ES2799439T3 - Compositions for the treatment of rheumatoid arthritis and methods of using them - Google Patents

Abstract

An anti-IL6R antibody comprising the heavy chain variable region of SEQ ID NO: 2 and the light chain variable region of SEQ ID NO: 3 for use in combination with methotrexate to inhibit the progression of structural damage in a subject suffering from rheumatoid arthritis, wherein an effective amount of the antibody and an effective amount of methotrexate are administered to the subject, and wherein the antibody is administered subcutaneously to the subject between 150 and 200 mg every two weeks.

Description

DESCRIPTION

Compositions for the treatment of rheumatoid arthritis and methods of using them

FIELD OF THE INVENTION

The present invention relates to the field of therapeutic treatment of rheumatoid arthritis. More specifically, the invention relates to the use of interleukin-6 receptor (IL-6R) antagonists, such as anti-IL-6R antibodies, combined with disease-modifying antirheumatic drugs, to treat rheumatoid arthritis.

BACKGROUND

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

The cause (s) of RA are not fully understood. RA is defined by a set of symptoms and 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 inflammatory process can also target other organs, characteristically the bone marrow (anemia), the eye (scleritis, episcleritis), the lung (interstitial pneumonitis, pleurisy), heart disease (pericarditis), and the skin (nodules, leukocytoclastic vasculitis). Systemic inflammation is characterized by laboratory abnormalities such as anemia, elevated 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 high polyclonal titer rheumatoid factors and anti-cyclic citrullinated peptide (anti-CCP) antibodies provide 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.

Treatments include both medication and non-pharmacological measures - the goal being to control joint inflammation and prevent joint damage and disability. Non-drug treatment, which includes physical therapy, braces and splints, occupational therapy, and dietary changes, does not stop the progression of joint destruction. Pain relievers and anti-inflammatory drugs, including steroids, suppress symptoms, but they don't stop progression either. Disease-modifying antirheumatic drugs (DMARDs) can slow the progress of the disease.

In addition to existing treatments that improve the symptoms (eg, inflammation) associated with RA, there is still a significant medical need for treatments that present or arrest the progression of structural damage (joint damage and destruction) in subjects with RA. There is also a need for additional treatments that improve physical function (eg, dressing and grooming, getting up, eating, walking, hygiene, reaching, grasping, and activities) of subjects suffering from RA.

Patent document WO2013 / 053751 discloses the clinical efficacy of sarilumab to treat RA based on ACR scores obtained at 12 weeks.

A clinical trial protocol for the evaluation of sarilumab in addition to methotrexate in RA patients has been disclosed in clinical trial identifier NTC01061736.

SUMMARY

The invention relates to an anti-IL6R antibody comprising the variable region of the heavy chain of SEQ ID NO: 2 and the variable region of the light chain of SEQ ID NO: 3 for use in combination with methotrexate to inhibit progression of structural damage in a subject suffering from rheumatoid arthritis, wherein an effective amount of the antibody and an effective amount of methotrexate are administered to the subject, and wherein the antibody is administered subcutaneously to the subject between 150 and 200 mg every two weeks.

The invention is further defined by the claims.

The present disclosure provides a method of inhibiting the progression of structural damage in a subject suffering from rheumatoid arthritis, which comprises administering an effective amount of sarilumab to the subject. Typically, inhibition of the progression of structural damage is assessed by the change from baseline (BL) in the Van der Heijde modified total Sharp score (mTSS).

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

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

In certain aspects, sarilumab and leflunomide are administered to the subject. Leflunomide can be given by mouth. Leflunomide can also be administered at 10-20 mg daily to the subject.

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

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

According to any of the embodiments described herein, the subject may be administered sarilumab and / or methotrexate for 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39 ,. 40, 41,42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 60 or more weeks. In certain embodiments, a subject is administered sarilumab and methotrexate for 12, 16, 24, or 52 weeks or longer. In certain embodiments, a subject is administered sarilumab and methotrexate for 52 weeks or longer. In particular, sarilumab is given at 150 or 200 mg every two weeks for at least 52 weeks. Sarilumab is administered subcutaneously at 150-200 mg every two weeks.

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

In some embodiments, as a result of treatment, the subject achieves a lower disease activity score after 12 weeks of treatment than the subject had prior to treatment. The disease activity score can be less than or equal to 2.6 in 12 weeks. The disease activity score may decrease more than 1.2 between the start of treatment and 12 weeks. The disease activity score can be less than or equal to 3.2 in 12 weeks. The disease activity score may decrease more than 0.6 between the start of treatment and 12 weeks. The disease activity score can be less than or equal to 5.1 in 12 weeks.

In some embodiments, as a result of treatment, the subject achieves a lower disease activity score after 24 weeks of treatment than the subject had prior to treatment. The disease activity score can be less than or equal to 2.6 in 24 weeks. The disease activity score may decrease more than 1.2 between the start of treatment and 24 weeks. The disease activity score can be less than or equal to 3.2 in 24 weeks. The disease activity score may decrease more than 0.6 between the start of treatment and 24 weeks. The disease activity score can be less than or equal to 5.1 in 24 weeks.

The present disclosure also provides a method of treating rheumatoid arthritis in a subject in need thereof which comprises administering to the subject an effective amount of sarilumab and methotrexate, wherein the subject was previously ineffectively treated for rheumatoid arthritis by administering an anti-TNF therapeutic. -to. In certain embodiments, the subject was previously ineffectively treated for rheumatoid arthritis by administering methotrexate. Methotrexate can be administered between 10 and 25 mg per week to the subject.

According to the invention, the subject is a mammal. The mammal can be a human. In certain embodiments, the human is descended from individuals from Asia or the Pacific. Humans of Asian or Pacific descent can be administered with between 6 and 25 mg per week of methotrexate.

In certain embodiments, the subject was previously ineffectively treated for rheumatoid arthritis by administering a TNF-α antagonist. Specifically, the subject may have been treated for at least three months with the TNF-α antagonist or may have been intolerant of the TNF-α antagonist. The TNF-a antagonist could be etanercept, infliximab, adalimumab, golimumab, or certolizumab. In other embodiments, the subject was previously ineffectively treated for rheumatoid arthritis by administering methotrexate.

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

In some embodiments, as a result of treatment, the subject achieves a lower disease activity score after 12 weeks of treatment than the subject had prior to treatment. The disease activity score can be less than or equal to 2.6 in 12 weeks. The disease activity score may decrease more than 1.2 between the start of treatment and 12 weeks. The disease activity score can be less than or equal to 3.2 in 12 weeks. The disease activity score may decrease more than 0.6 between the start of treatment and 12 weeks. The disease activity score can be less than or equal to 5.1 in 12 weeks.

In some embodiments, as a result of treatment, the subject achieves a lower disease activity score after 24 weeks of treatment than the subject had prior to treatment. The disease activity score can be less than or equal to 2.6 in 24 weeks. The disease activity score may decrease more than 1.2 between the start of treatment and 24 weeks. The disease activity score can be less than or equal to 3.2 in 24 weeks. The disease activity score may decrease more than 0.6 between the start of treatment and 24 weeks. The disease activity score can be less than or equal to 5.1 in 24 weeks.

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

In certain specific aspects, the composition includes sarilumab and leflunomide. Leflunomide can be present in an oral dosage form. Leflunomide can be present in the composition at between 10 and 20 mg per dose.

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

In other specific aspects, the composition includes sarilumab and hydroxychloroquine. Hydroxychloroquine can be present in an oral dosage form. Hydroxychloroquine can be present in the composition at between 200 and 400 mg per day to the subject.

In certain aspects, the disclosure also provides a method of treating rheumatoid arthritis in a previously treated subject by administering methotrexate, leflunomide, sulfasalazine, and / or hydroxychloroquine, which comprises administering to the subject an effective amount of sarilumab.

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

In another aspect, methotrexate, leflunomide, sulfasalazine, and / or hydroxychloroquine are administered in conjunction with sarilumab.

In another embodiment, sarilumab and methotrexate are administered together.

In one embodiment, methotrexate is administered between 6 and 25 mg per week.

In other embodiments, sarilumab is administered at 150 mg every two weeks. In other embodiments, sarilumab is administered at 200 mg every two weeks.

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

In certain embodiments, the subject was previously ineffectively treated for rheumatoid arthritis by administering a TNF-α antagonist. In one embodiment, the subject has been treated with an anti-TNF-α antagonist for at least 3 months in the past 2 years or the subject was intolerant to at least one TNF-α antagonist. In another embodiment, the TNF-α antagonist is a biological anti-TNF-α. In another embodiment, the TNF-α antagonist is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and / or certolizumab pegol.

In other aspects, the disclosure provides a pharmaceutical composition comprising an effective amount of sarilumab and a member of the group consisting of methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine.

In still other aspects, the disclosure provides a combination of: a pharmaceutical composition comprising sarilumab, and a pharmaceutical composition comprising methotrexate, leflunomide, sulfasalazine or hydroxychloroquine for sequential or simultaneous use as a medicament.

DETAILED DESCRIPTION

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

Anti-hIL-6R antibodies

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

Unless specifically stated otherwise, the term "antibody", as used herein, is to be understood to encompass antibody molecules that comprise two immunoglobulin heavy chains and two immunoglobulin light chains (i.e. , "whole antibody molecules"), as well as antigen-binding fragments thereof. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally-occurring, enzymatically obtainable, synthetic polypeptide or glycoprotein, or genetically engineered that specifically binds to an antigen to form a complex. Antigen-binding fragments of an antibody can be derived, for example, from whole antibody molecules using any suitable conventional technique such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of variable and (optionally) constant domains of DNA-encoding antibodies. Such DNA is known and / or readily available from, for example, commercial sources, DNA libraries (including, for example, phage-antibody libraries), or can be synthesized. DNA can be sequenced and manipulated chemically or using molecular biology techniques, for example, to arrange one or more variable and / or constant domains in a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids , etc.

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 molecules (scFv); (vi) dAb fragments; and (vii) minimal recognition units consisting of amino acid residues that mimic the hypervariable region of an antibody (eg, an isolated complementarity determining region (CDR)). Other engineered molecules, such as diabodies, tribodies, tetrabodies, and minibodies, are also encompassed within the term "antigen-binding fragment" as used herein.

An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain can be of any size or amino acid composition and will generally comprise at least one CDR that is adjacent or in frame with one or more framework region sequences. In antigen-binding fragments having a V ^h domain associated with a V ¹ domain, the V ^h and V ¹ domains can be positioned relative to each other in any suitable arrangement. For example, the variable region can be dimeric and contain V ^h -V ^h , V ^h -V ^l, or V ^l -V ^l dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.

In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Exemplary non-limiting configurations of variable and constant domains that may be found within an antigen-binding fragment of an antibody of the present invention include: (i) V ^h -C ^h 1; (ii) V ^h -C ^h 2; (iii) V ^h -C ^h 3; (iv) V ^h -C ^h 1 -C ^h 2; (v) V ^h -C ^h 1 -C ^h 2 -C ^h 3; (vi) V ^h -C ^h 2 -C ^h 3; (vii) V ^h -C ^l ; (viii) V ^l -C ^h 1, (ix) V ^l -C ^h 2; (x) V ^l -C ^h 3; (xi) V ^l -C ^h 1 -C ^h 2; (xii) V ^l -C ^h 1 -C ^h 2 -C ^h 3; (xiii) V ^l -C ^h 2 -C ^h 3; and (xiv) V ^l -C ^l . In any variable and constant domain configuration, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to each other or they may be linked by a complete or partial connector or hinge region . A hinge region can consist of at least 2 (eg, 5, 10, 15, 20, 40, 60 or more) amino acids that produce a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Furthermore, an antigen-binding fragment of an antibody of the present invention may comprise a homodimer or heterodimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with each other and / or with one or more monomeric V ^h or V ^l domains (eg, by disulfide bond (s)).

The term "specifically binds to" means that an antibody or antigen-binding fragment thereof forms a complex with an antigen that is relatively stable under physiological conditions. Specific binding can be characterized by a dissociation constant of at least about 1x10-6 M or less. In other embodiments, the dissociation constant is at least about 1x10-7 M, 1x10-8 M, or 1x10-9 M. They are very Methods for determining whether two molecules specifically bind are known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like.

As with full length antibody molecules, antigen-binding fragments can be monospecific or multispecific (eg, bispecific). A multispecific antigen-binding fragment of an antibody will typically comprise at least two different variable domains, where each variable domain is capable of specifically binding a separate antigen or a different epitope on the same antigen. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, can be adapted for use in the context of an antigen-binding fragment of an antibody of the present invention using available routine techniques. in technique.

In specific embodiments, the antibody or antibody fragment for use in the method of the disclosure herein may be a multispecific antibody, which may be specific for different epitopes of a target polypeptide or may contain specific antigen-binding domains for epitopes of more than one target polypeptide. An exemplary bispecific antibody format that can be used in the context of the present disclosure involves the use of a first immunoglobulin (Ig) Ch3 domain and a second Ig Ch3 domain, wherein the first and second Ch3 domains of Ig differ from each other by at least one amino acid, and wherein at least one amino acid difference reduces the binding of the bispecific antibody to protein A compared to a bispecific antibody lacking the amino acid difference. In one embodiment, the first CH3 domain of Ig binds to protein A and the second domain Ch ³ Ig contains a mutation that reduces or abolishes binding to protein A, such as a modification H95R (for numbering of exons IMGT ; H435R by EU numbering). The second Ch3 may further comprise a Y96F modification (for IMGT; Y436F for EU). Additional modifications that can be found within the second Ch3 include: D16E, L18M, N44S, K52N, V57M, and V82I (for IMGT; D356E, L358M, N384S, K392N, V397M, and V422I for EU) in the case of IgG1 antibodies; N44S, K52N and V82I (IMGT; N384S, K392N and V422I by EU) in the case of IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q and V422I by EU) in the case of IgG4 antibodies. Variations in the bispecific antibody format described above are contemplated within the scope of the present invention.

A "neutralizing" or "blocking" antibody, as used herein, is intended to refer to an antibody whose binding to hIL-6R results in inhibition of the biological activity of hIL-6. This inhibition of hIL-6 biological activity can be assessed by measuring one or more indicators of hIL-6 biological activity known in the art, such as hIL-6-induced cellular activity and hIL-6 binding to hIL. -6R (see examples below).

The fully human anti-IL-6R antibodies disclosed herein may comprise one or more amino acid substitutions, insertions, and / or deletions in the framework region and / or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences. Such mutations can be readily determined by comparing the amino acid sequences disclosed herein with germline sequences available from, for example, public antibody sequence databases. The present disclosure includes antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework regions and / or CDR regions are retro-mutated to the corresponding germline residue (s) or to a conservative amino acid substitution (natural or non-natural) of the corresponding germline residue (s) ( such sequence changes are referred to herein as "germline retro-mutations"). One of ordinary skill in the art, from the heavy and light chain variable region sequences disclosed herein, can readily produce numerous antibodies and antigen-binding fragments comprising one or more retro-mutations of the line individual germ cells or combinations thereof. In certain aspects, all framework and / or CDR residues within the VH and / or VL domains are back-mutated to the germline sequence. In other respects, only certain residues are retro-mutated to the germline sequence, for example, only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. In addition, the antibodies of the present disclosure may contain any combination of two or more germline back-mutations within the framework region and / or CDR regions, i.e., where certain individual residues are back-mutated to the sequence of the germ line, while certain other remnants are maintained that differ from the germ line sequence. Once obtained, antibodies and antigen-binding fragments containing one or more germline back mutations can be readily tested for one or more desired properties, such as improved binding specificity, high binding affinity, antagonist or agonist biological properties. enhanced or enhanced (as the case may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general way are encompassed within the present invention.

The term "epitope" refers to an antigenic determinant that interacts with a specific antigen-binding site in the variable region of an antibody molecule known as a paratope. A single antigen can have more than one epitope. Epitopes can 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 circumstances, an epitope may include saccharide moieties, phosphoryl groups, or sulfonyl groups on the antigen.

The anti-hIL-6R may be sarilumab (SAR153191). 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.

FARMES

Disease-modifying antirheumatic drugs (DMARDs) include methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide. Depending on the compositions and methods of the disclosure, the FARMEs can be administered as follows. Methotrexate from 10 to 25 mg per week can be administered orally or intramuscularly. In another embodiment, methotrexate from 6 to 25 mg / week is administered orally or intramuscularly to patients who are from the Asia-Pacific region or who are descendants of persons who are from the Asia-Pacific region. The Asia-Pacific region includes Taiwan, South Korea, Malaysia, the Philippines, Thailand, and India. In certain embodiments, methotrexate is administered at between 6 and 12, 10 and 15, 15 and 20 and 20 and 25 mg per week. In other embodiments, methotrexate is administered at 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 mg per week. Leflunomide can be given 10 to 20 mg orally per day. 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 per day. In certain 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, 2300, 2400, 2500, 2600, 2700, 2800, 2900, or 3000 mg per day. Hydroxychloroquine can be given 200 to 400 mg orally per day. 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, the 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 administration and formulations

The methods described herein comprise administering a therapeutically effective amount of an anti-hIL-6R antibody and, optionally, a DMARD to a subject. As used herein, the term "therapeutically effective amount" means a dose of the therapeutic that produces a detectable improvement in one or more symptoms associated with rheumatoid arthritis or that produces a biological effect (eg, a decrease in the level of a particular biomarker) that correlates with the underlying pathologic mechanism (s) leading to the rheumatoid arthritis condition or symptom (s). For example, a dose of anti-hIL-6R antibody that produces an improvement in any of the following symptoms or conditions is considered a "therapeutically effective amount": anemia of chronic disease, fever, depression, 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) classification criteria for rheumatoid arthritis. For example, an improvement of 20% (ACR20), 50% (ACR50), or 70% (ACR70) 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 a sensitive joint count based on 28 joints, a swollen joint count based on 28 joints, a general health assessment, and an inflammation marker that can be assessed by measuring C-reactive protein (CRP) levels. Response to disease can be presented using the European League Against Rheumatism (EULAR) response criteria. A good answer for this criterion is an improvement of more than 1.2 in the DAS28 score with a present score greater than or equal to 3.2. A moderate response is an improvement greater than 0.6 but less than or equal to 1.2 in the DAS28 score and a present score greater than 3.2. Non-response is an improvement of less than 0.6 in the DAS28 score and a present score greater than 5.1. DAS28 remission is a DAS28 score less than 2.6.

The Van der Heijde Modified Total Sharp Score (mTSS) can be used to show the degree of joint damage (also called structural damage). Typically, the progression of structural damage in a subject is measured by the change from baseline (BL) of the Van der Heijde modified total Sharp score (mTSS). Baseline level (BL) is defined as the score obtained by the subject before sarilumab is administered according to the invention. The change from baseline is defined as the difference between the score obtained by the subject at baseline and the score obtained by the subject after sarilumab is administered according to the invention, usually measured after 24 or 52 weeks of sarilumab treatment. By comparing mTSS at baseline and after sarilumab treatment, typically at 24 weeks or 52 weeks, it is possible to measure the progression of structural damage in the subject.

The mTSS methodology, which is common in the field of rheumatoid arthritis, quantifies the degree of bone erosions for 44 joints and narrowing of joint spaces for 42 joints, with higher scores representing greater damage. Van der Heijde's mTSS at a point in time is the sum of the scores of both the erosion score and the joint space narrowing score, for a maximum score of 448.

The joint erosion score is a summary of the intensity of erosion in 32 joints of the hands and 12 joints of the feet. Each joint is scored, based on the surface area involved, from 0 to 5 for the hand joints and 0 to 10 for the foot joints. The maximum erosion score (5 for the hand and 10 for the foot) indicates extensive bone loss from more than half the bone in the joint. A score of 0 on either the hand or the foot does not indicate erosion. The maximum erosion score is 280 (160 in the hands and 120 in the feet) for a moment of time.

The Joint Space Narrowing Score (JSN) summarizes the intensity of JSN in 30 joints in the hands and 12 joints in the feet. The JSN assessment for each hand (15 joints per hand) and foot (6 joints per foot), including subluxation, is scored from 0 to 4, with 0 indicating no JSN / normal and 4 indicating complete joint space loss, ankylosis bone or dislocation. Thus, the maximum JSN score is 168 at one point in time.

The improvement in physical function of a subject suffering from rheumatoid arthritis, after administration of sarilumab according to the invention, is normally assessed by looking for a change from baseline (BL) in the disability index scores of the Health Assessment Questionnaire (HAQ-DI). Baseline is defined as the score obtained by the subject before sarilumab is administered according to the invention. The change from baseline is defined as the difference between the score obtained by the subject at baseline and the score obtained by the subject after sarilumab is administered according to the invention, normally measured after 16, 24 or 52 weeks of treatment with sarilumab.

HAQ-DI is a standardized questionnaire developed at Stanford University for use in RA (available online). It is widely used throughout the world and has become a mandatory outcome measure for clinical trials in rheumatoid arthritis.

HAQ-DI, with the last week as the time period, focuses on whether the respondent "is capable of ..." doing the activity and covers eight categories in 20 points: dressing and grooming, getting up, eating, walking, hygiene, reach, grasp and activities, for which there are at least 2 questions per category. The four responses to the HAQ-DI questions are ranked as follows: no difficulty = 0; with some difficulty = 1; with great difficulty = 2; and unable to do so = 3. To calculate the standard HAQ-DI score (with aids / devices), there are three steps

1. Add the scores for 8 categories using the highest sub-category in each category.

- For example, in the category GET UP there are three subcategory points. A patient responds with a 1, 2 and 0, respectively; the category score is 2.

2. Adjust for the use of aids / devices and / or assistance from another person when indicated.

- Adjust the score for a category by increasing a zero or a one to a two.

- If a patient's highest score for that sub-category is a two, it is still a two, and if it is a three, it is still a three.

3. Divide the summed category scores by the number of categories answered (must be a minimum of 6) to obtain a HAQ-DI score of 0-3 (3 = worst performance).

A HAQ-DI score cannot be validly calculated when there are scores for fewer than six of the eight categories. The HAQ-DI score ranges from 0 to 3. A high HAQ-DI score has been found to be a strong prognostic factor for morbidity and mortality in RA.

According to the methods of the present disclosure, a therapeutically effective amount of anti-hIL-6R antibody that is administered to the patient will vary depending on the age and size (eg, body weight or body surface area) of the patient, in addition to the route of administration and other factors well known to those of ordinary skill in the art. In certain embodiments, the dose of anti-hIL-6R antibody administered to the patient is from about 10 mg to about 500 mg. For example, the present 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 60mg, about 65mg, about 70mg, about 75mg, about 80mg, about 85mg, about 90mg, about 95mg, about 100mg, about 105mg, about 110mg, about 115mg, 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-hIL-6R antibody is administered to the patient weekly.

In one aspect, the hIL-6R antibody is administered at 100-150 mg per week. In another aspect, the hIL-6R antibody is administered at 100-200 mg for every two weeks. In other aspects, the hIL-6R antibody is administered at about 100 or about 150 mg per week. In other aspects, the hIL-6R antibody is administered at about 100, 150, or 200 mg every two weeks.

The amount of anti-hIL-6R antibody that is administered to the patient can be expressed in terms of milligrams of antibody per kilogram of the patient's body weight (ie, mg / kg). For example, the methods of the present disclosure include administering an anti-hIL-6R 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 disclosure include administering multiple doses of an anti-hIL-6R antibody to a patient over a specified length of time. For example, the anti-hIL-6R antibody can be administered about 1 to 5 times a day, about 1 to 5 times a week, about 1 to 5 times a month, or about 1 to 5 times a year. In certain embodiments, the methods of the invention include administering a first dose of the anti-hIL-6R antibody to a patient at a first point in time, followed by administering at least a second dose of the anti-hIL-6R antibody to the patient in a second moment of time. The first and second doses, in certain embodiments, may contain the same amount of anti-hIL-6R antibody. For example, 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 can be from about a few hours to several weeks. For example, the second time point (i.e. the time when the second dose is given) can be from about 1 hour to about 7 weeks after the first time point (i.e. the time when the first dose is given) . According to certain exemplary embodiments of the present invention, the second time point may 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 more after the first moment of time. In certain embodiments, the second moment of time is about 1 week or about 2 weeks. Third and subsequent doses can similarly be administered throughout the course of the patient's treatment.

The disclosure provides methods of using therapeutic compositions comprising anti-IL-6R antibodies or antigen-binding fragments thereof and, optionally, one or more additional therapeutic agents, eg, FARMEs. Therapeutic compositions of the disclosure will be administered with suitable vehicles, excipients, and other agents that are incorporated into the formulations to provide delivery, tolerance, improved transfer, and the like. A multitude of suitable formulations can be found in the form known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. These formulations include, for example, powders, pastes, ointments, gelatins, waxes, oils, lipids, lipid-containing vesicles (cationic or anionic) (such as LIPOFECTIN ™), DNA conjugates, anhydrous absorption pastes, oil emulsions in water and water-in-oil, Carbowax emulsions (polyethylene glycols of various molecular weights), semisolid gels and semisolid mixtures containing Carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52: 238-311.

The dose may vary depending on the age and weight of a subject to be administered, target disease, conditions, route of administration, and the like. Various delivery systems are known and can be used to deliver the pharmaceutical composition of the disclosure, for example, encapsulation in liposomes, microparticles, microcapsules, receptor-mediated endocytosis (see, for example, Wu et al. (1987) J. Biol Chem. 262: 4429-4432). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition can be administered by any convenient route, for example by infusion or bolus injection, by absorption through the epithelial or mucocutaneous linings (eg, oral mucosa, rectal and intestinal mucosa, etc.) and can be administered in conjunction with others biologically active agents. Administration can be systemic or local. The hIL-6R antibody can be administered subcutaneously. DMARD can be administered orally or intramuscularly.

The pharmaceutical composition can also be administered into a vesicle, in particular a liposome (see Langer (1990) Science 249: 1527-1533). In certain situations, the pharmaceutical composition can be administered in a controlled release system, for example, with the use of a pump or polymeric materials. In another embodiment, a controlled release system can be placed in proximity to the target of the composition, thus requiring only a fraction of the systemic dose.

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

Advantageously, the pharmaceutical compositions for oral or parenteral use described above are prepared in dosage forms in a unit dose suitable for adjusting a dose of the active principles. Such unit dose dosage forms include, for example, tablets, pills, capsules, injections (ampoules), suppositories, etc. The amount of DMARDs contained is generally about 5 to 3000 mg per dosage form in an oral unit dose depending on the specific DMARD used. The amount of the hIL-6R antibody contained is generally about 100 to 200 mg per subcutaneous dosage form.

According to the methods disclosed herein, the anti-hIL-6R antibody (or pharmaceutical formulation comprising the antibody) can be administered to the patient using any acceptable device or mechanism. For example, administration can be carried out using a syringe and needle or with a reusable pen and / or autoinjector delivery device. The methods of the present disclosure include the use of numerous reusable pen delivery devices and / or autoinjectors that deliver an anti-hIL-6R antibody (or pharmaceutical formulation comprising the antibody). Examples of such devices include, but are not limited to, AUTOPEN ™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC ™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25 ™ pen, HUMALOG pen ™, HUMALIN 70/30 ™ pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN ™ I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR ™ (Novo Nordisk, Copenhagen, Denmark), BD pen ™ (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN ™, OPTIPEN PRO ™, OPTIPEN St A r LET ™ and OpTICLIK ™ (sanofi-aventis, Frankfurt, Germany), to name a few. Examples of disposable pen delivery devices and / or autoinjectors that have application in the subcutaneous administration of a pharmaceutical composition of the present disclosure 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 HUMIRA ™ pen (Abbott Labs, Abbott Park, IL), to name a few.

The use of a micro-infuser to deliver an anti-hIL-6R antibody (or pharmaceutical formulation comprising the antibody) to a patient is also contemplated herein. As used herein, the term "micro-infuser" means a subcutaneous administration device designed to slowly deliver large volumes (e.g., up to about 2.5 mL or more) of a therapeutic formulation over an extended period of time (for example, approximately 10, 15, 20, 25, 30 or more minutes). See, for example, U.S. 6,629,949; US 6,659,982; and Meehan et al., J. Controlled Release 46: 107-116 (1996). Microinfusors are particularly useful for the administration of large doses of therapeutic proteins contained within highly concentrated (eg, about 100, 125, 150, 175, 200 or more mg / mL) and / or viscous solutions.

Combination therapies

The present disclosure includes methods of treating rheumatoid arthritis which comprise administering to a patient in need of such treatment an anti-hIL-6R antibody. In certain embodiments, the anti-hIL-6R antibody is administered as a "monotherapy" or individual therapeutic agent. In alternative embodiments, the anti-hIL-6R antibody is administered in combination with at least one additional therapeutic agent. Examples of additional therapeutic agents that can be administered in combination with an anti-hIL-6R antibody in the practice of the methods of this disclosure include, but are not limited to, FARMEs, and any other compounds known to treat, prevent, or ameliorate rheumatoid arthritis in a human subject. Specific non-limiting examples of additional therapeutic agents that can be administered in combination with an anti-hIL-6R antibody in the Context of a method of the present disclosure include, but are not limited to, methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide. In the present methods, the additional therapeutic agent (s) can be administered simultaneously or sequentially with the anti-hIL-6R antibody. For example, for simultaneous administration, a pharmaceutical formulation may be prepared containing both an anti-hIL-6R antibody and at least one additional therapeutic agent. The amount of additional therapeutic agent that is administered in combination with the anti-hIL-6R antibody in the practice of the methods of the present disclosure can be readily determined using routine methods known and readily available in the art.

The disclosure provides pharmaceutical compositions comprising any of the following:

A composition comprising between 100 and 150 mg of sarilumab (SAR153191) and 10-25 mg of methotrexate. A composition comprising 100-200 mg sarilumab (SAR153191) and 10-25 mg methotrexate. A composition comprising 100-150 mg of sarilumab (SAR153191) and 6-25 mg of methotrexate. A composition comprising between 100 and 200 mg of sarilumab (SAR153191) and 6-25 mg of methotrexate. A composition comprising 100-150 mg of sarilumab (SAR153191) and 10-20 mg of leflunomide. A composition comprising 100-200 mg of sarilumab (SAR153191) and 10-20 mg of leflunomide. A composition comprising 100-150 mg of sarilumab (SAR153191) and 1000-3000 mg of sulfasalazine.

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

The disclosure of the invention provides methods of amelioration of symptoms associated with rheumatoid arthritis comprising any of the following:

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

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

A method comprising administering between 100-200 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 100-150 mg of sarilumab (SAR153191) per week and 1000-3000 mg of sulfasalazine per day to a subject in need thereof.

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

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

Biomarkers

The present disclosure includes methods of treating rheumatoid arthritis by administering to a patient in need of such treatment a therapeutically effective amount of a human antibody or antibody-binding fragment thereof that specifically binds hIL-6R and a therapeutically effective amount of one or more DMARDs, where the level of one or more biomarkers associated with RA in the patient is modified (for example, increases, decreases, etc., as the case may be) after administration. In a related aspect, the present disclosure includes methods of depleting an RA-associated biomarker in a patient by administering to the patient a therapeutically effective amount of a human antibody or antigen-binding fragment thereof that specifically binds to hIL-6R and a therapeutically effective amount of one or more FARMEs.

Examples of AR-associated biomarkers include, but are not limited to, for example, 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 appreciated by one of ordinary skill in the art, an increase or decrease in an AR-associated biomarker can be determined by comparing the level of the biomarker measured in the patient at a defined point in time after the administration of the anti-IL-6R antibody. with the level of the biomarker measured in the patient before administration (ie, the "initial measurement"). The defined time point in which the biomarker can be measured can 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, 40 days or more after the administration of the anti-hIL-6R antibody.

According to certain embodiments of the present invention, a patient may exhibit a decrease in the level of one or more of hsCRP, SAA, ESR, and / or hepcidin upon administration of an anti-hIL-6R antibody to the patient. For example, at approximately week 12 after weekly administration of anti-hIL-6R antibody and one or more DMARDs, the patient may exhibit one or more of the following: (i) a decrease in hsCRP of approximately 40%, 45% , 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more; (ii) a decrease in SAA of approximately 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more; (iii) a decrease in ESR of approximately 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% or more; and / or (iv) a decrease in hepcidin of 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 exhibit an increase in the level of one or more Hb or IL-6 upon administration of an anti-hIL-6R antibody and one or more FARMEs to the patient. For example, at approximately week 12 after weekly administration of anti-hIL-6R antibody and one or more DMARDs, the patient may have one or more of the following: (v) an increase in Hb of approximately 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 increase in IL-6 of approximately 100%, 150%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 550%, 600%, 650%, 700%, 750%, 800% or more.

The present disclosure includes methods of determining whether a subject is a suitable patient for whom administration of an anti-hIL-6R antibody would be beneficial. For example, if an individual, prior to receiving an anti-hIL-6R antibody and / or one or more FARMEs, exhibits a level of an AR-associated biomarker signifying disease state, the individual is therefore identified as a suitable patient for whom administration of an anti-hIL-6R antibody would be beneficial. According to certain exemplary embodiments, an individual can be identified as a good candidate for anti-hIL-6R / DMARD therapy if the individual exhibits one or more of the following: (i) an hsCRP level greater than about 4 mg / L (for example, about 4.5mg / L, about 5.0mg / L, about 5.5mg / L, about 6.0mg / L, about 7.0mg / L, about 10.0mg / L, about 15.0 mg / L, about 20.0 mg / L, or more); (ii) an SAA level greater than approximately 3800 ng / mL (for example, approximately 4000 ng / mL, 4500 ng / mL, approximately 5000 ng / mL, approximately 5500 ng / mL, approximately 6000 ng / mL, approximately 10,000 ng / mL, about 20,000 ng / mL, about 25,000 ng / mL, about 30,000 ng / mL, about 35,000 ng / mL, about 40,000 ng / mL, about 45,000 ng / mL, or more); (iii) an ESR greater than about 15mm / hr (for example, about 16mm / hr, about 17mm / hr, about 18mm / hr, about 19mm / hr, about 20mm / hr, about 21mm / hr. h, about 22 mm / h, about 25 mm / h, about 30 mm / h, about 35 mm / h, about 40 mm / h, about 45 mm / h, about 50 mm / h, or more); and / or (iv) a hepcidin level greater than approximately 60 ng / mL (for example, approximately 62 ng / mL, approximately 64 ng / mL, approximately 68 ng / mL, approximately 70 ng / mL, approximately 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, approximately 100 ng / mL, approximately 105 ng / mL, or more). Additional criteria, such as other clinical indicators of RA, in combination with any of the above biomarkers associated with RA, can be used to identify an individual as a suitable candidate for anti-hIL-6R therapy.

Patient population

In certain embodiments, the methods and compositions described herein are administered to specific patient populations. These populations include patients who have previously been treated for rheumatoid arthritis with treatment regimens other than the combination of an anti-hIL-6R antibody and one or more DMARDs. In other embodiments, sarilumab is administered to a patient who has previously been ineffectively treated with a DMARD and an anti-hIL-6R antibody other than sarilumab. These treatment regimens include anti-TNF-a therapy, eg, biological anti-TNF-a treatment regimens. Biological anti-TNF-a antagonists include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. These treatment regimens also include DMARD therapy in the absence of anti-hIL-6R antibody.

The DMARDs used in this therapy include methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide. FARMEs can be administered alone or in combination with other therapy that is not an anti-hIL-6R antibody, eg, sarilumab. In a specific embodiment, the prior treatment regimen was methotrexate. In another embodiment, methotrexate treatment is maintained in patients treated with an anti-hIL-6R antibody. In certain embodiments, the patient has previously been administered with both anti-TNF-α and DMARD therapies. Therapies can 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-hIL-6R antibody and one or more FARMEs. In other embodiments, these therapies have been received within 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years before receiving the combination of an anti-hIL-6R antibody and one or more FARMEs.

In certain aspects, the methods and compositions described herein are administered to specific patient populations who have received one or more of a treatment regimen described above where these treatments have not been effective. As used herein, a treatment has not been effective when treatment (for example, a dose of anti-TNF-α and / or a DMARD) does not produce a detectable improvement in one or more symptoms associated with rheumatoid arthritis. or that does not produce a biological effect (for example, a decrease in the level of a particular biomarker) that correlates with the underlying pathological mechanism (s) that give rise to the condition or symptom ( s) of rheumatoid arthritis. For example, a treatment that does not improve any of the following symptoms or conditions is considered ineffective: anemia from chronic disease, fever, depression, 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) classification criteria for rheumatoid arthritis. For example, an improvement of 20% (ACR20), 50% (ACR50), or 70% (ACR70) from baseline can be used to show detectable improvement. Instead, the ACR classification criteria can be used to select patients who have previously been ineffectively treated prior to treatment with anti-IL6R therapy. For example, a patient may be ineffectively treated if he no longer exhibits at least 10% detectable improvement (eg, 10%, 20%, 50%, or 70% improvement) according to the ACR criteria.

In other embodiments, the disease activity score (DAS28) can be used to show detectable improvement or, instead, ineffective treatment. DAS28 is a composite score of the sensitive joint count based on 28 joints, a swollen joint count based on 28 joints, a general health assessment, and an inflammation marker that can be assessed by measuring C-reactive protein (CRP) levels. Response to disease can be presented using the European League Against Rheumatism (EULAR) response criteria. A good answer for this criterion is an improvement of more than 1.2 in the DAS28 score with a present score greater than or equal to 3.2. A moderate response is an improvement greater than 0.6 but less than or equal to 1.2 in the DAS28 score and a present score greater than 3.2. Non-response is an improvement of less than 0.6 in the DAS28 score and a present score greater than 5.1. DAS28 remission is a DAS28 score less than 2.6. A detectable improvement can also be shown by measuring an improvement in any of the components of the DAS28 score.

In other exemplary embodiments, a treatment has not been effective when a patient still has "active disease" after treatment. For example, patients have "active disease" when they have at least 8 of the 68 tender joints and 6 of the 66 swollen joints, and / or high-sensitivity C-reactive protein (hs-CRP)> 10 mg / L (> 1.0 mg / dL). In a specific embodiment, sarilumab is administered to a patient who has previously been ineffectively treated with methotrexate (MTX). In such an example, patients may have received continuous treatment with MTX 10 to 25 mg / week (or by local labeling requirements if the dose interval differs) for at least 12 weeks and at a stable dose of MTX for a minimum of 8 weeks and still have moderate to intensely active RA, defined as: (i) at least 8 of 68 tender joints and 6 of 66 swollen joints, and (ii) highly sensitive C-reactive protein (hs-CRP) > 10 mg / L (> 1.0 mg / dL).

In one embodiment, the patient population comprises subjects who have not received a biological agent within the past three months. In certain embodiments, a biological agent is a protein. According to other embodiments, the protein is an antibody or a fragment thereof. According to other embodiments, the protein is a cytokine or a fragment or derivative thereof. In other embodiments, the protein is recombinant. In other embodiments, the biological agent is a vaccine, blood, blood component, allergen, somatic cell, gene therapy, or biological tissue. Biologics include blood factors, thrombolytic agents, hormones, hepatopoietic growth factors, interferons, interleukin-based products, vaccines, and monoclonal antibodies. In certain embodiments, the biological agent is abatacept. In other embodiments, the biological agent is adalimumab. In other embodiments, the biological agents include but are not limited to: TNFa blockers such as infliximab (Remicade®), adalimumab (Humira®), golimumab (Simponi®), etanercept (Enbrel®), certolizumab (Cimzia®); IL-1 blockers such as anakinra (Kineret®), anti-CD20 antibodies such as rituximab (Rituxan®), T-cell costimulation blocker such as abatacept (Orencia®), and anti-IL6 antibodies such as sirukumab, clazakizumab or olokizumab.

According to other embodiments, the biological is a biological medical product. A biological medical product is a medical product that is manufactured or extracted from biological sources. In certain embodiments, biologics are defined as the exclusion of biologics that are consumed by animals for nutrition. In these embodiments, the biologics must have a specific therapeutic consequence for the target population beyond nutrition.

In another embodiment, the patient population comprises subjects who have received treatment for methotrexate for at least 6 weeks. In other embodiments, subjects have received methotrexate for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 weeks. In more specific embodiments, subjects have received methotrexate but have not received other DMARDs for at least 6 weeks. In other embodiments, subjects have not received a DMARD other than methotrexate for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, 24, 25 or 26 weeks. DMARDs other than methotrexate include leflunomide, sulfasalazine, and hydroxychloroquine.

In another embodiment, the patient population comprises subjects who do not have an autoimmune disease other than rheumatoid arthritis. In certain embodiments, the autoimmune disease other than arthritis is one or more pathologies selected from the group consisting of acute disseminated encephalomyelitis (ADE), Addison's disease, agammaglobulinemia, alopecia areata, amyotrophic lateral sclerosis (also Lou Gehrig's disease; motor neurons), ankylosing spondylitis, antiphospholipid syndrome, antisynthetase syndrome, atopic allergy, atopic dermatitis, autoimmune aplastic anemia, autoimmune cardiomyopathy, autoimmune enteropathy, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune disease of the inner ear, autoimmune lymphoproliferative neuropathy, autoimmune peripheral neuropathy autoimmune, autoimmune poliendocrine syndrome, autoimmune progesterone dermatitis, autoimmune thrombocytopenic purpura, autoimmune urticaria, autoimmune uveitis, Balo's disease / Balo's concentric sclerosis, Behget's disease, Berger's disease, Bickerstaff's encephalitis, yes Blau's syndrome, bullous pemphigus, cancer, Castleman's disease, celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy, chronic recurrent multifocal osteomyelitis, chronic obstructive pulmonary disease, Churg-Strauss syndrome, cicatricial pemphigoid, Cogan's syndrome, agglutinin disease colds, complement component 2 deficiency, contact dermatitis, cranial arteritis, Crohn's disease, Cushing's syndrome, cutaneous leukocytoclastic angeitis, Dego's disease, Dercum's disease, dermatitis herpetiformis, dermatomyositis, type 1 diabetes mellitus, diffuse cutaneous systemic sclerosis , Dressler's syndrome, drug-induced lupus, discoid lupus erythematosus, eczema, endometriosis, enthesitis-related arthritis, eosinophilic fasciitis, eosinophilic, eosinophilic pneumonia, acquired epidermolysis bullosa, erythema nodosum, erythroblastosis fetalismia, essential myxoglobuldysinemia, myxoglobulis syndrome osif Progressive itching, fibrosing alveolitis, gastritis, gastrointestinal pemphigoid, glomerulonephritis, Goodpasture syndrome, Graves disease, Guillain-Barré syndrome (GBS), Hashimoto encephalopathy, Hashimoto's thyroiditis, Henoch-Schonlein purpura, gestational herpes, hidradenitis suppurativa, Hughes-Stovin syndrome, hypogammaglobulinaemia, idiopathic inflammatory demyelinating diseases, idiopathic pulmonary fibrosis, idiopathic thrombocytopenic purpura, IgA nephropathy, inclusion body myositis, chronic inflammatory demyelinating polyneuropathy, interstitial cystitis, juvenile idiopathic arthritis, Kawasaki disease Lambert-Eaton, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, linear IgA disease (LAD), lupoid hepatitis, lupus erythematosus, Majeed, Méniere's syndrome, microscopic polyangiitis, Miller-Fisher syndrome, mixed connective tissue disease, morphea , Mucha-Haberman disease n, multiple sclerosis, myasthenia gravis, microscopic colitis, myositis, narcolepsy, neuromyelitis optica, neuromyotonia, ocular cicatricial pemphigoid, opsoclonus-myoclonus syndrome, Ord's thyroiditis, palindromic rheumatism, PANDAS (pediatric neuropsychiatric disorders, autoimmune degeneration associated with cerebrospinal fibrosis) paraneoplastic, paroxysmal nocturnal hemoglobinuria, Parry Romberg syndrome, Parsonage-Turner syndrome, pars planitis, pemphigus vulgaris, pernicious anemia, perivenous encephalomyelitis, Poems syndrome, polyarteritis nodosa, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, cholangitis sclerosing progressive inflammatory, psoriasis, psoriatic arthritis, pyoderma gangrenous, pure red cell aplasia, Rasmussen encephalitis, Raynaud's phenomenon, relapsing polychondritis, Reiter's syndrome, restless legs syndrome, retroperitoneal fibrosis, rheumatic fever, sarcoidosis, schizophrenia, syndrome Schmidt syndrome, Schnitzler syndrome, scleritis, scleroderma, serum sickness, Sjogren's syndrome, spondyloarthropathy, Still's disease, stiff person syndrome, subacute bacterial endocarditis, Susac's syndrome, Sweet's syndrome, Sydenham's disease, sympathetic ophthalmia, Systemic lupus erythematosus, Takayasu arteritis, temporal arteritis, thrombocytopenia, Tolosa-Hunt syndrome, transverse myelitis, ulcerative colitis, undifferentiated connective tissue disease, undifferentiated spondyloarthropathy, urticarial vasculitis, vasculitis, vitiligo, and Wegener's granulomatosis.

In another embodiment, the patient population comprises subjects who have not received parenteral or intra-articular glucocorticoid administration for four weeks. In other embodiments, subjects have not received parenteral or intra-articular glucocorticoid administration for at least 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16. 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26 weeks. In certain embodiments, glucocorticoids include one or more selected from the group consisting of cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, fludrocortisone, deoxycorticosterone acetate, and aldosterone.

Examples

Example 1. The combination of sarilumab and methotrexate is effective in the treatment of rheumatoid arthritis in patients where methotrexate treatment is ineffective.

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

The study included two parts. The first part (Part A) of the study was a 12-week 6-group dose-finding part planned to select the two dose schedules based on efficacy (reduction in signs and symptoms) and safety. The second part (Part B) of the study was a 52-week part to confirm the efficacy and safety of these two selected dose regimens on reduction in signs and symptoms, inhibition of the progression of structural damage, improvement in physical function. and induction of significant clinical response.

The operationally continuous nature of the design of this study lay in the fact that Part B began testing patients right after the last patient was randomized to Part A without waiting for dose selection based on their results. Thus, the patients in part B belong to 2 different cohorts according to the moment of their recruitment:

Patient cohort 1 was randomized prior to dose selection: these patients were randomized into six groups (as in Part A). After dose selection, patients were randomized to the two selected doses and placebo regimens continued the 52-week trial, but those randomized to the other three groups withdrew from the present study, but were proposed to join. an open tag extension (see LTS11210).

Cohort 2 of patients randomized after dose selection: These patients were randomized into three groups, the two selected and placebo.

Part A

Patients were evaluated at a screening visit for confirmation of diagnosis, disease activity, study eligibility, and verification of concomitant therapy. Comprehensive examination and laboratory tests including hematology, chemistry profile, lipid profile, liver enzymes and acute phase reactants, HbA1c, hepatitis B and C, and serum pregnancy test were performed for women of childbearing age. An ECG evaluation was also performed. A PPD and QuantiFERON test were performed to exclude any tuberculosis, in addition to a chest radiograph (if a documented negative radiograph performed within the last 3 months is not available).

After confirmation of eligibility, patients were randomized in a balanced manner, to this treatment from the 6-group international multicenter, double-blind, parallel-group 12-week placebo-controlled study of SAR153191 or weekly subcutaneous placebo with therapy. joint MTX:

Methotrexate was administered to each patient as before the study. This was at 10 to 25 mg / week, or 6 to 25 mg / week for patients within the Asia-Pacific region; Taiwan, South Korea, Malaysia, the Philippines, Thailand, and India.

During the first visit, patients were reminded of the list of prohibited medications, and that they should continue to take MTX at its current stable dose until the end of the folic acid study as per local recommendation to prevent MTX toxicity. Patients were instructed in the preparation and self-administration of IMP and reminded to inject themselves strictly 7 days apart. At dose time points that occur outside of site visits, SAR153191 was injected by the patient himself, a trained professional caregiver, or a trained qualified person.

Patients had six additional visits at weeks 2, 4, 6, 8, 10, and 12. Efficacy evaluation and laboratory testing including hematology, chemistry profile, lipid profile, liver enzymes, and phase reactants were evaluated. acute throughout the study to allow calculation of the main efficacy scores, and monitoring of safety aspects. At the randomization visit and at Week 2, 4, 8, and 12, a comprehensive joint examination for tender joint count and swollen joint count was performed by an independent assessor of investigator and patient data, with the purpose of calculating the ACR score (primary endpoint). In order to maintain blinding, the investigator, sponsor, and patient will be blinded to CRP and serum IL6 levels during the study.

Adverse events were closely monitored including possible infections assessed in part by monitoring body temperature at each visit. The presence of tuberculosis was verified by specific evaluation of the patient (verification of any signs or symptoms, or contact with active TB). Neurological abnormalities (history and physical examination) or autoimmune diathesis (ANA, bc-DNA antibodies) were tested at baseline and at the end of the treatment visit.

Specific blood and urine samples were taken during the study to test for potential biomarkers that could be predictive of disease response or adverse events. These include a single sample for DNA (after the patient has signed a specific informed consent) and multiple samples obtained sequentially throughout the study for RNA expression profiling and protein biomarker analysis. Samples were also collected at time points appropriate for pharmacokinetic parameters and antibody against SAR153191.

Patients withdrawn prematurely were evaluated at the end of the treatment visit with full clinical and laboratory evaluation. They were considered as non-responders with respect to the ACR score.

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

Results

Human patients treated with sarilumab (REGN88 / SAR153191) in combination with the standard RA treatment, methotrexate (MTX), achieved significant and clinically important improvement in signs and symptoms of moderate to severe rheumatoid arthritis (RA) compared to patients treated with MTX alone. A multinational, multi-group, dose-finding, double-blind, placebo-controlled study of 306 patients was conducted comparing five different dose regimens of sarilumab in combination with MTX with placebo plus MTX. The primary endpoint of the study was the proportion of patients who achieved at least a 20% improvement in RA symptoms (ACR20) after 12 weeks.

A dose response was observed in patients receiving sarilumab in combination with MTX. An ACR20 response was seen after 12 weeks in 49.0% of patients receiving the lowest sarilumab dose and 72.0% of patients receiving the highest dose regimen compared to 46, 2% of patients who received placebo and MTX (see the following table, the asterisk (*) indicates significance versus placebo by the Cochran-Mantel-Haenszel test (p <0.05), correcting for multiplicity by the procedure of Hommel).

The most common adverse events (> 5%) reported more frequently in the active treatment groups included infections (non-serious), neutropenia, and liver function test abnormalities. The types and frequencies of adverse events were in agreement with those previously reported with IL-6 inhibition. The incidence of serious adverse events was comparable between the five sarilumab treatment groups and the placebo group.

Sarilumab also demonstrated significant benefit compared to placebo in secondary endpoints, including ACR 50, ACR 70, and DAS 28 scores, additional measures of clinical activity used in RA trials. More specifically:

- An ACR50 response was observed after 12 weeks in 22% of patients who received the lowest sarilumab dose regimen and 30% of patients who received the highest dose regimen compared to 15% of patients who received placebo and MTX (see table below, double asterisk (**) indicates statistical significance versus placebo (p <0.01, posteriorly adjusted for multiplicity).

- ACR70 response was significantly higher in the 200 mg q2w group versus placebo. An ACR70 response was observed after 12 weeks in 16% of patients receiving the highest dose regimen compared to 2% of patients receiving placebo and MTX ((see table below, double asterisk ( **) indicates statistical significance versus placebo (p <0.01, posteriorly adjusted for multiplicity).

- Statistically significant improvement in DAS28 score observed after 12 weeks in all but the lowest two regimens (see table below, which represents clinical trial results with respect to secondary endpoint of improved DAS28 score or remission of DAS28 after 12 weeks in patients who received one of the 5 treatment groups of joint sarilumab / MTX therapy compared to placebo.LM (Least squares), SE (standard error). fp <0.01; ffp <0.0 or i; p <0.01 is considered statistically significant versus placebo after a posteriori adjustment for multiplicity).

At the four highest dosing schedules, a reduced DAS score of at least 2.0 (versus baseline) was observed at the four highest dosing schedules after week 12. In addition, DAS remissions (patients with a DAS28 score of <2.6) were significantly higher in the 200 mg q2w and 150 mg qw treatment groups relative to placebo after 12 weeks.

- Significant improvements in the ACR criteria of the swollen joint count (SJC) and the sensitive joint count (TJC). For example, TJC decreased by 10 at all dosing schedules after 12 weeks, while SJC decreased by 8 at the four highest treatment doses. In contrast, the placebo group had a decrease in TJC and SJC of 7 and 9, respectively. The results are presented in the following table (SJC = count of swollen joints; TJC = count of tender joints; after 12 weeks in patients who received one of the 5 treatment groups of sarilumab / MTX joint therapy compared to placebo ):

- Significant improvements in the disability index of the Health Assessment Questionnaire (HAQ-DI). For example, HAQ-DI scores decreased by at least 0.3 from baseline for all treatment groups, and by at least 0.5 in the 150 mg 2qw and 200 mg 2qw treatment groups. The results are presented in the following table (HAQ-DI after 12 weeks in patients who received one of the 5 treatment groups of joint sarilumab / MTX therapy compared to placebo):

- Significant improvements in the visual acuity score (VAS). For example, the physician's VAS decreased by at least 30 (from baseline) at the four highest dose schedules. In addition, the patient's VAS and pain VAS decreased by at least 25 (from baseline) in the four highest dose regimens. The results are presented in the following table (visual analog scale (VAS) after 12 weeks in patients who received one of the 5 treatment groups of joint sarilumab / MTX therapy compared to placebo; VAS (mm) was evaluated in terms of Patient VAS, Physician VAS and Pain VAS):

- Significant improvements in the level of C-reactive protein (CRP). For example, CRP levels decreased by at least 1 mg / dL in all treatment groups. Furthermore, CRP levels decreased by at least 2 mg / dL for all but the lowest dosing regimens. The results are presented in the following table (increase in C-reactive protein (CRP) after 12 weeks in patients who received one of the 5 treatment groups of joint sarilumab / MTX therapy compared to placebo):

- An EULAR (European League Against Rheumatism) index improved at 12 weeks. For example, a "good response" according to the EULAR index was achieved in at least 18% of patients for all treatment groups. In fact, a good response was seen in at least 30% of patients for all but the lowest dosage treatment group.

The results are presented in the following table (EULAR (European League Against Rheumatism) index improvement after 12 weeks in patients who received one of the 5 treatment groups of sarilumab / MTX co-therapy compared to placebo. aThe Cochran-Mantel-Haenszel test stratified by prior biological use and region comparing non-responders versus responders (good and moderate response combined). fp <0.01; ffp <0.001; p <0.01 is considered statistically significant versus to placebo after posterior adjustment for multiplicity):

These results provide evidence that blocking IL-6R with sarilumab represents a promising new investigational anti-inflammatory therapy for reducing the symptoms of RA disease.

Part b

Patients were evaluated at a screening visit for confirmation of diagnosis and disease activity, eligibility for study, and verification of concomitant therapy. The investigator verified that the patient was either positive anti-cyclic citrullinated peptide (CCP) antibody or positive rheumatoid factor (RF) or that he / she had bone erosion confirmed on x-ray. If necessary, for patients who were both CCP and RF negative and did not have radiography, an radiograph was performed on the centrally reviewed screen and was also considered as the initial radiographic evaluation for the study.

Cohort 1: Patients Randomized Before Dose Selection

Recruitment for the long-term safety extension study started just after the last patient had been randomized to Part A. After confirmation of eligibility, patients were randomized, in a balanced way stratified by prior use of biologic and region-wise, in a 6-group international multicenter double-blind parallel group placebo-controlled study treatment of SAR153191 (5-active-dose regimens) or weekly subcutaneously administered placebo with MTX co-therapy.

At the beginning of each patient visit for patients in Cohort 1, the investigator verified using the SIRV list that the patient was still "eligible" for the study, that is, that the patient should not be withdrawn due to randomization in an unselected group. In fact, when the essential dose regimens from Part A were selected, only patients randomized to the corresponding or placebo groups were still considered eligible for the study and continued in the study for a total of 52 weeks. The other patients (randomized to unselected dose schedules) were no longer considered eligible by SIRV. The investigator proposed that these patients participate in an open label extension study with SAR153191 at the highest dose schedule available at the time the patient was recruited.

Initial randomization remained blinded for all patients.

Cohort 2: Randomized patients after dose selection - Essential part.

On day 1, after confirmation of eligibility, patients were randomized, in a balanced manner stratified by prior use of biologics and by region, in a 3-group international multicenter, double-blind, parallel-group placebo-controlled study SAR153191 (essential 2-dose regimens) or placebo administered subcutaneously with MTX co-therapy.

Both cohorts:

In any cohort, patients were evaluated at Week 2, Week 4, and every 4 weeks through Week 28, and then every 8 weeks through Week 52 for efficacy and safety evaluations and laboratory testing.

The same procedures were applied in Part B as described in Part A. In addition, a radiological evaluation of the hands and foot joints was performed at baseline, Week 24 and Week 52. Radiographs de-identified from any information of patients were sent to central evaluators for the calculation of the Sharp score (a specific scoring system for joint destruction). Economic health assessments such as SF-36 were also added.

Starting at Week 16, it was proposed that patients with lack of efficacy defined as less than a 20% improvement from baseline in either swollen joint count (SJC) or tender joint count (TJC) for 2 consecutive visits, or any other clear lack of efficacy based on investigator judgment, were rescued with the highest possible dose of open-label SAR153191 at the time of transfer into the salvage treatment group, and continued in the study as per your planned visitation schedule. Blood samples were taken for laboratory analysis two weeks after the switch for safety purposes. Non-responders were considered for the primary endpoint (ACR20). These patients remained in the study and continued with all visits.

In selected countries, patients who met the lack of efficacy criteria at Visit 7 / Week 16 of Part B treatment, or thereafter, were permanently withdrawn from treatment, and were not eligible to participate in the treatment group. open treatment rescue. Instead, patients had a follow-up visit to assess safety 6 weeks after the end of treatment visit.

For any patient who was prematurely withdrawn or prematurely rescued with open SAR153191, an additional radiographic examination was performed at the time of removal or salvage, unless a study radiographic examination had been performed within the preceding 3 months (A 3-month window should be considered between 2 radiological evaluations to avoid excessive radiological exposure).

Patients who completed Part B (including those in the open-label rescue group) were proposed to be recruited into an open-label extension study at the maximum dose schedule at the time of enrollment. All patients were scheduled to complete the post-treatment follow-up visit. If the patient agreed to enter the long-term open-label extension study of SAR153191, and was confirmed eligible, the post-treatment follow-up visit was not completed.

Example 2. The combination of sarilumab and FARMEs are effective in the treatment of rheumatoid arthritis in patients where the TNF-α antagonist and methotrexate treatment are ineffective.

A worldwide randomized, double-blind, placebo-controlled study was conducted in rheumatoid arthritis patients with an inadequate response to methotrexate (MTX) and at least one TNF-α antagonist. The patients who were included in the study had the following criteria. Patients who had, in the opinion of the investigator, an inadequate response to at least one TNF-a antagonist, after being treated for at least 3 months in the past 2 years, or patients who were intolerant to at least 1 TNF-antagonist a, leading to the outage. TNF-a antagonists included etanercept, infliximab, adalimumab, golimumab, and / or certolizumab pegol. The patients needed to have active disease defined as: at least 6 of the 66 inflamed joints and 8 of the 68 tender joints and; hs-CRP> 8 mg / L. Patients also needed to have had continuous treatment with one or a combination of DMARDs for at least 12 weeks prior to baseline and at a stable dose (s) 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 within the Asia-Pacific region; leflunomide (LEF) - 10 to 20 mg daily; sulfasalazine (SSZ) - 1000 to 3000 mg per day; or hydroxychloroquine (HCQ) - 200 to 400 mg per day.

Table 1 - Groups and forms for both the investigational drug and the non-investigational drug

Subcutaneous administration will occur in the abdomen or thigh. Each dose will be self-administered (whenever possible), in a single injection. SC injection sites can be alternated between the 4 quadrants of the abdomen (except the navel or the waist area) or the thigh (front and side).

Patients and / or their non-professional caregivers will be instructed to prepare and administer the IMP at the beginning of the double-blind treatment period. This training must be documented in the patient study file. The study coordinator or representative can administer the first injection comprising the starting 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 clinical procedures and blood draw. For doses not given at the study site, diaries will be provided to record information regarding these injections; These diaries will be kept as source data in the patient's study file. If the patient is unable or reluctant to administer the IMP, an arrangement must be made for the trained site staff and / or caregiver to administer the IMP for the dose that is not scheduled to be administered at the study site.

If the study visit is not conducted on site as scheduled, the dose will be administered by the patient and / or their caregiver (s) as scheduled.

The treatment will last for 24 weeks. Beginning at Week 12, patients with lack of efficacy defined as less than 20% improvement from baseline in both SJC and TJC for 2 consecutive visits will be proposed for rescue with open-label sarilumab at the highest dose in essay. These patients will continue in the trial according to the visiting schedule.

In this study, sarilumab is administered, in addition to DMARD therapy, which is considered a background therapy. All patients should continue to receive continuous treatment with one or a combination of non-biological DMARD (s) as background therapy for at least 12 weeks prior to baseline and at a stable dose (s) for at least 6 weeks before the selection:

• methotrexate (MTX) - 10 to 25 mg / week (or 6 to 25 mg / week for patients within the Asia-Pacific region) supplemented with folic / folinic acid

• leflunomide (LEF) - 10 to 20 mg daily

• sulfasalazine (SSZ) - 1000 to 3000 mg daily

• hydroxychloroquine (HCQ) - 200 to 400 mg daily

Each dose of DMARD will be recorded throughout the study in the data collection notebook. The DMARD dose can be reduced at any time for safety or tolerability reasons. Any change in dose and the start date of the new dose should be recorded in the e-CRF at each visit. The DMARD (s) will not be dispensed or supplied by the sponsor as an IMP.

All patients taking MTX will receive folic / folinic acid as recommended locally in the country where the study is conducted. The dose, route and schedule of administration of folic / folinic acid will be recorded with concomitant medications.

Sarilumab and equivalent placebo will be provided in identically equivalent glass pre-filled syringes. Each pre-filled syringe contains 1.14 mL of sarilumab (SAR153191) or equivalent placebo solution.

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

Treatment kit numbers will be obtained by the investigator at the time of patient randomization and subsequent scheduled patient visits via SIRV that will be available 24 hours a day.

Under the double-blind design, investigators will remain blinded to study treatment and will not have access to randomization (treatment codes), except under the circumstances described in Section 8.7.

Patients will be randomized to one of the treatment groups using a centralized randomization system using a SIRV. A patient will be considered randomized when the treatment number has been provided by the SIRV.

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

The treatment assignment will be assigned to the patient according to the central randomization list using the SIRV stratified by region and number of previous anti-TNFs (1 vs> 1). At Visit 2 (Day 1), after confirming that the patient is eligible for entry into the treatment period, the site coordinator will contact the SIRV in order to receive the first treatment assignment kit (numbers kit). Patients will be randomized to receive either one of the 2 treatment groups of sarilumab or its equivalent placebo. The randomization ratio is 1: 1: 1 (sarilumab 150 mg: sarilumab 200 mg: placebo equivalent). At subsequent dispensing visits during the treatment period, the site coordinator will call the SIRV to obtain the subsequent assignment of treatment kits. A confirmation fax / email will be sent to the site after each assignment.

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

Example 3. Positive results with sarilumab in the first phase 3 rheumatoid arthritis registry trial

Sarilumab, administered subcutaneously every two weeks, meets all three primary endpoints.

Sarilumab is the first fully human monoclonal antibody directed against the interleukin-6 receptor (IL-6R).

The results of the SARIL-RA-MOBILITY phase 3 clinical trial in adult patients with active rheumatoid arthritis (RA) who were inadequate responders to methotrexate (MTX) therapy show that treatment with sarilumab in combination with MTX improved signs and disease symptoms, as well as physical function, and inhibited the progression of joint damage.

The 52-week SARIL-RA-MOBILITY phase 3 trial recruited approximately 1,200 patients with moderate to severe active rheumatoid arthritis who were inadequate responders to MTX therapy. Patients were randomized to one of three subcutaneous treatment groups, all in combination with MTX, and administered every two weeks: sarilumab 200 milligrams (mg), sarilumab 150 mg, or placebo.

Both sarilumab groups showed clinically relevant and statistically significant improvements compared to the placebo group in all three primary endpoints (p <0.0001).

(1) Improvement in RA signs and symptoms within 24 weeks, as measured by the American College of Rheumatology score of 20 percent improvement (ACR20).

• 66 percent, 58 percent, and 33 percent in the sarilumab 200 mg, sarilumab 150 mg, and placebo groups, respectively, all in combination with MTX.

(2) Improvement in physical function, as measured by change from baseline on the Health-Disability Assessment Questionnaire (HAQ-DI) at week 16.

(3) Inhibition of progression of structural damage at Week 52, as measured by change in Van der Heijde modified total Sharp score (mTSS).

• 0.25, 0.90 and 2.78 in the sarilumab 200 mg, sarilumab 150 mg and placebo groups, respectively, all in combination with MTX.

• The group that received the 200 mg dose of sarilumab MTX had an approximately 90 percent reduction in radiographic progression assessed by mTSS compared to radiographic progression with MTX placebo at Week 52.

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

Methods:

In Phase 3 of the MOBILITY study, MTX-IR adults with moderate to severe RA were randomized (1: 1: 1) to placebo and one of two subcutaneous doses of sarilumab (150 mg q2w or 200 mg q2w) plus MTX previous. The inclusion and exclusion criteria are shown in Table 2. The disposition of patients within the study is provided in Table 3. The baseline characteristics of the subjects are provided in Tables 4 and 5.

Table 2 Inclusion and exclusion criteria

Table 3. Patient disposition

Table 4. Baseline demographic characteristics of the subjects.

Table 5. Baseline characteristics of rheumatoid arthritis of subjects.

The aim of the study was to evaluate the clinical efficacy, radiographic and functional improvement, and the safety profile of sarilumab dosing regimens. Radiographic variables of interest included: 1) change from baseline in Van der Heijde modified total Sharp score (mTSS) at Week 52 (primary endpoint); 2) sensitivity analysis to assess the impact on mTSS of patients without post-baseline radiographic data; 3) radiographic progression of joint space erosion and narrowing (JSN) scores (subsets of mTSS); 4) Proportion of patients without radiographic progression from baseline to Week 52 in mTSS, erosion, or JSN scores. All radiographic evaluations were performed using standard technique with electronic images independently analyzed by at least 2 trained readers and the average of the 2 scores was used for analysis.

Results:

At weeks 24 and 52, smaller, statistically significant increases from baseline in mTSS were observed in sarilumab-treated patients compared to placebo, indicating inhibition of structural damage, as shown in Table 6.

Table 6. Efficacy of sarilumab on clinical, functional and radiographic outcomes

The sensitivity analyzes planned for mTSS were in agreement with the main results. At Weeks 24 and 52, smaller increases from baseline were also observed in erosion and JSN scores with sarilumab compared to placebo. The proportion of patients without progression in mTSS, erosion score, and JSN score was numerically higher in the sarilumab groups compared to placebo. The adverse events (AEs) observed were similar to those reported with other IL-6 inhibitors.

Subjects treated with sarilumab and methotrexate showed, among other things, an improvement in RA signs and symptoms at 24 and 52 weeks, as measured by the American College of Rheumatology score of 20 percent improvement (ACR20) , see Table 6b below (asterisk (*) = P <0.0001 vs. Placebo MTX). These results were 66 percent, 58 percent, and 33 percent in the sarilumab 200 mg, sarilumab 150 mg, and placebo groups, respectively, at 24 weeks and 59 percent, 54 percent, and 32 percent at 52 weeks. all in combination with MTX.

Table 6b. Sarilumab efficacy results

by ACR

Placebo MTX 150 mg q2w MTX 200 mg q2w MTX (n = 398) (n = 400) (n = 399)

Response from ACR20 - Sem. 24, (%) 33.4% 58.0% * 66.4% *

Response from ACR50 - Sem. 24, (%) 16.6% 37.0% * 45.6% *

Response from ACR70 - Sem. 24, (%) 7.3% 19.8% * 24.8% *

Response from ACR20 - Sem. 52, (%) 31.7% 53.5% * 58.6% *

Response from ACR50 - Sem. 52, (%) 18.1% 40.0% * 42.9% *

Response from ACR70 - Sem. 52, (%) 9.0% 24.8% * 26.8% *

Subjects treated with sarilumab and methotrexate achieved an ACR70 response for 24 consecutive weeks more frequently than subjects given placebo, as shown in Table 7.

Table 7 ACR70 Response of Subjects

Subjects treated with sarilumab and methotrexate also showed an improvement in physical function, as measured by change from baseline on the Health-Disability Assessment Questionnaire (HAQ-DI) at Week 16, as shown in Table 8 below.

Table 8. Efficacy results

Table. Sarilumab efficacy results

Placebo MTX 150 mg q2w MTX 200 mg q2w MTX (n = 398) (n = 400) (n = 399) Response of ACR20 - Sem. 24, n (%) 133 (33.4%) 232 (58.0%) * 265 (66.4%) * Response of ACR50 - Sem. 24, n (%) 66 (16.6%) 148 (37.0%) * 182 (45.6%) * Response of ACR70 - Sem. 24, n (%) 29 (7.3%) 79 (19.8%) * 99 (24.8%) * mTSS, mean change from BL - Sem. 52 2.8 0.9 * 0.3 * Primary clinical response (ACR70 response 12 (3.0%) 51 (12.8%) * 59 (14.8%) * maintained for 24 weeks), n ( %)

ACR disease activity measures,

mean change aj. from BL - Sem. 24

Swollen joint count -6.6 -10.6 * -11.2 * Tender joint count -10.1 -16.9 * -17.4 * HAQ-DI, mean change aj. from BL

- Sem .16 -0.3 -0.5 * -0.6 * - Sem .24 -0.4 -0.6 * -0.6 * - Sem .52 -0.5 -0.7 * - 0.8 * DAS28-CRP

Change in mean by MC from BL - Sem. 24 -1.17 -2.45 * -2.82 * Change in the mean by MC from BL - Sem. 52 -1.36 -2.78 * -2.95 * Clinical remission # - Sem. 24, n (%) 40 (10.1%) 111 (27.8%) * 136 (34.1%) * Clinical remission # - Sem. 52, n (%) 34 (8.5%) 124 (31.0%) * 136 (34.1%) * CDAI

Change in mean by MC from BL - Sem. 24 -14.47 -23.89 * -25.79 * Change in the mean by MC from BL - Sem. 52 -17.50 -26.96 * -27.26 * Remission (<2.8) - Sem. 24, n (%) 20 (5.0%) 41 (10.3%) t 55 (13.8%) * Remission (<2.8) - Sem. 52, n (%) 19 (4.8%) 59 (14.8%) * 72 (18.0%) * No radiographic progression in Sem. 52, n (%) 154 (38.7%) 191 (47.8%) * 222 (55.6%) * * P <0.0001 vs placebo MTX; f p = 0.0053; * p <0.01 vs. placebo MTX; # score <2.6; MTX, methotrexate; BL, initial level; MC, least squares; ACR 20/50/70, 20% / 50% / 70% improvement criteria from the American College of Rheumatology; mTSS, Van der Heijde modified total Sharp score; HAQ-DI, Health Assessment Questionnaire-Disability Index; HAQ-DI responders,> 0.3 improvement in HAQ-DI from baseline; DAS28-CRP, 28 Joint Disease Activity Score Using C-Reactive Protein; DAS28-CRP remission, DAS28-CRP <2.6; CDAI, index of clinical disease activity; CDAI remission, CDAI <2.8.

Subjects treated with sarilumab and methotrexate also showed inhibition of the progression of structural damage at Week 52, as measured by the change in the Van der Heijde modified total Sharp score (mTSS).

0.25, 0.90, and 2.78 in the sarilumab 200 mg, sarilumab 150 mg, and placebo groups, respectively, all in combination with MTX. The group that received the 200 mg dose of sarilumab MTX had an approximately 90 percent reduction in radiographic progression assessed by mTSS compared to progression X-ray with placebo MTX at Week 52. Subjects treated with sarilumab and methotrexate also showed a decrease in mean DAS28-CRP (Table 8a) and mean CDAi (Table 8b) compared to placebo.

Table 8a:

Table 8b:

In the SARIL-RA-MOBILITY trial, there was a higher incidence of treatment-emergent adverse events leading to withdrawal in the sarilumab treatment groups compared to placebo (13.9 percent at 200 mg, 12.5 percent). percent in 150 mg and 4.7 percent in placebo). In conclusion, blocking IL-6 is an important therapeutic approach for rheumatoid arthritis, as these phase 3 results demonstrated efficacy at both doses of sarilumab, each administered every two weeks. This is summarized below in Tables 9-14.

Table 9. Treatment-emergent adverse events (TEAEs).

Table 10. Most frequent TEAEs (> 5% in any treatment group)

Table 11. Serious adverse events (SAEs) by system (> 0.5% in any treatment group)

Table 12. Adverse events of special interest

Table 13. Incidence: Neutropenia and thrombocytopenia

Claims (12)

1. An anti-IL6R antibody comprising the heavy chain variable region of SEQ ID NO: 2 and the light chain variable region of SEQ ID NO: 3 for use in combination with methotrexate to inhibit the progression of structural damage in a subject suffering from rheumatoid arthritis, wherein an effective amount of the antibody and an effective amount of methotrexate are administered to the subject, and wherein the antibody is administered subcutaneously to the subject between 150 and 200 mg every two weeks. 2. The antibody for use in combination with methotrexate according to claim 1, wherein the inhibition of the progression of structural damage is characterized in that the subject achieves after at least 24 weeks of treatment a change from the initial level (BL) in the Van der Heijde Modified Total Sharp Score (mTSS) of at most 0.6. 3. The antibody for use in combination with methotrexate according to claim 1 or 2, wherein the inhibition of the progression of structural damage is characterized in that the subject achieves after at least 52 weeks of treatment a change from the initial level ( BL) in the Van der Heijde Modified Total Sharp Score (mTSS) of maximum 1. The antibody for use in combination with methotrexate according to any one of claims 1 to 3, wherein the subject was previously ineffectively treated for rheumatoid arthritis by administering methotrexate. The antibody for use in combination with methotrexate according to any one of claims 1-4, wherein the methotrexate is administered between 6 and 25 mg per week. 6. The antibody for use in combination with methotrexate according to any of claims 1-5, wherein the antibody is administered to the subject for at least 52 weeks. 7. The antibody for use in combination with methotrexate according to any of claims 1-6, wherein the inhibition of the progression of structural damage is characterized in that the subject achieves after at least 24 weeks of treatment a change from the level Baseline (BL) on Van der Heijde Modified Total Sharp Score (mTSS) of at most 0.2. 8. The antibody for use in combination with methotrexate according to any of claims 1-7, wherein the inhibition of the progression of structural damage is characterized in that the subject achieves after at least 24 weeks of treatment a change from the level baseline (BL) on Van der Heijde Modified Total Sharp Score (mTSS) of approximately 0.13. 9. The antibody for use in combination with methotrexate according to any of claims 1-8, wherein the inhibition of the progression of structural damage is characterized in that the subject achieves after at least 52 weeks of treatment a change from the level Baseline (BL) in Van der Heijde Modified Total Sharp Score (mTSS) of maximum 0.3. 10. The antibody for use in combination with methotrexate according to any of claims 1-9, wherein inhibition of the progression of structural damage is characterized in that the subject achieves after at least 52 weeks of treatment a change from the initial level (BL) in Van der Heijde Modified Total Sharp Score (mTSS) of approximately 0.25. 11. The antibody for use in combination with methotrexate according to any of claims 1-10, wherein the antibody is administered at 150 mg every two weeks. 12. The antibody for use in combination with methotrexate according to any of claims 1-10, wherein the antibody is administered at 200 mg every two weeks.