherein the DAS28 score is less than 2.6 after 12 weeks of treatment.

  Embodiment 34: The method of any of embodiments 1-18, wherein the subject shows an improvement in the American College of Rheumatology (ACR) standard joint swelling number (SJC) after 12 weeks of treatment.

  Embodiment 35: SJC is reduced by at least 8 (eg, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) during the 12th week from the start of treatment. The method of Embodiment 34.

  Embodiment 36: The method of any of embodiments 1-18, wherein the subject shows improvement in tender joint count (TJC) by American College of Rheumatology (ACR) standards after 12 weeks of treatment.

  Embodiment 37: The TJC of Embodiment 36, wherein the TJC is reduced by at least 10 (eg, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) during the 12th week from the start of treatment. Method.

  Embodiment 38: The method of any of embodiments 1-18, wherein the subject shows an improvement in the American College of Rheumatology (ACR) criteria health assessment questionnaire disability index (HAQ-DI) after 12 weeks of treatment.

  Embodiment 39: The ACR Health Assessment Questionnaire Disability Index (HAQ-DI) score is at least 0.3 (eg, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 and 1.0).

  Embodiment 40: The method of any of embodiments 1-18, wherein the subject exhibits improvement in the American College of Rheumatology (ACR) criteria visual analog score of pain (VAS pain).

  Embodiment 41: ACR VAS Pain score is at least 25 (eg, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40) The method of embodiment 40, wherein the method is reduced.

  Embodiment 42: The method of any of embodiments 1-18, wherein the subject shows an improvement in a physician-rated visual analog score (physician VAS) of pain according to the American College of Rheumatology (ACR) criteria.

  Embodiment 43: An ACR physician VAS score is reduced by at least 30 (eg, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40) during the 12th week from the start of treatment. Aspect 42. The method of aspect 42.

  Embodiment 44: The method of any of embodiments 1-18, wherein the subject shows improvement in a patient-rated visual analog score of pain (Patient VAS) according to the American College of Rheumatology (ACR) criteria.

  Embodiment 45: The ACR patient VAS score is at least 25 (eg, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40) The method of embodiment 42, wherein the method is reduced.

  Embodiment 46: The method of any of embodiments 1-18, wherein the subject shows improvement in C-reactive protein (CRP) levels according to the American College of Rheumatology (ACR) criteria.

  Embodiment 47: CRP levels are reduced by at least 30 mg / dL (eg, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 mg / dL) during the first 12 weeks of treatment The method of embodiment 46, wherein

  Embodiment 48: The method of embodiment 47, wherein the subject shows a good response according to the EULAR (European Rheumatology Association) index 12 weeks after receiving the treatment.

  Embodiment 49: The method of any of embodiments 1-18, wherein the subject achieves a lower disease activity score after 24 weeks of treatment compared to the pre-treatment subject.

  Embodiment 50: The method of any of embodiments 1-18, wherein the disease activity score is 2.6 or less at 24 weeks.

  Embodiment 51: The method of any of embodiments 1-18, wherein the disease activity score is reduced by more than 1.2 during the 24th week from the start of treatment.

  Embodiment 52: The method of any of embodiments 1-18, wherein the disease activity score is 3.2 or less at 24 weeks.

  Embodiment 53: The method of any of embodiments 1-18, wherein the disease activity score is reduced by more than 0.6 during the 24th week from the start of treatment.

  Embodiment 54: The method of any of embodiments 1-18, wherein the disease activity score is 5.1 or less at 24 weeks.

  Embodiment 55: comprising administering to a subject an effective amount of salilumab and methotrexate, wherein the subject has previously been treated for ineffective rheumatoid arthritis by administering an anti-TNF-α antagonist. A method of treating rheumatoid arthritis in a subject.

  Embodiment 56: The method of Embodiment 55, wherein the subject has previously been treated for ineffective rheumatoid arthritis by administering methotrexate.

  Embodiment 57: The method of Embodiment 55, wherein the methotrexate is administered to the subject at 10 mg to 25 mg per week.

  Embodiment 58: A method according to embodiment 55, wherein the subject is a mammal.

  Embodiment 59: The method of Embodiment 58, wherein the mammal is a human.

  Embodiment 60: The method of Embodiment 59, wherein the human is a progeny of an individual from the Asia or Pacific region.

  Embodiment 61: The method of Embodiment 60, wherein the human being a progeny of an individual from the Asia or Pacific region is administered 6 to 25 mg of methotrexate per week.

  Embodiment 62: A method according to embodiment 55, wherein the subject has been treated with a TNF-α antagonist for at least 3 months.

  Embodiment 63: A method according to embodiment 55, wherein the subject is intolerant to a TNF-α antagonist.

  Embodiment 64: A method according to any one of embodiments 55 to 63, wherein the TNF-α antagonist is a biological anti-TNF-α antagonist.

  Embodiment 65: The method of Embodiment 45, wherein the TNF-α antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab.

  Embodiment 66: A method according to embodiment 55, wherein salilumab is administered from 50 mg to 150 mg per week.

  Embodiment 69: The method of Embodiment 55, wherein salilumab is administered from 100 mg to 200 mg every two weeks.

  Embodiment 70: The method of any of embodiments 55 to 70, wherein the subject achieves a 20% improvement in the American College of Rheumatology Core Set Disease Index after 12 weeks of treatment.

  Embodiment 71: The method of any of embodiments 55 to 70, wherein the subject achieves a 50% improvement in the American College of Rheumatology Core Set Disease Index after 12 weeks of treatment.

  Embodiment 72: The method of any of embodiments 55 to 70, wherein the subject achieves a 20% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

  Embodiment 73: The method of any of embodiments 55 to 70, wherein the subject achieves a 50% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

  Embodiment 74: The method of any of embodiments 55 to 70, wherein the subject achieves a 70% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

  Embodiment 75: The method of any of embodiments 55 to 70, wherein the subject achieves a lower disease activity score after 12 weeks of treatment compared to the subject prior to treatment.

  Embodiment 76: The method of any of embodiments 55 to 70, wherein the disease activity score is 2.6 or less at 12 weeks.

  Embodiment 77: The method of any of embodiments 55 to 70, wherein the disease activity score decreases by more than 1.2 during the 12th week from the start of treatment.

  Embodiment 78: The method of any of embodiments 55 to 70, wherein the disease activity score is 3.2 or less at 12 weeks.

  Embodiment 79: The method of any of embodiments 55 to 70, wherein the disease activity score decreases by more than 0.6 during the 12th week from the start of treatment.

  Embodiment 80: The method of any of embodiments 55 to 70, wherein the disease activity score is 5.1 or less at 12 weeks.

  Embodiment 81: Embodiment 55 wherein the disease activity score decreases by more than 2.0 (eg, 2.2, 2.3, 2.4, 2.5 or more) during the 12th week from the start of treatment. The method of any one of to 70.

  Embodiment 82: The method of any of embodiments 55 to 70, wherein the subject achieves DAS remission after 12 weeks of treatment.

  Embodiment 83: A method according to any of embodiments 55 to 70, wherein the disease activity score (DAS) is a DAS28 score.

  Embodiment 84: The method of Embodiment 83, wherein the DAS28 score is less than 2.6 after 12 weeks of treatment.

  Embodiment 85: The method of any of embodiments 55 to 70, wherein the subject shows an improvement in the number of joint swellings (SJC) according to the American College of Rheumatology (ACR) standard after 12 weeks of treatment.

  Embodiment 86: SJC is reduced by at least 8 (eg, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20) during the 12th week from the start of treatment. The method of Embodiment 85.

  Embodiment 87: The method of any of embodiments 55 to 70, wherein the subject shows an improvement in tender joint count (TJC) by American College of Rheumatology (ACR) standards after 12 weeks of treatment.

  Embodiment 88: The TJC of Embodiment 87, wherein the TJC is reduced by at least 10 (eg, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) during the 12th week from the start of treatment. Method.

  Embodiment 89: The method of any of embodiments 55 to 70, wherein the subject shows an improvement in the American College of Rheumatology (ACR) Health Assessment Questionnaire Disability Index (HAQ-DI) after 12 weeks of treatment.

  Embodiment 90: The ACR Health Assessment Questionnaire Disability Index (HAQ-DI) score is at least 0.3 (e.g., 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 and 1.0).

  Embodiment 91: The method of any of embodiments 55 to 70, wherein the subject exhibits improvement in the American College of Rheumatology (ACR) criteria visual analog score of pain (VAS pain).

  Embodiment 92: An ACR VAS Pain score of at least 25 (eg, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40) The method of embodiment 91, wherein the method is reduced.

  Embodiment 93: The method of any of embodiments 55 to 70, wherein the subject shows improvement in a physician-rated visual analog score of pain (physician VAS) according to the American College of Rheumatology (ACR) criteria.

  Embodiment 94: An ACR physician VAS score is reduced by at least 30 (eg, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40) during the 12th week from the start of treatment. The method of embodiment 93.

  Embodiment 95: The method of any of embodiments 55 to 70, wherein the subject shows improvement in a patient-rated visual analog score (patient VAS) for pain according to the American College of Rheumatology (ACR) criteria.

  Embodiment 96: The ACR patient VAS score is at least 25 (eg, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40) The method of embodiment 95, wherein the method is reduced.

  Embodiment 97: The method of any of embodiments 55 to 70, wherein the subject exhibits an improvement in C-reactive protein (CRP) levels according to the American College of Rheumatology (ACR) criteria.

  Embodiment 98: CRP levels are reduced by at least 30 mg / dL (eg, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 mg / dL) during the first 12 weeks of treatment The method of embodiment 97, wherein

  Embodiment 99: The method of any of embodiments 55 to 70, wherein the subject shows a good response according to the EULAR (European Rheumatology Association) index at 12 weeks of treatment.

  Embodiment 100: The method of any of embodiments 55 to 70, wherein the subject achieves a lower disease activity score after 24 weeks of treatment compared to the pre-treatment subject.

  Embodiment 101: The method of any of embodiments 55 to 70, wherein the disease activity score is 2.6 or less at 24 weeks.

  Embodiment 102: The method of any of embodiments 55 to 70, wherein the disease activity score decreases by more than 1.2 during the 24th week from the start of treatment.

  Embodiment 103: The method of any of embodiments 55 to 70, wherein the disease activity score is 3.2 or less at 24 weeks.

  Embodiment 104: The method of any of embodiments 55 to 70, wherein the disease activity score decreases by more than 0.6 during the 24th week from the start of treatment.

  Embodiment 105: The method of any of embodiments 55 to 70, wherein the disease activity score is 5.1 or less at week 24.

  Embodiment 106: A pharmaceutical composition comprising an effective amount of salilumab and a member of the group consisting of leflunomide, sulfasalazine and hydroxychloroquine.

Embodiment 107: A method of treating rheumatoid arthritis in a subject previously receiving treatment by administering methotrexate, leflunomide, sulfasalazine and / or hydroxychloroquine, wherein an effective amount of salilumab (SAR153191) is administered to the subject. A method that includes:

  Embodiment 108: The method of Embodiment 107, wherein the subject has previously been treated for ineffective rheumatoid arthritis by administering methotrexate, leflunomide, sulfasalazine, and / or hydroxychloroquine.

  Embodiment 108: The method of Embodiment 107, wherein salilumab is administered as a monotherapy.

  Embodiment 109: A method according to embodiment 108, wherein methotrexate, leflunomide, sulfasalazine and / or hydroxychloroquine are administered together with salilumab.

  Embodiment 110: The method of Embodiment 108, wherein salilumab and methotrexate are administered together.

  Embodiment 111: The method of Embodiment 110, wherein the methotrexate is administered from 6 mg to 25 mg per week.

  Embodiment 112: The method of any of embodiments 107-111, wherein salilumab is administered from 50 mg to 150 mg per week.

  Embodiment 113: The method of any of embodiments 107-111, wherein salilumab is administered from 100 mg to 200 mg every two weeks.

  Embodiment 113B: The method of any of Embodiments 1-6, wherein salilumab is administered at 100 mg every 2 weeks.

  Embodiment 114: The method of any of embodiments 107-111, wherein salilumab is administered at 150 mg every two weeks.

  Embodiment 115: The method of any of embodiments 107-111, wherein salilumab is administered at 200 mg every two weeks.

  Embodiment 116: The method of any of embodiments 107-115, wherein the subject achieves a 20% improvement in the American College of Rheumatology Core Set Disease Index (ACR20) after 12 weeks of treatment.

  Embodiment 117: The method of any of embodiments 107-115, wherein the subject achieves a 50% improvement in the American College of Rheumatology Core Set Disease Index (ACR50) after 12 weeks of treatment.

  Embodiment 118: The method of any of embodiments 107 to 115, wherein the subject achieves a 70% improvement in the American College of Rheumatology Core Set Disease Index (ACR70) after 12 weeks of treatment.

Embodiment 119:
a. A pharmaceutical composition comprising salilumab, and b. A combination of pharmaceutical compositions comprising methotrexate, leflunomide, sulfasalazine or hydroxychloroquine for sequential or simultaneous use as a medicament.

  Embodiment 120: The method of any of embodiments 107-119, wherein the subject achieves a 20% improvement (ACR20) in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

  Embodiment 121: A method of Embodiment 120, wherein a dose of 200 mg salilumab achieves a 66% improvement in the American College of Rheumatology Core Set Disease Index (ACR20) after 24 weeks of treatment.

  Embodiment 122: A method of Embodiment 120, wherein a dose of salilumab 150 mg achieves a 58% improvement in the American College of Rheumatology Core Set Disease Index (ACR20) after 24 weeks of treatment.

  Embodiment 123: The method of embodiment 120, wherein the improvement in physical function is achieved as measured by a change in the baseline of the Health Assessment Questionnaire Disability Index (HAQ-DI) at 16 weeks.

  Embodiment 124: The method of embodiment 120, wherein the inhibition of structural damage progression is achieved at 52 weeks, as measured by changes in the Van der Heide-Total Sharp Score Modification (mTSS).

  Embodiment 125: The method of Embodiment 124, wherein a dose of 200 mg of salilumab achieves an mTSS score of 0.25.

  Embodiment 126: An embodiment 120 that achieves about a 90% reduction in radiographic progression at 52 weeks compared to placebo plus methotrexate radiographic progression as assessed by mTSS. the method of.

  Embodiment 127: A method according to embodiment 120, wherein the dose of salilumab 150 mg achieves an mTSS score of 0.90.

  Embodiment 128: The method of Embodiment 120, wherein salilumab is administered in combination with an antibiotic.

Embodiment 129: The antibiotic is amikacin, gentamicin, kanamycin, neomycin, netilmycin, tobramycin, paromomycin, spectinomycin, geldanamycin, herbimycin, rifaximin, streptomycin, loracarbef, ertapenem, doripenem, 'imipenem' / cilastatin, meropenem. , Cefadroxil, cefazolin, 'cephalotin' or cephalotin, cephalexin, cefaclor, cefamandol, cefoxitin, cefprodil, cefuroxime, cefixime, cefdinil, cefdicetren, cefoperixetif, cefoperixeth, cefoperixeth, cefoperixeth Liaxon, Cefepim, Ceftaroline fosamil, cefbiprole, teicoplanin, vancomycin, telavancin, clindamycin, lincomycin, daptomycin, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandmycin, terithromycin, spiramycin Mycin, aztreonam, furazolidone, nitrofurantoin, linezolid, posizolid, radezolid, trezolide, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin,
Nafucilin, oxacillin, penicillin G, penicillin V, piperacillin, penicillin G, temocillin, ticarcillin, amoxicillin / clavulanate, ampicillin / sulbactam, piperacillin / tazobactam, ticarcillin / clavulanate, bacitracin, colistin, promyxin B , Enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, temafloxacin, mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine , Sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasa Gin, sulfisoxazole, 'trimethoprim'-sulfamethoxazole (cotrimoxazole) (TMP-SMX), sulfonamidochrysoidin, demeclocycline, doxycycline, minocycline, oxytetracycline, tetracycline, clofazimine, dapsone , Capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, 'rifampicin', rifabutin, rifapentin, arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platencimycin, quinupristin / dalhopristin, thiampian Embodiment 129. The method of embodiment 128 selected from the group consisting of phenicol, tigecycline, tinidazole and trimethoprim

Embodiment 130:
a) Packaging material b) Antibodies comprising SEQ ID NO: 2 and SEQ ID NO: 3, or biosimilars thereof, and c) Antibodies or biosimilars thereof are discontinued in patients with severe infection or sepsis A product comprising an indication or package insert in the packaging indicating that it should.

  Embodiment 131: The product of embodiment 130, further comprising a single use vial containing the antibody or its biosimilar 150 mg / 1 mL.

  Embodiment 132: The product of embodiment 130, further comprising a single use vial containing the antibody or its biosimilar 200 mg / 1 mL.

  Embodiment 133: The product of embodiment 130, further comprising a single use pre-filled syringe comprising the antibody or its biosimilar 150 mg / 1 mL.

  Embodiment 134: A product according to embodiment 130, further comprising a single use pre-filled syringe comprising 200 mg / 1 mL of antibody or biosimilar thereof.

  Embodiment 135: The product of Embodiment 130, wherein the display or package insert includes a printed description that includes the following information:

  Embodiment 136: A method of treating rheumatoid arthritis in a subject in need thereof, comprising administering to a subject a therapeutically effective amount of salilumab, wherein the subject has not received a biological agent within the previous three months .

  Embodiment 137: The method of Embodiment 136, wherein salilumab is administered from about 150 mg to about 200 mg every two weeks.

  Embodiment 138: The method of Embodiment 136, wherein the subject is also administered methotrexate.

  Embodiment 139: The method of Embodiment 138, wherein the subject has received methotrexate for at least 6 weeks prior to salilumab administration.

  Embodiment 140: The method of Embodiment 138, wherein the subject has received methotrexate for at least 12 weeks prior to salilumab administration.

  Embodiment 141: A method of Embodiment 138, wherein the subject has not received another leflunomide, sulfasalazine or hydroxychloroquine within 3 months prior to salilumab administration.

  Embodiment 142: A method according to embodiment 138, wherein the methotrexate is administered at about 6 mg to 25 mg per week.

  Embodiment 143: The method of Embodiment 136, wherein the subject does not have an autoimmune disease other than rheumatoid arthritis.

  Embodiment 144: The method of Embodiment 136, wherein the subject has not received parenteral or intra-articular administration of glucocorticoid for 4 weeks when administering salilumab.

  Embodiment 145: A method of treating rheumatoid arthritis in a subject population in need thereof comprising administering to the subject population a therapeutically effective amount of salilumab, wherein more than 50% of the subject population exhibits an ACR20 response after 52 weeks .

  Embodiment 146: The method of Embodiment 145, wherein more than 35% of the subject population shows an ACR50 response after 52 weeks.

  Embodiment 147: The method of Embodiment 145, wherein more than 20% of the subject population shows an ACR70 response after 52 weeks.

  Embodiment 148: The method of Embodiment 145, wherein more than 10% of the subject population exhibits an ACR70 response for at least 24 consecutive weeks.

  Embodiment 149: The method of Embodiment 145, wherein salilumab is administered from about 150 mg to about 200 mg every two weeks.

  Embodiment 150: The method of Embodiment 145, wherein the subject population is also administered methotrexate.

  Embodiment 151: A method of Embodiment 150, wherein about 6 mg to 25 mg of methotrexate are administered per week.

  Embodiment 152: The method of Embodiment 145, wherein the subject population has an average HAQ-DI of less than 1.0 after 52 weeks.

  Embodiment 153: The method of Embodiment 145, wherein the average modified total sharp score of the subject population is less than 1.0 after 52 weeks.

  Embodiment 154: The method of Embodiment 145, wherein the average DAS28-CRP of the subject population is less than 3 after 52 weeks.

  Embodiment 155: The method of Embodiment 145, wherein the average bone erosion score of the subject population is less than 0.5 after 52 weeks.

  Embodiment 156. The method of Embodiment 145, wherein the average JSN score of the subject population is less than 0.5 after 52 weeks.

Embodiment 157:
a. Salilumab at 150 mg every two weeks or 200 mg every two weeks, and b. Comprising administering methotrexate to the subject,
A method of treating rheumatoid arthritis in a subject in need thereof, wherein the subject has received methotrexate for at least 6 weeks prior to methotrexate administration.

  Embodiment 158: The method of Embodiment 157, wherein the subject has received methotrexate for at least 12 weeks prior to salilumab administration.

  Embodiment 159: The method of Embodiment 157 or 158, comprising administering to the subject 6 mg to 25 mg of methotrexate per week.

  Embodiment 160: A method of inhibiting the development of structural damage in a subject suffering from RA, comprising administering to the subject an effective amount of salilumab.

  Embodiment 161: The embodiment 160, wherein the subject achieves a change in the modified Van der Heide total sharp score (mTSS) from the baseline (BL) of at most 0.6 after at least 24 weeks of treatment. The described method.

  Embodiment 162: The embodiment 160 or 161 wherein the subject achieves a maximum change of 1 from the baseline (BL) of the modified Van der Heide total sharp score (mTSS) after at least 52 weeks of treatment. The described method.

  Embodiment 163: The subject has previously been treated for ineffective rheumatoid arthritis by administering at least one disease modifying antirheumatic drug (DMARD) selected from the group consisting of methotrexate, leflunomide, sulfasalazine and hydroxychloroquine. 163. The method of any one of embodiments 160-162.

  Embodiment 164: The method of any of embodiments 160-163, comprising administering to the subject an effective amount of salilumab and an effective amount of methotrexate, leflunomide, sulfasalazine, and / or hydroxychloroquine.

  Embodiment 165: The method of any of embodiments 160-164, comprising administering to the subject an effective amount of salilumab and an effective amount of methotrexate.

  Embodiment 166: The method of Embodiment 165, wherein the salilumab and methotrexate are administered for at least 52 weeks.

  Embodiment 167: The method of any of embodiments 165 to 166, wherein methotrexate is administered from 6 mg to 25 mg per week.

  Embodiment 168: The method of any of embodiments 160-167, wherein the salilumab is administered subcutaneously.

  Embodiment 169: The method of any of embodiments 160-168, wherein salilumab is administered at 150 mg every two weeks.

  Embodiment 170: The method of any of embodiments 160-168, wherein salilumab is administered at 200 mg every two weeks.

  Embodiment 171. The method of any of embodiments 160 to 168 wherein salilumab is administered from 100 mg to 250 mg every two weeks.

  Embodiment 172: The method of any of embodiments 160-168, wherein salilumab is administered from 150 mg to 200 mg every two weeks.

  Embodiment 173: The subject of Embodiment 169, wherein the subject achieves a change from the baseline (BL) of the modified Van der Heide total sharp score (mTSS) of at least 0.6 after at least 24 weeks of treatment. Method.

  Embodiment 174: The method of Embodiment 169, wherein the subject achieves a change from the baseline (BL) of the modified Van der Heide total sharp score (mTSS) of about 0.54 after at least 24 weeks of treatment. .

  Embodiment 175: The method of Embodiment 169, wherein the subject achieves a change from the baseline (BL) of the modified Van der Heide total sharp score (mTSS) of at least 52 weeks after treatment for at least 52 weeks, at most 1 or less. .

  Embodiment 176: The method of Embodiment 169, wherein the subject achieves a change from the baseline (BL) of the modified Van der Heide total sharp score (mTSS) of about 0.90 after at least 52 weeks of treatment. .

  Embodiment 177: The subject of Embodiment 170, wherein the subject achieves a change from the baseline (BL) of the Modified Van der Heide Total Sharp Score (mTSS) of at least 0.2 after at least 24 weeks of treatment. Method.

  Embodiment 178: The method of Embodiment 170, wherein the subject achieves a change from the baseline (BL) of the modified Van der Heide total sharp score (mTSS) of about 0.13 after at least 24 weeks of treatment. .

  Embodiment 179: The subject of Embodiment 170, wherein the subject achieves a change from the baseline (BL) of the Modified Van der Heide Total Sharp Score (mTSS) of at least 52 weeks after treatment for at least 52 weeks. Method.

  Embodiment 180: The method of Embodiment 170, wherein the subject achieves a change from the baseline (BL) of the modified Van der Heide total sharp score (mTSS) of about 0.25 after at least 52 weeks of treatment. .

  Embodiment 181: A method of improving physical function in a subject suffering from rheumatoid arthritis, comprising administering to the subject an effective amount of salilumab.

  Embodiment 182: The method of Embodiment 181, wherein the subject achieves at least a change in the Health Assessment Questionnaire Disability Index (HAQ-DI) from baseline (BL) of at least -0.5 after at least 16 weeks of treatment.

  Embodiment 183: The method of Embodiment 181, wherein the subject achieves at least a 24-week change in health assessment questionnaire disability index (HAQ-DI) from baseline (BL) of at least -0.6.

  Embodiment 184: The method of Embodiment 181, wherein the subject achieves at least a 52 week change in the health assessment questionnaire disability index (HAQ-DI) from baseline (BL) of at least -0.7.

Embodiment 185: A subject has previously been treated for ineffective rheumatoid arthritis by administering at least one disease modifying antirheumatic drug (DMARD) selected from the group consisting of methotrexate, leflunomide, sulfasalazine and hydroxychloroquine. 181. The method of any one of embodiments 181-185.

  Embodiment 186: The method of any of embodiments 181-185, comprising administering to a subject an effective amount of salilumab and an effective amount of methotrexate, leflunomide, sulfasalazine, and / or hydroxychloroquine.

  Embodiment 187: The method of any of embodiments 181-185, comprising administering to a subject an effective amount of salilumab and an effective amount of methotrexate.

  Embodiment 188: The method of Embodiment 187, wherein the salilumab and methotrexate are administered for at least 16, 24, or 52 weeks.

  Embodiment 189: The method of any of embodiments 186-188, wherein the methotrexate is administered from 6 mg to 25 mg per week.

  Embodiment 190: The method of any of embodiments 181-189, wherein salilumab is administered subcutaneously.

  Embodiment 191. The method of any of embodiments 181-190, wherein salilumab is administered at 150 mg every two weeks.

  Embodiment 192: The method of any of embodiments 181-190, wherein salilumab is administered at 200 mg every two weeks.

  Embodiment 193: The method of any of embodiments 181-190, wherein salilumab is administered from 100 mg to 250 mg every two weeks.

  Embodiment 194: The method of any of embodiments 181-190, wherein salilumab is administered from 150 mg to 200 mg every two weeks.

  Embodiment 195: The method of Embodiment 191, wherein the subject achieves at least a change in the Health Assessment Questionnaire Disability Index (HAQ-DI) from the baseline (BL) of at least -0.5 after at least 16 weeks of treatment.

  Embodiment 196: The method of Embodiment 191, wherein the subject achieves a change from baseline (BL) in the Health Assessment Questionnaire Disability Index (HAQ-DI) of at least -0.6 after at least 24 weeks of treatment.

  Embodiment 197: The method of Embodiment 191, wherein the subject achieves at least a 52 week change in the health assessment questionnaire disability index (HAQ-DI) from baseline (BL) of at least -0.7.

  Embodiment 198: The method of embodiment 192, wherein the subject achieves at least a 16 week change in the health assessment questionnaire disability index (HAQ-DI) from a baseline (BL) of at least -0.6.

  Embodiment 199: The method of Embodiment 192, wherein the subject achieves a change from baseline (BL) of the Health Assessment Questionnaire Disability Index (HAQ-DI) of at least -0.6 after at least 24 weeks of treatment.

  Embodiment 200: The method of Embodiment 192, wherein the subject achieves at least a 52 week change in the health assessment questionnaire disability index (HAQ-DI) from a baseline (BL) of at least -0.8.

  Embodiment 201: Salilumab for use in a method of inhibiting the progression of structural damage in a subject suffering from rheumatoid arthritis.

  Embodiment 202: Salilumab for use in a method of improving physical function in a subject suffering from rheumatoid arthritis.

  Embodiment 203: Use of salilumab for manufacturing a pharmaceutical composition for use in a method of improving physical function in a subject suffering from rheumatoid arthritis.

  Embodiment 204: Use of salilumab for the manufacture of a pharmaceutical composition for use in a method of inhibiting the development of structural damage in a subject suffering from rheumatoid arthritis.

  The present disclosure provides pharmaceutical compositions and methods of using these compositions for treating rheumatoid arthritis (RA) and ameliorating at least one symptom of RA. These compositions comprise at least one antibody that specifically binds to the human interleukin-6 receptor (hlL-6R) and, optionally, at least one additional therapeutic agent, such as a disease modifying antirheumatic drug (DMARD). including.

Anti-hlL-6R Antibodies The present disclosure includes methods that include administering to a patient a human antibody or an antigen-binding fragment thereof that specifically binds hlL-6R. As used herein, the term "hlL-6R" refers to a human cytokine receptor that specifically binds to human interleukin-6 (IL-6). In certain embodiments, the antibody administered to the patient specifically binds to the extracellular domain of hlL-6R. The extracellular domain of hlL-6R is shown in the amino acid sequence of SEQ ID NO: 1.

  Unless otherwise indicated, the term "antibody," as used herein, refers to an antibody molecule comprising two immunoglobulin heavy chains and two immunoglobulin light chains (ie, a "whole antibody molecule") and It should be understood that these antigen-binding fragments are included. Terms such as the `` antigen-binding portion '' of an antibody, the `` antigen-binding fragment '' of an antibody, as used herein, are any naturally occurring or specific binding to an antigen to form a complex, Includes polypeptides or glycoproteins that can be obtained enzymatically, synthetically or engineered. Antigen-binding fragments of an antibody can be prepared using any suitable standard technique, such as proteolysis or recombinant genetic engineering techniques, including manipulation and DNA expression of the antibody variable domain and (optionally) the antibody constant domain, including expression. , Obtained from whole antibody molecules. Such 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 by using molecular biology techniques to place, for example, one or more variable and / or constant domains in an appropriate structure. Or introduce codons, create cysteine residues, modify, add, or delete amino acids.

Non-limiting examples of antigen binding fragments include: (i) Fab fragment; (ii) F (ab ') 2 fragment; (iii) Fd fragment; (iv) Fv fragment; Main chain Fv (
(vi) dAb fragments; and (vii) a minimal recognition unit consisting of amino acid residues that mimic the hypervariable regions (eg, isolated complementarity determining regions (CDRs)) of an antibody. Other engineered molecules, such as diabodies, triabodies, tetrabodies and minibodies, as used herein, are also encompassed within the expression "antigen binding fragment".

Antigen binding fragments of an antibody typically include at least one variable domain. A variable domain may be of any size or of any amino acid composition, and generally comprises at least one CDR adjacent to one or more framework sequences, or one or more CDRs. At least one CDR that is in frame with the framework sequence of For antigen-binding fragments that have a _VH domain that is related to a _VL domain, the _VH domain and the _VL domain can be located in any suitable configuration relative to each other. For example, the variable region may be a dimer and include a _VH - _VH dimer, a _VH - _VL dimer, or a _VL - _VL dimer. Alternatively, an antigen-binding fragment of an antibody may include a monomeric _VH or _VL domain.

In certain embodiments, an antigen-binding fragment of an antibody may include at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary structures of variable and constant domains that may be found in the antigen-binding fragments of the antibodies of the invention include the following: (i) _{VH- CH1} ; (ii) V _{H -C H2; (iii) V} H -C H3; (iv) V H -C H1 -C H2; (v) V H -C H1 -C H2 -C H3; (vi) V H -C H2 - _{C H3; (vii) V H} -C L; (viii) V L -C H1; (ix) V L -C H2; (x) V L -C H3; (xi) V L -C H1 -C H2 _{; (xii) V L -C H1} -C H2 -C H3; (xiii) V L -C H2 -C H3; and _(xiv) V L _-C L. For variable and constant domains of any structure, including the exemplary structures listed above, the variable and constant domains may be directly linked to each other, or may contain all or one of the hinge or linker regions. It may be connected by a part. The hinge region has at least two (eg, 5, 10, 15, 20, 40) flexible or semi-flexible linkages between adjacent variable and / or constant domains in a single polypeptide molecule. , 60 or more) amino acids. Further, the antigen-binding fragments of the antibodies of the invention are non-covalently associated with each other and / or non-covalently with one or more monomeric V _H or V _L domains (eg, by disulfide bonds). ), Homodimers or heterodimers (or other multimers) of any of the variable and constant domain structures listed above.

The term "specifically binds" means that the antibody or antigen-binding fragment thereof forms a complex with the antigen that is relatively stable under physiological conditions. Specific binding can be characterized by a dissociation constant of at least about 1 × 10 ⁻⁶ M or less. In other embodiments, the dissociation constant is at least about 1 × 10 ⁻⁷ M, 1 × 10 ⁻⁸ M, or 1 × 10 ⁻⁹ M. Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like.

  As with whole antibody molecules, antigen-binding fragments can be monospecific or multispecific (eg, bispecific). Multispecific antigen-binding fragments of an antibody typically comprise at least two different variable domains, each variable domain being capable of specifically binding a distinct antigen or being capable of binding to a different epitope of the same antigen. Specific binding is possible. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be prepared using standard techniques available in the art for antigen binding of the antibodies of the invention. It can be applied for use in connection with fragments.

In a specific embodiment, the antibody or antibody fragment for use in the methods of the invention may be a multispecific antibody, wherein the multispecific antibody comprises various epitopes of one target polypeptide. Or may include an antigen binding domain specific for an epitope of more than one target polypeptide. The present invention and related to available exemplary bispecific antibody formats includes the use of a first immunoglobulin (Ig) C _H3 domains and second IgC _H3 domain, the first and second IgC _H3 domains differ from each other by at least one amino acid, and by at least one amino acid difference, compared to the bispecific antibody with no amino acid differences, binding of bispecific antibodies to the protein a is Is declining. In one embodiment, the first IgC _H3 domain binds protein A and the second IgC _H3 domain has a mutation that reduces or abolishes protein A binding, such as an H95R modification (by IMGT exon numbering; EU). H435R) is included in the numbering. The second _{C H3} further, Y96F modification (by IMGT; In EU Y436F) can contain. Additional modifications that may find in the second _{C H3:} In the case of lgG1 antibody, D16E, L18M, N44S, K52N , by V57M and V82I (IMGT; in the EU, D356E, L358M, N384S, K392N , V397M And V422I); for the IgG2 antibody, N44S, K52N and V82I (IMGT; N384S, K392N and V422I in the EU); and for the IgG4 antibody, Q15R, N44S, K52N, V57M, R69K, E79Q and V82I (by IMGT; in the EU, Q355R, N384S, K392N, V397M, R409K, E419Q and V422I). Variations of the above bispecific antibody format are contemplated to be within the scope of the present invention.

  In another specific embodiment, the antibody is salilumab (SAR153191). The heavy chain variable region of salilumab comprises the sequence of SEQ ID NO: 2.

  The light chain variable region of salilumab comprises the sequence of SEQ ID NO: 3.

  An antibody that "neutralizes" or "blocks" as used herein is intended to refer to an antibody whose binding to hlL-6R inhibits hlL-6 biological activity. Inhibition of hlL-6 biological activity measures one or more indicators of hlL-6 biological activity known in the art, such as hlL-6 induced cell activation and hlL-6 binding to hlL-6R. (See example below).

All human anti-IL-6R antibodies disclosed herein have one or more heavy and light chain variable domain framework and / or CDR regions as compared to the corresponding germline sequences. Amino acid substitutions, insertions and / or deletions. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with germline sequences, for example, available from public antibody sequence databases. The present invention includes antibodies and antigen-binding fragments thereof obtained from any of the amino acid sequences disclosed herein, including one or more of one or more framework and / or CDR regions. The amino acid is backmutated to the corresponding germline residue or a conservative amino acid substitution (natural or unnatural) of the corresponding germline residue (such sequence changes are referred to herein as "reproductive" Cell line reversion ”). One skilled in the art will recognize a variety of antibodies and antigens, including one or more individual germline backmutations or combinations thereof, including the sequences of the variable regions of the heavy and light chains disclosed herein. Binding fragments can be easily generated. In certain embodiments, all the framework residues and / or CDR residues within V _H domains and / or V _L domains are backmutated to germline sequences. In other embodiments, only certain residues are mutated, for example, only in the first 8 amino acids of FR1 or in the last 8 amino acids of FR4, or in CDR1, CDR2 or CDR3. Only the mutated residues found therein are backmutated to germline sequences. Further, the antibodies of the invention may comprise any combination of two or more germline backmutations within the framework and / or CDR regions, ie, certain individual residues are not reproductive. Certain other residues that differ from the germline sequence are retained while backmutated to the cell line sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline reversions can be used to improve improved binding specificity, increased binding affinity, improved or enhanced antagonist biological properties Alternatively, one or more desirable properties, such as agonist biological properties (as the case may be), reduced immunogenicity, etc., can be easily tested. Antibodies and antigen-binding fragments obtained by such general methods are included in the present invention.

  The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule known as a paratope. A single antigen can have more than one epitope. An epitope may be conformational or linear. Conformational epitopes are created by spatially juxtaposed amino acids from various segments of a linear polypeptide chain. Linear epitopes are those created by adjacent amino acid residues in a polypeptide chain. In certain cases, the epitope may include a sugar moiety, a phosphoryl group, or a sulfonyl group on the antigen.

  The anti-hlL-6R can be salilumab (SAR153191). In one embodiment, salilumab is defined as an antibody comprising the heavy chain variable region of SEQ ID NO: 2 and the light chain variable region of SEQ ID NO: 3.

DMARD
Disease modifying antirheumatic drugs (DMARDs) include methotrexate, sulfasalazine, hydroxychloroquine and leflunomide. According to the compositions and methods of the present disclosure, DMARD can be administered as follows. Methotrexate can be administered orally or intramuscularly from 10 mg to 25 mg per week. In another embodiment, a patient from the Asia-Pacific region or a patient descended from a human from the Asia-Pacific region is administered methotrexate orally or intramuscularly from 6 mg to 25 mg per week. The Asia-Pacific region includes Taiwan, Korea, Malaysia, Philippines, Thailand and India. In certain embodiments, methotrexate is administered from 6 mg to 12 mg, 10 mg to 15 mg, 15 mg to 20 mg, and 20 mg to 25 mg per week. In other embodiments, methotrexate is administered at 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or weekly. Administer 25 mg. Leflunomide can be administered orally at 10 mg to 20 mg per day. In certain embodiments, leflunomide can be administered from 10 mg to 12 mg, 12 mg to 15 mg, 15 mg to 17 mg, and 18 mg to 20 mg per day. In other embodiments, leflunomide is administered at 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg per day. Sulfasalazine can be administered orally at 1000-3000 mg per day. In certain embodiments, sulfasalazine can be administered from 1000 mg to 1400 mg, 1400 mg to 1800 mg, 1800 mg to 2200 mg, 2200 mg to 2600 mg, and 2600 mg to 3000 mg per day. In other embodiments, sulfasalazine is administered at 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, per day. Administer 2900 or 3000 mg. Hydroxychloroquine can be administered orally at 200 mg to 400 mg per day. In certain embodiments, hydroxychloroquine can be administered from 200 mg to 240 mg, 240 mg to 280 mg, 280 mg to 320 mg, 320 mg to 360 mg, and 360 mg to 400 mg per day. In other embodiments, the hydroxychloroquine is added at 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380 per day. 390 or 400 mg.

Therapeutic Administration and Formulation The methods described herein comprise administering to a subject a therapeutically effective amount of an anti-hlL-6R antibody, and optionally DMARD. As used herein, the phrase "therapeutically effective amount" refers to a therapeutic dose that results in a detectable improvement in one or more symptoms associated with rheumatoid arthritis, or a condition or symptom of rheumatoid arthritis. A dose of a treatment that produces a biological effect (eg, a reduction in the amount of a particular biomarker) that is correlated with the underlying pathological mechanism. For example, a dose of an anti-hlL-6R antibody that ameliorates any of the following symptoms or conditions is said to be a “therapeutically effective amount”: chronic disease anemia, fever, depression, malaise, rheumatoid nodules, vascular Inflammation, neuropathy, scleritis, pericarditis, Felty syndrome and / or joint destruction.

  Detectable improvements can also be detected using the American College of Rheumatology (ACR) Rheumatoid Arthritis classification criteria. For example, a 20% improvement from baseline (ACR20), 50% improvement (ACR50) or 70% improvement (ACR70) can be used to indicate a detectable improvement.

  A disease activity score (DAS28) can be used to indicate a detectable improvement. DAS 28 is a comprehensive score of inflammatory markers that can be assessed by measuring tender joint count based on 28 joints, joint swelling count based on 28 joints, overall health assessment and C-reactive protein (CRP) levels. is there. Disease response can be expressed using the European Society of Rheumatology (EULAR) response criteria. A good response by this criterion is an improvement in the DAS28 score of greater than 1.2 with a current score of 3.2 or higher. A moderate response is an improvement in the DAS28 score of greater than 0.6 and less than 1.2, and a current score of greater than 3.2. No response is an improvement in the DAS28 score of less than 0.6 and the current score is greater than 5.1. A DAS28 remission has a DAS28 score of less than 2.6.

  The Van der Heide Modified Total Sharp Score (mTSS) can be used to indicate the degree of joint damage (also referred to as structural damage). Typically, the progress of structural damage in a subject is measured by the change of the Van der Heide modified total sharp score (mTSS) from the baseline (BL). Baseline (BL) is defined as the score obtained by a subject before administration of salilumab according to the present invention. A change from baseline is defined as the difference that exists between the score obtained by the subject at baseline and the score obtained by the subject after administration of salilumab according to the present invention, and 24 weeks after treatment with salilumab Or typically after 52 weeks. Comparison of mTSS at baseline and mTSS after treatment with salilumab, typically at week 24 or week 52, can measure the progress of structural damage in a subject.

  The mTSS methodology, which is standard in the field of rheumatoid arthritis, quantifies the degree of bone erosion for 44 joints and joint space narrowing for 42 joints, with higher scores meaning greater damage. The Van der Heide mTSS at a point in time is the sum of the scores from both the erosion score and the joint space narrowing score for a maximum score of 448.

The joint erosion score is the total erosion severity at 32 joints of the hand and 12 joints of the foot. Each joint is scored from 0 to 5 for the wrist joint and from 0 to 10 for the foot joint according to the surface area involved. Maximum erosion scores (5 for hands and 10 for feet) indicate massive bone loss from more than half of the joint bones. A score of 0 for either hand or foot indicates no erosion. The maximum erosion score is 280 (160 in hands and 120 in feet) for some time points.

  The joint space narrowing (JSN) score summarizes the severity of JSN in 30 joints of the hand and 12 joints of the foot. JSN ratings for each hand (15 joints per) and each foot (6 joints per), including subluxation, are scored from 0 to 4, with 0 indicating no JSN / normal JSN is indicated, 4 indicates complete loss of joint space, osseous ankylosis or dislocation. Therefore, the maximum JSN score is 168 at some point.

  Improvement in physical function of a subject suffering from rheumatoid arthritis is typically achieved by looking at changes in the Health Assessment Questionnaire Disability Index (HAQ-DI) score from baseline (BL) following administration of salilumab according to the present invention. Will be evaluated. Baseline is defined as the score obtained by a subject before administration of salilumab according to the present invention. A change from baseline is defined as the difference that exists between the score obtained by the subject at baseline and the score obtained by the subject after administration of salilumab according to the present invention, and 16 weeks after treatment with salilumab , 24 or 52 weeks later.

  HAQ-DI is a standardized questionnaire developed at Stanford University for use in RA (available online). HAQ-DI has been widely used worldwide and has become a required endpoint for clinical trials in rheumatoid arthritis.

HAQ-DI focuses on whether respondents are "capable" of performing their activities, along with past weeks as a time frame, and includes eight categories of 20 items: clothing and grooming, standing up, eating, It covers walking, hygiene, movement, grip strength and other activities, for which there are at least two questions by category. The four answers to the HAQ-DI question are graded as follows: no difficulty = 0, somewhat difficult = 1, fairly difficult = 2 and impossible = 3. There are three steps to calculate a standard HAQ-DI score (with assistive devices / prostheses)
1. Summing eight category scores by using the highest subcategory score from each category.
-For example, the ARISING category has three sub-category items. If a patient answers 1, 2, and 0, respectively, this category score is 2.
2. When indicated, adjust for use of assistive devices / prostheses and / or for assistance from another person.
Adjusting the score for a category by raising 0 or 1 to 2;
-If the subject's highest score is 2 for that subcategory, the highest score remains 2, and if it is 3, the highest score remains 3.
Divide the totaled category score (must be 6 or more) by the number of categories answered to get an HAQ-DI score of 3.0-3 (3 = worst activity).

  When there are less than 6 scores for 8 categories, the HAQ-DI score cannot be calculated correctly. HAQ-DI scores range between 0 and 3. A high HAQ-DI score has been found to be a strong predictor of morbidity and mortality in RA.

According to the methods of the present invention, the therapeutically effective amount of the anti-hlL-6R antibody administered to the patient will depend on the age and size (eg, weight or body surface area) of the patient and the route of administration and other well known to those skilled in the art. It will depend on the factors. In certain embodiments, the dose of anti-hlL-6R antibody administered to a patient is from about 10 mg to about 500 mg. For example, the present invention provides that the present invention provides about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg of the anti-hlL-6R antibody per week. About 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg , About 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200, about 205 mg, about 210 mg, about 215 mg, about 220 mg, about 225 mg, about 230 mg, about 230 mg, 235mg, about 240mg, 245 mg, about 250 mg, about 255 mg, about 260 mg, about 265 mg, about 270 mg, about 275 mg, about 280 mg, about 285 mg, about 290 mg, about 295 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, Methods of administering about 450 mg, about 475 mg, about 500 mg or more to a patient.

  In one embodiment, the hlL-6R antibody is administered from 100 mg to 150 mg per week. In another embodiment, the hlL-6R antibody is administered from 100 mg to 200 mg every two weeks. In other embodiments, the hlL-6R antibody is administered at about 100 mg or about 150 mg per week. In another embodiment, the hlL-6R antibody is administered at about 100 mg, 150 mg, or 200 mg every two weeks.

  The amount of anti-hlL-6R antibody administered to a patient can be expressed in units of milligrams of antibody per kilogram of body weight of the patient (ie, mg / kg). For example, the method of the present invention comprises administering to a patient an anti-hlL-6R antibody at a daily dose of about 0.01 mg to about 100 mg, about 0.1 mg to about 50 mg, or about 1 mg to about 10 mg per kg of the patient's body weight. Including doing.

  The method of the invention comprises administering to the patient multiple doses of the anti-hlL-6R antibody over a specified time course. For example, the anti-hlL-6R antibody is administered about 1 to 5 times a day, about 1 to 5 times a week, about 1 to 5 times a month, or about 1 to 5 times a year. can do. In certain embodiments, the methods of the present invention comprise administering a first dose of an anti-hlL-6R antibody to a patient at a first time, followed by at least a second dose of an anti-hlL-6R at a second time. Administering the antibody to the patient. The first dose and the second dose may, in certain embodiments, include the same amount of an anti-hlL-6R antibody. For example, the first dose and the second dose may include about 10 mg to about 500 mg, about 20 mg to about 300 mg, about 100 mg to about 200 mg, or about 100 mg to about 150 mg of the antibody, respectively. The time between the first dose and the second dose may be from about several hours to several weeks. For example, the second time point (ie, the time when administering the second dose) can be from about 1 hour to about 7 weeks after the first time point (ie, the time when administering the first dose). It may be. According to certain exemplary embodiments of the invention, the second time point is about 1 hour, about 4 hours, about 6 hours, about 8 hours, about 10 hours after the first time point. After about 12 hours, about 24 hours, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 2 weeks, about 4 weeks After about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks or more. In certain embodiments, the second time point is about one week or about two weeks. The third dose and subsequent doses can be similarly administered throughout the course of treatment of the patient.

The present invention provides methods of using a therapeutic composition comprising an anti-IL-6R antibody or an antigen-binding fragment thereof, and, optionally, one or more additional therapeutic agents, eg, DMARD. The therapeutic compositions of the present invention will be administered with suitable carriers, excipients, and other agents that may be included in the formulation to provide improved mobility, delivery, resistance, and the like. A number of suitable formulations are available on prescriptions known to all pharmacists: Remington's Pha
rmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, vesicles containing lipids (cationic or anionic) (eg, LIPOFECTIN ™), DNA conjugates, anhydrous absorbent pastes, water Examples include oils and water-in-oil emulsions, emulsion carbowaxes (polyethylene glycols of various molecular weights), semi-solid gels and semi-solid mixtures containing carbowaxes. See also Powell et al., "Compendium of excipients for parental formations", PDA (1998) J Pharm Sci Technology 52: 238-311.

  The dose can vary depending on the age and weight of the subject to be administered, the target disease, the condition, the route of administration, and the like. Various delivery systems are known, eg, encapsulation in liposomes, microparticles, microcapsules, receptor-mediated endocytosis (see, eg, Wu et al. (1987) J. Biol. Chem. 262: 4429-4432). These can be used to administer the pharmaceutical compositions of the present invention. Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, nasal, epidural and oral routes. The composition can be administered by any convenient route, for example, by infusion or bolus injection, by absorption through epithelial or dermal mucosa (eg, oral mucosa, rectal and intestinal mucosa, etc.), and other bioactive It can be administered together with certain drugs. It can be administered systemically or locally. The hlL-6R antibody can be administered subcutaneously. DMARD can be administered orally or intramuscularly.

  Pharmaceutical compositions can also be delivered in vesicles, especially liposomes (see Langer (1990) Science 249: 1527-1533). In certain situations, the pharmaceutical composition can be delivered in a controlled release system, for example, using a pump or a polymeric material. In another embodiment, the sustained release system can be placed near the target of the composition, and thus need only a small portion of the systemic dose.

  Injectable preparations can include dosage forms for intravenous, subcutaneous, intradermal and intramuscular injection, topical injection, infusion, and the like. These injectable preparations can be prepared according to publicly known methods. For example, an injectable preparation can be prepared by dissolving, suspending, or emulsifying the above-mentioned antibody or a salt thereof in a sterile aqueous or oily medium commonly used for injection. Aqueous vehicles for injection include, for example, isotonic solutions containing saline, glucose and other adjuvants, which are admixed with alcohols (eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol) , A nonionic surfactant [eg, polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], and the like. As the oily medium, for example, sesame oil, soybean oil and the like can be used, and these can be used in combination with a solubilizing agent such as benzyl benzoate or benzyl alcohol. The injection solution thus prepared can be filled in an appropriate ampule.

  Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared in unit dose dosage forms suitable to make up the dose of active ingredient. Such unit dose dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, and the like. The amount of DMARD included will generally be from about 5 mg to 3000 mg per oral unit dose dosage form depending on the particular DMARD used. The amount of hlL-6R antibody included is generally about 100 mg to 200 mg per subcutaneous dosage form.

According to the methods disclosed herein, an anti-hlL-6R antibody (or pharmaceutical formulation comprising the antibody) can be administered to a patient using any acceptable device or mechanism. For example, administration can be performed using a syringe and needle, or using a reusable pen and / or an autoinjector delivery device. The methods of the invention involve the use of various reusable pens and / or auto-injector delivery devices to administer the anti-hlL-6R antibody (or a pharmaceutical formulation comprising the antibody). Examples of such devices include, but are not limited to, AUTOPEN ™ (Owen Mumford, Inc., Woodstock, UK), DISTRONIC ™ Pen (Distronic Medical Systems, Bergdorf, Switzerland) to name a few. , HUMALOG MIX 75/25 (TM) pens, HUMALOG (TM) pens, HUMALIN 70/30 (TM) pens (Eli Lilly and Co., Indianapolis, IN), NOVOPEN (TM) I, II and III (Novo Nordisk) , Copenhagen, Denmark), NOVOPEN JUNIOR ™ (Novo Nordisk, Copenhagen, Denmark), BD ™ pen (Becton Dickinson). , Franklin Lakes, NJ), OPTIPEN (TM), OPTIPEN PRO (TM), OPTIPEN STARLET (TM) and OPTICLIK (TM) (sanofi-aventis, Frankfurt, Germany). Examples of disposable pens and / or auto-injector delivery devices that have applications in subcutaneous delivery of the pharmaceutical compositions of the present invention include, but are not limited to, SOLOSTAR ™ sanofi-aventis, FLEXPEN. (Trademark) (Novo Nordisk) and KWIKPEN (trademark) (Eli Lilly), SURECLICK (trademark) Autoinjector (Amgen, Thousand Oaks, CA), PENLET (trademark) (Haselmeier, Stuttgart, Germany), EPIPEND P.) and HUMIRA ™ Pen (Abbott Labs, Abbott Park, IL).

  The use of a microinfuser to deliver an anti-hlL-6R antibody (or a pharmaceutical formulation comprising the antibody) to a patient is also contemplated herein. As used herein, the term "microinfuser" refers to a large volume (eg, up to about 2.5 mL or more) of a therapeutic formulation over an extended period of time (eg, about 10, 15, 20, 25, 30 minutes). Above) means a subcutaneous delivery device designed to be administered slowly. See, for example, US Pat. No. 6,629,949; US Pat. No. 6,659,982; and Meehan et al. See Controlled Release 46: 107-116 (1996). Microinfusors are particularly useful for delivering highly concentrated (eg, about 100, 125, 150, 175, 200 mg / mL or more) and / or large doses of therapeutic proteins contained in viscous solutions. .

Combination Therapy The invention includes a method of treating rheumatoid arthritis, comprising administering to a patient in need thereof an anti-hlL-6R antibody. In certain embodiments, the anti-hlL-6R antibody is administered as "monotherapy" or as a monotherapeutic. In an alternative embodiment, the anti-hlL-6R antibody is administered in combination with at least one additional therapeutic agent. Examples of additional therapeutic agents that can be administered in combination with the anti-hlL-6R antibody in practicing the methods of the invention include, but are not limited to, treating, preventing, or ameliorating DMARD and rheumatoid arthritis in a human subject. Any other compound known to be included. Specific, non-limiting examples of additional therapeutic agents that can be administered in combination with the anti-hlL-6R antibodies in connection with the methods of the present invention include, but are not limited to, methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide. . In the method of the present invention, the additional therapeutic agent can be administered simultaneously or sequentially with the anti-hlL-6R antibody. For example, a pharmaceutical formulation can be made that contains both an anti-hlL-6R antibody and at least one additional therapeutic agent for combination administration. The amount of additional therapeutic agent to be administered in combination with the anti-hlL-6R antibody in practicing the methods of the present invention is readily determined using routine methods known in the art and readily available. Can be.

  The present disclosure provides a pharmaceutical composition comprising any of the following:

  A composition comprising 100 mg to 150 mg of salilumab (SAR153191) and 10 to 25 mg of methotrexate.

  A composition comprising 100 mg to 200 mg of salilumab (SAR153191) and 10 to 25 mg of methotrexate.

  A composition comprising 100 mg to 150 mg of salilumab (SAR153191) and 6 to 25 mg of methotrexate.

  A composition comprising 100 mg to 200 mg of salilumab (SAR153191) and 6 to 25 mg of methotrexate.

  A composition comprising 100 mg to 150 mg of salilumab (SAR153191) and 10 to 20 mg of leflunomide.

  A composition comprising 100 mg to 200 mg of salilumab (SAR153191) and 10 to 20 mg of leflunomide.

  A composition comprising 100 mg to 150 mg of salilumab (SAR153191) and 1000 to 3000 mg of sulfasalazine.

  A composition comprising 100 mg to 200 mg of salilumab (SAR153191) and 1000 to 3000 mg of sulfasalazine.

  A composition comprising 100 mg to 150 mg of salilumab (SAR153191) and 200 to 400 mg of hydroxychloroquine.

  A composition comprising 100 mg to 200 mg of salilumab (SAR153191) and 200 to 400 mg of hydroxychloroquine.

  The present disclosure provides a method for ameliorating a condition associated with rheumatoid arthritis, comprising any of the following:

  A method comprising administering to a subject in need thereof salilumab (SAR153191) 100 mg to 150 mg and methotrexate 10 to 25 mg per week.

  A method comprising administering to a subject in need thereof 100 mg to 200 mg of salilumab (SAR153191) every two weeks and 10 to 25 mg of methotrexate per week.

  A method comprising administering to a subject in need thereof salilumab (SAR153191) 100 mg to 150 mg and methotrexate 6 to 25 mg per week.

A method comprising administering to a subject in need thereof salilumab (SAR153191) 100 mg to 200 mg every two weeks and methotrexate 6 to 25 mg per week.

  A method comprising administering to a subject in need thereof salilumab (SAR153191) 100 mg to 150 mg per week and leflunomidet 10 to 20 mg per day.

  A method comprising administering to a subject in need thereof 100 mg to 200 mg of salilumab (SAR153191) every two weeks and 10 to 20 mg of leflunomide per day.

  A method comprising administering to a subject in need thereof salilumab (SAR153191) from 100 mg to 150 mg per week, and 1000 to 3000 mg of sulfasalazine per day.

  A method comprising administering to a subject in need thereof 100 mg to 200 mg of salilumab (SAR153191) every two weeks and 1000 to 3000 mg of sulfasalazine per day.

  A method comprising administering to a subject in need thereof salilumab (SAR153191) 100 mg to 150 mg per week and 200 to 400 mg hydroxychloroquine per day.

  A method comprising administering to a subject in need thereof salilumab (SAR153191) 100 mg to 200 mg every two weeks and hydroxychloroquine 200 to 400 mg per day.

Biomarkers The present disclosure requires a therapeutically effective amount of a human antibody or antibody-binding fragment thereof that specifically binds hlL-6R, and a therapeutically effective amount of one or more DMARDs. A method of treating rheumatoid arthritis by administering to a patient, wherein the level of one or more RA-associated biomarkers in the patient is altered (optionally, eg, increased, Etc.). In a related aspect, the invention relates to administering to a patient a therapeutically effective amount of a human antibody or antigen-binding fragment thereof that specifically binds hlL-6R and a therapeutically effective amount of one or more DMARDs. And reducing the biomarkers associated with RA in the patient.

  Examples of biomarkers associated with RA include, but are not limited to, for example, sensitive C-reactive protein (hsCRP), serum amyloid A (SAA), erythrocyte sedimentation rate (ESR), serum hepcidin, interleukin-6 (IL -6) and hemoglobin (Hb). As will be appreciated by those skilled in the art, the increase or decrease in the biomarkers associated with RA will be determined by the biomarker levels measured in the patient prior to administration (ie, "baseline measurements") and after administration of the anti-IL-6R antibody. At a particular time, can be determined by comparing the biomarker levels measured in the patient. The specific time point at which the biomarker can be measured is, for example, about 4 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days after administration of the anti-hlL-6R antibody. Day 5, day 6, day 6, day 7, day 8, day 9, day 10, day 15, day 20, day 35, day 40, or more.

According to certain embodiments of the invention, the patient exhibits a reduced level of one or more of hsCRP, SAA, ESR and / or hepcidin after administering the anti-hlL-6R antibody to the patient. Can be. For example, at about week 12 after administration of an anti-hlL-6R antibody and one or more DMARDs once a week, a patient can show one or more of the following: (i) hsCRP Is reduced by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more; (ii) SAA is reduced by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more reduced; (iii) ESR is about 15%, 20%, 25% , 30%, 35%, 40%, 45%, 50%, 55% or more; and / or (iv) about 30%, 35%, 40%, 45%, 50%, 55%, 60% of hepcidin. %, 65%, 70%, 75% or more.

  According to certain other embodiments of the present invention, the patient is administered one or more of Hb or IL-6 after administering the anti-hlL-6R antibody and one or more DMARDs to the patient. Can indicate an increase in level. For example, at about week 12 after administration of an anti-hlL-6R antibody and one or more DMARDs once a week, the patient can show one or more of the following: (v) Hb About 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5. 0%, 5.5%, 6.0% or more increase; and / or (vi) IL-6 is increased by about 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450% , 500%, 550%, 600%, 650%, 700%, 750%, 800% or more.

  The invention includes a method of determining whether a subject is a suitable patient for whom administration of an anti-hlL-6R antibody is beneficial. For example, if an individual exhibits levels of a biomarker associated with RA that is indicative of a disease state prior to receiving an anti-hlL-6R antibody and / or one or more DMARDs, the individual may have anti-hlL-R The patient is identified as a suitable patient for whom administration of the 6R antibody would be beneficial. According to certain exemplary embodiments, an individual can be identified as a good candidate for anti-hlL-6R / DMARD therapy if the individual exhibits one or more of the following: : (I) The level of hsCRP is greater than about 4 mg / L (eg, about 4.5 mg / L, about 5.0 mg / L, about 5.5 mg / L, about 6.0 mg / L, about 7.0 mg). / L, about 10.0 mg / L, about 15.0 mg / L, about 20.0 mg / L or more); (ii) SAA levels greater than about 3800 ng / mL (eg, about 4000 ng / mL, about 4500 ng / L) mL, about 5000 ng / mL, about 5500 ng / mL, about 6000 ng / mL, about 10,000 ng / mL, about 20,000 ng / mL, about 25,000 ng / mL, about 30,000 ng / mL, about 3 (3,000 ng / mL, about 40,000 ng / mL, about 45,000 ng / mL or more); (iii) an ESR of more than about 15 mm / hr (eg, about 16 mm / hr, about 17 mm / hr, about 18 mm / hr) About 19 mm / hr, about 20 mm / hr, about 21 mm / hr, about 22 mm / hr, about 25 mm / hr, about 30 mm / hr, about 35 mm / hr, about 40 mm / hr, about 45 mm / hr, about 50 mm / hr And / or (iv) the level of hepcidin is greater than about 60 ng / mL (eg, about 62 ng / mL, about 64 ng / mL, about 68 ng / mL, about 70 ng / mL, about 72 ng / mL, about 74 ng). / ML, about 76 ng / mL, about 78 ng / mL, about 80 ng / mL, about 82 ng / mL, about 84 ng / mL, about 85 ng / mL. L, about 90 ng / mL, about 95 ng / mL, about 100 ng / mL, greater than about 105ng / mL). Additional criteria, such as other clinical indicators of RA, may be used in combination with any of the biomarkers associated with RA described above to identify an individual as a suitable candidate for anti-hlL-6R therapy. .

Patient Populations In certain embodiments, the methods and compositions described herein are administered to a specific patient population. Such a population includes patients who have previously been treated for rheumatoid arthritis with a treatment regimen other than the combination of an anti-hlL-6R antibody and one or more DMARDs. In another embodiment, salilumab is administered to a patient who has previously received ineffective treatment with DMARD and an anti-hlL-6R antibody other than salilumab. These treatment regimens include anti-TNF-α therapy, eg, a biological anti-TNF-α treatment regimen. Biological anti-TNF-α antagonists include etanercept, infliximab, adalimumab, golimumab and sertolizumab pegol. These treatment regimens also include DMARD therapy in the absence of anti-hlL-6R antibodies.

  DMARDs used in this therapy include methotrexate, sulfasalazine, hydroxychloroquine and leflunomide. DMARD may be administered alone, or may be administered in combination with another therapy that is not an anti-hlL-6R antibody, for example, salilumab. In a specific embodiment, the previous treatment regimen was methotrexate. In another embodiment, treatment with methotrexate is continued in a patient treated with an anti-hlL-6R antibody. In certain embodiments, the patient has previously received both anti-TNF-α therapy and DMARD therapy. Therapies may be given sequentially or simultaneously in any order. In certain embodiments, the patient has received these therapies within two years prior to receiving the combination of the anti-hlL-6R antibody and one or more DMARDs. In other embodiments, these treatments are received within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years prior to receiving a combination of an anti-hlL-6R antibody and one or more DMARDs. Is receiving.

  In certain embodiments, the methods and compositions described herein are administered to a particular population of patients who have received one or more of the treatment regimens described above and for whom these treatments have not been effective. As used herein, when treatment (eg, a dose of anti-TNF-α and / or DMARD) does not produce a detectable improvement in one or more symptoms associated with rheumatoid arthritis, or A treatment was not effective when the treatment did not produce a biological effect (eg, a reduction in the level of a particular biomarker) that correlates with the underlying pathological mechanism that causes the condition or symptom of rheumatoid arthritis. For example, treatments that do not improve any of the following symptoms or conditions are not considered effective: chronic disease anemia, fever, depression, malaise, rheumatoid nodules, vasculitis, neuropathy, scleritis, heart Meningitis, Felty syndrome and / or joint destruction.

  Detectable improvements can also be detected using the American College of Rheumatology (ACR) Rheumatoid Arthritis classification criteria. For example, a 20% improvement from baseline (ACR20), 50% improvement (ACR50) or 70% improvement (ACR70) can be used to indicate a detectable improvement. Conversely, ACR classification criteria can be used to select patients who have previously received ineffective treatment prior to treatment with anti-hlL-6R therapy. For example, if a patient fails to show at least a 10% detectable improvement (eg, a 10%, 20%, 50% or 70% improvement) according to ACR criteria, the patient is receiving an ineffective treatment There is a risk.

In other embodiments, the Disease Activity Score (DAS28) can be used to indicate a detectable improvement or, conversely, a treatment that is not effective. DAS 28 is a comprehensive score of inflammatory markers that can be assessed by measuring tender joint count based on 28 joints, joint swelling count based on 28 joints, overall health assessment and C-reactive protein (CRP) levels. is there. Disease response can be expressed using the European Society of Rheumatology (EULAR) response criteria. A good response by this criterion is an improvement in the DAS28 score of greater than 1.2 with a current score of 3.2 or higher. A moderate response is an improvement in the DAS28 score of greater than 0.6 and less than 1.2, and a current score of greater than 3.2. No response is an improvement in the DAS28 score of less than 0.6 and the current score is greater than 5.1. A DAS28 remission has a DAS28 score of less than 2.6. Measuring the improvement in any component of the DAS28 score can also indicate a detectable improvement.

  In another exemplary embodiment, the treatment was not effective when the patient still exhibited "active disease" after treatment. For example, a patient may have at least 8 tender joints out of 68, have joint swelling in 6 out of 66, and / or have high sensitivity C-reactive protein (hs-CRP)> 10 mg / L (> 1.0 mg / When indicating dL), the patient presents "active disease". In a specific embodiment, salilumab is administered to patients who have previously received ineffective treatment with methotrexate (MTX). In such an example, the patient would receive continuous treatment with MTX 10 mg to 25 mg / week (or, if the dose range is different, depending on local requirements) for at least 12 weeks and a minimum of 8 weeks MTX But still exhibit moderate to severe active RA as defined below: (i) at least 8 tender joints out of 68 and 6 out of 66 joint swelling, and ( ii) High sensitivity C-reactive protein (hs-CRP)> 10 mg / L (> 1.0 mg / dL).

  In one embodiment, the patient population comprises subjects who have not received a biological agent within the last three months. In certain embodiments, the biological agent is a protein. According to another embodiment, the protein is an antibody or a fragment thereof. According to another embodiment, the protein is a cytokine or a fragment or derivative thereof. In another embodiment, the protein is recombinant. In another embodiment, the biological agent is a vaccine, blood, blood component, allergenic, somatic cell, gene therapy or biological tissue. Biopharmaceuticals include blood factors, thrombolytics, hormones, hematopoietic growth factors, interferons, interleukin-based products, vaccines and monoclonal antibodies. In certain embodiments, the biological agent is abatacept. In another embodiment, the biological agent is adalimab. In other embodiments, the biological agent includes: infliximab (Remicade®), adalimab (Humira®), golimumab (Simponi®), etanercept (Enbrel®), sertolizumab ( TNFα blockers such as Cimzia®); IL-1 blockers such as anakinra (Kineret®); anti-CD20 antibodies such as rituximab (Rituxan®); abatacept (Orencia®) ), And anti-IL6 antibodies such as cirumab, clazazizumab, or olokizumab, are non-exhaustively mentioned.

  According to another embodiment, the biopharmaceutical is a biological medical product. Biological medical products are medical products manufactured or extracted from biological sources. In certain embodiments, biopharmaceuticals are defined as excluding biological products consumed by animals for nutrition. In such embodiments, the biopharmaceutical must have a specific therapeutic outcome in the patient population beyond nutrition.

  In another embodiment, the patient population comprises subjects who have been treated with methotrexate for at least 6 weeks. In other embodiments, the subject receives methotrexate for at least 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 or 26 weeks. In a more specific embodiment, the subject has received methotrexate but has not received any other DMARDs for at least 6 weeks. In other embodiments, the subject is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, No DMARDs other than methotrexate for 21, 22, 23, 24, 25 or 26 weeks. DMARDs other than methotrexate include leflunomide, sulfasalazine and hydroxychloroquine.

In another embodiment, the patient population comprises subjects who do not have an autoimmune disease other than rheumatoid arthritis. In certain embodiments, the autoimmune disease other than arthritis is acute sporadic encephalomyelitis (ADEM), Addison's disease, agammaglobulinemia, alopecia areata, amyotrophic lateral sclerosis (also Lou. Gehrig's disease; motor neuron disease), ankylosing spondylitis, antiphospholipid antibody syndrome, antisynthetase syndrome, rheumatoid arthritis, atopic allergy, atopic dermatitis, autoimmune aplastic anemia, autoimmune cardiomyopathy, Autoimmune bowel disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease, autoimmune lymphoproliferative syndrome, autoimmune peripheral neuropathy, autoimmune pancreatitis, autoimmune polyendocrine syndrome, Autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Baro disease / Baro concentric sclerosis, Bechet Syndrome, Burger disease, Vickerstaff encephalitis, Blau syndrome, pemphigus bullosa, cancer, Castleman disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Chronic obstructive pulmonary disease, Churg-Strauss syndrome, pemphigus foliaceus, Kogan syndrome, cold agglutinin disease, complementary component 2 deficiency, contact dermatitis, cranial arteritis, Crohn's disease, Cushing's syndrome, cutaneous leukocyte crushing Vasculitis, Dego's disease, Darkham's disease, Herpetic dermatitis, Dermatomyositis, Diabetes type 1, Diffuse cutaneous systemic sclerosis, Dresler syndrome, Drug-induced lupus, Disk lupus erythematosus, Eczema, Endometriosis, Tendon Attachitis-related arthritis, eosinophilic fasciitis, eosinophilic, eosinophilic lung disease, acquired epidermolysis bullosa, erythema nodosum, fetal erythroblastosis, essential mixed-type chestnut Globulinemia, Evan syndrome, progressive ossifying fibrosis, fibrosing alveolitis; gastritis, gastrointestinal pemphigus, glomerulonephritis, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto Encephalitis, Hashimoto's thyroiditis, Henoch-Schoenlein purpura, gestational herpes, sweat gland abscess, Huge-Stobin syndrome, hypogammaglobulinemia, idiopathic inflammatory demyelinating disease, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia Purpura, IgA nephropathy, inclusion body myositis, chronic inflammatory demyelinating polyneuritis, interstitial cystitis, juvenile idiopathic arthritis, Kawasaki disease, Lambert-Eaton myasthenic syndrome, leukocytic vasculitis, Lichen planus, lichen sclerosus, linear IgA disease (LAD), lupoid hepatitis, lupus erythematosus, Magiede's syndrome, Meniere's disease, microscopic polyangiitis, mirror Schör syndrome, mixed connective tissue disease, scleroderma scleroderma, Mucha-Haberman disease, multiple sclerosis, myasthenia gravis, microscopic colitis, myositis, narcolepsy, neuromyelitis optica, neuromyotonia, eyeball Scarring pemphigoid, opsoclonus myoclonus syndrome, Ordo thyroiditis, relapsing rheumatism, PANDAS (pediatric autoimmune streptococcal infection-related neuropsychiatric disorder), paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parrionberg Syndrome, Parsonage-Turner Syndrome, Pars planitis, Pemphigus vulgaris, pernicious anemia, perivenous encephalomyelitis, POEMS syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis , Primary sclerosing cholangitis, progressive inflammatory neuropathy, psoriasis, psoriatic arthritis, gangrenous pyoderma, erythroblastosis, Rasmussen encephalitis, Raynaud's phenomenon Relapsing polychondritis, Reiter's syndrome, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, sarcoidosis, schizophrenia, Schmidt syndrome, Schnitzler syndrome, scleritis, scleroderma, serum disease, Sjogren's syndrome, spinal joint Syndrome, Still disease, Stiff person syndrome, Subacute bacterial endocarditis, Suzaku syndrome, Sweet syndrome, Sydenham chorea, Sympathetic ophthalmitis, Systemic lupus erythematosus, Takayasu arteritis, Temporal arteritis, Thrombocytopenia, Selected from the group consisting of Trosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, undifferentiated spondyloarthritis, hives-like vasculitis, vasculitis, vitiligo and Wegener's granulomatosis One or more lesions.

  In another embodiment, the patient population comprises subjects who have not received parenteral or intra-articular administration of glucocorticoids for 4 weeks. In other embodiments, the subject is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, No parenteral or intra-articular administration of glucocorticoid for 21, 22, 23, 24, 25 or 26 weeks. In certain embodiments, the glucocorticoid comprises one or more selected from the group consisting of cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, fludrocortisone, deoxycorticosterone acetate and aldosterone. Is included.

The combination of salilumab and methotrexate is effective in the treatment of rheumatoid arthritis in patients who do not respond to methotrexate treatment In patients with rheumatoid arthritis with an inadequate response to methotrexate (MTX), a global, double-blind, placebo control, A randomized trial was performed. Patients enrolled in this study had the following criteria: Patients needed to have an active disease defined as follows: at least 6 joint swelling out of 66 and 8 tender joints out of 68, and hs-CRP> 6 mg / L. Patients also needed to be on continuous treatment with methotrexate (MTX)-10 mg to 25 mg / week for 12 weeks (or 6 mg to 25 mg / week for patients in the Asia-Pacific region).

  This study included two parts. The first part of the study (Part A) was a 12-week, 6-group dose range part intended to select the two best dose regimens based on efficacy (reduction of signs and symptoms) and safety. Was. The second part of the study (Part B) involved the reduction of signs and symptoms, the inhibition of the progression of structural damage, the improvement of physical function and the induction of a major clinical response, the efficacy and safety of the two selected dose regimens It was a 52 week part to check the sex.

  The uniqueness of this study being an operationally seamless design is that part B does not require waiting for dose selection based on the results of part A, and immediately after the last patient is randomized in part A There was in the fact that we started testing. Thus, patients in Part B belong to two separate cohorts according to the time of enrollment.

  Patients in Cohort 1 were randomized prior to dose selection: that is, these patients were randomized into 6 groups (as one of Part A). After dose selection, patients who had been randomized to two selected dose regimens and a placebo regimen continued the 52 week trial. Patients who had been randomized to the other three groups discontinued the study but were offered to participate in an open-label extension study (see LTS 11210).

  Patients in Cohort 2 were randomized after dose selection: these patients were randomized into three groups, two selected dose groups and a placebo.

Part A
Patients were evaluated at the screening visit for confirmation of diagnosis, disease activity, eligibility for this trial, and validation of combination therapy. Workup and laboratory tests were performed, including hematology, chemical and lipid profiles, liver enzymes and acute phase reactants, HbA1c, hepatitis B and C, and serum pregnancy tests for fertile women . An ECG evaluation was also performed. To rule out tuberculosis, a PPD test and a QuantiFERON and chest x-ray (if negative x-rays made during the last three months were not available) were performed.

  After confirming eligibility, such an international multicenter, double-blind, parallel-group comparison with placebo control, 12 weeks with 6 groups of SAR153191 or placebo given subcutaneously once a week with MTX concomitant therapy In the study treatment, patients were randomized in a balanced manner.

  Each patient received methotrexate as was administered prior to the study. Doses were 10 mg to 25 mg / week, or 6 mg to 25 mg / week for patients in Asia-Pacific; Taiwan, Korea, Malaysia, Philippines, Thailand and India.

  During the first visit, patients will be reminded of the list of banned drug treatments and will use their folic acid by local recommendations to prevent MTX toxicity, until their trials are completed, It reminded me that MTX had to be taken continuously at a stable dose. Patients were trained to prepare and self-administer IMPs, reminding them to inject strictly 7 days apart. At the time of dosing outside of the facility visit, SAR153191 was injected by the patient himself, by a trained professional caregiver, or by a trained professional.

  The patient had another six visits at 2, 4, 6, 8, 10 and 12 weeks. Evaluate efficacy and clinical tests including hematology, chemistry, lipid profiles, liver enzymes and acute phase reactants throughout the study to calculate key efficacy scores and monitor safety aspects did. At random visits and visits at Weeks 2, 4, 8, and 12, the tender joint count and the patient data were used by evaluators independent of the investigator and by patient data to calculate ACR scores (primary endpoints). A precision joint test was performed on the number of joint swellings. To remain blind, investigators, sponsors and patients are unaware of CRP and serum IL6 levels during the study.

  Close monitoring of adverse events, including the possibility of partially assessed infection, was performed at each visit by monitoring body temperature. The presence of tuberculosis was determined by specific patient assessment (investigation for any signs or symptoms or contact with active TB). Neurological abnormalities (history and physical examination) or predisposition to autoimmunity (ANA, ds-DNA antibodies) were examined at baseline and at the end of treatment visit.

  Specific blood and urine samples were taken during the study to look for potential biomarkers that could be predictive of disease response or adverse events. These samples included a single sample for DNA (after the patient signed a particular informed consent form) and several samples obtained continuously throughout the study for RNA expression profiling and protein biomarker analysis. Samples were included. Samples were also taken at appropriate time points for pharmacokinetic parameters and antibodies to SAR153191.

  Precise clinical and laboratory evaluations were used to evaluate patients who discontinued early when treatment visits ended. These patients were non-responders for ACR scores.

  At the end of the treatment visit, all patients were scheduled to complete a post-treatment follow-up visit. Patients who completed the treatment period were proposed to enter an open-label, long-term safety extension study using SAR153191.

RESULTS Human patients treated with salilumab (REGN88 / SAR153191) in combination with the standard RA treatment methotrexate (MTX) had moderate to severe rheumatoid arthritis (RA) compared to patients treated with MTX alone. Significant and clinically significant improvements in signs and symptoms were achieved. 306 patients, dose range, multi-national, randomized, multi-group comparison, double-blind, placebo-controlled trial, which showed five different dose regimens of salilumab in combination with MTX, placebo + MTX And compared. The primary endpoint of the study was the percentage of patients achieving at least a 20% improvement in RA symptoms (ACR20) after 12 weeks.

A dose response was observed in patients receiving salilumab in combination with MTX. The ACR20 response at 12 weeks received 49.0% of patients receiving the lowest salilumab dose regimen and the highest dose regimen as compared to 46.2% of patients receiving placebo and MTX Found in 72.0% of patients (see table below, asterisk ( ^* ) indicates significance to placebo by Cochran-Mantel-Haenszel test (p <0.05); Fix).

  The most common adverse events (> 5%) reported more frequently in the active treatment group included infections (not severe), neutropenia, and abnormal liver function tests. The type and frequency of adverse events were consistent with those previously reported for IL-6 inhibition. The incidence of serious adverse events was comparable between salilumab 5 treatment and the placebo group.

  Salilumab also showed significant effects compared to placebo on secondary endpoints, including ACR50, ACR70 and DAS28 scores, additional items of clinical activity used in RA trials. More specifically:

-ACR50 response after 12 weeks was found in 22% of patients receiving the lowest salilumab dose regimen and 30% of patients receiving the highest dose regimen compared to 15% of patients receiving placebo and MTX. % (See table below, double asterisk ( ^** ) indicates statistical significance to placebo (p <0.01), post hoc adjustment for multiplicity).

-The ACR70 response was also significantly higher in the 200 mg q2w group versus placebo. At 12 weeks, ACR70 responses were seen in 16% of patients receiving the highest dose regimen compared to 2% in patients receiving placebo and MTX (see table below, double asterisk). ( ^** ) indicates statistical significance to placebo (p <0.01), post hoc adjustment for multiplicity).

  -A statistically significant improvement in the DAS28 score was seen after 12 weeks in all but the lowest dose regimen (see table below, which compared salilumab / MTX co-treatment with placebo) 12 shows the results of trials on improved DAS28 scores or secondary endpoints of DAS28 remission after 12 weeks in patients receiving one of the 5 treatment groups: LS (least squares), SE (standard). P). <P <0.01; p <0.001; p <0.01 is considered statistically significant to placebo after post-hoc multiple adjustment).

  At the four highest dose regimens, a reduced DAS score (relative to baseline) of at least 2.0 was observed at the four highest dose regimens after 12 weeks. Furthermore, DAS remissions (patients with a DAS score <2.6) were significantly higher in the 200 mg q2W and 150 mg qw treatment groups compared to placebo after 12 weeks.

  -Significant improvement in joint swelling number (SJC) and tender joint number (TJC) in ACR criteria. For example, after 12 weeks TJC decreased by 10 in all dose regimens, while SJC decreased by 8 at the four highest therapeutic doses. In contrast, the placebo group showed 7 and 9 reductions in TJC and SJC, respectively. The results are shown in the table below (SJC = number of joint swelling; TJC = number of tender joints; after 12 weeks in patients receiving one of the 5 treatment groups of salilumab / MTX co-therapy compared to placebo) Is:

  -Significant improvement in the Health Assessment Questionnaire Disability Index (HAQ-DI). For example, the HAQ-DI score was reduced by at least 0.3 compared to baseline for all treatment groups and by at least 0.5 in the 150 mg 2qw and 200 mg 2qw treatment groups. The results are shown in the table below (HAQ-ID after 12 weeks in patients receiving one of the 5 treatment groups of salilumab / MTX co-therapy compared to placebo):

  -Significant improvement in Visual Acuity Score (VAS). For example, physician VAS was reduced by at least 30 (compared to baseline) in the four highest dose regimens. In addition, patient VAS and pain VAS were reduced by at least 25 (compared to baseline) at the four highest dose regimens. The results are shown in the table below (compared to placebo, visual analog score (VAS) after 12 weeks in patients receiving one of the 5 treatment groups of salilumab / MTX co-therapy; VAS (mm) is the patient VAS, physician (As assessed by VAS and pain VAS):

  -Significant improvement in C-reactive protein (CRP) levels. For example, CRP levels were reduced by at least 1 mg / dL in all treatment groups. In addition, CRP levels were reduced by at least 2 mg / dL in all but the lowest dose regimen. The results are shown in the table below (compared to placebo, increase in C-reactive protein (CRP) after 12 weeks in patients receiving one of the 5 treatment groups of salilumab / MTX co-treatment):

  -Improved EULAR (European Rheumatology Association) index at 12 weeks. For example, a "good response" according to the EULAR index was achieved in at least 18% of patients for all treatment groups. In fact, a good response was observed in at least 30% of the patients for all but the lowest dose treatment group.

The results are shown in the table below (improvement in the EULAR (European Rheumatology Association) index after 12 weeks in patients receiving one of the 5 treatment groups of salilumab / MTX co-treatment compared to placebo). The previous biological use and tiered ^a Cochran-Mantel-Haenszel test by region are compared responder (a combination of good response and moderate responses) to non-responders. † p <0.01; †† p <0.001; p <0.01 is considered statistically significant relative to placebo after post hoc multiple adjustment):

  These results provide evidence that IL-6R blockade by salilumab is a promising new anti-inflammatory research therapy for reducing the symptoms of RA disease.

Part B
Patients were evaluated at the screening visit for confirmation of diagnosis, disease activity, eligibility for this trial, and validation of combination therapy. The investigator determined that the patient was either anti-cyclic citrullinated peptide antibody (CCP) -positive or rheumatoid factor (RF) -positive, or that the patient had radiographically confirmed bone erosion. Was. If necessary, patients with both negative CCP and RF and no X-ray erosion were subjected to a central screening X-ray, which was used as the study baseline X-ray assessment.

Cohort 1: Patients Randomized Prior to Dose Selection Immediately after randomizing the last patient in Part A, recruitment to a long-term safety extension study was initiated. After qualification, international, multicenter, double-blind, parallel-group comparison with placebo control, SAR153191 (5 active dose regimens) given subcutaneously once a week with MTX concomitant therapy or placebo In the study treatment with 6 groups, patients were randomized by previous biological use and in a balanced manner stratified by region.

  At the start of all patient visits for cohort 1 patients, the investigator, through the IVRS list, that the patients were still "eligible" for this study, ie, patients were randomized in the unselected arm I investigated that it should not be stopped. In fact, when the main dose regimen was selected from Part A, only patients who were randomized to the corresponding group or placebo were still eligible for this study and continued the study for a total of 52 weeks Will do. Other patients (randomized to a non-selected dose regimen) were no longer eligible for IVRS. The investigator suggested that such patients participate in an open-label extension study using SAR153191 with the highest dose regimen available at the time the patient was enrolled.

  Initial randomization remained blind to all patients.

Cohort 2: Patients randomized after dose selection-Principal part On day 1, after eligibility was confirmed, international, multicenter, double-blind, placebo-controlled, parallel group comparison, MTX co-therapy In a study with 3 groups of SAR153191 (two main dose regimens) given subcutaneously or placebo, patients were randomized by previous biological use and in a well-balanced manner stratified by region.

Both cohorts:
In both cohorts, patients were evaluated every 4 weeks until weeks 2, 4, and 28, and then every 8 weeks until week 52, for efficacy and safety assessment and clinical testing.

  The same procedure described in Part A was applied to Part B. X-ray evaluations of the joints of the hands and feet were also performed at the baseline, 24 weeks and 52 weeks. Unspecified radiographs, which are any patient information, were sent to a central reader to calculate a Sharp score (a specific scoring system for joint destruction). Health economic evaluations such as SF-36 were also added.

  From week 16 onwards, less than 20% improvement in either joint swelling (SJC) or tender joints (TJC) from baseline over two consecutive visits It is suggested that patients, or other apparently ineffective patients at the discretion of the investigator, be rescued in the highest available dose of the SAR153191 open-label trial at the time of transition to the salvage treatment arm Was done. These patients continued the study according to their planned visit schedule. Blood samples for clinical analysis were collected two weeks after switching for safety purposes. These patients were non-responders on the primary endpoint (ACR20). These patients remained in the study and continued all visits.

In selected countries, patients who do not meet the efficacy criteria for Part B treatment on Visit 7 / Week 16 or later are eligible to permanently discontinue treatment and participate in the open label rescue arm There was no. Instead, these patients underwent a follow-up visit and were evaluated for safety 6 weeks after the end of the treatment visit.

  For any patient who discontinued early or rescued early with open-label SAR153191, additional X at the time of discontinuation or rescue unless a study x-ray assessment was performed within the preceding three months. A line assessment was performed (a three month window should be considered between the two X-ray assessments to avoid excessive X-ray exposure).

  Patients completing Part B (including patients in the open-label rescue arm) were proposed to proceed to an open-label extension study at maximum dose regimen at enrollment. All patients were scheduled to complete a post-treatment follow-up visit. If the patient agreed to enter an open-label, long-term extension study of SAR153191 and was qualified, the post-treatment follow-up visit was not completed.

Combination of salilumab and DMARD is effective in treating rheumatoid arthritis in patients who are not effective with TNF-α antagonist treatment and methotrexate treatment Poor response to methotrexate (MTX) and at least one TNF-α antagonist A global, double-blind, placebo-controlled, randomized trial was performed in patients with rheumatoid arthritis. Patients participating in this study had the following criteria: In the investigator's opinion, the patient had an inadequate response to at least one TNF-α antagonist after treatment for at least three months in the last two years, or It was intolerant to the TNF-α antagonist and was discontinued as a result. TNF-α antagonists included etanercept, infliximab, adalimumab, golimumab and / or sertolizumab pegol. Patients needed to have an active disease defined as follows: at least 6 joint swelling out of 66, 8 tender joints out of 68, and hs-CRP ≧ 8 mg / L. Patients had been on continuous treatment with one DMARD or a combination of DMARDs for at least 12 weeks prior to baseline and continued at a stable dose for at least 6 weeks prior to screening. It was also necessary that treatment had been performed. These DMARDs include methotrexate (MTX) -10 mg to 25 mg / week (or 6 to 25 mg / week for patients in the Asia-Pacific region); leflunomide (LEF) -10 mg to 20 mg per day; sulfasalazine (SSZ) -1000 mg to 3000 mg per day; or hydroxychloroquine (HCQ)-200 mg to 400 mg per day.

  Subcutaneous administration is performed in the abdomen or thigh. Each dose is self-administered in a single injection (whenever possible). The SC injection site can alternate between the four quadrants of the abdomen (excluding the navel or waist) or the thighs (anterior and lateral).

  Patients and / or their non-expert caregivers are trained to prepare and administer IMP at the beginning of the double-blind treatment period. This training must be documented in the patient's test file. The study coordinator or delegate may administer the first injection, including the first dose, as part of the training procedure on day 1 (second visit). On the day of the patient's visit, IMP will be administered following clinical procedures and blood collection. If no dose is given at the study site, a diary is provided to record information related to such injections: such a diary is stored as source data in the patient's test file. If the patient is unable to administer or does not wish to administer the IMP, qualified field personnel and / or caregivers may administer the IMP for doses not intended to be taken at the study site. Should be taken to administer.

  If the study visit is not performed at the scheduled location, the dose will be administered by the scheduled patient and / or their caregiver.

Treatment lasts 24 weeks. From week 12, ineffective patients with less than 20% improvement from baseline in both SJC and TJC between two consecutive visits will receive the highest dose of salilumab in the study It is proposed to be rescued in an open label trial. These patients will continue the study according to the visit schedule.

In this study, salilumab is administered at the top of the DMARD regimen, which is considered a basic therapy. All patients were treated with one of the non-biological DMARDs or a combination of non-biological DMARDs as a basal therapy for at least 12 weeks before baseline and at a stable dose for at least 6 weeks before screening. Must continue to be treated:
Methotrexate (MTX)-10 mg to 25 mg / week (or 6 mg to 25 mg / week for patients in the Asia-Pacific region), with folate / folinic acid supplements Leflunomide (LEF)-10 mg to 20 mg per day
・ Sulfasalazine (SSZ)-1000 mg to 3000 mg per day
• Hydroxychloroquine (HCQ)-200 mg to 400 mg per day

  Each DMARD dose is recorded throughout the study on a case report form. At any time, the DMARD dose can be reduced for safety or tolerability reasons. Any dose changes and the start date of the new dose must be recorded on the e-CRF at every visit. The sponsor does not prescribe or deliver DMARD as an IMP.

  All patients receiving MTX will receive folate / folinic acid according to local recommendations in the country of study. The folic / folinic acid dose, route and dosing schedule will be recorded with the concomitant medication.

  Salilumab and the corresponding placebo are supplied in equally matched glass pre-filled syringes. Each pre-filled syringe contains 1.14 mL of salilumab (SAR153191) or the corresponding placebo solution.

  Make a list of treatment kit numbers. Create a randomized list with the interactive voice response system (IVRS). Load both the randomized list and the treatment kit list into the IVRS.

  The Investigator will obtain a list of treatment kit numbers via IVRS, available 24 hours a day, at the time the patient is randomized and at the time of the patient's scheduled visit.

  In accordance with the double-blind design, the investigator is blinded to the study treatment and uses randomization (treatment code) except under the conditions described in Chapter 8.7. I will not do it.

  Patients are randomized to one of the treatment groups using a central registry system using IVRS. Patients are considered randomized when given a treatment number by IVRS.

  At the first visit of the screening visit, the field coordinator connects to the IVRS and obtains a patient number for each patient to give informed consent. Each patient is assigned a patient number associated with the center and at each center in the order of entry.

Treatment assignments are assigned to patients according to a central randomized list, via IVRS, stratified by region and previous number of anti-TNFs (one-to-one). The second visit (
On day 1), after confirming that the patient is eligible for the treatment period, the field coordinator connects to the IVRS to receive the first treatment assignment (kit number). Patients are randomized to receive either one of two treatment groups of salilumab or a corresponding placebo of salilumab. The randomization ratio is 1: 1: 1 (salilumab 150 mg: salilumab 200 mg: corresponding placebo). On subsequent prescription visits during the treatment period, the field coordinator will call the IVRS to obtain a subsequent treatment kit assignment. After each assignment, a confirmation fax / email is sent to the site.

  A randomized patient, when documented from an IVRS log file, is defined as a patient who has been enrolled and has been assigned a randomization number from the IVRS. The IMP is also recorded and tracked in the center's IMP inventory form.

Positive results with salilumab in the first phase 3 rheumatoid arthritis registry trial Salilumab, administered subcutaneously every two weeks, met all three primary co-primary endpoints.

  Salilumab is the first fully human monoclonal antibody specific for the interleukin 6 receptor (IL-6R).

  According to the results of the SARIL-RA-MOBILITY Phase 3 clinical trial in adult patients with active rheumatoid arthritis (RA) and in responders who were poor responders to methotrexate (MTX) therapy, It has been shown that salilumab treatment in combination with improves the signs and symptoms of disease and physical function and inhibits the progression of joint damage.

  In a 52-week SARIL-RA-MOBILITY phase 3 trial, active, moderate to severe rheumatoid arthritis (RA), responders with inadequate response to MTX therapy, 200 patients were enrolled. Patients were randomized to one of three subcutaneous treatment groups, receiving 200 mg of salilumab (mg), 150 mg of salillumab or placebo every two weeks, all in combination with MTX.

  Both salilumab groups showed a clinically relevant and statistically significant improvement (p <0.0001) compared to the placebo group in all three coprimary endpoints.

(1) Improvement in signs and symptoms in RA at 24 weeks as measured by a 20 percent improvement in American College of Rheumatology score (ACR20).
• 66%, 58%, and 33% in the salilumab 200 mg, salilumab 150 mg, and placebo groups, respectively, all in combination with MTX.

(2) Improvement in physical function as measured by changes from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 16

(3) Inhibition of the progression of structural damage at 52 weeks as measured by changes in Van der Heide-Total Sharp Score Modification (mTSS).
-0.25, 0.90, and 2.78 in the salilumab 200 mg, salilumab 150 mg, and placebo groups, respectively, all in combination with MTX.
The group receiving the salilumab 200 mg dose + MTX has about a 90 percent reduction in mTSS-assessed radiographic progression at week 52 compared to placebo + MTX radiographic progression I was

  In the SARIL-RA-MOBILITY trial, the incidence of treatment-emergent adverse events leading to discontinuation in the salilumab-treated group was higher (13.9 percent at 200 mg, 12.5 percent at 150 mg and 150 mg) compared to placebo. 4.7% for placebo). In conclusion, IL-6 blockade is an important therapeutic approach to rheumatoid arthritis, as these Phase 3 results demonstrated efficacy at both doses of salilumab, each administered every two weeks. .

Method:
In the third phase of the MOBILITY trial, MTX-IR adults with moderate to severe RA were randomized to placebo and one of two subcutaneous doses of salilumab (150 mg q2w or 200 mg q2w) + basal MTX. (1: 1: 1). Inclusion and exclusion criteria are shown in Table 2. Patient treatment within the study is given in Table 3. Baseline characteristics of the subjects are given in Tables 4 and 5.

  The purpose of this study was to evaluate the clinical efficacy, radiographic and functional improvement and safety profile of the salilumab dosing regimen. Variables of interest on x-ray examinations were: 1) change from baseline in Van der Heide-Total Sharp Score Modification (mTSS) at 52 weeks (co-primary endpoint); 2) post-baseline Sensitivity analysis to assess effects on mTSS in patients without X-ray data; 3) Radiographic progression of erosions and joint space narrowing (JSN) score (subset of mTSS); 4) mTSS, erosions, or Included in the JSN score was the percentage of patients with no radiographic progression from baseline until week 52. All radiographic assessments were performed using a standardized procedure with electronic images independently analyzed by at least two trained readers, and the average of the two scores was used for analysis.

result:
At weeks 24 and 52, a statistically significant increase in mTSS from baseline compared to placebo was observed in patients treated with salilumab and inhibition of structural damage as shown in Table 6. It has been shown.

The sensitivity analysis planned for mTSS was consistent with the primary results. At week 24 and week 52, a smaller increase from baseline in erosion and JSN score compared to placebo was also observed with salilumab. The proportion of patients with no progress in mTSS, erosion and JSN scores was numerically higher in the salilumab group compared to placebo. The observed adverse events (AEs) were similar to those reported for other IL-6 inhibitors.

Subjects treated with salilumab and methotrexate specifically showed an improvement in RA signs and symptoms at weeks 24 and 52 as measured by a 20 percent improvement in the American College of Rheumatology Score (ACR20), but the table below shows 6b (asterisk ( ^* ) = P <0.0001 vs. placebo + MTX). The results were 66 percent, 58 percent, and 33 percent at week 24 and 59 percent, 54 percent, and 32 percent, respectively, at week 24 in the salilumab 200 mg, salilumab 150 mg, and placebo groups, and All were in combination with MTX.

  As shown in Table 7, subjects treated with salilumab and methotrexate achieved more ACR70 responses than subjects who received placebo for 24 consecutive weeks.

As shown in Table 8 below, subjects treated with salilumab and methotrexate also showed improvements in physical function as measured by changes from baseline in the Health Assessment Questionnaire Disability Index (HAQ-DI) at 16 weeks. Indicated.

Subjects treated with salilumab and methotrexate also showed an inhibition of the progression of structural damage at 52 weeks, as measured by changes in the Van der Heide-Total Sharp Score Modification (mTSS). All in combination with MTX, 0.25, 0.90, and 2.78 in the salilumab 200 mg, salilumab 150 mg, and placebo groups, respectively. The group receiving the salilumab 200 mg dose + MTX had a placebo + MT at 52 weeks.
It had about a 90 percent reduction in x-ray progress as assessed by mTSS, as compared to x-ray progress with X. Subjects treated with salilumab and methotrexate also showed a reduction in mean DAS28-CRP (Table 8a) and mean CDAI (Table 8b) compared to placebo.

  In the SARIL-RA-MOBILITY trial, the incidence of treatment-emergent adverse events leading to discontinuation was higher in the salilumab-treated group compared to placebo (13.9% at 200 mg, 12.5% at 150 mg and 4.7% for placebo). In conclusion, IL-6 blockade is an important therapeutic approach to rheumatoid arthritis, as these Phase 3 results demonstrated efficacy at both doses of salilumab, each administered every two weeks. It is. This is summarized below in Tables 9-14.

Conclusion:
Treatment with both salilumab doses in combination with MTX is associated with a significantly reduced radiographic progression for structural damage as compared to placebo as measured by mTSS, erosion and JSN score I was Adverse events observed with salilumab were consistent with IL-6 blockade.

  The compositions and methods of the present disclosure should not be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

Claims (23)

  A method of inhibiting the development of structural damage in a subject suffering from rheumatoid arthritis, said method comprising administering to said subject an effective amount of salilumab.   The method of claim 1, wherein the subject achieves a change in the modified Van der Heide total sharp score (mTSS) from baseline (BL) of at most 0.6 after at least 24 weeks of treatment.   3. The method of claim 1 or 2, wherein the subject achieves a maximum change of 1 from a baseline (BL) of a modified Van der Heide total sharp score (mTSS) after at least 52 weeks of treatment.   The subject has previously been treated for ineffective rheumatoid arthritis by administering at least one disease modifying antirheumatic drug (DMARD) selected from the group consisting of methotrexate, leflunomide, sulfasalazine and hydroxychloroquine. The method according to any one of claims 1 to 3.   5. The method of any one of claims 1-4, comprising administering to the subject an effective amount of salilumab and an effective amount of methotrexate, leflunomide, sulfasalazine and / or hydroxychloroquine.   6. The method of any one of claims 1 to 5, comprising administering to the subject an effective amount of salilumab and an effective amount of methotrexate.   7. The method according to any one of claims 4 to 6, wherein methotrexate is administered from 6 mg to 25 mg per week.   The method according to any one of claims 1 to 7, wherein salilumab is administered subcutaneously.   9. The method of any one of claims 1 to 8, wherein salilumab is administered at about 150 mg every two weeks.   9. The method of any one of claims 1 to 8, wherein salilumab is administered at about 200 mg every two weeks.   11. The method of any one of claims 1 to 10, wherein salilumab is administered to the subject for at least 52 weeks.   10. The method of claim 9, wherein the subject achieves a change in the modified Van der Heide total sharp score (mTSS) from baseline (BL) of at most 0.6 after at least 24 weeks of treatment.   10. The method of claim 9, wherein the subject achieves a change in the modified Van der Heide total sharp score (mTSS) from baseline (BL) of about 0.54 after at least 24 weeks of treatment.   10. The method of claim 9, wherein the subject achieves a change in the modified Van der Heide total sharp score (mTSS) from baseline (BL) of at most 1 after at least 52 weeks of treatment.   10. The method of claim 9, wherein the subject achieves a change from a baseline (BL) of a modified Van der Heide total sharp score (mTSS) of about 0.90 after at least 52 weeks of treatment.   11. The method of claim 10, wherein the subject achieves a change in the modified Van der Heide total sharp score (mTSS) from baseline (BL) of at most 0.2 after at least 24 weeks of treatment.   11. The method of claim 10, wherein the subject achieves a change in the modified Van der Heide total sharp score (mTSS) from baseline (BL) of about 0.13 after at least 24 weeks of treatment.   11. The subject of claim 10, wherein the subject achieves a change from the baseline (BL) of the modified Van der Heide total sharp score modified (mTSS) of at most 0.3 after at least 52 weeks of treatment. Method.   11. The method of claim 10, wherein the subject achieves a change from the baseline (BL) of the modified Van der Heide total sharp score (mTSS) of about 0.25 after at least 52 weeks of treatment.   A method of improving physical function in a subject suffering from rheumatoid arthritis, said method comprising administering to the subject an effective amount of salilumab.   21. The method of claim 20, wherein the subject achieves a change in the health assessment questionnaire disability index (HAQ-DI) from baseline (BL) of at least -0.5 after at least 16 weeks of treatment.   21. The method of claim 20, wherein the subject achieves at least a 24-week change in health assessment questionnaire disability index (HAQ-DI) from baseline (BL) of at least -0.6.   21. The method of claim 20, wherein the subject achieves at least a 52 week change in the health assessment questionnaire disability index (HAQ-DI) from a baseline (BL) of at least -0.7.