Composition for treating rheumatoid arthritis and method for using the same

Abstract

To provide a method for treating rheumatoid arthritis when administration of methotrexate, leflunomide, sulfasalazine and / or hydroxychloroquine is ineffective.SOLUTION: Provided is a method of administering an effective dose of sarilumab, an antibody that specifically binds to human interleukin-6 receptor (hIL-6R), together with methotrexate, leflunomide, sulfasalazine and / or hydroxychloroquine.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the field of treatment for 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 for the treatment of rheumatoid arthritis. [Background technology]

[0002] In North America and Europe, it is estimated that approximately 0.5% to 1% of adults suffer from rheumatoid arthritis (RA). RA is twice as common in women as in men, with the highest incidence occurring in women over 40 years of age.

[0003] Rheumatoid arthritis (RA) is characterized by persistent synovitis, as well as progressive cartilage and bone destruction in multiple joints. A defining feature of the disease is a characteristic systemic polyarthritis involving the small joints of the hands and feet. The inflammatory process may also target other organs, typically the bone marrow (anemia), eyes (scleritis, episcleritis), lungs (interstitial pneumonia, pleurisy), heart (pericarditis), and skin (nodules, leukocytoclastic vasculitis). Systemic inflammation is characterized by abnormal laboratory findings, such as anemia, elevated erythrocyte sedimentation rate, increased fibrinogen and C-reactive protein (CRP), and clinical symptoms including fatigue, weight loss, and muscle atrophy in the affected joints. The presence of polyclonal high-titer rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies provides evidence of immunomodulatory abnormalities. It was estimated that 65% to 70% of RA patients suffer from a progressive disease that causes joint destruction, disability, and premature death. [Overview of the project] [Problems that the invention aims to solve]

[0004] In this field, improved treatment plans are needed to alleviate symptoms associated with rheumatoid arthritis (RA). [Means for solving the problem]

[0005] The present disclosure provides a method for treating rheumatoid arthritis in a subject who needs to treat rheumatoid arthritis. This method includes administering to the subject an effective amount of sarilumab (SAR153191) and one of the group consisting of leflunomide, sulfasalazine, and hydroxychloroquine. In certain embodiments, the subject has previously received ineffective treatment of rheumatoid arthritis by administering a TNF-α antagonist. Specifically, the subject has been treated with a TNF-α antagonist for at least three months or is intolerant to a TNF-α antagonist. The TNF-α antagonist may be etanercept, infliximab, adalimumab, golimumab, or certolizumab. In other embodiments, the subject has previously received ineffective treatment of rheumatoid arthritis by administering methotrexate.

[0006] Sarilumab can be administered at 50 mg to 150 mg per week or 100 mg to 200 mg every two weeks.

[0007] In certain specific embodiments, sarilumab and leflunomide are administered to the subject. Leflunomide can be administered orally. Leflunomide can also be administered to the subject at 10 mg to 20 mg per day.

[0008] In other specific embodiments, sarilumab and sulfasalazine are administered to the subject. Sulfasalazine can be administered orally. Sulfasalazine can also be administered to the subject at 1000 mg to 3000 mg per day.

[0009] In other specific embodiments, sarilumab and hydroxychloroquine are administered to the subject. Hydroxychloroquine can be administered orally. Hydroxychloroquine can also be administered to the subject at 200 mg to 400 mg per day.

[0010] In one embodiment, as a result of treatment, subjects achieve a 20% or 50% improvement in the American College of Rheumatology (ACR) core set disease index after 12 weeks of treatment. In other embodiments, as a result of treatment, subjects achieve a 20%, 50%, or 70% improvement in the ACR core set disease index after 24 weeks of treatment.

[0011] In one embodiment, as a result of treatment, subjects achieve a lower disease activity score after 12 weeks of treatment compared to subjects before treatment. The disease activity score may be 2.6 or less at week 12. The disease activity score can be reduced by more than 1.2 between the start of treatment and week 12. The disease activity score may be 3.2 or less at week 12. The disease activity score can be reduced by more than 0.6 between the start of treatment and week 12. The disease activity score may be 5.1 or less at week 12.

[0012] In one embodiment, as a result of treatment, subjects achieve a lower disease activity score after 24 weeks of treatment compared to subjects before treatment. The disease activity score may be 2.6 or less at 24 weeks. The disease activity score can be reduced by more than 1.2 between the start of treatment and 24 weeks. The disease activity score may be 3.2 or less at 24 weeks. The disease activity score can be reduced by more than 0.6 between the start of treatment and 24 weeks. The disease activity score may be 5.1 or less at 24 weeks.

[0013] This disclosure further provides a method for treating rheumatoid arthritis in a subject who needs treatment for rheumatoid arthritis and who has previously received ineffective treatment for rheumatoid arthritis with anti-TNF-α therapeutics. In certain embodiments, the subject has previously received ineffective treatment for rheumatoid arthritis with methotrexate. Methotrexate may be administered to the subject at a dose of 10 mg to 25 mg per week.

[0014] In certain embodiments, the subject is a mammal. The mammal may be a human. In certain embodiments, the human is a descendant of an individual from the Asia-Pacific region. Humans who are descendants of individuals from the Asia-Pacific region may be administered 6 mg to 25 mg of methotrexate per week.

[0015] In certain embodiments, subjects had previously received ineffective treatment for rheumatoid arthritis with TNF-α antagonists. Specifically, subjects could have been treated with TNF-α antagonists for at least three months or were intolerant to TNF-α antagonists. The TNF-α antagonist could be etanercept, infliximab, adalimumab, golimumab, or certolizumab. In other embodiments, subjects had previously received ineffective treatment for rheumatoid arthritis with methotrexate.

[0016] Sarilumab could be administered at doses of 50 mg to 150 mg per week, or 100 mg to 200 mg every two weeks.

[0017] In one embodiment, as a result of treatment, subjects achieve a 20% or 50% improvement in the American College of Rheumatology (ACL) Core Set Disease Index after 12 weeks of treatment. In another embodiment, as a result of treatment, subjects achieve a 20%, 50%, or 70% improvement in the ACL Core Set Disease Index after 24 weeks of treatment.

[0018] In one embodiment, as a result of treatment, subjects achieve a lower disease activity score after 12 weeks of treatment compared to subjects before treatment. The disease activity score may be 2.6 or less at week 12. The disease activity score can be reduced by more than 1.2 between the start of treatment and week 12. The disease activity score may be 3.2 or less at week 12. The disease activity score can be reduced by more than 0.6 between the start of treatment and week 12. The disease activity score may be 5.1 or less at week 12.

[0019] In one embodiment, as a result of treatment, subjects achieve a lower disease activity score after 24 weeks of treatment compared to subjects before treatment. The disease activity score may be 2.6 or less at 24 weeks. The disease activity score can be reduced by more than 1.2 between the start of treatment and 24 weeks. The disease activity score may be 3.2 or less at 24 weeks. The disease activity score can be reduced by more than 0.6 between the start of treatment and 24 weeks. The disease activity score may be 5.1 or less at 24 weeks.

[0020] This disclosure also provides a pharmaceutical composition comprising an effective amount of sarilumab and one of the group consisting of leflunomide, sulfasalazine, and hydroxychloroquine. Sarilumab may be present in amounts of 50 mg to 150 mg per dose, or 100 mg to 200 mg per dose.

[0021] In certain specific embodiments, the composition comprises sarilumab and leflunomide. Leflunomide may be present in an oral dosage form. Leflunomide may be present in the composition in amounts of 10 mg to 20 mg per dose.

[0022] In other specific embodiments, the composition comprises sarilumab and sulfasalazine. Sulfasalazine may be present in an oral dosage form. Sulfasalazine may be present in the composition in an amount of 1000 mg to 3000 mg per day to the subject.

[0023] In other specific embodiments, the composition comprises sarilumab and hydroxychloroquine. Hydroxychloroquine may be present in an oral dosage form. Hydroxychloroquine may be present in the composition in an amount of 200 mg to 400 mg per day to a subject.

[0024] Examples of embodiments of the present invention are listed below.

[0025] Embodiment 1: A method for treating rheumatoid arthritis in a subject who requires treatment for rheumatoid arthritis, comprising administering to the subject an effective amount of sarilumab (SAR153191) and one of the group consisting of leflunomide, sulfasalazine, and hydroxychloroquine.

[0026] Embodiment 2: The method of Embodiment 1, wherein the subject has previously received ineffective treatment for rheumatoid arthritis by administering a TNF-α antagonist.

[0027] Embodiment 3: The method of Embodiment 2, wherein the TNF-α antagonist is a biological anti-TNF-α antagonist.

[0028] Embodiment 4: Subjects were treated with a TNF-α antagonist for at least 3 months. The method of Embodiment 2 or 3.

[0029] Embodiment 5: The method of Embodiment 2 or 3, wherein the subject was intolerant to the TNF-α antagonist.

[0030] 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.

[0031] Embodiment 7: The method of Embodiment 2 or 3, wherein the subject has previously received treatment for rheumatoid arthritis that is ineffective with the administration of methotrexate.

[0032] Embodiment 8: The method of Embodiment 1, in which sarilumab is administered at a dose of 50 mg to 150 mg per week.

[0033] Embodiment 9: The method of Embodiment 1, in which sarilumab is administered at a dose of 100 mg to 200 mg every two weeks.

[0034] Embodiment 10: The method of Embodiment 1, wherein sarilumab and leflunomide are administered to a subject.

[0035] Embodiment 11: The method of Embodiment 10, wherein leflunomide is administered orally.

[0036] Embodiment 12: The method of Embodiment 10, wherein leflunomide is administered to the subject at a dose of 10 mg to 20 mg per day.

[0037] Embodiment 13: The method of Embodiment 1, wherein sarilumab and sulfasalazine are administered to the subject.

[0038] Embodiment 14: The method of Embodiment 13, wherein sulfasalazine is administered orally.

[0039] Embodiment 15: The method of Embodiment 13, wherein sulfasalazine is administered to the subject at a dose of 1000 mg to 3000 mg per day.

[0040] Embodiment 16: The method of Embodiment 1, wherein sarilumab and hydroxychloroquine are administered to a subject.

[0041] Embodiment 17: The method of Embodiment 16, wherein hydroxychloroquine is administered orally.

[0042] Embodiment 18: The method of Embodiment 16, wherein hydroxychloroquine is administered to the subject at a dose of 200 mg to 400 mg per day.

[0043] Embodiment 19: Any method of Embodiments 1 to 18, wherein the subject achieves a 20% improvement in the American College of Rheumatology Core Set Disease Index after 12 weeks of treatment.

[0044] Embodiment 20: Any method of Embodiments 1 to 18, wherein the subject achieves a 50% improvement in the American College of Rheumatology Core Set Disease Index after 12 weeks of treatment.

[0045] Embodiment 21: Any method of Embodiments 1 to 18, wherein the subject achieves a 20% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

[0046] Embodiment 22: Any method of Embodiments 1 to 18, wherein the subject achieves a 50% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

[0047] Embodiment 23: Any method of Embodiments 1 to 18, wherein the subject achieves a 70% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

[0048] Embodiment 24: A method according to any of Embodiments 1 to 18, wherein a subject achieves a lower disease activity score after 12 weeks of treatment compared to a subject before treatment.

[0049] Embodiment 25: Any method of Embodiments 1 to 18, wherein the disease activity score is 2.6 or less at week 12.

[0050] Embodiment 26: Any method of Embodiments 1 to 18, wherein the disease activity score decreases by more than 1.2 between the start of treatment and 12 weeks.

[0051] Embodiment 27: Any method of Embodiments 1 to 18, wherein the disease activity score is 3.2 or less at week 12.

[0052] Embodiment 28: Any method of Embodiments 1 to 18, wherein the disease activity score decreases by more than 0.6 between the start of treatment and 12 weeks.

[0053] Embodiment 29: Any method according to Embodiments 1 to 18, wherein the disease activity score is 5.1 or less at week 12.

[0054] Embodiment 30: A method according to any of Embodiments 1 to 18, wherein the subject achieves a lower disease activity score after 24 weeks of treatment compared to the subject before treatment.

[0055] Embodiment 31: Any method of Embodiments 1 to 18, wherein the disease activity score is 2.6 or less at week 24.

[0056] Embodiment 32: Any method of Embodiments 1 to 18, wherein the disease activity score decreases by more than 1.2 between the start of treatment and 24 weeks.

[0057] Embodiment 33: Any method of Embodiments 1 to 18, wherein the disease activity score is 3.2 or less at week 24.

[0058] Embodiment 34: Any method of Embodiments 1 to 18, wherein the disease activity score decreases by more than 0.6 between the start of treatment and 24 weeks.

[0059] Embodiment 35: Any method of Embodiments 1 to 18, wherein the disease activity score is 5.1 or less at week 24.

[0060] Embodiment 36: A method for treating rheumatoid arthritis in a subject who needs treatment for rheumatoid arthritis, comprising administering an effective dose of sarilumab and methotrexate to the subject, wherein the subject has previously received ineffective treatment for rheumatoid arthritis with TNF-α antagonists.

[0061] Embodiment 37: The method of Embodiment 36, wherein the subject has previously received ineffective treatment for rheumatoid arthritis with methotrexate.

[0062] Embodiment 38: The method of Embodiment 36, wherein methotrexate is administered to the subject at a dose of 10 mg to 25 mg per week.

[0063] Embodiment 39: The method of Embodiment 36, wherein the subject is a mammal.

[0064] Embodiment 40: The method of Embodiment 37, wherein the mammal is a human.

[0065] Embodiment 41: The method of Embodiment 38, wherein the human is a descendant of an individual from the Asia-Pacific region.

[0066] Embodiment 42: The method of Embodiment 39, wherein a human being who is a descendant of an individual from the Asia or Pacific region is administered 6 mg to 25 mg of methotrexate per week.

[0067] Embodiment 43: The method of Embodiment 36, wherein the subject was treated with a TNF-α antagonist for at least 3 months.

[0068] Embodiment 44: The method of Embodiment 36, wherein the subject was intolerant to the TNF-α antagonist.

[0069] Embodiment 45: Any one of Embodiments 36 to 44, wherein the TNF-α antagonist is a biological anti-TNF-α antagonist.

[0070] Embodiment 46: The method of Embodiment 44, wherein the TNF-α antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab.

[0071] Embodiment 47: The method of Embodiment 36, wherein sarilumab is administered at a dose of 50 mg to 150 mg per week.

[0072] Embodiment 48: The method of Embodiment 36, wherein sarilumab is administered at a dose of 100 mg to 200 mg every two weeks.

[0073] Embodiment 49: Any method of Embodiments 36 to 48, wherein the subject achieves a 20% improvement in the American College of Rheumatology Core Set Disease Index after 12 weeks of treatment.

[0074] Embodiment 50: Any method of Embodiments 36 to 48, wherein the subject achieves a 50% improvement in the American College of Rheumatology Core Set Disease Index after 12 weeks of treatment.

[0075] Embodiment 51: Any method of Embodiments 36 to 48, wherein the subject achieves a 20% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

[0076] Embodiment 52: Any method of Embodiments 36 to 48, wherein the subject achieves a 50% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

[0077] Embodiment 53: Any method of Embodiments 36 to 48, wherein the subject achieves a 70% improvement in the American College of Rheumatology Core Set Disease Index after 24 weeks of treatment.

[0078] Embodiment 54: A method according to any of Embodiments 36 to 48, wherein a subject achieves a lower disease activity score after 12 weeks of treatment compared to a subject before treatment.

[0079] Embodiment 55: Any method according to Embodiments 36 to 48, wherein the disease activity score is 2.6 or less at week 12.

[0080] Embodiment 56: Any method of Embodiments 36 to 48, wherein the disease activity score decreases by more than 1.2 between the start of treatment and 12 weeks.

[0081] Embodiment 57: Any method of Embodiments 36 to 48, wherein the disease activity score is 3.2 or less at week 12.

[0082] Embodiment 58: Any method according to Embodiments 36 to 48, wherein the disease activity score decreases by more than 0.6 between the start of treatment and 12 weeks.

[0083] Embodiment 59: Any method of Embodiments 36 to 48, wherein the disease activity score is 5.1 or less at week 12.

[0084] Embodiment 60: A method according to any of Embodiments 36 to 48, wherein a subject achieves a lower disease activity score after 24 weeks of treatment compared to a subject before treatment.

[0085] Embodiment 61: Any method of Embodiments 36 to 48, wherein the disease activity score is 2.6 or less at week 24.

[0086] Embodiment 62: Any method of Embodiments 36 to 48, wherein the disease activity score decreases by more than 1.2 between the start of treatment and 24 weeks.

[0087] Embodiment 63: Any method of Embodiments 34 to 45, wherein the disease activity score is 3.2 or less at week 24.

[0088] Embodiment 64: Any method of Embodiments 34 to 45, wherein the disease activity score decreases by more than 0.6 between the start of treatment and 24 weeks.

[0089] Embodiment 65: Any method according to Embodiments 34 to 45, wherein the disease activity score is 5.1 or less at week 24.

[0090] Embodiment 66: A pharmaceutical composition comprising an effective amount of sarilumab and one of the group consisting of leflunomide, sulfasalazine, and hydroxychloroquine. [Brief explanation of the drawing]

[0091] [Figure 1] The dosage for Example 1 is shown. [Figure 2] The ACR20 response of Example 1 is shown. [Figure 3] The ACR50 and ACR70 responses of Example 1 are shown. [Modes for carrying out the invention]

[0092] This disclosure provides pharmaceutical compositions and methods for using these compositions to treat rheumatoid arthritis (RA) and to improve 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 at least one disease-modifying antirheumatic drug (DMARD).

[0093] Anti-hlL-6R antibody This disclosure includes a method comprising administering to a patient a human antibody or an antigen-binding fragment that specifically binds to hlL-6R. In use herein, "hlL-6R" and The term 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 by the amino acid sequence of SEQ ID NO: 1.

[0094] Unless otherwise specified, the term “antibody” as used herein should be understood to encompass an antibody molecule (i.e., the “whole antibody molecule”) containing two immunoglobulin heavy chains and two immunoglobulin light chains, and this antigen-binding fragment. Terms such as the “antigen-binding portion” of an antibody and the “antigen-binding fragment” of an antibody, as used herein, include any naturally occurring, enzymatically obtained, synthetically produced, or genetically engineered polypeptide or glycoprotein that specifically binds to an antigen to form a complex. The antigen-binding fragment of an antibody may be derived, for example, from the whole antibody molecule using any appropriate standard technique, such as protein digestion or recombinant genetic engineering techniques, including manipulation and expression of DNA encoding the antibody variable region and (optionally) the constant region. Such DNA is known and / or readily available, for example, from commercial suppliers, DNA libraries (e.g., phage-antibody libraries), or can be synthesized. DNA may be sequenced, chemically, or manipulated by molecular biological techniques such as aligning one or more variable and / or constant regions to form a suitable structure, or by introducing codons, creating cysteine ​​residues, or altering, adding, or deleting amino acids.

[0095] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv(scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity-determining region (CDR)). Other manipulated molecules, such as diabodies, triabodies, tetrabodies, and minibodies, are also included within the scope of the expression “antigen-binding fragment” as used herein.

[0096] An antigen-binding fragment of an antibody will typically include at least one variable region. The variable region can be of any size or amino acid composition and will generally include at least one CDR adjacent to one or more framework sequences or will include at least one CDR within the framework. The V L region linked to the V H region in an antigen-binding fragment having a V H region and a V L region can be positioned in any suitable arrangement relative to each other. For example, the variable regions can be a dimer, such as a V H -V H dimer, a V H -V L dimer or a V L -V L dimer. Alternatively, an antigen-binding fragment of an antibody can include a monomeric VH region or VL region.

[0097] In certain embodiments, an antigen-binding fragment of an antibody can include at least one variable region covalently bound to at least one constant region. Non-limiting and exemplary structures of variable and constant regions that can be found among the antigen-binding fragments of the antibodies of the present invention include the following. (i) V H -C H1 ; (ii) V H -C H2 ; (iii) V H -C H3 ; (iv) V H -C H1 -C H2 ; (V) V H -C[[ID=IS=45]] H1 [[ID=S=45]] 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 -CH3 ;(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 In any structure, including any exemplary structure listed above, the variable and constant regions may be directly linked to each other, or they may be linked by all or part of a hinge region or linker region. A hinge region is a flexible or semi-flexible linkage between adjacent variable and / or constant regions in a polypeptide molecule. The antigen-binding fragment of the antibody of the present invention may consist of at least two (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids that form a covalent bond. Furthermore, the antigen-binding fragment of the antibody of the present invention may consist of non-covalent bonds to one or more monomers and / or V bonds to one or more monomers. H or V L The region may include homodimers or heterodimers (or other multimers) of the region and any of the variable and constant region structures listed above (for example, by disulfide bonds).

[0098] The term "specifically binds" means that the antibody or this antigen-binding fragment forms a complex with an antigen that is relatively stable under physiological conditions. Specific binding is characterized by a dissociation constant of at least approximately 1 × 10⁻¹⁶. -6 It can be characterized by M or a smaller value. In other embodiments, the dissociation constant is at least about 1 × 10⁻⁶ -7 M, 1×10 -8 M, or 1 × 10 -9 M is the molecule. Methods for determining whether two molecules specifically bind are well known in this field, and examples include equilibrium dialysis and surface plasmon resonance.

[0099] When the whole antibody molecule is used, the antigen-binding fragment may be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody typically comprises at least two distinct variable regions, each of which is either specifically capable of binding to a different antigen or specifically capable of binding to a different epitope of the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, may be adapted using conventional techniques available in the art to be used in terms of the antigen-binding fragment of the antibody of the present invention.

[0100] In specific embodiments, the antibody or antibody fragment for use in the method of the present invention may be a multispecific antibody, specific to a different epitope of a single target polypeptide, or may contain antigen-binding regions specific to epitopes of more than one target polypeptide. An exemplary bispecific antibody format usable in view of the present invention is a first immunoglobulin (Ig) C H3 Region and second Ig C H3 Including the use of the region, the first and second Ig C H3 The regions are distinguished from each other by at least one amino acid, and the difference of at least one amino acid reduces the binding of the bispecific antibody to protein A compared to a bispecific antibody without amino acid differences. In one embodiment, the first Ig C H3 The region binds to protein A and the second IgC H3 The region contains mutations that reduce or eliminate protein A binding, such as the H95R modification (according to IMGT exon numbering; H435R according to EU numbering). Second C H3 This may further include the Y96F modification (according to IMGT; Y436F according to the EU). Second C H3Further modifications that may be found include, in the case of IgG1 antibodies, D16E, L18M, N44S, K52N, V57M and V82I (according to IMGT; according to the EU, D356E, L358M, N384S, K392N, V397M and V422I); in the case of IgG2 antibodies, N44S, K52N and V82I (according to IMGT; according to the EU, N384S, K392N and V422I); and in the case of IgG4 antibodies, Q15R, N44S, K52N, V57M, R69K, E79Q and V82I (according to IMGT; according to the EU, Q355R, N384S, K392N, V397M, R409K, E419Q and V422I). The above-mentioned variations in the bispecific antibody format are assumed to be within the scope of the present invention.

[0101] In another specific embodiment, the antibody is sarilumab (SAR153191). The heavy chain variable region of sarilumab is shown below as Sequence ID No. 2.

[0102] The light chain variable region of sarilumab is shown below as Sequence ID No. 3.

[0103] "Neutralizing" or "blocking" an antibody, as used herein, refers to hlL-6 This term refers to antibodies that inhibit the bioactivity of hlL-6 by binding to R. Inhibition of hlL-6 bioactivity can be evaluated by measuring one or more indicators of hlL-6 bioactivity known in this field, such as hlL-6-induced cell activation and hlL-6 binding to hlL-6R (see examples below).

[0104] The whole-human anti-IL-6R antibodies disclosed herein may contain one or more amino acid substitutions, insertions, and / or deletions in the framework and / or CDR regions of the variable regions of the heavy and light chains compared to the corresponding germ cell sequences. Such mutations can be readily identified by comparing the amino acid sequences disclosed herein with germ cell sequences available, for example, from public antibody sequence databases. The present invention comprises antibodies and antigen-binding fragments derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids in one or more framework regions and / or CDR regions are backmutated to the corresponding germ cell residues or conserved amino acid substitutions (natural or unnatural) of the corresponding germ cell residues (such sequence changes are referred to herein as “germ cell backmutations”). Those skilled in the art will readily be able to produce many antibodies and antigen-binding fragments containing one or more individual germ cell backmutations or combinations thereof, starting with the sequences of the variable regions of the heavy and light chains disclosed herein. In certain embodiments, all framework residues and / or CDR residues within the VH region and / or VL region are backmutated to germ cell sequences. In other embodiments, only specific residues, for example, only mutated residues found in the first eight amino acids of FR1 or the last eight amino acids of FR4, or only mutated residues found in CDR1, CDR2, or CDR3, are reverse-mutated into germ cell sequences. Furthermore, the antibodies of the present invention may contain any combination of two or more germ cell reverse mutations within the framework region and / or CDR region, i.e., certain individual residues are reverse-mutated into germ cell sequences while certain other residues that are not germ cell sequences are maintained. Once obtained, antibodies and antigen-binding fragments containing one or more germ cell reverse mutations can be easily tested for one or more desirable properties, such as improved binding specificity, enhanced binding affinity, improved or enhanced antagonist or agonist biocompatibility (in some cases), or reduced immunogenicity. Antibodies and antigen-binding fragments obtained in this general manner are encompassed by the present invention.

[0105] The term "epitope" refers to an antigen-determining factor that interacts with a specific antigen-binding site in the variable region of an antibody molecule, also known as a paratope. A single antigen may have more than one epitope. Epitopes may be three-dimensional or linear. Three-dimensional epitopes are made up of spatially parallel amino acids from different segments of a linear polypeptide chain. Linear epitopes are made up of adjacent amino acid residues in a polypeptide chain. In certain cases, epitopes may contain sugar, phosphoryl, or sulfonyl groups on the antigen.

[0106] The anti-hlL-6R may be sarilumab (SAR153191). In one embodiment, sarilumab 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.

[0107] DMARD Disease-modifying antirheumatic drugs (DMARDs) include methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide. According to the compositions and methods of this disclosure, DMARDs can be administered as follows: Methotrexate can be administered orally or by intramuscular injection at a dose of 10 mg to 25 mg per week. In another embodiment, methotrexate may be administered orally or by intramuscular injection at a dose of 6 mg per week to patients of Asian-Pacific origin or descendants of people of Asian-Pacific origin. 25 mg is administered. The Asia-Pacific region includes Taiwan, South Korea, Malaysia, the Philippines, Thailand, and India. In certain embodiments, methotrexate is administered at doses of 6 mg to 12 mg, 10 mg to 15 mg, 15 mg to 20 mg, and 20 to 25 mg per week. In other embodiments, methotrexate is administered at doses of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg per week. Leflunomide can be administered orally at doses of 10 mg to 20 mg per day. In certain embodiments, leflunomide can be administered at doses of 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 a dose of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg per day. Sulfasalazine can be administered orally at a dose of 1000 mg to 3000 mg per day. In specific embodiments, sulfasalazine can be administered at a dose of 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 doses of 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or 3000 mg per day. Hydroxychloroquine can be administered orally at doses of 200 mg to 400 mg per day. In specific embodiments, hydroxychloroquine can be administered at doses of 200 to 240, 240 to 280, 280 to 320, 320 to 360, and 360 to 400 per day. In other embodiments, hydroxychloroquine may be administered at doses of 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, or 400 mg per day.

[0108] Administration and formulations for treatment The methods described herein involve administering a therapeutically effective dose of anti-hlL-6R antibody and DMARDs to a patient. As used herein, the phrase “therapeutically effective dose” means a dose of anti-hlL-6R antibody and DMARDs that produces a detectable improvement in one or more symptoms associated with rheumatoid arthritis, or a biological effect correlated with the pathological mechanism underlying the rheumatoid arthritis condition or symptoms (e.g., a reduction in the amount of a particular biomarker). For example, a dose of anti-hlL-6R antibody including one or more DMARDs that improve any symptom or condition such as chronic disease anemia, fever, depression, fatigue, rheumatoid nodules, vasculitis, neuropathy, scleritis, pericarditis, Felty syndrome, and / or joint destruction is considered a “therapeutically effective dose.”

[0109] Detectable improvements can also be identified using the American College of Rheumatism (ACR) rheumatoid arthritis classification criteria. For example, detectable improvements can be indicated using a 20% improvement from baseline (ACR20), a 50% improvement (ACR50), or a 70% improvement (ACR70).

[0110] The Disease Activity Score (DAS28) can be used to indicate detectable improvement. The DAS28 is a composite score combining the number of tender joints based on 28 joints, the number of joint swellings based on 28 joints, an overall health assessment, and inflammatory markers that can be assessed by measuring C-reactive protein (CRP) levels. Disease response can be expressed using the European League against Rheumatism (EULAR) response criteria. A good response according to these criteria is an improvement of greater than 1.2 in the DAS28 score, with a current score of 3.2 or higher. A moderate response is an improvement of greater than 0.6 and less than or equal to 1.2 in the DAS28 score, with a current score of 3.2 or higher. No response is an improvement of less than 0.6 in the DAS28 score, with a current score greater than 5.1. S28 remission is defined as a DAS28 score of less than 2.6.

[0111] According to the method of the present invention, the therapeutically effective amount of anti-hlL-6R antibody administered to a patient will vary depending on the patient's age and size (e.g., body weight or body surface area), the route of administration, and other factors well known to those skilled in the art. In certain embodiments, the dosage of anti-hlL-6R antibody administered to a patient is approximately 10 mg to approximately 500 mg. For example, the present invention provides approximately 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, 170 mg, 175 mg, 180 mg, and 185 mg per week. This includes methods of administering to a patient approximately 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 255 mg, 260 mg, 265 mg, 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, or more of anti-hlL-6R antibody.

[0112] In one embodiment, 100 mg to 150 mg of hlL-6R antibody is administered per week. In another embodiment, 100 mg to 200 mg of hlL-6R antibody is administered every two weeks. In yet another embodiment, approximately 100 mg or approximately 150 mg of hlL-6R antibody is administered per week. In yet another embodiment, approximately 100, 150, or 200 mg of hlL-6R antibody is administered every two weeks.

[0113] The amount of anti-hlL-6R antibody administered to a patient can be expressed in milligrams of antibody per kilogram of the patient's body weight (i.e., mg / kg). For example, the method of the present invention involves administering anti-hlL-6R antibody to a patient at a daily dose of approximately 0.01 mg / kg to approximately 100 mg / kg, approximately 0.1 mg / kg to approximately 50 mg / kg, or approximately 1 mg / kg to approximately 10 mg / kg per kilogram of the patient's body weight.

[0114] The method of the present invention involves administering anti-hlL-6R antibody to a patient by multiple doses over a specific series of time periods. For example, anti-hlL-6R antibody may be administered about 1 to 5 times per day, about 1 to 5 times per week, about 1 to 5 times per month, or about 1 to 5 times per year. In certain embodiments, the method of the present invention involves administering a first dose of anti-hlL-6R antibody to a patient at a first time point, and then administering at least a second dose of anti-hlL-6R antibody to the patient at a second time point. In certain embodiments, the first and second doses may contain the same amount of anti-hlL-6R antibody. For example, the first and second doses may contain about 10 mg to about 500 mg of antibody, about 20 mg to about 300 mg, about 100 mg to about 200 mg, or about 100 mg to about 150 mg, respectively. The time between the first and second doses may range from a few hours to several weeks. For example, the second time point (i.e., the time when the second dose is administered) may be about one hour to about seven weeks after the first time point (i.e., the time when the first dose is administered). According to certain exemplary embodiments of the present invention, the second time point may be about one hour, about four hours, about six hours, about eight hours, about ten hours, about twelve hours, about twenty-four hours, about two days, about three days, about four days, about five days, about six days, about seven days, about two weeks, about four weeks, about six weeks, about eight weeks, about ten weeks, about twelve weeks, about fourteen weeks, or even later than that. In certain embodiments, the second time point is about one week or about two weeks. The third dose and subsequent doses may be administered similarly during a series of treatments for the patient.

[0115] The present invention provides a method for using a therapeutic composition comprising an anti-IL-6R antibody or this antigen-binding fragment and one or more DMARDs. The therapeutic composition of the present invention will be administered together with a suitable carrier, excipients and other agents incorporated into the formulation to provide improved mobility, delivery, tolerance, etc. A large number of suitable formulations can be found for all medicinal chemistry. Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) vesicles (e.g., LIPOFECTIN®), DNA conjugates, anhydrous absorbent pastes, oil-in-water and water-in-oil emulsions, emulsion carbowaxes (polyethylene glycol of various molecular weights), semi-solid gels and semi-solid mixtures containing carbowaxes. Also, see Powell et al., "Compendium of excipients for parenteral formulations," PDA (1998) J Pharm Sci. See Technol 52:238-311.

[0116] The dosage will vary depending on the age and weight of the subject receiving the drug, the target disease, condition, and route of administration. Various delivery systems are known, and the pharmaceutical composition of the present invention can be administered using, for example, liposomes, microparticles, microcapsules, and receptor-mediated endocytosis (see, for example, Wu et al. (1987) J. Biol. Chem. 262:4429-4432). Methods of delivery are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, nasal, epidural, and oral routes. The composition may be administered by any convenient route, for example, by infusion or bolus injection, by absorption through the epithelium or mucosa (e.g., oral mucosa, rectal and colonic mucosa), or together with other bioactive drugs. It can be administered systemically or topically. The hlL-6R antibody may be administered subcutaneously. DMARDs can be administered orally or intramuscularly.

[0117] Pharmaceutical compositions can also be delivered encapsulated in vesicles, particularly liposomes (see Langer (1990) Science 249:1527-1533). In certain circumstances, pharmaceutical compositions can be delivered by controlled-release systems, for example, using pumps or polymer materials. In another embodiment, the controlled-release system can be positioned near the target of the composition, thereby requiring only a portion of the systemic dose.

[0118] Injectable preparations may include dosage forms for intravenous, subcutaneous, intradermal, and intramuscular injection, local injection, and intravenous infusion. These injectable preparations may be prepared by publicly known methods. For example, injectable preparations may be prepared by dissolving, suspending, or emulsifying the antibodies or salts thereof described above in sterile aqueous or oily media commonly used for injection. Examples of aqueous media for injection include physiological saline, isotonic solutions containing sugar and other adjuvants, which may be used in combination with suitable solubilizers, such as alcohol (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants [e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)]. Examples of oily media include sesame oil and soybean oil, which may be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. The injection solutions thus prepared may be filled into appropriate ampoules.

[0119] Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared into dosage forms that result in unit doses suitable for adjusting the dosage of the active ingredient. Examples of such dosage forms include tablets, pills, capsules, injections (ampoules), and suppositories. These include: The amount of DMARD contained is generally about 5 mg to 3000 mg per oral dose, depending on the specific DMARD used. The amount of hlL-6R antibody contained is generally about 100 mg to 200 mg per subcutaneous dose.

[0120] According to the methods disclosed herein, an anti-hlL-6R antibody (or a pharmaceutical formulation containing 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 autoinjector delivery device. The methods of the present invention include the use of many reusable pen and / or autoinjector delivery devices for administering an anti-hlL-6R antibody (or a pharmaceutical formulation containing the antibody). Examples of such devices, but not limited to, include AUTOPEN (Owen Mumford, Inc., Woodstock, UK), DISETRONIC pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25 pen, HUMALOG pen, HUMALIN 70 / 30 pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR (Novo Nordisk, Copenhagen, Denmark), BD pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN (Trademark), OPTIPEN PRO (Trademark), OPTIPEN STARLET (Trademark), and OPTICLIK (Trademark) (sanofi-aventis, Frankfurt, Germany). Examples of disposable pen and / or auto-injector delivery devices for use in subcutaneous delivery of the pharmaceutical compositions of the present invention include, but are not limited to, SOLOSTAR® pen (sanofi-aventis), FLEXPEN® (Novo Nordisk), and KWIKPEN® (Eli Lilly), SURECLICK® Autoinjector (Amgen, Thousand Oaks, CA), PENLET® (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and the HUMIRA® Pen (Abbott Labs, Abbott Park, IL).

[0121] The use of microinfusers for delivering anti-hlL-6R antibodies (or pharmaceutical formulations containing this antibody) to patients is also envisioned herein. As used herein, the term “microinfuser” means a subcutaneous delivery device designed to slowly administer large volumes (e.g., up to approximately 2.5 mL or more) of therapeutic formulations over extended periods (e.g., approximately 10, 15, 20, 25, 30 minutes or more). See, for example, US 6,629,949; US 6,659,982; and Meehan et al., J. Controlled Release 46:107-116 (1996). Microinfusers are particularly useful for delivering large doses of therapeutic proteins contained in high concentrations (e.g., approximately 100, 125, 150, 175, 200 mg / mL or more) and / or viscous solutions.

[0122] Combination therapy The present invention includes a method for treating rheumatoid arthritis, comprising administering an anti-hlL-6R antibody in combination with at least one further therapeutic agent to a patient requiring treatment for rheumatoid arthritis. Examples of further therapeutic agents that can be administered in combination with the anti-hlL-6R antibody when carrying out the method of the present invention include, but are not limited to, disease-modifying disease-preventing agents (DMARDs) and any other compounds known to treat, prevent, or improve rheumatoid arthritis in human subjects. Specific and non-limiting examples of further therapeutic agents that can be administered in combination with the anti-hlL-6R antibody in the context of the method of the present invention include, but are not limited to, methotrexate. Examples include sulfasalazine, hydroxychloroquine, and leflunomide. In the method of the present invention, further therapeutic agents can be administered simultaneously with or sequentially with the anti-hlL-6R antibody. For example, in the case of simultaneous administration, a pharmaceutical formulation containing both the anti-hlL-6R antibody and at least one further therapeutic agent can be produced. The amount of further therapeutic agent administered in combination with the anti-hlL-6R antibody when carrying out the method of the present invention can be easily determined using conventional methods known and readily available in the art.

[0123] The disclosure of the present invention provides a pharmaceutical composition comprising any of the following:

[0124] A composition comprising 100 mg to 150 mg of sarilumab (SAR153191) and 10 to 25 mg of methotrexate.

[0125] A composition comprising 100 mg to 200 mg of sarilumab (SAR153191) and 10 to 25 mg of methotrexate.

[0126] A composition comprising 100 mg to 150 mg of sarilumab (SAR153191) and 6 to 25 mg of methotrexate.

[0127] A composition comprising 100 mg to 200 mg of sarilumab (SAR153191) and 6 to 25 mg of methotrexate.

[0128] A composition comprising 100 mg to 150 mg of sarilumab (SAR153191) and 10 to 20 mg of leflunomide.

[0129] A composition comprising 100 mg to 200 mg of sarilumab (SAR153191) and 10 to 20 mg of leflunomide.

[0130] A composition comprising 100 mg to 150 mg of sarilumab (SAR153191) and 1000 to 3000 mg of sulfasalazine.

[0131] A composition comprising 100 mg to 200 mg of sarilumab (SAR153191) and 1000 to 3000 mg of sulfasalazine.

[0132] A composition comprising 100 mg to 150 mg of sarilumab (SAR153191) and 200 to 400 mg of hydroxychloroquine.

[0133] A composition comprising 100 mg to 200 mg of sarilumab (SAR153191) and 200 to 400 mg of hydroxychloroquine.

[0134] The disclosure of the present invention provides a method for improving symptoms associated with rheumatoid arthritis, which includes any of the following:

[0135] A method comprising administering to subjects requiring the treatment 100 to 150 mg of sarilumab (SAR153191) and 10 to 25 mg of methotrexate per week.

[0136] A method comprising administering to subjects requiring the treatment 100 mg to 200 mg of sarilumab (SAR153191) every two weeks and 10 to 25 mg of methotrexate per week.

[0137] For subjects who require it, 100 mg to 150 mg of sarilumab (SAR15) per week is administered. A method comprising administering (3191) and 6 to 25 mg of methotrexate.

[0138] A method comprising administering to subjects requiring the treatment 100 mg to 200 mg of sarilumab (SAR153191) every two weeks and 6 to 25 mg of methotrexate per week.

[0139] A method comprising administering to subjects requiring the treatment 100 to 150 mg of sarilumab (SAR153191) per week and 10 to 20 mg of leflunomidot per day.

[0140] A method comprising administering to subjects requiring the treatment 100 to 200 mg of sarilumab (SAR153191) every two weeks and 10 to 20 mg of leflunomide daily.

[0141] A method comprising administering to subjects requiring the treatment 100 to 150 mg of sarilumab (SAR153191) per week and 1,000 to 3,000 mg of sulfasalazine per day.

[0142] A method comprising administering to subjects requiring the treatment 100 to 200 mg of sarilumab (SAR153191) every two weeks and 1,000 to 3,000 mg of sulfasalazine daily.

[0143] A method comprising administering to subjects requiring the treatment 100 to 150 mg of sarilumab (SAR153191) per week and 200 to 400 mg of hydroxychloroquine per day.

[0144] A method comprising administering to subjects requiring the treatment 100 to 200 mg of sarilumab (SAR153191) every two weeks and 200 to 400 mg of hydroxychloroquine daily.

[0145] biomarkers This disclosure includes a method for treating rheumatoid arthritis, in which, after administration, the levels of one or more RA-related biomarkers in the patient are altered (e.g., increased or decreased, depending on the case) by administering to the patient a therapeutically effective amount of a human antibody or an antibody-binding fragment that specifically binds to hlL-6R and one or more therapeutically effective amounts of a DMARD. In a related aspect, the present invention includes a method for reducing RA-related biomarkers in a patient by administering to the patient a therapeutically effective amount of a human antibody or an antigen-binding fragment that specifically binds to hlL-6R and one or more therapeutically effective amounts of a DMARD.

[0146] Examples of biomarkers associated with rheumatoid arthritis (RA) include, but are not limited to, high-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), erythrocyte sedimentation rate (ESR), serum hepcidin, interleukin-6 (IL-6), and hemoglobin (Hb). As will be understood by those skilled in the art, an increase or decrease in RA-related biomarkers can be determined by comparing the biomarker levels measured in the patient at a predetermined time point after administration of the anti-IL-6R antibody to the biomarker levels measured in the patient before administration (i.e., "baseline measurements"). The predetermined time points at which biomarkers can be measured may be, for example, approximately 4 hours, 8 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 15 days, 20 days, 35 days, or 40 days or more after administration of the anti-IL-6R antibody.

[0147] According to certain embodiments of the present invention, a patient may show a decrease in one or more levels of hsCRP, SAA, ESR, and / or hepcidin after being administered an anti-hlL-6R antibody. For example, after approximately 12 weeks of weekly administration of an anti-hlL-6R antibody and one or more DMARDs, a patient may show one or more of the following: (i) hsCRP decreases by approximately 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more; (ii) SAA decreases by approximately 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more; (iii) ESR decreases by approximately 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, or more; and / or (iv) hepcidin decreases by approximately 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or more.

[0148] According to certain other embodiments of the present invention, a patient may show an increase in one or more levels of Hb or IL-6 after being administered an anti-hlL-6R antibody and one or more DMARDs. For example, after about 12 weeks of weekly administration of an anti-hlL-6R antibody and one or more DMARDs, a patient may show one or more of the following: (v) Hb increases by 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; and / or (vi) IL-6 increases by about 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800%, or more.

[0149] The present invention includes a method for determining whether a subject is a suitable patient for whom administration of an anti-hlL-6R antibody would be beneficial. For example, if an individual exhibits levels of RA-related biomarkers indicating a disease state prior to taking an anti-hlL-6R antibody and / or one or more DMARDs, this individual is identified as a suitable patient for whom administration of an anti-hlL-6R antibody would be beneficial. According to certain exemplary embodiments, an individual may be identified as a good candidate for anti-hlL-6R / DMARD treatment if this individual exhibits one or more of the following: (i) The level of hsCRP is greater than approximately 4 mg / L (e.g., approximately 4.5 mg / L, approximately 5.0 mg / L, approximately 5.5 mg / L, approximately 6.0 mg / L, approximately 7.0 mg / L, approximately 10.0 mg / L, approximately 15.0 mg / L, approximately 20.0 mg / L, or greater); (ii) The level of SAA is greater than approximately 3800 ng / mL (e.g., approximately 4000 ng / mL, 4500 ng / mL); g / mL, approximately 5000 ng / mL, approximately 5500 ng / mL, approximately 6000 ng / mL, approximately 10,000 ng / mL, approximately 20,000 ng / mL, approximately 25,000 ng / mL, approximately 30,000 ng / mL, approximately 35,000 ng / mL, approximately 40,000 ng / mL, approximately 45,000 ng / mL, or greater. (iii) ESR greater than approximately 15 mm / hr For example, approximately 16 mm / hr, 17 mm / hr, 18 mm / hr, 19 mm / hr, 20 mm / hr, 21 mm / hr, 22 mm / hr, 25 mm / hr, 30 mm / hr, 35 mm / hr, 40 mm / hr, 45 mm / hr, 50 mm / hr, or greater); and / or (iv) hepcidin levels greater than approximately 60 ng / mL (for example, approximately 62 ng / mL, 64 ng / mL, 68 ng / mL, 70 ng / mL, 72 ng / mL, 74 ng / mL, 76 ng / mL, 78 ng / mL, 80 ng / mL, 82 ng / mL, 84 ng / mL, 85 ng / mL, 90 ng / mL, 95 ng / mL, 100 ng / mL, 105 ng / mL, or greater). Further criteria, such as other clinical indicators of RA, may be used in combination with any of the RA-related biomarkers mentioned above to identify individuals as suitable candidates for anti-hlL-6R therapy.

[0150] Patient group In certain embodiments, the methods and compositions described herein are administered to specific patient populations. These populations include patients who have already been treated for rheumatoid arthritis with a treatment regimen other than a combination of anti-hlL-6R antibodies and one or more DMARDs. These treatment regimens include anti-TNF-α therapies, such as biological anti-TNF-α therapy regimens. Examples of biological anti-TNF-α antagonists include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. These treatment regimens also include DMARD therapy in the absence of anti-hlL-6R antibodies.

[0151] Examples of DMARDs used for treatment include methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide. DMARDs may be administered alone or in combination with another treatment other than an anti-hlL-6R antibody. In a specific embodiment, the prior treatment plan was methotrexate. In another embodiment, treatment with methotrexate is continued in a patient being treated with an anti-hlL-6R antibody. In a particular embodiment, the patient had previously received both anti-TNF-α treatment and DMARD treatment. Treatments may be administered in any order or simultaneously. In a particular embodiment, the patient had received these treatments within two years prior to receiving a combination of anti-hlL-6R antibody and one or more DMARDs. In other embodiments, the patient had received these treatments within one, two, three, four, five, six, seven, eight, nine, or ten years prior to receiving a combination of anti-hlL-6R antibody and one or more DMARDs.

[0152] In certain embodiments, the methods and compositions described herein are administered to a specific patient population that has received one or more of the above-described treatment plans and for which these treatments have been ineffective. In use herein, treatment was ineffective when anti-TNF-α and DMARD administration did not result in a detectable improvement in one or more symptoms associated with rheumatoid arthritis, or produced a biological effect (e.g., a decrease in the amount of a specific biomarker) that correlates with the pathological mechanisms underlying the rheumatoid arthritis condition or symptoms.

[0153] In another example, anti-TNF-α therapy was deemed ineffective when it did not result in a detectable improvement in one or more symptoms associated with rheumatoid arthritis, or when it did not produce a biological effect (e.g., a decrease in the amount of a specific biomarker) that correlates with the pathological mechanisms underlying the rheumatoid arthritis condition or symptoms.

[0154] In another example, treatment was deemed ineffective when administration of anti-hlL-6R antibodies and DMARDs did not result in a detectable improvement in one or more symptoms associated with rheumatoid arthritis, or when it did not produce a biological effect correlated with the underlying pathological mechanism causing the rheumatoid arthritis condition or symptoms.

[0155] In certain embodiments, sarilumab is administered to patients who have previously received ineffective treatment for rheumatoid arthritis with DMARDs. As used herein, treatment with DMARDs was ineffective if the patient still claims to have “active disease” after treatment. A patient claims active disease if they exhibit tenderness in at least 8 of 68 joints, joint swelling in 6 of 66 joints, and a high-sensitivity C-reactive protein (hs-CRP) >10 mg / L (>1.0 mg / dL). In specific embodiments, the patient has previously received ineffective treatment for rheumatoid arthritis with MTX. In such cases, the patient may have received continuous treatment with MTX at a dose of 10 mg to 25 mg / week (or per regional labeling requirement, if the dosing range differs) for at least 12 weeks, or a stable dose of MTX for a minimum of 8 weeks, and has moderate to severe active RA as defined below. (i) at least 8 tender joints out of 68, joint swelling in 6 out of 66, and (ii) high-sensitivity C-reactive protein (hs-CRP) > 10 mg / L (> 1.0 mg / dL).

[0156] For example, treatment that does not improve any of the following symptoms or conditions is considered ineffective: chronic disease anemia, fever, depression, fatigue, rheumatic nodules, vasculitis, neuropathy, scleritis, pericarditis, Felty syndrome, and / or joint destruction.

[0157] Detectable improvements can also be identified using the American College of Rheumatism (ACR) rheumatoid arthritis classification criteria. For example, detectable improvements can be indicated using a 20% improvement from baseline (ACR20), a 50% improvement (ACR50), or a 70% improvement (ACR70).

[0158] The Disease Activity Score (DAS28) can be used to demonstrate detectable improvement. The DAS28 is a composite score combining the number of tender joints based on 28 joints, the number of joint swellings based on 28 joints, an overall health assessment, and inflammatory markers that can be assessed by measuring C-reactive protein (CRP) levels. Disease response can be expressed using the European League against Rheumatism (EULAR) response criteria. A good response according to these criteria is an improvement of greater than 1.2 in the DAS28 score, with a current score of 3.2 or higher. A moderate response is an improvement of greater than 0.6 and less than or equal to 1.2 in the DAS28 score, with a current score of 3.2 or higher. No response is an improvement of less than 0.6 in the DAS28 score, with a current score greater than 5.1. DAS28 remission is a DAS28 score less than 2.6. Detectable improvement can also be demonstrated by measuring improvement in any element of the DAS28 score. [Examples]

[0159] [Example 1] The combination of sarilumab and methotrexate is effective in treating rheumatoid arthritis in patients who do not respond to methotrexate therapy.

[0160] A global, double-blind, placebo-controlled randomized trial was conducted in rheumatoid arthritis patients with inadequate response to methotrexate (MTX). Patients participating in this trial had the following criteria: Patients had to have active disease as defined below: at least 6 of 66 joint swellings and at least 8 of 68 tender joints, and hs-CRP > 6 mg / L. Patients also had to be receiving continuous treatment with methotrexate (MTX) at a dose of 10 mg to 25 mg / week (or 6 mg to 25 mg / week for patients in the Asia-Pacific region) for 12 weeks.

[0161] This trial consisted of two parts. Part A of the trial was a 12-week study spanning six different dosing ranges aimed at selecting two best dosing plans based on efficacy (reduction of signs and symptoms) and safety. Part B of the trial was a 52-week study confirming the efficacy and safety of these two selected dosing plans in terms of reducing signs and symptoms, inhibiting the progression of structural damage, improving physical function, and inducing major clinical responses.

[0162] The operationally seamless design of this trial stems from the fact that Part B begins the patient trial immediately after the last patients in Part A are randomly assigned, without waiting for the dosage to be selected based on the results of Part A. In this way, patients in Part B belong to two distinct cohorts according to their enrollment time.

[0163] Patients in Cohort 1 are randomly selected before dose selection and then randomly divided into 6 groups (as one of Part A). After dose selection, patients are randomly divided into two selected dose and placebo plans to continue the 52-week trial, but are also randomly divided into the other 3 groups. Patients who do not meet the criteria will discontinue this trial, but are offered the opportunity to participate in an extended trial in an open-label setting (see LTS11210).

[0164] Patients in Cohort 2 were randomly divided after dosage selection, and these patients were then randomly assigned to one of three groups: one receiving the two selected dosages and one receiving placebo.

[0165] Part A Patients were evaluated during their screening visit to confirm diagnosis, disease activity, eligibility for this trial, and concomitant therapy. A complete set of tests and laboratory examinations were performed, including hematological tests, chemical profiles, lipid profiles, liver enzymes and acute phase reactants, HbA1c, hepatitis B and C, and serum pregnancy tests for women of childbearing potential. ECG evaluations were also performed. To rule out tuberculosis, PPD tests and QuantiFERON were performed, along with chest X-rays (if negative X-ray documentation from the most recent three months was not available).

[0166] After eligibility was confirmed, patients were randomly assigned in a balanced manner to this international multicenter, double-blind, placebo-controlled 12-week study treatment, receiving either SAR153191 administered subcutaneously once weekly in parallel with MTX, or placebo. Dosages are shown in Figure 1.

[0167] Each patient was administered methotrexate as they had been given prior to the trial. For patients in the Asia-Pacific region (Taiwan, South Korea, Malaysia, the Philippines, Thailand, and India), the dosage was 10 mg to 25 mg / week or 6 mg to 25 mg / week.

[0168] During the first visit, the patient was reminded of the list of prohibited drug therapies and cautioned that MTX should be continued at this current stable dose until the trial was completed with folic acid as per regional recommendations to prevent MTX toxicity. The patient was instructed to prepare and administer the IMP themselves and cautioned to strictly space injections between each. At administration time points occurring outside of on-site observation, SAR153191 was administered by the patient themselves, by a trained professional caregiver, or by a trained professional.

[0169] Patients underwent six additional visits at weeks 2, 4, 6, 8, 10, and 12. Throughout the study, efficacy assessments, including hematological tests, chemical profiles, lipid profiles, liver enzymes, and acute-phase reactants, as well as laboratory tests, were evaluated to calculate the primary efficacy score and monitor aspects of safety. At randomized visits and at weeks 2, 4, 8, and 12, a complete joint examination was performed by a separate evaluator from the laboratory staff, using patient data, to calculate the ACR score (primary endpoint), including the number of tender joints and joint swelling. To maintain blinding, the laboratory staff, sponsor, and patients were unaware of their CRP and serum IL-6 levels during the study.

[0170] Close monitoring of adverse events, including the possibility of infection partially assessed by monitoring body temperature, was performed at each visit. The presence of tuberculosis was investigated by specific patient assessments (investigating any signs or symptoms, or contact with active TB). Neurological abnormalities (medical history and physical examination) or autoimmune predisposition (ANA, ds-DNA antibodies) were examined at baseline and at the end of treatment visits.

[0171] To investigate potential biomarkers that may predict disease response or adverse events, specific blood and urine samples were collected during the study. These samples contained DNA. This included one sample (after the patient signed a specific informed consent form) and several samples obtained sequentially throughout the entire study for RNA expression profiling and protein biomarker analysis. Samples were also collected at appropriate time points for pharmacokinetic parameters and antibodies against SAR153191.

[0172] Patients who discontinued treatment early were evaluated when treatment visits, including complete clinical and laboratory evaluations, were completed. These patients were classified as non-responders for the ACR score.

[0173] At the end of the treatment visit, a schedule was set for all patients to complete follow-up visits. Patients who completed the treatment period were offered the opportunity to participate in a long-term safety extension study in an open-label trial using SAR153191.

[0174] result Human patients treated with sarilumab (REGN88 / SAR153191) in combination with methotrexate (MTX), the standard treatment for rheumatoid arthritis (RA), achieved significant and clinically meaningful improvement in signs and symptoms of moderate to severe rheumatoid arthritis (RA) compared to patients treated with MTX alone. A multi-group, double-blind, placebo-controlled randomized trial was conducted involving 306 patients of diverse nationalities, varying dosages and comparing five different dosages of sarilumab in combination with MTX to placebo and MTX. The primary endpoint of this trial was the proportion of patients achieving at least 20% improvement in RA symptoms (ACR20) after 12 weeks.

[0175] In patients receiving sarilumab in combination with MTX, the drug response was observed. At 12 weeks, the ACR20 response was observed in 46.2% of patients receiving placebo and MTX, compared to 49.0% in patients receiving the lowest-dose sarilumab regimen and 72.0% in patients receiving the highest-dose regimen (p=0.02, adjusted for multiplicity, for the highest-dose sarilumab regimen) (Figure 2). The most common adverse events (>5%) reported more frequently in the active treatment group included infection (non-severe), neutropenia, and abnormal liver function tests. The types and frequency of adverse events were consistent with those previously reported for IL-6 inhibition. The incidence of serious adverse events was similar in the sarilumab treatment group and the placebo group.

[0176] Sarilumab demonstrated significant benefits compared to placebo in secondary endpoints, including ACR 50, ACR 70, and DAS 28 scores, as well as further measurements of clinical activity used in RA trials. More specifically, - An ACR50 response at 12 weeks was observed in 15% of patients receiving placebo and MTX, compared to 22% of patients receiving the lowest-dose sarilumab regimen and 30% of patients receiving the highest-dose regimen (Figure 3). - The ACR70 score was also significantly higher in the 200 mg q2w group compared to placebo. The ACR70 response at 12 weeks was observed in 2% of patients receiving placebo and MTX, compared to 16% of patients receiving the highest dose regimen (Figure 3).

[0177] These results provide evidence that blocking IL-6R with sarilumab is a representative example of a promising new anti-inflammatory, experimental treatment for reducing the symptoms of rheumatoid arthritis (RA).

[0178] Part B Patients will be evaluated during the screening visit to confirm diagnosis, disease activity, eligibility for this trial, and confirmation of concomitant therapy. The laboratory will determine whether the patient is positive for anti-cyclic citrullinated peptide antibodies (CCP) or rheumatoid factor (RF), or whether the patient is X-ray confirmed. Check for the presence of bone erosions. If necessary, for patients who are negative for both CCP and RF and have no prior X-rays, perform a central re-observation screening X-ray, which will serve as the baseline X-ray assessment for the study.

[0179] Cohort 1: Patients randomly assigned before medication dosage selection. Immediately after the final patients are randomized in Part A, recruitment for a long-term safety extension trial will begin. After eligibility confirmation, patients will be randomized in a balanced manner, stratified by prior biouse and domain, in this international, multicenter, double-blind, placebo-controlled parallel study treatment using SAR153191 (five active drug groups) or six placebo groups, with MTX administered subcutaneously once weekly.

[0180] At the start of visits for all patients in Cohort 1, the examiner will review the IVRS list to determine that the patient is still “eligible” for the trial, i.e., that the patient should not be interrupted because they were randomly assigned to an unselected group. In fact, once a critical dosing plan is selected from Part A, only patients who were randomly assigned to the corresponding group or placebo will be considered still eligible for the trial and will continue for a total of 52 weeks. Other patients (randomly assigned to an unselected dosing plan) will be considered ineligible according to the IVRS. The examiner will propose that these patients participate in an extension trial in an open-label study using SAR153191 with the highest-dose dosing plan available at the time of patient enrollment.

[0181] The initial randomization remains blinded for all patients.

[0182] Cohort 2: Patients randomly assigned after dosage selection - key portion On day 1, after eligibility confirmation, patients will be randomly assigned in a balanced manner, stratified by prior biouse and domain, in this international multicenter, double-blind, placebo-controlled parallel trial, using three groups: SAR153191 (two critical dosing regimens) administered subcutaneously with MTX parallel therapy, or placebo.

[0183] Both cohorts: In any cohort, patients will be evaluated for efficacy and safety assessments, as well as laboratory trials, every four weeks until week 2, week 4, and week 28, and then every eight weeks until week 52.

[0184] Apply the same procedures described in Part A to Part B. In addition, perform X-ray evaluations of the hand and foot joints at baseline, week 24, and week 52. Send anonymized X-rays of any patient to the central leader to calculate the Sharp score (a specific scoring system for joint destruction). Also include a health economic assessment, such as SF-36.

[0185] From week 16 onward, patients who are unresponsive, or any other clearly unresponsive patients as determined by the examiner, defined as having less than a 20% improvement from baseline in either the number of joint swellings (SJC) or the number of tender joints (TJC) over two consecutive visits, are proposed to be aided in an open-label trial with SAR153191 at the highest available dose when moving to the rescue treatment group, and will continue the trial according to the planned visit schedule. Laboratory blood samples for analysis will be collected two weeks after the switch to safety purposes. These patients will be considered unresponsive to the primary endpoint (ACR20). These patients will remain in the trial and continue all visits.

[0186] In the selected country, patients who do not meet the efficacy criteria for Part B treatment by the 7th visit / 16th week or thereafter will have their treatment permanently discontinued and will not be eligible to participate in the open-label rescue group. Instead, these patients will have a follow-up visit 6 weeks after the end of their treatment visits to assess their safety.

[0187] For any patient who discontinues treatment early, or any patient who is rescued early with open-label SAR153191, perform a further radiographic evaluation at the time of withdrawal or rescue unless a radiographic evaluation has been performed within the preceding three weeks (a three-month interval should be considered between the two evaluations to avoid radiographic exposure).

[0188] Patients completing Part B (including those in the open-label rescue group) are proposed to enroll in an open-label extension trial with the maximum dose regimen at enrollment. For all patients, a date will be set to conclude post-treatment follow-up visits. If a patient consents to enter an open-label, long-term extension trial of SAR153191 and is confirmed to be eligible, post-treatment follow-up visits will not be terminated.

[0189] [Example 2] The combination of sarilumab and DMARDs is effective in treating rheumatoid arthritis in patients who do not respond to TNF-α antagonist therapy or methotrexate therapy.

[0190] A global, double-blind, placebo-controlled, randomized trial was conducted in patients with rheumatoid arthritis who had an inadequate response to methotrexate (MTX) and at least one TNF-α antagonist. Patients participating in this trial had the following criteria: In the opinion of the examiner, patients had an inadequate response to at least one TNF-α antagonist after at least three months of treatment in the past two years, or patients were intolerant to at least one TNF-α antagonist and discontinued treatment. TNF-α antagonists included etanercept, infliximab, adalimumab, golimumab, and / or certolizumab pegol. Patients had to have active disease as defined below: at least 6 joint swellings out of 66, at least 8 tender joints out of 68, and hs-CRP ≥ 8 mg / L. Patients were required to have received continuous treatment with a DMARD or combination of DMARDs for at least 12 weeks prior to baseline, and to have been on a stable medication regimen for at least 6 weeks prior to screening. These DMARDs included methotrexate (MTX) 10 to 25 mg / week (or 6 to 25 mg / week for patients in the Asia-Pacific region); leflunomide (LEF) 10 to 20 mg / day; sulfasalazine (SSZ) 1000 to 3000 mg / day; or hydroxychloroquine (HCQ) 200 to 400 mg / day.

[0191] [Table 1]

[0192] Subcutaneous administration is performed in the abdomen or thigh. Each dose is a single self-administered injection (whenever possible). SC injection sites may alternate between the quadrant of the abdomen (excluding the navel or lumbar region) or the thigh (anterior and lateral).

[0193] At the start of the double-blind treatment period, the patient and / or non-specialized caregivers will be trained to prepare and administer IMP. This training must be documented in the patient's study file. The study coordinator or delegate may administer the first injection, including the initial dose, as part of the training procedure on day 1 (second visit). On the day the patient visits the study, IMP will be administered and blood will be collected according to clinical procedure. If the patient does not take the dose at the study site, a diary will be provided to record information related to these injections. These diaries will be stored as original data in the patient's study file. If the patient is unable to take IMP or does not wish to take IMP, preparations must be made for qualified on-site personnel and / or caregivers to administer IMP for any doses that cannot be scheduled to be taken at the study site.

[0194] If the trial visit does not take place at the planned location, the medication will be administered by the patient and / or caregiver as planned.

[0195] Treatment will be continued for 24 weeks. From week 12 onward, patients who are not responsive, defined as having less than a 20% improvement from baseline in both SJC and TJC over two consecutive visits, will be offered assistance with sarilumab from the open-label trial at the highest dose of the trial. These patients will continue the trial according to the visit schedule.

[0196] In this trial, sarilumab is considered to be administered at the peak of DMARD treatment and as background therapy. All patients should continue treatment with a stable dose of non-biological DMARDs or a combination of non-biological DMARDs as background therapy for at least 12 weeks prior to baseline and at least 6 weeks prior to screening.

[0197] • Methotrexate (MTX) - 10 mg to 25 mg / week (or 6 mg to 25 mg / week for patients in the Asia-Pacific region), folic acid / folic acid added. Leflunomide (LEF) - 10 mg to 20 mg per day • Sulfasalazine (SSZ) - 1000mg to 3000mg per day Hydroxychloroquine (HCQ) - 200 mg to 400 mg per day During the trial, each DMARD dosage will be recorded on the patient report form. At any time, the DMARD dosage may be reduced for safety or tolerance reasons. Changes in dosage and the start date of the new medication must be recorded in the e-CRF at every visit. DMARDs will be distributed or supplied by the sponsor as IMP.

[0198] All patients receiving MTX will take folic acid / foline in accordance with the regional recommendations of the country where the trial is conducted. The dosage, route, and schedule of folic acid / foline administration will be recorded along with any concomitant medications.

[0199] Sarilumab and a matching placebo are administered in pre-filled syringes in identically matched glass bottles. Each pre-filled syringe contains 1.14 mL of either sarilumab (SAR153191) or a matching placebo solution.

[0200] Create a list of treatment kit numbers. Create a randomization list using an Interactive Voice Response System (IVRS). Enter both the randomization and treatment kit lists into the IVR.

[0201] Patients are randomly assigned a treatment kit number by the laboratory, and then patients determine their visit dates using the IVRS, which is available 24 hours a day.

[0202] In accordance with the double-blind design, examiners conduct the treatment trial in a blinded state and do not have access to randomization (treatment code), except in the circumstances described in Chapter 8.7.

[0203] Patients are randomly assigned to a single treatment group using an intensive randomization system with IVRS. Patients are considered to have been randomly assigned when they were assigned a treatment number by IVRS.

[0204] During the first screening visit, the field coordinator connects to the IVRS and obtains the patient number for each patient receiving informed consent. Each patient is assigned a patient number associated with the center, which is assigned in the order it is entered at each center.

[0205] Treatment assignments are made to patients according to a centralized randomization list (1:>1) via an IVRS stratified by previous anti-TNF area and number. On the second visit (day 1), after confirming that the patient is eligible to enter the treatment period, the field coordinator connects to the IVRS to receive the first treatment assignment (kit number). Patients are randomly divided to receive either one of two treatment groups of sarilumab or this matching placebo. The randomization ratio is 1:1:1 (sarilumab 150 mg: sarilumab 200 mg: matching placebo). During subsequent dispensing visits during the treatment period, the field coordinator calls the IVRS to obtain subsequent treatment kit assignments. A confirmation fax / email is sent to the field after each assignment.

[0206] Randomly assigned patients are registered with a randomization number by IVRS and defined as assigned patients, as documented in the IVRS log file. IMPs are also recorded and tracked in the center's IMP inventory form.

[0207] The compositions and methods disclosed herein are not limited in scope by the specific embodiments described herein. It should not be defined. In fact, various modifications of the present invention, in addition to those described herein, will be apparent to those skilled in the art from the above description. Such modifications are intended to be included in the appended claims.

Claims

1. A pharmaceutical composition for use in the treatment of rheumatoid arthritis in patients who have previously received ineffective treatment with one or more DMADs selected from methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine, The composition specifically binds to the human IL-6 receptor, The antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), The VH includes three complementarity-determining regions (CDRs) found within the sequence of SEQ ID NO: 2, and the VL includes three CDRs found within the sequence of SEQ ID NO:

3. The antibody is administered subcutaneously to the patient once every two weeks at a dose of approximately 100 mg to 200 mg. The pharmaceutical composition is used in combination with one or more DMADs selected from leflunomide, sulfasalazine, and hydroxychloroquine. The aforementioned pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, which is administered together with one or more DMARDs.

3. The pharmaceutical composition according to claim 1 or 2, used in combination with one or more DMADs containing leflunomide at a dose ranging from about 10 mg to about 20 mg per day.

4. The pharmaceutical composition according to any one of claims 1 to 3, used in combination with one or more DMADs containing sulfasalazine at a dose ranging from about 1,000 mg to about 3,000 mg per day.

5. The pharmaceutical composition is administered in a dose ranging from approximately 200 mg to approximately 400 mg per day, containing hydroxy A pharmaceutical composition according to any one of claims 1 to 4, to be used in combination with one or more DMADs containing chloroquine.

6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the antibody is administered in a dose of approximately 150 mg per two weeks or approximately 200 mg per two weeks.

7. The pharmaceutical composition according to claim 1, wherein the patient achieves a 20% improvement in the American College of Rheumatology's Core Set Disease Index after 12 weeks of treatment.

8. The pharmaceutical composition according to claim 1, wherein the patient achieves a 50% improvement in the American College of Rheumatology's Core Set Disease Index after 12 weeks of treatment.

9. The pharmaceutical composition according to claim 1, wherein the patient achieves a 70% improvement in the American College of Rheumatology's Core Set Disease Index after 12 weeks of treatment.

10. A pharmaceutical composition according to any one of claims 1 to 9, wherein the antibody is sarilumab.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the patient had previously received ineffective treatment for rheumatoid arthritis by administering a TNF-α antagonist in combination with one or more DMARDs selected from leflunomide, sulfasalazine, and hydroxychloroquine.

12. The pharmaceutical composition according to claim 11, wherein the TNF-α antagonist comprises etanercept, infliximab, adalimumab, golimumab, or certolizumab pegol.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein VH comprises the amino acid sequence of SEQ ID NO: 2 and VL comprises the amino acid sequence of SEQ ID NO: 3.

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