NZ623815A - Compositions for the treatment of rheumatoid arthritis and methods of using same - Google Patents

Abstract

The disclosure relates to a method of treating rheumatoid arthritis in a subject previously treated by administering methotrexate, leflunomide, sulfasalazine and/or hydroxychloroquine, comprising administering to the subject an effective amount of sarilumab (SAR153191). The subject may have been treated with an anti-TNF-a antagonist for at least 3 months in the last 2 years or the subject may have been intolerant to at least one TNF-a antagonist. ated with an anti-TNF-a antagonist for at least 3 months in the last 2 years or the subject may have been intolerant to at least one TNF-a antagonist.

Description

ITIONS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS AND METHODS OF USING SAME FIELD OF THE INVENTION The present invention relates to the field of therapeutic treatment of rheumatoid arthritis. More ically, the invention relates to the use of interleukin-6 receptor (lL—GR) antagonists, such as anti-lL-6R antibodies combined with disease ing antirheumatic drugs, to treat rheumatoid tis.

BACKGROUND It is estimated that approximately 0.5% to 1% of the adult population in North a and Europe is ed by rheumatoid arthritis (RA). RA affects women twice as often as men and the incidence is highest among women over 40 years of age.

RA is characterized by persistent synovitis and progressive destruction of cartilage and bone in multiple joints. The hallmark of the disease is a symmetric polyarthritis characteristically involving the small joints of the hands and feet. The matory process can also target other organs, characteristically bone marrow (anemia), eye (scleritis, episcleritis), lung (interstitial pneumonitis, pleuritis), cardiac (pericarditis) and skin (nodules, leukocytoclastic vasculitis).

Systemic inflammation is characterized by laboratory abnormalities, such as anemia, ed erythrocyte sedimentation rate, fibrinogen and C—reactive protein (CRP) and by clinical symptoms of fatigue, weight loss, muscle atrophy in affected joint areas. The presence of onal high—titer rheumatoid factors and anticyclic linated peptide (anti—CCP) dies provides evidence of immune dysregulation. it has been estimated that 65% to 70% of RA patients have progressive disease that leads to joint destruction, disability and premature death.

There is a need in the art for improved treatment regimens for the improvement of symptoms associated with RA.

SUMMARY The t disclosure provides a use of an antibody or binding fragment thereof in the manufacture of at least one medicament for the treatment of rheumatoid arthritis in a subject previously ineffectively treated for rheumatoid arthritis by the administration of methotrexate and previously treated ineffectively for rheumatoid arthritis by the administration of a TNF -α antagonist, wherein the antibod y or binding fragment thereof comprises the heavy chain variable region of SEQ ID No. 2 and the light chain le region of SEQ ID No. 3, and wherein the at least one medicament is formulated for administration to the patient in a dosing regime that pro vides between 100 mg and 200 mg of said antibody or binding fragment thereof, to the patient; the dosing regime ses at least one dosing cycle that is designed to provide the effective delivery of the at least one medicament in an effective amount per two weeks, and the dosing cycle is repeated for as long as necessary to achieve a desired biological se in a subject.

Throughout this specification, the term “comprises/comprising” and grammatical ions thereof when used in this specification a re to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

The use includes manufact ure of a medicament including an effective amount of sarilumab (SAR153191) and a member of the group consisting of leflunomide, sulfasalazine and ychloroquine. In certain embodiments, the subject was previously ineffectively treated for rheumatoid a rthritis by stering a TNF -α antagonist. Specifically, subject could have been treated for at least three months with the TNF -α antagonist or could have been intolerant of the TNF -α antagonist. The TNF -α nist could be etanercept, infliximab, umab, golimumab or certolizumab. In other embodiments, the subject was previously ineffectively treated for rheumatoid arthritis by administering rexate.

The sarilumab could be administered using the medicament at n 50 and 150 mg per we ek or between 100 and 200 mg per two weeks.

In certain specific embodiments, the medicament includes sarilumab and leflunomide . The leflunomide can be ster ed orally. The leflunomide can also be administered using the medicament at between 10 and 2 0 mg per day to the subject.

In other specific embodiments, the medicament includes for sarilumab and sulfasalazine administration. The sulfasalazine can be administered orally. The sulfasalazine can also be administered using the ment at between 1 000 to 3000 mg per day to the subject.

In other specific embodiments, mab and hydroxychloroquine are administered to the t using the medicament. The hydroxychloroquine can be administered orally. The ychloroquine can also be administere d at between 200 to 400 mg per day to the subject using the medicament.

In some embodiments, as a result of the treatment using the medicament using the medicament the subject achieves a 20% or 50% ement in the American College of Rheumatology core s et e index after 12 weeks of treatment. In other embodiments, 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 embodi ments, as a result of the ent using the medicament the subject achieves a lower disease activity score after 12 weeks of treatment than the subject had before treatment. The disease activity score can be less than or equal to 2.6 at 12 weeks. The d isease ty score can decrease by greater than 1.2 between start of treatment and 12 weeks. The disease activity score can be less than or equal to 3.2 at 12 weeks. The disease activity score can se by greater than 0.6 between start of en t and 12 weeks. The disease activity score can be less than or equal to 5.1 at 12 weeks.

In some embodiments, as a result of the treatment, using the medicament the subject achieves a lower disease activity score after 24 weeks of treatment than the sub ject had before treatment. The disease activity score can be less than or equal to 2.6 at 24 weeks. The disease activity score can decrease by greater than 1.2 between start of treatment and 24 weeks. The disease activity score can be less than or equal to 3.2 at 24 weeks.

The disease activity score can se by greater than 0.6 between start of ent and 24 weeks. The disease activity score can be less than or equal to 5.1 at 24 weeks.

The present disclosure also provides a method of treating rheumatoid arthritis in a t in need thereof comprising administering to the t an effective amount of sarilumab and methotrexate, wherein the subject was previously ineffectively treated for rheumatoid arthritis by administering an anti—TNF-d therapeutic. In certain embodiments, the subject was previously ineffectively treated for rheumatoid arthritis by administering methotrexate. The methotrexate can be stered at between 10 to mg per week to the subject.

In n embodiments, the t Is a mammal. The mammal can be a human. In certain embodiments, the human ls descended from individuals from Asia or the Pacific. Humans descended from individuals from Asia or the Pacific can be administered between 6 and 25 mg per week of methotrexate.

In n embodiments, the subject was previously ineffectively treated for rheumatoid arthritis by administering a TNF-d antagonist. Specifically, subject could have been treated for at least three months with the TNF-d antagonist or could have been intolerant of the TNF—d antagonist. The TNF-d antagonist could be etanercept, infliximab, adalimumab, mab or lzumab. In other embodiments, the subject was previously ineffectively treated for rheumatoid tis by administering methotrexate.

The sarilumab could be administered at between 50 and 150 mg per week or between 100 and 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 e index after 12 weeks of treatment. In other embodiments, as a result of the treatment, the t 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 than the subject had before treatment. The disease activity score can be less than or equal to 2.6 at 12 weeks.

The disease activity score can decrease by r than 1.2 between start of treatment and 12 weeks. The disease activity score can be less than or equal to 3.2 at 12 weeks.

The disease activity score can decrease by greater than 0.6 between start of treatment and 12 weeks. The disease activity score can be less than or equal to 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 than the subject had before treatment. The disease activity score can be less than or equal to 2.6 at 24 weeks.

The disease activity score can decrease by greater than 1.2 n start of treatment and 24 weeks. The disease activity score can be less than or equal to 3.2 at 24 weeks.

The e activity score can decrease by greater than 0.6 between start of treatment and 24 weeks. The disease activity score can be less than or equal to 5.1 at 24 weeks.

The disclosure also provides a pharmaceutical composition comprising an ive amount of sarilumab and a member of the group consisting of omide, sulfasalazine and ychloroquine. The sarilumab could be present at between 50 and 150 mg per dose or between 100 and 200 mg per dose.

In n specific embodiments, the composition includes sarilumab and leflunomide. The Ieflunomide can be present in an oral dosage form. The Ieflunomide can be present in the composition at between 10 and 20 mg per dose.

In other specific embodiments, the composition includes sarilumab and sulfasalazine. The alazine can be present in an oral dosage form. The sulfasalazine can be present in the composition at between 1000 to 3000 mg per day to the subject.

In other specific embodiments, the composition includes sarilumab and hydroxychloroquine. The hydroxychloroquine can be present in an oral dosage form.

The hydroxychloroquine can be present in the composition at between 200 to 400 mg per day to the t.

Examples of embodiments of the invention are listed below: Embodiment 12A method of treating rheumatoid arthritis in a subject in need thereof comprising administering to the subject an effective amount of sarilumab (SAR153191) and a member of the group consisting of leflunomide, sulfasalazine and hydroxychloroquine.

Embodiment 2: The method of embodiment 1, n the t was previously ineffectively treated for rheumatoid arthritis by administering a TNF-d antagonist.

Embodiment 3: The method of embodiment 2, wherein the TNF-d antagonist is a biologic anti-TN F-d antagonist.

Embodiment 4: The method of embodiment 2 or 3, wherein the subject was treated for at least three months with the TNF-d antagonist.

Embodiment 5: The method of embodiment 2 or 3, wherein the subject was intolerant of the TNF-d antagonist.

Embodiment 6: The method of embodiment 2 or 3, wherein the TNF-a antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab and certolizumab. ment 7: The method of embodiment 2 or 3, wherein the subject was previously ineffectively treated for rheumatoid arthritis by administering methotrexate.

Embodiment 8: The method of embodiment 1, wherein the sarilumab is administered at n 50 and 150 mg per week.

Embodiment 9: The method of embodiment 1, wherein the sarilumab is administered at between 100 and 200 mg per two weeks.

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

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

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

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

Embodiment 14: The method of embodiment 13, wherein the alazine is stered orally.

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

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

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

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

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 t es a 50% improvement in the American College of tology 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 e index after 24 weeks of ent.

Embodiment 22: The method of any of embodiments 1-18, wherein the subject achieves a 50% improvement in the American College of tology 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% ement in the American College of Rheumatology core set disease index after 24 weeks of treatment. ment 24: The method of any of embodiments 1-18, wherein the subject achieves a lower disease activity score after 12 weeks of treatment than the subject had before treatment.

Embodiment 25: The method of any of embodiments 1-18, wherein the disease activity score is less than or equal to 2.6 at 12 weeks.

Embodiment 26: The method of any of embodiments 1—18, wherein the disease activity score decreases by greater than 1.2 n start of treatment and 12 weeks.

Embodiment 27: The method of any of embodiments 1—18, wherein the e activity score is less than or equal to 3.2 at 12 weeks.

Embodiment 28: The method of any of embodiments 1~18, wherein the disease activity score decreases by greater than 0.6 n start of treatment and 12 weeks.

Embodiment 29: The method of any of embodiments 1-18, wherein the disease activity score is less than or equal to 5.1 at 12 weeks.

Embodiment 30: The method of any of embodiments 1-18, wherein the t achieves a lower disease activity score after 24 weeks of treatment than the subject had before treatment.

Embodiment 31 : The method of any of embodiments 1-18, wherein the disease activity score is less than or equal to 2.6 at 24 weeks.

Embodiment 32: The method of any of embodiments 1—18, wherein the disease activity score decreases by greater than 1.2 between start of treatment and 24 weeks.

Embodiment 33: The method of any of embodiments 1-18, wherein the disease activity score is less than or equal to 8.2 at 24 weeks. 3O Embodiment 34: The method of any of embodiments 1—1 8, wherein the disease activity score decreases by greater than 0.6 n start of treatment and 24 weeks.

Embodiment 35: The method of any of embodiments 1-18, n the disease activity score is less than or equal to 5.1 at 24 weeks.

Embodiment 36: A method of treating rheumatoid arthritis in a subject in need f comprising administering to the subject an effective amount of sarilumab and methotrexate, wherein the subject was usly ineffectively treated for rheumatoid arthritis by administering an anti—TNF-d antagonist.

Embodiment 37: The method of embodiment 36, wherein the subject was previously ineffectively d for rheumatoid arthritis by administering methotrexate.

Embodiment 38: The method of embodiment 36, wherein the methotrexate is administered at between 10 to 25 mg per week to the subject.

Embodiment 39: The method of embodiment 36, wherein the subject is a mammal.

Embodiment 40: The method of embodiment 37, wherein the mammal is a human.

Embodiment 41 : The method of ment 38, wherein the human is descended from duals from Asia or the Pacific.

Embodiment 42: The method of ment 39, wherein the humans descended from individuals from Asia or the Pacific are administered between 6 and 25 mg per week of methotrexate.

Embodiment 43: The method of embodiment 36, wherein the subject was treated for at least three months with the TNF-d antagonist.

Embodiment 44: The method of embodiment 36, wherein the subject was intolerant of the TNF-d antagonist.

Embodiment 45: The method of embodiment any one of embodiments 3644, wherein the TNF—d antagonist is a biologic anti-TNF-d nist.

Embodiment 46: The method of embodiment 44, wherein the TNF-d antagonist is selected from the group ting of etanercept, infliximab, adalimumab, golimumab and certolizumab.

Embodiment 47: The method of embodiment 36, wherein the mab is administered at between 50 and 150 mg per week.

Embodiment 48: The method of embodiment 36, wherein the sarilumab is administered at between 100 and 200 mg per two weeks.

Embodiment 49: The method of any of embodiments 36—48, wherein the subject achieves a 20% improvement in the American College of Rheumatology core set disease index after 12 weeks of treatment.

Embodiment 50: The method of any of embodiments 36-48, wherein the subject achieves a 50% improvement in the American College of Rheumatology core set disease index after 12 weeks of treatment. ment 51 : The method of any of embodiments 36-48, wherein the subject achieves a 20% ement in the an College of tology core set disease index after 24 weeks of treatment.

Embodiment 52: The method of any of embodiments 36-48, wherein the t achieves a 50% improvement in the American College of Rheumatology core set disease index after 24 weeks of treatment.

Embodiment 53: The method of any of embodiments 36-48, wherein the subject achieves a 70% ement in the American College of Rheumatology core set e index after 24 weeks of treatment.

Embodiment 54: The method of any of embodiments 36-48, wherein the subject achieves a lower e activity score after 12 weeks of treatment than the subject had before treatment.

Embodiment 55: The method of any of embodiments 36-48, wherein the disease activity score is less than or equal to 2.6 at 12 weeks.

Embodiment 56: The method of any of embodiments 36-48, wherein the disease activity score decreases by greater than 1.2 between start of treatment and 12 weeks.

Embodiment 57: The method of any of ments 36-48, wherein the disease activity score is less than or equal to 3.2 at 12 weeks. ment 58: The method of any of embodiments 36-48, wherein the disease ty score decreases by greater than 0.6 between start of treatment and 12 weeks.

Embodiment 59: The method of any of embodiments 36-48, wherein the disease activity score is less than or equal to 5.1 at 12 weeks.

Embodiment 60: The method of any of embodiments 36-48, wherein the subject achieves a lower disease ty score after 24 weeks of treatment than the subject had before treatment.

Embodiment 61 : The method of any of embodiments 36-48, wherein the disease activity score is less than or equal to 2.6 at 24 weeks.

Embodiment 62: The method of any of embodiments 36-48, wherein the disease activity score decreases by greater than 1.2 between start of treatment and 24 weeks.

Embodiment 63: The method of any of embodiments 34-45, wherein the disease ty score is less than or equal to 3.2 at 24 weeks.

Embodiment 64: The method of any of embodiments 34—45, wherein the disease activity score decreases by greater than 0.6 between start of treatment and 24 weeks.

Embodiment 65: The method of any of ments 34-45, n the disease activity score is less than or equal to 5.1 at 24 weeks.

Embodiment 66: A pharmaceutical composition comprising an effective amount of sarilumab and a‘member of the group consisting of leflunomide, sulfasalazine and hydroxychloroquine.

DETAILED DESCRIPTION The disclosure provides pharmaceutical compositions and methods of using these compositions for the ent of rheumatoid arthritis (RA) and the improvement of at least one symptom of RA. These compositions include at least one antibody that specifically binds human interleukin~6 receptor (hlL-GR) and at least one disease modifying antirheumatic drug (DMARD).

Anti—h/L—6Fi’ Ant/bodies The present disclosure includes methods that comprise administering to a patient a human antibody, or an antigen—binding fragment thereof, that binds specifically to hlL-BR. As used herein, the term "hlL~6R" means a human cytokine receptor that specifically binds human interleukin-6 (IL—6). in certain embodiments, the antibody that is administered to the patient binds specifically to the extracellular domain of hlL-6R.

The extracellular domain of hlL-6R is shown in the amino acid sequence of SEQ ID NO:1.

Unless specifically indicated otherwise, the term "antibody," as used , shall be tood to encompass antibody molecules comprising two immunoglobulin heavy chains and two immunoglobulin light chains (i.e., "full dy molecules") as well as antigen-binding fragments thereof. The terms "antigen-binding portion" of an dy, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically able, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic ion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding dy variable and nally) constant domains. Such DNA is known and/or is readily available from, e.g., commercial sources, DNA ies (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be 3O sequenced and lated chemically or by using molecular biology techniques, for example, to arrange one or more variable and/or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

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

An antigen—binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more ork sequences. In antigen-binding fragments having a VH domain associated with a VL , the VH and VL domains may be situated relative to one another in any suitable arrangement. For example, the variable region may be dimeric and n VH-VH, VH-VL or VL—VL . Alternatively, the antigen—binding fragment of an antibody may contain a monomeric VH or VL domain. in certain ments, an n-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non- limiting, ary configurations of variable and constant s that may be found within an antigen~binding fragment of an dy of the present invention include: (i) VH'CHi; (ll) VH'CH2§ (iii) VH'CHB; (1V) VH'CHt'CH2§ (V) VH‘CHt-CHz-CHai (Vi) VH'CHZ‘CHS; (Vii) VH-CL; (viii) VL-Cm; (ix) VL-CHZ; (x) VL-CHS; (xi) VL-CH1—CH2; (xii) VL-CH1—CH2—CH3; (xiii) VL— CHZ'CHg; and (xiv) VL-CL. in any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi—flexible linkage between adjacent variable and/or constant domains in a single polypeptide molecule. Moreover, an n-binding fragment of an antibody of the present invention may comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non—covalent association with one r and/or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)).

The term "specifically binds," means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions. ic binding can be characterized by a dissociation nt of at least about 1x10'E3 M or smaller. in other embodiments, the dissociation constant is at least about 1x10'7 M, 1x10‘8 M , or 1x10‘9 M. Methods for ining whether two molecules specifically bind are well known in the art and include, for example, equilibrium is, surface plasmon resonance, and the like.

As with full antibody molecules, antigen-binding fragments may be monospecific or multispecific (e.g., bispecific). A multispecific antigen-binding fragment of an antibody will typically comprise at least two ent le domains, wherein each variable domain is capable of specifically binding to a separate antigen or to a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, may be adapted for use in the context of an antigen-binding fragment of an antibody of the present ion using routine techniques available in the art.

In specific ments, the antibody or antibody fragment for use in the method of the ion may be a pecific antibody, which may be specific for different es of one target polypeptide or may contain antigen-binding s specific for epitopes of more than one target polypeptide. An exemplary bi-specific antibody format that can be used in the context of the present invention involves the use of a first immunoglobulin (lg) CH3 domain and a second lg CH3 domain, wherein the first and second lg CH3 s differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bispecific antibody to Protein Alas compared to a bi-specific antibody lacking the amino acid difference. in one embodiment, the first lg CH3 domain binds Protein A and the second lg CH3 domain contains a on that reduces or abolishes Protein A binding such as an H95R modification (by lMGT exon ing; H435R by EU numbering). The second CH3 may further comprise an Y96F modification (by lMGT; Y436F by EU). Further modifications that may be found within the second CH3 include: D16E, L18M, N448, K52N, V57M, and V82l (by llleT; D356E, L358M, N384S, K392N, V397M, and V422l by EU) in the case of lng antibodies; N448, K52N, and V82l (lMGT; N384S, K392N, and V422| by EU) in the case of lgG2 antibodies; and 015R, N448, K52N, V57M, R69K, E790, and V82l (by lMGT; Q355R, N384S, K392N, V397M, R409K, E4190, and V422l by EU) in the case of lgG4 antibodies. Variations on the bi-specific dy 3O format described above are contemplated within the scope of the present invention.

In other specific embodiments, the antibody is sarilumab (SAR153191). The heavy chain variable region of sarilumab is shown below as SEQ ID N022.

The light chain variable region of sarilumab is shown below as SEQ ID NO:3.

A "neutralizing” or “blocking” antibody, as used herein, is intended to refer to an antibody whose binding to hlL-6R results in inhibition of the ical activity of hlL-6.

This inhibition of the biological activity of hlL-G can be assessed by measuring one or more indicators of hlL-6 biological activity known to the art, such as induced cellular activation and hlL—6 binding to hlL~6R (see examples .

The human L-6R dies disclosed herein may comprise one or more amino acid substitutions, insertions and/or deletions in the framework and/or CDR regions of the heavy and light chain variable domains as ed to the ponding germline sequences. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present invention includes antibodies, and antigen—binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and/or CDR regions are back-mutated to the corresponding germline residue(s) or to a conservative amino acid substitution (natural or non-natural) of the corresponding germline e(s) (such sequence s are referred to herein as "germline back-mutations"). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen—binding fragments which comprise one or more individual germline back-mutations or combinations thereof. in certain embodiments, all of the framework and/or CDR residues within the VH and/or VL domains are mutated back to the germline ce. in other embodiments, only certain residues are mutated back to the germline sequence, e.g., only the mutated es found within the first 8 amino acids of FRt or within the last 8 amino acids of FR4, or only the mutated residues found within CDRi, CDR2 or CDR3. Furthermore, the antibodies of the present invention may contain any combination of two or more germline back- mutations within the framework and/or CDR regions, i.e., wherein n individual residues are mutated back to the germline sequence while certain other residues that differ from the germline sequence are maintained. Once obtained, dies and antigen-binding fragments that n one or more germline back-mutations can be easily tested for one or more desired property such as, improved binding icity, increased binding affinity, improved or enhanced antagonistic or agonistic biological ties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen- binding fragments obtained in this general manner are encompassed within the present invention.

The term ”epitope” refers to an antigenic inant that interacts with a specific antigen g site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstance, an epitope may e moieties of saccharides, phosphoryl groups, or sufonyl groups on the antigen.

The anti—hlL-BR can 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 lD N023.

DMAFz’Ds Disease modifying antirheumatic drugs (DMARDs) e methotrexate, alazine, hydroxychloroquine and leflunomide. According to the itions and methods of the disclosure, DMARDs can be administered as follows. Methotrexate can be administered from 10 to 25 mg per week orally or intramuscularly. in r embodiment, methotrexate is administered from 6 to 25 mg/week orally or intramuscularly for patients who are from the Asia-Pacific region or who are descended from people who are from the Asia—Pacific region. The Asia-Pacific region includes Taiwan, South Korea, Malaysia, Philippines, Thailand and lndia. in n embodiments, methotrexate is administered at between 6 and 12, 10 and 15, 15 and 20 and 20 and 25 mg per week. in other ments, methotrexate is administered at 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 mg perweek. omide can be administered from 10 to 20 mg orally daily. In certain embodiments, leflunomide can be administered at between 10 and 12, 12 and 15, 15 and 17 and 18 and 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 from 1000 to 3000 mg orally daily. in n embodiments, sulfasalazine can be administered at between 1000 and 1400, 1400 and 1800, 1800 and 2200, 2200 and 2600, and 2600 and 3000 mg per day. in other embodiments, sulfasalazine is administered at 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2800, 2400, 2500, 2600, 2700, 2800, 2900 or 3000 mg per day.

Hydroxychloroquine can be administered from 200 to 400 mg orally daily. In certain embodiments, hydroxychloroquine can be administered at between 200 and 240, 240 and 280, 280 and 320, 320 and 360 and 360 and 400 per day. In other embodiments, hydroxychloroquine can be administered at 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.

Therapeutic stration and Formulations The methods described herein se administering a therapeutically effective amount of an anti-hlL—6R antibody and a DMARD to a patient. As used herein, the phrase "therapeutically effective amount" means a dose of anti-hlL-GR antibody and a DMARD that results in a able improvement in one or more symptoms associated with rheumatoid arthritis or which causes a ical effect (e.g., a decrease in the level of a particular ker) that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s) of toid arthritis. For example, a dose of anti—hlL-6R antibody with one or more DMARDs which causes an improvement in any of the following symptoms or conditions is deemed a "therapeutically effective amount": chronic disease anemia, fever, depression, fatigue, rheumatoid nodules, vasculitis, neuropathy, scleritis, pericarditis, Felty’s syndrome and/orjoint destruction.

A able ement can also be detected using the American College of Rheumatism (ACR) rheumatoid arthritis classification criteria. For example a 20% (ACR20), 50% (ACRSO) or 70% (ACR70) improvement from baseline can be used to show detectable improvement.

The disease activity score (DAS28) can be used to show detectable improvement. DAS28 is a composite score of tender joints count based on 28 joints, a n joints count based on 28 joints, a general health assessment and a marker of mation which can be assessed by ing C-reactive protein (CRP) levels. The disease response can be presented using the European League against Rheumatism (EULAR) response criteria. A good response by this criteria is an improvement of greater than 1.2 in DAS28 score with a present score of greater than or equal to 3.2. A moderate se is an improvement of greater than 0.6 but less than or equal to 1.2 in DAS28 score and a present score of r than 3.2. sponse is an improvement of less than 0.6 in DAS28 score and a present score of greater than 5.1.

DAS28 remission is a DAS28 score of less than 2.6. in accordance with the methods of the present invention, a therapeutically effective amount of anti-hlL-BR antibody that is administered to the patient will vary depending upon the age and the size (e.g., body weight or body surface area) of the patient as well as the route of administration and other factors well known to those of ordinary skill in the art. In n ments, the dose of anti-hIL-6R antibody administered to the patient is from about 10 mg to about 500 mg. For example, the t invention includes methods wherein 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, 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 235 mg, about 240 mg, about 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, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, or more of anti-hlL-SR dy is administered to the patient per week.

In one embodiment, the hlL-GR antibody is administered at 100-150 mg per week. In r embodiment, the hlL-6R antibody is administered at 100-200 mg per ever two weeks. In other embodiments, the hlL~6R antibody is administered at about 100 or about 150 mg per week. in other embodiments, the hlL—GR antibody is administered at about 100, 150 or 200 mg per every two weeks.

The amount of anti—hIL—BR antibody that is administered to the patient may be expressed in terms of milligrams of antibody per kilogram of patient body weight , mg/kg). For example, the methods of the present invention include administering an anti-hIL—SR antibody to a patient at a daily dose of about 0.01 to about 100 mg/kg, about 0.1 to about 50 mg/kg, or about 1 to about 10 mg/kg of patient body weight.

The methods of the present invention include administering multiple doses of an anti-hlL-BR antibody to a t over a specified time course. For example, the anti— hIL-6R antibody can 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 methods of the invention include administering a first dose of anti- hIL—6R antibody to a patient at a first time point, followed by administering at least a second dose of anti-hIL-BR antibody to the patient at a second time point. The first and second doses, in certain embodiments, may contain the same amount of anti-hIL-BR antibody. For instance, the first and second doses may each contain 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. The time between the first and second doses may be from about a few hours to several weeks. For example, the second time point (i.e., the time when the second dose is administered) can be from about 1 hour to about 7 weeks after the first time point (i.e., the time when the first dose is administered).

According to certain exemplary ments of the present invention, the second time point can be about 1 hour, about 4 hours, about 6 hours, about 8 hours, about 10 hours, 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, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks or longer after the first time point. in certain embodiments, the second time point is about 1 week or about 2 weeks.

Third and subsequent doses may be rly administered throughout the course of treatment of the patient.

The ion provides methods of using therapeutic compositions comprising anti-lL-6R antibodies or antigen-binding fragments f and one or more DlVlARDs.

The therapeutic compositions of the invention will be administered with suitable rs, excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Pubiishing Company, Easton, PA. These formulations 2O include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LlPOFECTlNTM), DNA conjugates, ous absorption , oil-in-water and water—in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of ents for eral formulations" PDA (1998) J Pharm Sci Technol 52:238~311.

The dose may vary depending upon the age and the weight of a subject to be stered, target disease, conditions, route of administration, and the like. Various delivery systems are known and can be used to administer the pharmaceutical composition of the invention, e.g., encapsulation in liposomes, microparticles, apsules, receptor mediated endocytosis (see, e.g., Wu etal. (1987) J. Biol.

Chem. 262244294432). Methods of uction include, but are not d to, intradermal, uscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered er with other biologically active agents. Administration can be systemic or local. The hlL-GR antibody can be administered subcutaneously. The DMARD can be administered orally or uscularly.

The pharmaceutical composition can also be delivered in a vesicle, in particular a liposome (see Langer (1990) Science 249215274538). In n situations, the pharmaceutical composition can be delivered in a controlled release system, for example, with the use of a pump or polymeric materials. In r ment, a controlled release system can be placed in proximity of the composition’s target, thus requiring only a fraction of the ic dose.

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

Advantageously, the pharmaceutical compositions for oral or parenteral use described above are ed into dosage forms in a unit dose suited to fit a dose of the active ingredients. Such dosage forms in a unit close include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of the DMARD contained is generally about 5 to 3000 mg per dosage form in an oral unit dose depending on the ic DMARD used. The amount of the hlL-BR antibody contained is generally about 100 to 200 mg per subcutaneous dosage form.

In accordance with the methods disclosed herein, the anti-hlL-6R antibody (or pharmaceutical formulation comprising the antibody) can be administered to the patient using any able device or mechanism. For example, the administration can be accomplished using a syringe and needle or with a reusable pen andfor autoinjector delivery device. The methods of the present invention e the use of numerous reusable pen and/or autoinjector delivery devices to administer an anti-hlL-BR antibody (or pharmaceutical formulation comprising the antibody). Examples of such devices include, but are not limited to AUTOPENTM (Owen Mumford, lnc., Woodstock, UK), DISETRONICTM pen ronic l Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25TM pen, HUMALOGTM pen, HUMALlN 70/30TM pen (Eli Lilly and Co., lndianapolis, lN), NOVOPENTM i, ll and ill (Novo Nordisk, Copenhagen, Denmark), N JUNlORTM (Novo Nordisk, Copenhagen, Denmark), BDTM pen (Becton Dickinson, in Lakes, NJ), OPTlPENTM, OPTlPEN PROTM, OPTlPEN TTM, and OPTlCLIKTM (sanofi-aventis, Frankfurt, Germany), to name only a few. Examples of disposable pen and/or autoinjector delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present invention e, but are not limited to the ARTM pen (sancfi—aventis), the FLEXPENTM (Novo Nordisk), and the NTM (Eli Lilly), the SURECLICKTM Autoinjector (Amgen, Thousand Oaks, CA), the F’ENLETTM (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, LP), and the HUMlRATM Pen (Abbott Labs, Abbott Park, IL), to name only a few.

The use of a microinfusor to r an anti-hlL-6R dy (or pharmaceutical formulation comprising the antibody) to a patient is also contemplated herein. As used herein, the term "microinfusor" means a subcutaneous delivery device designed to 2O slowly administer large volumes (e.g., up to about 2.5 mL or more) of a therapeutic formulation over a prolonged period of time (e.g., about 10, 15, 20, 25, 30 or more minutes). See, 9.9., US. 6,629,949; US 6,659,982; and Meehan etal., J. Controlled Release 46:107-116 (1996). Microinfusors are ularly useful for the delivery of large doses of therapeutic ns contained within high concentration (e.g., about 100, 125, 150, 175, 200 or more mg/mL) and/or viscous ons.

Combination Therapies The present invention includes methods of treating rheumatoid arthritis which comprise administering to a patient in need of such treatment an anti-hlL-6R antibody in 3O combination with at least one additional therapeutic agent. Examples of additional therapeutic agents which can be administered in combination with an anti—hlL-6R dy in the ce of the methods of the present invention e, but are not limited to DMARDs, and any other compound known to treat, prevent, or ameliorate rheumatoid arthritis in a human subject. Specific, non-limiting examples of additional therapeutic agents that may be administered in combination with an anti-hlL-SR antibody in the context of a method of the present invention include, but are not limited to methotrexate, sulfasalazine, ychloroquine and leflunomide. In the present methods, the additional therapeutic agent(s) can be stered rently or sequentially with the anti-hlL-6R dy. For example, for concurrent administration, a pharmaceutical formulation can be made which contains both an anti—hlL-BR antibody and at least one additional eutic agent. The amount of the additional therapeutic agent that is administered in combination with the anti-hlL—BR antibody in the practice of the s of the present ion can be easily determined using routine methods known and readily available in the art.

The disclosure of the invention provides for ceutical itions sing any of the following: A composition comprising between 100 and 150 mg of sarilumab (SAR153191) and 10-25 mg of methotrexate.

A composition comprising between 100 and 200 mg of sarilumab (SAR153191) and 10-25 mg of methotrexate.

A composition comprising between 100 and 150 mg of sarilumab (SAR153191) and 6-25 mg of methotrexate.

A ition comprising between 100 and 200 mg of sarilumab (SAR153191) and 6-25 mg of methotrexate.

A composition comprising between 100 and 150 mg of sarilumab (SAR153191) and 10—20 mg of leflunomide.

A composition comprising between 100 and 200 mg of sarilumab (SAR153191) and 10—20 mg of leflunomide.

A ition comprising between 100 and 150 mg of sarilumab (SAR153191) and 1000-3000 mg of sultasalazine.

A composition comprising between 100 and 200 mg of sarilumab (SAR153191) and 1000—3000 mg of sulfasalazine.

A composition comprising between 100 and 150 mg of sarilumab (SAR153191) and 200-400 mg of hydroxychloroquine.

A composition comprising between 100 and 200 mg of sarilumab (SAR153191) and 200—400 mg of hydroxychloroquine.

The disclosure of the invention provides for methods of improving symptoms associated with rheumatoid arthritis comprising any of the following: A method comprising administering between 100 and 150 mg of sarilumab (SARi 53191) and 10—25 mg of methotrexate per week to a subject in need thereof.

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

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

A method comprising administering between 100 and 200 mg of sarilumab 3191) every two weeks and 6-25 mg of methotrexate per week to a subject in need thereof.

A method comprising administering between 100 and 150 mg of sarilumab (SAR153191) per week and 10-20 mg of leflunomide per day to a t in need thereof.

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

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

A method comprising administering between 100 and 200 mg of sarilumab (SAR153191) every two weeks and 1000—3000 mg of sulfasalazine per day to a subject 2O in need thereof.

A method comprising administering between 100 and 150 mg of sarilumab (SAR153191) per week and 0 mg of hydroxychloroquine per day to a subject in need thereof.

A method comprising administering between 100 and 200 mg of sarilumab (SAR153191) every two weeks and 200-400 mg of ychloroquine per day to a subject in need thereof.

Biomarkers The present disclosure includes methods of treating rheumatoid tis by administering to a t in need of such treatment a therapeutically effective amount of a human antibody or dy binding fragment thereof which specifically binds to hlL-6R and a therapeutically effective amount of one or more DMARDs, wherein the level of one or more RA-associated biomarkers in the patient is modified (e.g., increased, decreased, etc, as the case may be) following administration. in a related aspect, the present invention includes methods for decreasing an RA-associated ker in a patient by administering to the patient a therapeutically-effective amount of a human antibody or antigen-binding fragment thereof which specifically binds to hlL- BR and a therapeutically effective amount of one or more DMARDs.

Examples of RA—associated biomarkers include, but are not limited to, e.g., high— sensitivity C-reaotive protein ), serum amyloid A (SAA), erythrocyte sedimentation rate (ESR), serum hepcidin, interleukin-6 (lL—6), and hemoglobin (Hb).

As will be iated by a person of ordinary skill in the art, an increase or decrease in an RA-associated biomarker can be determined by comparing the level of the biomarker measured in the patient at a defined time point after administration of the L-SR antibody to the level of the biomarker measured in the patient prior to the administration (i.e., the "baseline measurement"). The defined time point at which the biomarker can be measured can be, e.g., at about 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, 40 days or more after administration of the anti-hlL-6R antibody.

According to certain ments of the present invention, a t may exhibit a decrease in the level of one or more of hsCRP, SAA, ESR and/or hepcidin following administration of an anti—hlL-6R antibody to the patient. For example, at about week 12 following weekly administration of anti-hlL-6R antibody and one or more DMARDs the patient may exhibit one or more of the following: (i) a decrease in hsCRP by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more; (ii) a decrease in SAA by about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more; (iii) a decrease in ESR by about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or more; and/or (iv) a decrease in in by about 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or more.

According to certain other embodiments of the present invention, a patient may t an increase in the level of one or more of Hb or lL—6 following administration of an anti-hlL-6R antibody and one or more DMARDs to the patient. For example, at about week 12 following weekly administration of lL-6R antibody and one or more DMARDs the patient may exhibit one or more of the ing: (v) an se in Hb 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) an se in lL-6 by about 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800% or more.

The present invention includes methods 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, prior to receiving an anti-hlL—6R antibody and/or one or more DMARDs, exhibits a level of an ociated biomarker which signifies the disease state, the individual is therefore identified as a suitable patient for whom administration of an anti-hlL-6R antibody would be beneficial. According to certain exemplary embodiments, an dual may be fied as a good candidate for anti- hlL-BR/DMARD therapy it the individual exhibits one or more of the following: (i) a level of hsCRP greater than about 4 mg/L (e.g., 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) a level of SAA greater than about 3800 ng/mL (e.g., about 4000 ng/mL, 4500 ng/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 ,000 ng/mL, about 40,000 ng/mL, about 45,000 ng/mL, or more); (iii) an ESR greater than about 15 mm/hr (e.g., 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, or more); and/or (iv) a level of hepcidin greater than about 60 ng/mL (e.g., 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, about 90 ng/mL, about 95 ng/mL, about 100 ng/mL, about 105 ng/mL, or more).

Additional criteria, such as other clinical indicators of RA, may be used in combination with any of the ing RA-associated biomarkers to identify an individual as a suitable candidate for anti—hlL-BR therapy.

Patient Population In certain embodiments, the methods and itions described herein are administered to specific patient populations. These populations include ts that have previously been treated for rheumatoid arthritis with treatment regimens other than the combination of an anti—hlL-GR antibody and one or more DMARDs. These treatment regimens include anti-TNF-d therapy, e.g., biologic anti-TNF-o treatment regimens. ic NF-d antagonists include etanercept, intliximab, adalimumab, golimumab and certolizumab pegol. These treatment regimens also include DMARD therapy in the absence of anti-hIL-6R antibody.

DMARDs used in this therapy include methotrexate, sulfasalazine, hydroxychloroquine and letlunomide. The DMARDs may be administered alone or in combination with another therapy that is not an anti—hlL-BR antibody. In a specific ment, the previous treatment regimen was rexate. In another embodiment, treatment with methotrexate is maintained in patient treated with an anti- hlL-6R antibody. In certain embodiments, the patient has usly been administered both anti-TNF-d and DMARD ies. The therapies may be performed sequentially in any order or simultaneously. in certain embodiments, these therapies have been received by the patient within 2 years prior to receiving the combination of an anti—hlL— 6R antibody and one or more DMARDs. in other embodiments, these therapies have been ed within 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 years prior to receiving the combination of an anti—hlL~6R antibody and one or more DMARDs.

In certain embodiments, the s and compositions described herein are administered to specific patient tions that have ed one or more of the treatment regimens described above wherein these treatments have not been effective.

As used , a treatment has not been effective when a dose of NF—d and a DMARD do not result in a detectable improvement in one or more symptoms associated with rheumatoid arthritis or do not cause a biological effect (e.g., a decrease in the level of a particular ker) that is correlated with the ying pathologic mechanism(s) giving rise to the condition or symptom(s) of rheumatoid arthritis.

In another example, a treatment has not been effective when a dose of anti- TNF-d does not result in a detectable improvement in one or more symptoms associated with rheumatoid arthritis or does not cause a biological effect (e.g., a decrease in the level of a particular biomarker) that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s) In another example, a treatment has not been effective when a dose of anti-hlL- 6R antibody and a DMARD that does not result in a detectable improvement in one or more symptoms ated with rheumatoid arthritis or which does not cause a biological effect that is ated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s) of rheumatoid arthritis. in certain embodiement, sarilumab is administered to a patient who has previously been inefficiently treated with a DMARD. As used herein, a treatment with a DMARD has not been effective when a patient still presents an “active e” after treatment. Patients present an active e when they exhibit at least 8 of 68 tender joints and 6 of 66 swollen joints, and high sensitivity C-reactive n (hs-CRP) >10 mg/L (>1.0 mgidL). in a specific embodiment, patients have previously been inefficiently treated with MTX. in such example, patients may have received continuous treatment with MTX 10 to 25 mg/week (or per local labeling requirements if the dose range differs) for at least 12 weeks and on a stable dose of MTX for a minimum of 8 weeks and still present a te-to-severely active RA, defined as: (i) at least 8 of 68 tender joints and 6 of 66 swollen joints, and (if) high sensitivity C-reactive protein (hs-CRP) >10 mg/L (>1.0 mg/dL).

For example, a treatment which does not cause an improvement in any of the following symptoms or conditions is deemed ineffective: chronic disease anemia, fever, sion, fatigue, rheumatoid nodules, vasculitis, neuropathy, scleritis, pericarditis, Felty’s syndrome and/or joint destruction.

A detectable improvement can also be detected using the American College of Rheumatism (ACR) toid arthritis classification criteria. For example a 20% (ACRZO), 50% (ACRSO) or 70% (ACR70) improvement from baseline can be used to show detectable improvement.

The disease activity score (DASZS) can be used to show able improvement. DAS28 is a composite score of tender joints count based on 28 joints, a swollen joints count based on 28 joints, a general health assessment and a marker of inflammation which can be ed by measuring C-reactive protein (CRP) levels.

The disease response can be presented using the European League against Rheumatism (EULAR) se criteria. A good response by this criteria is an improvement of greater than 1.2 in DA828 score with a present score of r than or equal to 3.2. A moderate response is an improvement of greater than 0.6 but less than or equal to 1.2 in DAS28 score and a present score of greater than 3.2. Non—response is an improvement of less than 0.6 in DA828 score and a present score of greater than .1. DA828 remission is a DAS28 score of less than 2.6. A detectable improvement can also be shown by measuring an improvement in any of the components of the DAS28 score.

EXAMPLES Example 1. Combination of Sarilumab and rexate is Effective in Treatment of toid Arthritis in Patients where Methotrexate Treatment is ctive.

A ide, double-blind, placebo-controlled, randomized study was performed in patients with rheumatoid arthritis with an inadequate response to rexate (MTX). Patients who were included in the study had the following criteria. ts needed to have active disease defined as: at least 6 of 66 swollen joints and 8 of 68 tender joints and; hs-CRP > 6 mg/L. Patients also needed to have had continuous treatment with methotrexate (MTX) — 10 to 25 mg/wk (or 6 to 25 mg/wk for patients within Asia-Pacific region for 12 weeks.

The study includes two parts. The first part (Part A) of the study was a 12-week, 6-arm dose-ranging part intended to select the two best dose regimens based on efficacy (reduction in signs and symptoms) and safety. The second part (Part B) of the study is a k part to confirm the efficacy and safety of these two selected dose regimens on reduction in signs and symptoms, inhibition of ssion of structurai damage, improvement in physical function, and induction of major clinical response.

The operationally seamless design nature of this study resides in the fact that Part B is starting to test patients just after the last patient was randomized in Part A without waiting for the dose selection based on its resuits. Thus part B patients belong to 2 distinct cohorts according to the time of their enroilment: Cohort 1 of patients randomized before the dose selection: these patients are randomized into six arms (as the ones of Part A). After dose ion, the patients randomized in the two selected doses and the placebo regimens continue the 52—week trial but those randomized in the three other arms are discontinued from the present study but proposed to join an open iabel extension (see LTSt 1210).

Cohort 2 of patients randomized after the dose selection: these ts are randomized into three arms, the two selected ones and placebo.

PartA Patients were assessed at a screening visit for confirmation of the diagnosis, e activity, eligibility to the study and verification of concomitant y. te examination and iaboratory tests including hematology, try profile, lipid profile, liver enzymes and acute phase reactants, HbAic, hepatitis B and C and serum pregnancy test for women of childbearing potential were performed. An ECG evaluation was also performed. A PPD test and QuantiFEFtON were performed to exclude any tuberculosis as weli as a chest X-ray (if a nted negative X~ray performed in the last 3 months is not ble).

After confirmation of eiigibiiity, patients were randomized in a balanced manner, in this international multi—center, doubie-biind, parallel group placebo—controlled, 12- week study treatment of six arms of SAR153191 or o given subcutaneously weekly with MTX cotherapy. The doses are shown in Figure 1.

Methothrexate was stered for each patient as it had been before the study. This was at 10 to 25 mg/wk, or 6 to 25 mg/wk for patients within Asia-Pacific region; Taiwan, South Korea, Maiaysia, Philippines, Thailand, and india.

During the first visit, patients were reminded of the list of prohibited medications, and that they should continue taking MTX at their current stable dose untii the end of the study with folic acid as per local recommendation to prevent MTX ty. The patients were trained to prepare and self administer the IMP and were reminded to have injection strictly 7 days apart. At closing time points occurring outside site visits, SAR153191 was injected by the patient himself, by a trained professional ver or by a trained qualified person.

Patients had six additional visits at weeks 2, 4, 6, 8, 10, and 12. Efficacy ment and laboratory test including hematology, chemistry profile, lipid profile, liver enzymes and acute phase reactants were ed throughout the study to allow calculation of the main efficacy scores, and follow up of safety aspects. At randomization visit and at Week 2, 4, 8, and 12, a complete joint ation for tender joint count and swollen joint count was med by an assessor independent from the Investigator and the patient’s data, in order to calculate the ACR score (primary end- point). In order to maintain the blind, the Investigator, the Sponsor and the patient will be blind to CRP and serum lL6 levels during the study.

A close monitoring of adverse events including ial infections assessed in part by monitoring of body temperature was performed at every visit. Presence of tuberculosis was checked through specific patient assessment (check for any signs or symptoms, or contact with active TB). Neurological abnormalities (history and physical examination) or autoimmune diatheses (ANA, ds—DNA dies) were tested at 2O baseline and end of treatment visit.

Specific blood and urine samples were taken during the study to test potential biomarkers that may be predictive of disease response or adverse . These included a single sample for DNA (after the patient has signed a specific ed consent form) and several samples obtained sequentially throughout the study for RNA expression-profiling and protein biomarker analyses. Samples were also collected at appropriate time points for pharmacokinetic ters and antibody to SAR153191.

Patients prematurely discontinued were evaluated at an end of treatment visit with complete clinical and laboratory evaluation. They were considered as non- responders with regard to the ACR score.

At the end of ent visit, all patients were scheduled to complete a Post Treatment Follow—up Visit. Patients who had ted the treatment period were proposed to enter an open-label long-term safety extension study with SARf 53191.

Results Human ts treated with sarilumab (REGN88/SAR153191) in combination with the standard RA treatment, methotrexate (MTX), achieved a significant and clinically meaningful improvement in signs and symptoms of moderate-to-severe rheumatoid arthritis (RA) compared to patients treated with MTX alone. The 306- patient, dose-ranging, multinational, randomized, multi-arm, double-blind, placebo- controlled study was performed that ed five different dose regimens of sarilumab in combination with MTX to placebo plus MTX. The primary endpoint of the study was the proportion of patients achieving at least a 20% improvement in RA symptoms (ACRZO) after 12 weeks.

A dose response was observed in patients receiving sarilumab in combination with MTX. An ACR2O response after 12 weeks was seen in 49.0% of patients receiving the lowest mab dose regimen and 72.0% of patients receiving the highest dose regimen compared to 46.2% of patients receiving o and MTX (p:0.02, corrected for multiplicity, for the highest sarilumab dose regimen) (Figure 2). The most common e events (>5%) reported more frequently in active—treatment arms ed infections (non-serious), neutropenia, and liver—function test abnormalities. The types and frequencies of adverse events were consistent with those previously reported with lL—6 inhibition. The incidence of serious adverse events among the five sarilumab treatment groups and the o group were comparable.

Sarilumab also trated icant benefit compared to placebo in secondary endpoints, including ACR 50, ACR 70, and DAS 28 , onal measures of clinical activity used in RA . More specifically: - An ACRSO response after 12 weeks was seen in 22% of patients receiving the lowest sarilumab dose regimen and 30% of patients receiving the highest dose n compared to 15% of patients receiving o and MTX e 3) - The ACR7O was also significantly higher in the 200 mg q2w group versus placebo. An ACR7O response after 12 weeks was seen in 16% of patients receiving the highest dose regimen compared to 2% of patients receiving placebo and MTX e 3).

These results provide evidence that lL-GR blockade with sarilumab represents a promising new anti-inflammatory investigational therapy for reducing RA disease symptoms.

Part B Patients will be assessed at a screening visit for confirmation of the diagnosis disease activity, eligibility to the study and verification of concomitant therapy. The investigator will check that the patient is either positive anticyclic citrullinated peptide antibody (CCP) or positive rheumatoid factor (RF) or that he/she has a confirmed bone erosion on an X-ray. If necessary, for patients who are both GOP and RF negative and have no X-ray, a centrally-reviewed screening X-ray will be performed and considered also as the baseline X—ray assessment for the study.

Cohort 1: Patients randomized before the dose selection.

Recruitment in for the long term safety extension study will start just after the last patient has been randomized in Part A. After mation of eligibility, patients will be randomized, in a ed manner fied by prior biologic use and by regions, in an international, multi—center, double-blind, parallel group placebo-controlled, study treatment of 6 arms of SAR153191 (5 active dose regimens) or placebo given aneously weekly with MTX cotherapy.

At the beginning of every patient visit for Cohort 1 patients, the investigator will check through lVRS list that the patient is still “eligible” for the study, i.e., that the patient is not to be tinued because of randomization in a nonselected arm. indeed, when the pivotal dose regimens are selected from Part A, only patients randomized in the corresponding arms or placebo will still be considered eligible for the study and will ue in the study for a total of 52 weeks. The other patients (randomized in the nonselected dose regimens) will be considered no longer eligible by lVRS. The investigator will propose these patients to participate in an open extension study with SAR153191 at the highest dose regimen available at the time the patient is enrolled.

The initial ization will remain blinded for all patients.

Cohort 2: Patients randomized after the dose ion — Pivotal Part.

At day 1, after confirmation of ility, patients will be randomized, in a balanced manner stratified by prior biologic use and by regions, in an international, multi—center, double-blind, parallel group, placebo-controlled, study of 3 arms of SAR153191 (2 pivotal dose regimens) or placebo given subcutaneously with MTX cotherapy.

Both Cohorts: in either cohort, patients will be ted at Week 2, at Week 4, and every 4 3O weeks until Week 28 and then every 8 weeks until Week 52 for efficacy and safety assessments and tory tests.

The same procedures as described in Part A will be applied in Part B. in addition, an X-ray evaluation of the hands and feet joints will be performed at baseline, Week 24 and Week 52. Radiographs de-identified of any patient information will be sent to central readers for calculation of the Sharp score (a specific scoring system of joints destruction). Health economic ments will be also added such as SF-36.

From Week 16, patients with lack of efficacy defined as less than 20% improvement from ne in either swollen joints count (SJC) or tender joints count (TJC) for 2 consecutive visits, or any other clear lack of cy based on Investigator judgment will be proposed to be rescued with abel SAR153191 highest available dose at the time of transfer into the rescue treatment arm, and will continue in the study according to their planned visit schedule. Blood samples for laboratory analysis will be taken two weeks after the switch for safety purpose. They will be ered ponders for the primary endpoint (ACRZO). These patients will stay in the study and ue all .

In selected countries, ts who meet lack of efficacy criteria at Part B treatment Visit 7/Week 16, or thereafter, will be permanently discontinued from treatment, and will not be eligible to participate in the open treatment rescue arm.

Instead, the patients will have a follow-up visit to evaluate safety 6 weeks after the End of Treatment visit.

For any t who discontinues prematurely or who is prematurely rescued with open SAR153191, an additional X-ray evaluation will be performed at the time of withdrawal or rescue, unless a study X—ray assessment has been performed within the preceding 3 months (a window of 3 months between 2 X-ray evaluations should be considered to avoid over X-ray exposure).

Patients completing Part B (including those in the open-label rescue arm) will be proposed to be rolled into an open label ion study at the maximum dose regimen at the time of enrollment. All patients will be scheduled to complete the Post Treatment Follow-up Visit. If the patient agrees to enter the SAR153191 open-label long—term extension study, and is confirmed to be eligible, the Post Treatment Follow-up Visit will not be completed.

Example 2. Combination of Sarilumab and DMARDs are Effective in Treatment of 3O Rheumatoid Arthritis in Patients where TNF-or Antagonist and Methotrexate Treatment are Ineffective.

A worldwide, double-blind, placebo-controlled, randomized study was performed in patients with toid arthritis with an inadequate response to methotrexate (MTX) and at least one TNF-a antagonist. Patients who were included in the study had the following ia. Patients had, in the opinion of the investigator, an inadequate response to at least one TNF-o antagonist, after being treated for at least 3 months in the last 2 years, or patients being intolerant to at least 1 TNF-d antagonist, resulting in tinuation. TNF-o antagonists included etanercept, infliximab, adalimumab, golimumab and/or izumab pegol. Patients needed to have active e defined as: at least 6 of 66 swollen joints and 8 of 68 tender joints and; hs-CRP 28 mgiL. ts also needed to have had continuous treatment with one or a combination of DMARDs for at least 12 weeks prior to baseline and on a stable dose(s) for at least 6 weeks o ing. These DMARDs included methotrexate (MTX) - 10 to 25 mg/wk (or 6 to 25 mg/wk for patients within Asia—Pacific region; leflunomide (LEF) — 10 to 20 mg daily; sulfasalazine (SSZ) - 1000 to 3000 mg daily; or hydroxychloroquine (HCQ) — 200 to 400 mg daily.

Table 1 - Groups and forms for both investigational medicinal product and noninvestigational medicinal product Group Treatment Sarilumab Sarilumab Placebo Background 150 mg 200 mg medication as erapy or in combination I BT + 1 SC Including: sarilumab injection — Methotrexate — 10 to 25 every 2 mg/wk (or 6 to 25 mg/wk weeks (q2w) for patients within Asia- Pacitic region) with tolic/folinic acid supplement - Leflunomide — 10 to 20 mg daily - Sulfasalazin — 1000 to 3000 mg daily — Hydroxychloroquin — 200 to 400 mg daily I] BT + -— 1 SC -— Same as above sarilumab injection lll BT + -- -- 1 SC Same as above placebo q2w injection From Week 12 patients with lack of efficacy d as less than 20% improvement from baseline in both swollen joint count and tender joint count for 2 consecutive visits will be proposed to be rescued with open label sarilumab at the highest dose in the trial. These patients will continue the trial according to the schedule of visits.

BT = background therapy; q2w = every other week; SC = subcutaneous Subcutaneous administration will occur in the abdomen or thigh. Each dose will be self-administered (whenever le), in a single injection. The SC injection sites can be alternated between the 4 quadrants of the n t the navel or waist area) or the thigh (front and side).

Patients and/or their nonprofessional vers will be trained to prepare and administer IMP at the start of the double-blind treatment period. This training must be documented in the patients’ study tile. The study coordinator or ee may administer the first injection comprising the initial dose as part of the training procedure on Day 1 (Visit 2). On days when the patient has a study visit, the IMP will be administered following clinic procedures and blood collection. For doses not given at the study site, diaries will be provided to record information pertaining to these injections; these diaries will be kept as source data in the patients’ study file. if the patient is unable or unwilling to ster lMP, arrangements must be made for qualified site personnel and/or caregiver to administer IMP for the doses that are not scheduled to be given at the study site. it the study visit is not performed at the site as scheduled, the dose will be administered by the patient and/or their caregiver(s) as scheduled.

Treatment will last for 24 weeks. From Week 12, ts with lack of efficacy defined as less than 20% improvement from baseline in both SJC and TJC for 2 utive visits will be proposed to be rescued with open label sarilumab at the highest dose in the trial. These patients will continue the trial according to the schedule of visits. in this study, sarilumab is administered on top of DMARD therapy, considered as a background therapy. All patients should continue to receive continuous treatment with one or a combination of nonbiologic DMARD(s) as ound therapy for at least 12 weeks prior to baseline and on a stable dose(s) for at least 6 weeks prior to ing: . methotrexate (MTX) - 10 to 25 mg/wk (or 6 to 25 mg/wk for patients within Asia-Pacific region) with folic/folinic acid supplement - leflunomide (LEF) — 10 to 20 mg daily - sulfasalazin (SSZ) — 1000 to 3000 mg daily - hydroxychloroquin (HCQ) — 200 to 400 mg daily Each DMARD dose will be recorded throughout the study on the case report form. At any time, the DMARD dose can be reduced for safety or tolerability reason.

Any change in dose and the start date of the new dose should be recorded on the e- CRF at every visit. s) will not be dispensed or supplied by the Sponsor as an IMP.

All patients taking MTX will receive folic/tolinic acid according to local recommendation in the country where the study is conducted. The dose, route and administration schedule of tolic/folinic acid will be recorded with concomitant medications.

Sarilumab and matching placebo will be provided in identically matched glass led syringes. Each prefilled syringe contains 1.14 mL of mab (SAR153191) or matching placebo solution.

A list of treatment kit numbers will be generated. A randomization list will be ted by the interactive voice response system (lVRS). Both the randomization and treatment kit lists will be loaded into the lVRS.

The treatment kit numbers will be obtained by the Investigator at the time of patient randomization and subsequent patient scheduled visits via lVRS that will be available 24 hours a day.

In accordance with the double-blind design, igators will remain blinded to study treatment and will not have access to the randomization ment codes) except under circumstances described in Section 8.7.

Patients will be randomized to one of the treatment arms via a centralized ization system using an IVRS. A patient will be considered randomized when the treatment number has been provided by the lVRS.

At the screening visit, Visit 1, the site coordinator will t the IVRS to obtain a patient number for each patient who gives informed consent. Each t will be allocated a patient number associated with the center and allocated in chronological order in each center.

The treatment assignment will be ted to the patient according to the central randomization list via the lVRS stratified by region and number of previous anti- TNFs (1 versus > 1) . At Visit 2 (Day 1), after confirming the patient is eligible for entry into the treatment period, the site coordinator will contact the lVRS in order to e 3O the first treatment ments (kit numbers). Patients will be randomized to receive either one of the 2 treatment arms of sarilumab or its matching placebo. The randomization ratio is 1:1 :1 (sarilumab 150 mg 2 sarilumab 200 mg : matching placebo).

At subsequent dispensation visits during the treatment period, the site coordinator will call lVRS to obtain the subsequent treatment kits assignment. A mation fax/e-mail will be sent to the site after each assignment.

A randomized patient is defined as a patient who is registered and assigned a randomization number from the lVRS, as documented from the lVRS log file. IMP will also be recorded and tracked on the center IMP inventory forms.

The itions and methods of the present disclosure are not to be limited in scope by the specific embodiments describe herein. indeed, s modifications of the invention in addition to those described herein will become nt to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

THE

Claims (11)

CLAIMS :

1. Use of an antibody or binding fragment thereof in the cture of at least one ment for the ent of rheumatoid arthritis in a subject previously ineffectively trea ted for rheumatoid arthritis by the administration of methotrexate and previously ineffectively treated for rheumatoid arthritis by the administration of a TNF -α antagonist , wherein the antibody or binding fragment thereof comprises the heavy chain variable region of SEQ ID No. 2 and the light chain le region of SEQ ID No. 3, and wherein the at least one medicament is formulated for administration to the pa tient in a dosing regime that es between 100 mg and 200 mg of said antibody or binding fragment thereof, to the patient; the dosing regime comprises at least one dosing cycle that is designed to provide the effective delivery of the at least one medi cament in an effective amount per two weeks, and the dosing cycle is repeated for as long as necessary to achieve a desired biological se in a subject , and wherein the antibody of binding fragment thereof is formulated for subcutaneous administration .

2. The use according to claim 1, n the at least one medicament includes methotrexate .

3. The use ing to claim 2, wherein the dosing regime provides a dosage of methotrexate of between 6 -25 mg per week.

4. The use acc ording to any one of the p receding claims wherein the dosing regime provides a dosage of said antibody or fragment thereof o f 150 mg per two weeks or 200 mg per two weeks.

5. The use according to any one of the previous claims, wherein the subject is capable of achieving at least a 20 % improvement in the American College of Rheumatology core set disease index after treatment.

6. The use according to any one of claims 1 to 4, wherein the subject is capable of achieving at least a 50% improvement in the American College of Rheumatology core set disease index after treatment.

7. The use according to any one of claims 1 to 4, n the subject is capable of achieving at least a 70% improvement in the American College of Rheumatology core set disease index after treatment.

8. The use according to any one of claims 5 to 7, wherein the treatment lasts for at least 12 weeks.

9. The use according to any one of the previous claims, wherein the t was previously ineffectively treated for toid arthritis by the administration of a TNF -α antagonist selected from the group consisting of etanercept, infliximab, adalimumab, golimumab and/or cert olizumab pegol.

10. The use ing to claim 9, wherein the subject was treated with an anti - TNF -α antagonist for at least 3 months, or the subject was intolerant to at least one TNF -α antagonist.

11. The use according to any one of the previous claims, wherein the antibody is sarilumab. REGENERON CEUT ICALS, INC SANOFI WATERMARK PATENT AND TRADE MARKS ATTORNEY S P38820NZ00