Methods of treating autoimmune diseases using interleukin-17 (il-17) antagonists

Abstract

To provide methods for treating psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA), e.g., non-radiographic axial spondyloarthritis (nr-axSpA) or ankylosing spondylitis (AS).SOLUTION: Methods are provided for treating PsA or axSpA using an IL-17 antagonist, such as an IL-17 antibody, such as secukinumab. Also provided herein are methods for inhibiting the progression of structural damage in PsA and axSpA patients using IL-17 antagonists, e.g., IL-17 antibodies, such as secukinumab.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure is incorporated herein by reference in its entirety. U.S. Provisional Patent Application No. 62 / 903,070 filed September 20, 2019 and Priority is claimed to specification No. 62 / 911394, filed on the 7th.

[0002] Technical Field The present disclosure provides therapeutic options for patients with autoimmune diseases, such as psoriatic arthritis (PsA) and axial spinal cord injury. In some cases, methods for treating patients with arthritis (axSpA) include administering IL-1 7 antagonists, e.g., secukinumab, to prevent structural joint damage in these patients. inhibits the progression of

[0003] Background to the disclosure Autoimmune diseases occur as a result of the immune system attacking the patient's own organs, tissues, and cells Common autoimmune diseases include psoriasis, type 1 diabetes, rheumatoid arthritis, and inflammatory bowel disease. Diseases include psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA).

[0004] PsA is a chronic, debilitating disease affecting peripheral, synovial, axial, and entheseal structures. It is associated with skin psoriasis and nail complications. PsA is associated with significant morbidity and disability. This therefore places a heavy socio-economic burden.

[0005] axSpA primarily affects the axial skeleton, characterized by spinal cord inflammation and inflammatory back pain axSpA is a type of spondyloarthritis. It is one of the most common chronic inflammatory joint disorders. Recent prevalence estimates in the Caucasian population range from 1 to 2% (Kiltz, et al. l Clin Exp Rheumat(2017)35(Suppl 107):S1 02-S107). Patients with chronic back pain (onset before age 45) were evaluated by the International Society for Spondyloarthritis ( Assessment of Spondyloarthritis Internat ional Society) (ASAS) classification criteria (Rudwaleit et al. (2009) Ann Rheum Dis;68:777-83) clinical arm or imaging If any of the arms are met, the patient is classified as having axSpA.

[0006] Based on the presence or absence of sacroiliac joint inflammation on conventional radiographs, patients with axSpA are classified into two categories: Condition: Non-radiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (A The 1984 Revised New York Diagnostic Criteria (van der Lin S) den et al(1984)Arthritis Rheum;27:361-8) Patients with radiographic evidence of sacroiliitis meeting the criteria were classified as having AS. While X-rays may not show sacroiliac joint inflammation, MRI may show evidence of sacroiliac joint inflammation. Patients who may present with SpA are classified as having non-r-axSpA.

[0007] AS is characterized by joint involvement primarily of the axial skeleton and sacroiliac (SI) joints, but also peripheral joints, tendons, and Enthesitis and extra-articular organs are also affected. A significant proportion of AS patients develop uveitis, psoriasis, and inflammation. There may be associated extra-articular manifestations such as inflammatory bowel disease (IBD), cardiovascular and pulmonary abnormalities. Systemic osteoporosis, as well as focal osteopenia, is common in AS patients, mostly Although younger and more likely to be male, they are more likely to suffer non-traumatic fractures The presence of human leukocyte antigen (HLA)-B27 is strongly associated with AS; 90-95% of AS patients have this marker. AS affects up to 1.1% of the population. It affects people up to 100 years old and is associated with significant morbidity and disability, thus resulting in a significant socio-economic burden. It becomes a burden.

[0008] Trial and registry data suggest that patients with nr-axSpA have similar clinical outcomes to those observed in patients with AS. have a high level of disease activity, pain, and impairment in health-related quality of life It has been shown (Wallis et al (2013) J Rheumatol;40 :2038-41). Disease parameters and response to treatment with TNF-α antagonists The efficacy was similar in patients with AS and nr-axSpA, suggesting that axSpA is a distinct This supports the concept that cerebrospinal fluid (CSF) may be a stage-specific disease (Song et al. (2013) Ann Rheum Dis;72:823-5). Additionally, symptoms last longer. In this case, most patients who begin with nr-axSpA eventually develop radiological findings consistent with AS. In a study of 329 axSpA patients, the severity of symptoms was assessed according to the duration of symptoms ( <10->20 years), radiological evidence of sacroiliitis present in 40-86% of subjects (Said-Nahal et al (2000) Arthritis Rheum; 43(6):1356-65), many patients with nr-axSpA progressed to AS over time. nr-axSpA and AS can be considered two stages of one disease (axSpA). However, there are nonetheless cases of stages that do not progress to documented AS and do not fulfill radiographic criteria. There are patients (10-15%) with an abortive course of the disease who remain in the field (Sieper et al., 2004). nd van der Heijde(2013)Arthritis Rheum;6 5:543-51;Poddubnyy(2013)Ther.Adv.Musculo skelet.Dis.5:1:45-54). Therefore, non-rx-SpA causes severe pain. While this may lead to structural changes in the axial skeleton (Baraliako s X,Braun J(2015)RMD Open;1(Suppl.1):e00 0053)).

[0009] Nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment for all patients with axSpA. Traditional disease-modifying antirheumatic drugs such as methotrexate and sulfasalazine Medications (DMARDs) are not effective in treating axSpA. Anti-TNF agents are NSAIDs. It is an approved treatment for AS patients who continue to have active disease despite In the US, several anti-TNF agents are also approved for nr-axSpA. However, more than 60% of patients with nr-axSpA treated with adalimumab or etanercept had leukemia. did not achieve an ASAS40 response in a randomized clinical trial (Sieper et al. (2012) 013)Ann Rheum Dis;72:815-22;Dougados et al. al(2014)Arthritis Rheum;66:2091-2102). Furthermore, TNF blockade does not result in long-term remission in axSpA, and responders usually remain in remission after treatment. Relapse occurs within a few weeks of discontinuation (Baraliakos et al (2005) Arthr itis Res. Ther.;7:R439-R444) in the treatment of inflammatory conditions. While effective, TNF antagonists do not prevent structural joint damage in axSpA. However, this has been mainly tested in AS (van der Heijde et al. (2014) 08a),Arthritis Rheum;58:3063-70;van der Heijde et al(2008b),Arthritis Rheum;58:1 324-31).

[0010] Disclosure Overview Secukinumab, known by the trade name Cosentyx®, was first marketed on December 26, 2014. Cosentyx® is a treatment for psoriasis, psoriatic arthritis, and other conditions in many countries. Approved for the treatment of psoriasis (PsA) and AS. Approved for psoriasis and PsA. The dosage regimen is for weeks 0, 1, 2, 3, and 4, and then monthly thereafter (every 4 weeks [ Completely subcutaneous (SC) administration using an induction dose of 150 mg or 300 mg antibody (Q4W [Q4W]). For AS, the approved dosage regimen is Use an induction dose of 150 mg antibody, followed by monthly (every 4 weeks [Q4W]) doses thereafter. Approval for use of the 300 mg dose in AS is also being sought. SC secukinumab 150 mg Q4W dose vs. placebo in patients with non-rx-axSpA Studies are currently underway to evaluate the efficacy and safety of Sebo (CAIN475H2315). do.

[0011] While fixed-dose SC administration of secukinumab is convenient for patients, it may be more invasive. Does not provide the flexibility of weight-based dosing, which is desirable for heavier patients. This regimen is suitable for patients with high disease activity who require a more rapid response and for patients with SC-based treatment. Benefits patients who cannot tolerate the treatment (e.g., due to pain at the injection site, fear of injections, etc.) Furthermore, the level tested in CAIN475H2315 (nr-axSpA patient) Currently approved regimens for treating PsA and AS include induction phase Four initial weekly doses (weeks 0, 1, 2, 3, and 4) are required during the treatment period, which may vary in frequency. Therefore, while maintaining a favorable safety / benefit ratio, A method for treating patients with PsA or axSpA that provides patients with flexible dosing and fewer induction doses. Administration regimens using IL-17 antagonists (e.g., secukinumab) to treat patients We need to develop Jimen.

[0012] Therefore, approximately 4 mg / kg to approximately 9 mg / kg of an IL-17 antagonist (e.g., secukinumab) Patients will receive a single intravenous (IV) dose of 10 mg / kg (preferably about 6 mg / kg) during week 0. and then every 4 weeks (monthly) starting during the 4th week, at about 2 to about 4 mg / kg (preferably Patients are given an IL-17 antagonist (e.g., secukinumab) at a dose of approximately 3 mg / kg. psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) (i.e., Non-radiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) Described herein are methods for treating patients with SpA (e.g., non-r-axSpA, e.g., AS). Furthermore, the dose is about 4 mg / kg to about 9 mg / kg (preferably about 6 mg / kg). Patients were given a single intravenous ( IV) and then every 4 weeks (monthly) starting during the 4th week, approximately 2 mg / kg to approximately 4 mg / kg. g / kg (preferably about 3 mg / kg) of an IL-17 antagonist (e.g., secukinumab) and administering to a patient with PsA or axSpA (i.e., non-rapid-acting axSpA and axSpA). Suppression of progression of structural damage in patients with SpA (e.g., non-rx-SpA, e.g., AS) Disclosed herein are methods for inhibiting the growth of inflammatory bowel disease.

[0013] In some embodiments, the patient meets the ASAS classification criteria for axSpA. and, in addition, abnormal CRP and / or MRI, and have a revised New York standard of care for AS. No radiological evidence of changes in the sacroiliac joints meeting the criteria, NSAIDs, non-biological Despite current or previous treatment with clinically relevant DMARDs and / or anti-TNF-alpha therapy Male or female patients with non-rxSpA who have active disease.

[0014] In some embodiments of the disclosed uses, methods, and kits, an IL-17 antagonist The antibody is an IL-17 antibody or an antigen-binding fragment thereof. In some embodiments, the IL-17 antibody or antigen-binding fragment thereof is selected from the group consisting of: Selected from: a) Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His12 9; b) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of IL-17, including IL-17 epitopes containing Tyr43, Tyr44, Arg46, Ala79, and Asp80 c) an IL-17 antibody or antigen-binding fragment thereof that binds to the IL-17 antibody; and c) two mature IL-17 molecules. Epitope of IL-17 homodimer with protein chain (said epitope is Leu74, Tyr85, His86, Met87, Asn88, Val124, T hr125, Pro126, Ile127, Val128, His129 and on the other strand I binds to Tyr43, Tyr44, Arg46, Ala79, and Asp80 of d) an IL-17 antibody or an antigen-binding fragment thereof; and d) an IL-17 antibody or an antigen-binding fragment thereof having two mature IL-17 protein chains. The epitope of the IL-17 homodimer (the epitope is located at Leu74 on one chain, T yr85, His86, Met87, Asn88, Val124, Thr125, Pro 126, Ile127, Val128, His129 on the other chain and Tyr43, Ty IL-17 antibodies that bind to IL-17 The antigen-binding fragment (herein, the IL-17 antibody or the antigen-binding fragment thereof) is about 100 to 200 pM K D and the IL-17 antibody or antigen-binding fragment thereof is administered in an amount of about 23 to about 35 days. and e) an IL-17 antibody or an antigen thereof, comprising: Binding fragment: i) an immunoglobulin heavy chain variable domain comprising the amino acid sequence set forth as SEQ ID NO: 8; Main (V H ii) an immunoglobulin comprising the amino acid sequence set forth as SEQ ID NO: 10; Light chain variable domain (V L iii) an immunization vector comprising the amino acid sequence set forth as SEQ ID NO: 8; Globulin V H domain and an immunoglobulin comprising the amino acid sequence set forth as SEQ ID NO: 10. Rin V L domain; iv) the frequent domains described as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 Immunoglobulin V containing the variable region H domain; v) SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: Immunoglobulin V containing the hypervariable region designated as number 6 L domain; vi) sequence number Immunoglobulins containing the hypervariable regions set forth as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 Brin V H vii) the domains set forth as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 Immunoglobulin V containing hypervariable regions H Domains and SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: Immunoglobulin V containing the hypervariable region described as column number 6 L domain;viii) Immunoglobulins containing the hypervariable regions set forth as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 Epidemic globulin V H domains and described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 Immunoglobulin V containing hypervariable regions L Domain; ix) as set forth in SEQ ID NO: 14 x) an immunoglobulin light chain comprising the amino acid sequence set forth as SEQ ID NO: 15; or xi) an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 14. an immunoglobulin light chain and an immunoglobulin comprising the amino acid sequence set forth as SEQ ID NO: 15 In preferred embodiments of the disclosed uses, methods, and kits, the heavy chain comprises an IL-17 antibody or The antigen-binding fragment is secukinumab.

[0015] In a preferred embodiment of the disclosed uses, methods and kits, the disorder to be treated is P In a preferred embodiment of the disclosed uses, methods and kits, the target of treatment is In some embodiments of the disclosed uses, methods and kits, In other words, ax-SpA is nr-axSpA. Other embodiments of the disclosed uses, methods and kits include: In an embodiment, ax-SpA is AS. [Brief explanation of the drawings]

[0016] [Figure 1] Figure 1 shows modeled secukinumab concentrations in AS and PsA patients, respectively, over 64 weeks for a single 4, 6, or 9 mg / kg loading dose followed by 2, 3, or 4 mg / kg q4w IV q4w (monthly) regimen from week 4 compared with a SC regimen (150 mg or 300 mg SC weekly during weeks 0, 1, 2, 3, and 4, then q4w from week 8). [Figure 2] Figure 2 shows modeled secukinumab concentrations over 64 weeks in AS and PsA patients, respectively, for a single 4, 6, or 9 mg / kg loading dose followed by 2, 3, or 4 mg / kg q4w IV q4w (monthly) regimen from week 4 compared with a SC regimen (150 mg or 300 mg SC weekly during weeks 0, 1, 2, 3, and 4, then q4w from week 8). [Figure 3A] Figure 3: Figure 3 shows modeled secukinumab concentrations in AS and PsA patients, respectively, by weight category (<74 kg; >74 to <88 kg; >88 kg) over 64 weeks for a single 4 mg / kg (Figure 3A), 6 mg / kg (Figure 3B), or 9 mg / kg (Figure 3C) loading dose followed by IV q4w (monthly) regimen at 2, 3, or 4 mg / kg q4w starting in week 4 compared with a SC regimen (150 mg or 300 mg SC weekly during weeks 0, 1, 2, 3, and 4, then q4w starting in week 8). Subparts A–C of Figure 3 are separated for presentation purposes only. [Figure 3B] (As mentioned above.) [Figure 3C] (As mentioned above.) [Figure 4A]Figure 4: Figure 4 shows modeled secukinumab concentrations in AS and PsA patients, respectively, by weight category (<74 kg; >74 to <88 kg; >88 kg) over 64 weeks for a single 4 mg / kg (Figure 4A), 6 mg / kg (Figure 4B), or 9 mg / kg (Figure 4C) loading dose followed by IV q4w (monthly) regimen at 2, 3, or 4 mg / kg q4w starting in week 4 compared with a SC regimen (150 mg or 300 mg SC weekly during weeks 0, 1, 2, 3, and 4, then q4w starting in week 8). Subparts A–C of Figure 4 are separated for presentation purposes only. [Figure 4B] (As mentioned above.) [Figure 4C] (As mentioned above.) [Figure 5A] Figure 5: Figure 5 shows the study design for the most preferred secukinumab IV regimen, i.e., 6 mg / kg IV (loading) and 3 mg / kg IV (maintenance), in human clinical trials in patients with PsA (Figure 5A) and ax-SpA (Figure 5B). [Figure 5B] (As mentioned above.) [Figure 6] Figure 6 shows the median steady-state concentration profiles for a secukinumab 150 mg fixed SC regimen (weekly during weeks 0, 1, 2, and 3, then monthly starting during week 4 [q4w]), a secukinumab 300 mg fixed SC regimen (weekly during weeks 0, 1, 2, and 3, then monthly starting during week 4 [q4w]), and a secukinumab IV regimen (6 mg / kg at baseline (week 0) and then 3 mg / kg monthly [q4w]) in patients with PsA. [Figure 7] Figure 7 shows the median steady-state concentration profiles for a secukinumab 150 mg fixed SC regimen (weekly during weeks 0, 1, 2, and 3, then monthly starting during week 4 [q4w]), a secukinumab 300 mg fixed SC regimen (weekly during weeks 0, 1, 2, and 3, then monthly starting during week 4 [q4w]), and a secukinumab IV regimen (6 mg / kg at baseline (week 0) and then 3 mg / kg monthly [q4w]) in patients with AS.

[0017] Detailed Description of Disclosure As used herein, IL-17 refers to interleukin-17A (IL-17A). Refers to...

[0018] The term "comprising" encompasses "including" as well as "consisting of", e.g. For example, a composition "comprising" X may consist exclusively of X, or may contain something additional. It may be included (e.g., X+Y).

[0019] The term "about" in connection with a numerical value x means, for example, + / - 10%. When used before a list of numbers, the term "about" applies to each number in the series. For example, the expression "about 1 to 5" should be interpreted as "about 1 to about 5", or, for example, the expression "About 1, 2, 3, 4" should be interpreted as "about 1, about 2, about 3, about 4, etc."

[0020] The word "substantially" does not exclude "completely." For example, a group "substantially free" of Y The composition may be completely free of Y. Where necessary, the word "substantially" may be used in conjunction with the present disclosure. can be omitted from the definition of

[0021] The term "antibody" as referred to herein includes whole antibodies and any of their antigens. The binding portion or single chain. Naturally occurring "antibodies" are inter-connected by disulfide bonds. It is a glycoprotein containing at least two heavy (H) chains and two light (L) chains. The heavy chain comprises a heavy chain variable region (referred to herein as V H and the heavy chain constant region. The constant region consists of three domains, CH1, CH2 and CH3. Each light chain contains a light chain variable domain. region (herein V LThe light chain constant region consists of one V consists of domains CL. H and V L The regions are called framework regions (FR). hypervariable regions or complementarity determining regions (CDRs) interrupted by more conserved regions Each V can be further subdivided into regions of hypervariability called Vs. H and V L Is, A From amino-terminus to carboxy-terminus, the order is: FR1, CDR1, FR2, CDR2, FR The heavy and light chains consist of three CDRs and four FRs arranged as follows: CDR3, CDR4, and FR5. The variable region of an antibody contains a binding domain that interacts with an antigen. The constant region of an antibody is responsible for the immune system various cells (e.g., effector cells) and the first component of the classical complement system (C1q) It can mediate the binding of immunoglobulins to host tissues or factors, including:

[0022] The term "antigen-binding fragment" of an antibody, as used herein, refers to a fragment that binds to an antigen (e.g., IL-17 The antigen-binding function of an antibody is maintained by a fragment of the full-length antibody. It has been shown that this function can be fulfilled by fragments of the antibody. Examples of binding fragments encompassed by the formula include Fab fragments, i.e., V L , V H , CL and CH1 A monovalent fragment consisting of a domain; F(ab)2 fragment, i.e., a disulfide bond in the hinge region A bivalent fragment containing two Fab fragments linked by a bridge; V H and CH1 domain Fd fragment consisting of V of a single arm of an antibody L and V H Fv fragment consisting of domains; V H Do The dAb fragment consisting of the main :544-546); and isolated CDRs. Exemplary antigen-binding sites include The CDRs of secukinumab as set forth in SEQ ID NOS: 1-6 and 11-13 (Table 1), Preferably, the heavy chain CDR3 is included. Furthermore, the two domains of the Fv fragment, V L and V H are encoded by separate genes, but they form a single protein chain (here, V L Area and V H The domains are paired to form monovalent molecules (known as single-chain Fvs (scFvs); e.g., , Bird et al., 1988 Science 242:423-426; and Huston et al.,1988 Proc.Natl.Acad.Sci.85 :5879-5883) The synthetic linker allows them to be linked using recombinant methods. Single chain antibodies are also intended to be encompassed by the term "antibody." Single chain antibodies and antigen-binding portions , can be obtained using conventional techniques known to those skilled in the art.

[0023] An "isolated antibody," as used herein, is an antibody that is isolated from other antibodies with different antigen specificities. (e.g., an isolated antibody that specifically binds to IL-17) (The antibody is substantially free of antibodies that specifically bind to antigens other than IL-17.) The term "monoclonal antibody" or "monoclonal antibody composition" when used herein refers to a single molecule. The term "human antibody" as used herein refers to a preparation of antibody molecules of the same composition. Antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin are included. A "human antibody" is intended to be an antibody produced by a human, human tissue, or human cells. Human antibodies of the present disclosure may contain amino acid residues that are not encoded by human sequences (e.g., For example, in vitro random or site-directed mutagenesis can be used to modify the intron during recombination of antibody genes. by N-nucleotide addition at the junction in vivo or by somatic mutation in vivo Some of the disclosed processes and compositions may include mutations introduced by mutations. In some embodiments, the IL-17 antibody is a human antibody, an isolated antibody, and / or a monoclonal antibody. It is a clonal antibody.

[0024] The term "IL-17" refers to IL-17A, formerly known as CTLA8; Wild-type IL-17A from various species (e.g., human, mouse, and monkey), IL-17A Polymorphic variants and functional equivalents of IL-17A are included. The functional equivalent preferably has at least one homologue to wild-type IL-17A (e.g., human IL-17A). At least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, and even 99% of the total It has substantial sequence identity with the IL-6 gene and has substantially demonstrated the ability to induce IL-6 production by human skin fibroblasts. Maintain a stable position.

[0025] The term “K D " is intended to refer to the off-rate of a particular antibody-antigen interaction. "K D " as used herein means K d K a The ratio of (i.e., K d / K a )mosquito The term "antibody dissociation constant" is intended to refer to the dissociation constant obtained from the antibody and expressed as a molar concentration (M). Teno K DThe K value can be determined using methods established in the art. D Methods for determining the ion exchange potential are to use surface plasmon resonance or Biacore (registered trademark). This is achieved by using biosensor systems such as the NIRS (NIR Registered Trademark) system. In some embodiments, the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, has a molecular weight of about K between 100 and 250 pM D and binds to human IL-17.

[0026] The term "affinity" refers to the strength of the interaction between an antibody and an antigen at a single antigenic site. Within the antigen site, the variable regions of the antibody "arms" bind to the antigen through weak non-covalent forces at numerous sites. The more interactions there are, the stronger the affinity becomes. Standard assays for assessing the binding affinity of an antibody to a target protein include, for example, ELISA, gel electrophoresis, and immunohistochemistry. These methods are well known in the art, including immunoblots and RIAs. , binding affinity) can be determined by standard assays known in the art, such as biosensor assays. , for example, using BIACORE® analysis.

[0027] These IL-1s determined according to methodologies known in the art and described herein 17 Functional properties (e.g., biochemical, immunochemical, cellular, physiological, or other biologically active properties) An antibody that "inhibits" one or more of the following (or a target of unrelated specificity, etc.) is one that inhibits the activity of the target in the absence of the antibody (or a target of unrelated specificity, etc.). A statistically significant decrease in the specific activity relative to that seen in the presence of a control antibody It will be understood that antibodies that inhibit IL-17 activity are useful in, for example, measuring A statistically significant difference of at least about 10%, at least 50%, 80%, or 90% of the parameters and in certain embodiments of the disclosed methods and compositions, The IL-17 antibodies inhibit IL-17 functional activity by more than 95%, 98%, or 99%. It is possible.

[0028] As used herein, "inhibiting IL-6" refers to the administration of an IL-17 antibody or antigen-binding fragment thereof. The ability of anti-inflammatory drugs (e.g., secukinumab) to reduce IL-6 production from primary human dermal fibroblasts IL-6 production in primary human (skin) fibroblasts is dependent on IL-17. (Hwang et al.,(2004)Arthritis Res Ther; 6:R120-128). Briefly, human dermal fibroblasts were incubated with various antibodies containing the Fc portion. Recombinant IL-17 was detected in the presence of an IL-17 binding molecule or human IL-17 receptor at a concentration of 1000 kJ / mL. The chimeric anti-CD25 antibody Simulect® (basiliximab) was administered to This can be conveniently used as a negative control. After 16 hours of stimulation, the supernatant was removed and IL-6 is quantified by LISA. IL-17 antibody or antigen-binding fragment thereof, e.g. For example, secukinumab is tested as above, i.e., the inhibitory activity is determined by the following: The results were measured for human IL-17-induced IL-6 production in blast cells. In this case, the concentration is typically about 50 nM or less (e.g., about 0.01 to about 50 nM). It has an IC50 for inhibition of IL-6 production (in the presence of 0.5 nM human IL-17). In some embodiments of the methods and compositions provided, an IL-17 antibody or antigen-binding fragment thereof is Fragments such as secukinumab and functional derivatives thereof are preferably at about 20 nM or less, more preferably at about 10 nM or less, more preferably about 5 nM or less, more preferably about 2 nM or less, even more preferably and an IC50 for inhibition of IL-6 production, as defined above, of about 1 nM or less. Has.

[0029] The term "derivative" refers, unless otherwise indicated, to a derivative of a specific sequence (e.g., , variable domain), an amino acid sequence of an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab Acid sequence variants and covalent modifications (e.g., pegylation, deamidation, hydroxylation, phosphate "Functional derivatives" are used to define the disclosed I These include molecules that share qualitative biological activity with the L-17 antibody. Functional derivatives include: , fragments and peptide analogs of the IL-17 antibodies disclosed herein. This includes regions within the sequence of a polypeptide of a particular sequence, for example, according to the present disclosure. The functional derivatives of the IL-17 antibodies (e.g., functional derivatives of secukinumab) are V of the IL-17 antibodies and antigen-binding fragments thereof disclosed herein H and / or V L Arrays (e.g. For example, V in Table 1 H and / or V L sequence) and at least about 65%, 75%, 85%, 95% , V with 96%, 97%, 98%, and even 99% overall sequence identity. H and / or V L domain and substantially retain the ability to bind human IL-17, or Inhibition of IL-17-induced IL-6 production in human dermal fibroblasts It's nice.

[0030] The phrase "substantially identical" refers to a sequence of related amino acids or nucleotides (e.g., V H also is V Ldomain) compared to a particular reference sequence, or Insubstantial differences (e.g., conservative substitutions of In particular regions (e.g., V H or V L 1 or 2 in the 5 amino acid sequence of the domain In the case of antibodies, the second antibody contains the same specific amino acid changes, such as two substitutions. and have at least 50% affinity to the sequences disclosed herein. Substantially identical sequences (e.g., at least about 85% sequence identity) are also part of this application. In some embodiments, derivative IL-17 antibodies (e.g., derivatives of secukinumab) are used. The sequence identity of the disclosed sequences is approximately Over 90%, e.g. 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% , 98%, 99% or more.

[0031] "Identity" in relation to naturally occurring polypeptides and their functional derivatives is defined herein as up to After aligning the sequences and introducing gaps as necessary to obtain the percent identity of is defined as the percentage of amino acid residues in the candidate sequence that are identical to residues in the corresponding native polypeptide. Any conservative substitutions are not considered part of the sequence identity. Insertions shall not be construed as reducing identity. Computer programs are well known. Percent identity can be calculated using standard alignment algorithms. algorithms, e.g., Altshul et al. ((1990) J. Mol. Biol. ,215:403 410) nment Search Tool(BLAST);Needleman et al. (1970) J. Mol. Biol., 48:444-453) algorithm; Meyers et al. ((1988) Comput. Appl. Biosci. ,4:11 17) algorithm. The set of parameters is , a gap penalty of 12, a gap extension penalty of 4 and a frameshift gap penalty of 5. It can be a Blosum 62 score matrix with a nucleotide penalty. Percent identity between nucleotide sequences is calculated using the PAM120 weight remainder table, 12 gaps The ALIGN program (ver. 1) was used with a fragment length penalty of 1 and a gap penalty of 4. sion 2.0) by E. Meyers and W. Miller (19 89) CABIOS, 4:11-17) algorithm can also be used to determine .

[0032] "Amino acid" refers to all naturally occurring L-α-amino acids, e.g., D-amino acids The expression "amino acid sequence variant" refers to a variant of an amino acid sequence that is different from the amino acid sequence of the present disclosure. refers to molecules that differ somewhat in sequence. For example, the amino acid sequence of an antibody according to the present disclosure of a particular sequence The mutants still retain the ability to bind human IL-17 or, for example, For example, it inhibits IL-17-induced IL-6 production in human skin fibroblasts. Acid sequence variants include substitution variants (where at least one amino acid in a polypeptide according to the disclosure is an acid residue has been removed and another amino acid inserted at the same position instead), an insertion mutant ( One or more amino acids immediately adjacent to an amino acid at a particular position within a polypeptide according to the present disclosure and deletion mutants (insertion of one or more amino acids within a polypeptide according to the present disclosure). (from which the acid has been removed).

[0033] The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). This refers to the material.

[0034] The term "administering" with respect to a compound, e.g., an IL-17 binding molecule or another agent, , is used to refer to the delivery of the compound to a patient by any route.

[0035] As used herein, a "therapeutically effective amount" refers to a single dose or multiple doses administered to a patient (such as a human). Upon administration of the dose, treat or prevent at least one symptom of the disorder or a recurring disorder, Prevent, cure, delay, reduce severity, or reverse the onset of the disease or to prolong the survival of a patient beyond that expected in the absence of such treatment. IL-17 antagonists, such as IL-17 binding molecules (e.g., IL-1 7 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor-binding molecule (e.g., The amount of an individual active ingredient (e.g., an IL-17 antibody or an antigen-binding fragment thereof) administered alone. When applied to a compound (e.g., an IL-17 antagonist, e.g., secukinumab), this When applied to a combination, the term refers to that component alone. The combination of active ingredients that produces a therapeutic effect, whether administered sequentially or simultaneously. It refers to the amount of

[0036] As used herein, the terms "treatment" or "treating" refer to a method according to the present disclosure. IL-17 antagonists (e.g., IL-17 antibodies, e.g., secukinumab) or is defined as the application or administration to a subject of a pharmaceutical composition containing a β-17 antagonist, The elephant is a specific disease (e.g., PsA, AS, axSpA, nr-axSpA), with accompanying symptoms or predisposition to the development of the disease (if applicable), the purpose of which is to Cure (if applicable), delay the onset of, reduce the severity of, or alleviate one or more symptoms; Recovery, amelioration of disease, reduction or modification of any accompanying symptoms of disease or predisposition to the development of disease The term "treatment" or "treating" refers to the treatment of a patient suspected of having a disease. and patients who are ill or have been diagnosed with a disease or medical condition. This includes treating the disease, which includes suppressing clinical relapse. The phrase refers to delaying the onset or development or progression of a disease, infection or disorder.

[0037] Psoriatic arthritis (PsA) is a chronic, global disease affecting peripheral joints, connective tissue, and the axial skeleton. PsA is a multifaceted disease that can be accompanied by psoriasis of the skin and nails. , synovitis, enthesitis, dactylitis, spondylitis, uveitis and inflammatory bowel disease. Disease-modifying antirheumatic drugs (DMARDs) include methotrexate (MTX), sulfa These include salazine, cyclosporine, and leflunomide, which are drugs used to treat established diseases. It is insufficient for many patients because it only partially controls tumor necrosis factor (TNF). Although TNF inhibitors have improved the management of PsA in recent years, many patients still require anti-TNF medications, the current standard Approximately 45% of people are dissatisfied with their current treatment because they do not respond to or cannot tolerate it ( Boehncke and Menter(2013) Am J Clin Derma tol 2013;14:377-88;Gladman et al.(2005)A nn Rheum Dis.;64(Suppl 2):ii14-17;Gossec et al.Ann Rheum Dis.2012;71:4-12;Menter et al.J Am Acad Dermatol.2011;65:137-74 Secukinumab significantly improved the signs and symptoms, physical function, and patient-reported outcomes of arthritis and skin Rapid onset of response and response across multiple clinical domains, including measures of and superior efficacy over placebo (Mease and McInnes (201 6) Rheumatol Ther 3:5-29). Furthermore, secukinumab has been shown to be effective in the treatment of PsA. It has been shown to be effective in preventing structural damage in patients (Mease (2018) Ann R heum Dis 77:890-897).

[0038] Spondyloarthritis (SpA) is classified into axial SpA (AS and nr-axSpA), reactive arthritis, and , arthritis / spondylitis associated with inflammatory bowel disease, arthritis / spondylitis associated with psoriasis, and undifferentiated spondyloarthritis SpA is a group of related disorders that includes axial skeletal symptoms. It is said that the patient has axSpA. of SpondyloArthritis international Socie The ASAS criteria are for both radiological axial SpA (AS) and nonradiographic axial SpA (nr-axSpA). It was developed as a classification standard for axial spondyloarthritis (axSpA), which includes Rudwaleit et al. (2004), which is incorporated by reference herein in its entirety. 2009) Ann. Rheum. Dis. 68:777-83). Briefly, AS The AS axSpA criteria are: a) radiological (revised New York criteria for radiology) sacroiliitis) or MRI evidence of sacroiliitis, plus at least one S pA characteristics (image analysis arm); or b) presence of HLA-B27 + at least 2 The clinical arm has three SpA characteristics. The "SpA characteristics" are inflammatory back pain, C Elevated RP (in terms of inflammatory back pain), HLA-B27 positivity, family history of SpA, NSA Good response to ID, Crohn's disease / ulcerative colitis, psoriasis, dactylitis, uveitis, tendonitis All patients who meet the ASAS axSpA criteria are In the specification, this is referred to as having AS. Patients without radiological sacroiliitis according to the criteria herein are considered to have axial sacroiliitis that does not meet the radiographic criteria. They are referred to as having spondyloarthritis (nr-axSpA).

[0039] As used herein, the phrase "inhibiting the progression of structural damage" means "inhibiting the progression of structural damage." "prevents progression of damage" and is used to treat PsA or axSpA (i.e., non-rx-axSpA and AxSpA). reduce bone and joint damage associated with SpA (e.g., non-rx-SpA, e.g., AS); It is used to mean to inhibit or slow down. This is a response to bone and / or joint damage, including pathological new bone formation, in patients with PsA or axSpA. X-ray and magnetic resonance imaging Imaging (MRI) to analyze bone and / or joint damage associated with PsA or axSpA Various methods for imaging and scoring axSpA are available, e.g. For example, Braun and Baraliakos (2011) Ann Rheum Di s 70(Suppl 1):i97-i103;Rudwaleit(2009)An n.Rheum.Dis.68:1520-7; and IH Song et al.A See nn Rheum Dis.2011 Jul;70(7):1257-63 The preferred method for scoring spine and sacroiliac joint (SIJ) MRI images is , Berlin MRI spine score (Lu Kas C,et al.J Rheumatol.2007;34:862-70), Berlin SIJ score (Hermann KG, et al.Radiologe.2004;44:217-28,Song et a l.2000, supra), Ankylosing Spondylitis Spine MRI Scoring System for Disease Activity ( the ankylosing spondylitis spine MRI sco ring system for disease activity)(ASspiM RI-a) and ASspiMRI-a Berlin Modification (Berlin modification of ASspiMRI-a)” (Lukas C et al(2007)J.Rheumatol;34(4):862-70;Rudwale it et al.(2008)Arthritis Rheum 67:1276-1 281;Rudwaleit et al(2005)[abstract]Arthr itis Rheum 50:S211). The SIJ is also called the Canadian spinal joint. Spondyloarthritis Research Consortium Society of Canada (SPARCC) scoring system (Maks ymowych et al.(2005)Arthritis Rheum.53:7 Inhibition can be scored using a control, such as the disclosed IL-17 antibody. Patients not treated with an antagonist or with a known progression rate (e.g., mean, median, or range) can be identified against

[0040] As used herein, "naive to prior treatment with a TNF antagonist" and "TNF-naive" refers to a patient who has received TNF-alpha inhibition for PsA or axSpA. Patients with PsA or axospasm (e.g., AS, e.g., nr As used herein, "TNF antagonists" refers to patients with cerebrospinal fluid (cerebrospinal fluid) and cerebrospinal fluid (cerebrospinal fluid) axonal spastic angina (SpA). The phrases "previously treated" and "TNF-experienced" refer to those who have been treated with a TNF alpha inhibitor (e.g., , infliximab, etanercept, adalimumab, certolizumab, golimumab) This refers to patients who have been previously treated, such as those with PsA or axSpA. Patients who have been resistant to or have had an inadequate response to NF-alpha inhibitor treatment and patients who discontinued TNF-alpha inhibitor treatment due to safety or tolerability responses. As used herein, "previously responsive to treatment with a TNF-alpha antagonist" means "Inadequate response to TNF-α or inadequate response to TNF-α" The phrases "TNF-alpha inhibitor" and "TNF-IR" refer to a TNF-alpha inhibitor administered to a patient with PsA or axSpA. Anti-inflammatory drugs (e.g., infliximab, etanercept, adalimumab, certolizumab, golipirin, Previously treated with thrombolytic therapy (e.g., thrombolytic therapy), but symptoms (e.g., pain, bone and / or joint symptoms) persisted after TN Patients who are not adequately controlled by F alpha inhibitors, such as those with PsA or axSpA Patients (e.g., those taking an approved dose of an anti-TNF alpha agent) for at least 2 weeks, 4 weeks, or at least at least 8 weeks, at least 3 months, at least 14 weeks, or at least 4 months of treatment. The methods, regimens, uses, kits, etc. disclosed herein are intended to In some embodiments of the compounds and pharmaceutical compositions, patients with, for example, PsA or axSpA (e.g., Patients with AS (e.g., non-r-axSpA) who have previously responded to treatment with TNF-alpha inhibitors either not been able to or the response to it was inadequate.

[0041] As used herein, "previously treated with a nonsteroidal anti-inflammatory drug (NSAID)" refers to a patient with a history of inflammatory bowel disease. The phrase "failure to respond or inadequate response to it" was previously used in the context of PsA. or one or more NSAIDs (e.g., COX-1 or COX-2 inhibitors) for axSpA ) but the symptoms (e.g., pain, bone and / or joint symptoms) are not related to NSA Patients who were not adequately controlled by ID, such as PsA or axSpA (e.g., AS, e.g., (e.g., non-rx-SpA) patients (e.g., those taking at least one approved dose of an NSAID) 2 weeks, 4 weeks, at least 8 weeks, at least 3 months, at least 14 weeks or less (Patients with active PsA or active axSpA despite 4 months of treatment) In some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions, Patients, e.g., with PsA or axSpA (e.g., AS, e.g., nr-axSpA), Previous failure or inadequate response to treatment with one or more NSAIDs It was.

[0042] As used herein, "previously treated with a disease-modifying antirheumatic drug (DMARD)" refers to a condition in which the patient is refractory to rheumatic disease. The phrase "failure to respond or inadequate response to it" was previously used in the context of PsA. or one or more DMARDs (e.g., TNF-alpha inhibitors, sulfonamides, have been treated with antihistamines (e.g., acetaminophen, methotrexate) but the symptoms (e.g., pain, bone and / or joint symptoms) not adequately controlled by DMARDs, e.g., PsA or Patients with axSpA (e.g., AS, e.g., nr-axSpA) (e.g., those not approved for DMARDs) at least 2 weeks, 4 weeks, at least 8 weeks, at least 3 months, using the prescribed dose; Active PsA or active PsA despite treatment for at least 14 weeks or at least 4 months Disclosed methods, regimens, uses, kits and pharmaceutical compositions In some embodiments of the invention, the patient has previously failed to respond to treatment with one or more DMARDs. There was either no response or the response was inadequate.

[0043] In some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions, Patients are on steroids despite current or previous NSAID, DMARD and / or anti-TNF therapy , active psoriatic arthritis (PsA), active AS or active nr-axSpA.

[0044] As used herein, "previously known as non-biologic disease-modifying antirheumatic drugs (DMARDs)" refers to The phrase "failed to respond to or responded inadequately to treatment with" is used to For PsA or axSpA, there are no biological drugs (e.g., DMARDs) that are activated by cells. are not produced by the action of other chemical compounds, but rather by small molecules, e.g., sulfasalazine, methionine, one or more DMARDs (non-biologic DMARDs are "conventional," " have been previously treated with conventional or targeted therapy (also called "targeted therapy"); The symptoms (e.g., pain, bone and / or joint symptoms) are not adequately controlled by DMARDs Patients with PsA or axSpA (e.g., AS, e.g., nr-axSpA) For example, at least 2 weeks, 4 weeks, or at least 8 weeks of treatment with approved doses of DMARDs despite treatment for at least 14 weeks, at least 3 months, at least 14 weeks, or at least 4 months The disclosed methods, regimens, and In some embodiments of the methods, the uses, the kits and the pharmaceutical compositions, the patient has previously Failure to respond or inadequate response to treatment with biologic DMARDs .

[0045] As used herein, "selecting" and "selected" with respect to a patient are used to identify of patients based on the specific patient having pre-defined criteria (attributable to is used to mean individually selected from a larger group of patients. Similarly, "selectively treating" refers to treating patients with a particular disease (where the patient is a (certain patients are individually selected based on having predefined criteria) Similarly, "selectively administering" refers to providing a Individuals from a larger group of patients based on (or due to) having predefined criteria It refers to administering drugs to individually selected patients. and selective dosing allows patients to receive standard treatments based solely on their membership within a larger group. Rather than delivering a treatment regimen, the patient's individual medical history (e.g., previous therapeutic interventions, e.g., prior treatment with a biologic), biology (e.g., specific genetic markers), and / or symptoms to be delivered personalized treatment based on symptoms (e.g., failure to meet certain diagnostic criteria) As used herein, selection regarding a method of treatment means selection with specific criteria. It does not refer to the lucky treatment of patients who have a particular condition, but rather to the treatment of patients based on the patient's specific criteria. It refers to the deliberate choice to administer a treatment. Therefore, selective treatment / administration is the Specific to all patients with a specific disease, regardless of their individual medical history, disease manifestations and / or biology This differs from standard treatment / administration of the drug.

[0046] In some embodiments, the axSpA patient meets the ASAS axSpA criteria and Occasionally, radiological criteria according to the revised New York diagnostic criteria for ankylosing spondylitis are not met The disclosed methods, regimens, uses, kits and In some embodiments of the pharmaceutical composition, the patient is treated with a steroid drug based on having nr-axSpA. are selected for treatment.

[0047] In some embodiments, the axSpA patient is treated with the Revised New York Clinical Trial for Ankylosing Spondylitis. Meet all ASAS axSpA criteria, including radiological criteria, according to diagnostic criteria Thus, they are selected for treatment. In some embodiments of the composition, the patient is selected for treatment based on having AS. In some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions In the past, patients were selected for treatment based on having PsA.

[0048] Bilateral SI of at least Grade II or unilateral Grade III or IV Radiological changes in J are required to make a diagnosis of AS according to the revised New York criteria. (Van der Linden et al. (1984) Arthritis Rheum 27:361-8). These changes are referred to herein as "ankylosing spondylitis." "Radiological Criteria for Ankylosing Spondylitis According to the Revised New York Diagnostic Criteria" and "Radiological Criteria for Ankylosing Spondylitis" This is called "research evidence."

[0049] As used herein, a clinical test (e.g., flow cytometry or PC If the presence of the HLA-B27 antigen or allele is revealed (using genotyping), The patient is "HLA-B27 positive."

[0050] As used herein, the phrase "inflammatory back pain" refers to back pain that is not organic. This refers to, for example, gradual onset, duration of at least 3 months, onset at a relatively young age, alternating Symptoms include: persistent buttock pain, morning stiffness lasting more than 30 minutes, pain at night, and lack of improvement with rest. It is not caused by strain or injury and has a rapid onset. are not prone to or have variable onset and can be diagnosed by a skilled physician or healthcare provider .

[0051] As used herein, "active PsA" refers to PsA of at least 6 months duration. together with symptoms of, for example, Classification Criteria 2 for psoriatic arthritis (Cla. 2). n criteria for Psoriatic ARthritis 2)(Ta Ylor et al. (2006) Arthritis Rheum 54:2665 -73) refers to signs and symptoms consistent with active disease: nonsteroidal anti-inflammatory ≥ 3 tender joints and ≥ 3 swollen joints despite ≥ 4 weeks of treatment with anti-inflammatory drugs (NSAIDs) intolerance to psoriasis or NSAIDs, activity of psoriasis vulgaris or psoriatic nail changes, or Some of the disclosed methods, regimens, uses, kits and pharmaceutical compositions In some embodiments, the patient has active PsA.

[0052] As used herein, "moderate to severe PsA" refers to a patient with a tenderness index of ≥ 3 out of 78. Signs and symptoms consistent with swollen joints in ≥ 3 of 76 joints, rheumatoid factor (RF) ) and anti-cyclic citrullinated peptide (anti-CCP) antibodies negative and active plaque psoriasis or nail changes consistent with psoriasis or a proven history of plaque psoriasis. In some embodiments of the methods, regimens, uses, kits and pharmaceutical compositions, the patient is Have moderate to severe PsA, for example, moderate to severe active PsA.

[0053] For an explanation of the severity classification for PsA, see Ritchlin et al. (2009), Ann. Rheum. Dis. 68:1387-94. Active PsA refers to all three severity categories of PsA disease (mild, moderate, and severe). It will be understood that the present invention may include PsA (or other forms of PsA).

[0054] As used herein, "active nr-axSpA" is defined as a range of symptoms on a scale of 0 to 10. A total Bath Ankylosing Spondylitis Disease Activity Index score of 4 or higher was pondylitis Disease Activity Index)(BASDA I) Refers to disease signs and symptoms consistent with the score. In some embodiments of the method and pharmaceutical composition, the patient has active nr-axSpA. In some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions, the patient Patients had a total BASDAI of ≥ 4 cm (0-10 cm) at baseline and a BAS of ≥ 10 cm at baseline. Spinal pain and baseline pain as measured by DAI Question No. 2 ≥ 4 cm (0-10 cm) Patients had total back pain as measured by VAS ≥ 40mm (0-100mm) at baseline.

[0055] As used herein, "severe nr-axSpA" and "moderate to severe nr "-axSpA" refers to disease signs and symptoms that require treatment with a biological therapeutic agent. SAS recommendations for the use of anti- TNF agents in patients with axial spondyles loarthritis” (van der Heijde et al(2011)A According to Rheum Dis.2011 Jun;70(6):905-8, Patients with r-axSpA should receive at least 1 dose of cefotaxime at the maximum recommended dose for a total of 4 weeks unless contraindicated. After treatment with both NSAIDs, the total Bath Ankylosing Spondylitis Disease Activity Index (BASDA) was significantly higher than that of the control group. kylosing Spondylitis Disease Activity In dex) score of 4 or higher on a scale of 0 to 10, indicating active disease. Some of the disclosed methods, regimens, uses, kits and pharmaceutical compositions are In some embodiments, the patient has severe nr-axSpA.

[0056] As used herein, "active AS" refers to active disease, such as ankylosing vertebrae of the Barth. Bath Ankylosing Spondylitis Activity Index The BSEAS Activity Index (BASDAI) (0-10) was 4. If the score is above 4cm (0-10cm) or higher, measured by BASDAI Question No. 2 spinal pain and total back pain measured by VAS ≥ 40mm (0-100mm) Disclosed methods, regimens, uses, kits and pharmaceutical compositions In some embodiments of the subject matter, the patient has active AS.

[0057] As used herein, "moderate to severe AS" refers to the condition described in the Revised New York Standards for AS. Refers to disease for which there is radiological evidence that meets the criteria for the study. In some embodiments of the uses, kits and pharmaceutical compositions, the patient has moderate to severe AS, For example, people with moderate to severe active AS.

[0058] In some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions, The patient has severe AS. The disclosed methods, regimens, uses, kits and pharmaceutical compositions In some embodiments, the patient has moderate to severe AS.

[0059] As used herein, "elevated CRP and / or objective signs of inflammation by MRI" means and "objective signs of inflammation by CRP and / or MRI" refer to the sacroiliac joint (SI J) MRI evidence of inflammation, elevated C-reactive protein (CRP), or both Some embodiments of the disclosed methods, regimens, uses, kits and pharmaceutical compositions In this condition, patients have no radiological evidence of ankylosing spondylitis but have sacroiliac joint (SIJ) inflammation. as either MRI evidence of glaucoma and / or elevated C-reactive protein (CRP) Patients with objective signs of inflammation and axSpA (e.g., severe, moderate-to-severe, active) Another objective sign of inflammation is inflammation of the spine, which can also be seen by MRI. Spinal inflammation was assessed using the Ankylosing Spondylitis Spine MRI Scoring System (ASS) for disease activity. spiMRI-a) and ASspiMRI-a Berlin Modification (Berlin Score using the "lin modification of ASspiMRI-a" can be converted into erythropoietin (Lukas C et al (2007) J. Rheumatol; 34 ( 4):862-70;Rudwaleit et al.(2008) Arthriti s Rheum 67:1276-1281;Rudwaleit et al(200 5)[abstract]Arthritis Rheum 50:S211).

[0060] Recent MRI techniques have demonstrated the SIJ in patients with axSpA and normal radiological findings. The presence of active inflammation in the spine and other skeletal elements (e.g., Rudwaleit et al. l.(2009)Ann.Rheum Dis.68:1520-7;Braun et al 1994,Arthritis Rheum 37:1039-45; veen et al 1999, J.Rheumatol.26:1953-58;H euft-Dorenbosch et al 2006,Ann.Rheum.Dis .65:804-08;Heuft-Dorenbosch et al.2006 A rthritis Res.Ther.8:R11;Braun and Barali akos(2011)Ann Rheum Dis 70(Suppl 1):i97- i103; and for a review, Ambak et al. 2012 Arthritis Res. & Therapy 14:R55), and in both the SIJ and spine It is possible to demonstrate the delineation of acute inflammatory lesions and chronic / structural changes. There are various scoring methods that can be used to identify highly suggestive MRI evidence: This is referred to herein as "MRI evidence of sacroiliac joint (SIJ) inflammation." The preferred MRI scoring system for use in the method is the Berlin SIJ score ( Berlin SIJ score) (Hermann KG, et al. Diologe. 2004;44:217-28). The disclosed methods, regimens, uses, In some embodiments of the kits and pharmaceutical compositions, the patient is screened for MRI evidence of SIJ inflammation. It has

[0061] As used herein, "elevated CRP" refers to the CRP blood level measured by an assaying laboratory. The above normal CRP levels are based on the 2010 ACR / EULAR criteria ( Aletaha et al.(2010)Ann.Rheum.Dis.69:158 According to the 2010 ACR / EULAR criteria, normal / abnormal Normal CRP is based on local laboratory standards. Each local laboratory calculates the normal maximum CRP. Use a cutoff value for abnormal (high) CRP based on laboratory specific rules for Physicians generally order CRP tests from local laboratories, which may The laboratory uses the rules used to calculate normal CRP to determine whether it is normal or abnormal (low or In some cases, the laboratory simply reports that the CRP is above the "upper limit of normal ( Therefore, unless the context indicates otherwise, When used in this context, what is considered a normal CRP value varies between laboratories and assays. In some embodiments of the present disclosure, "CRP elevation" does not refer to a specific numerical value. CRP is measured using a highly sensitive assay; elevated CRP (i.e., h) by this assay is sCRP) is, for example, > about 3 mg / L (e.g., 3 mg / L), > about 10 mg / L (e.g., 10mg / L), > about 20mg / L (e.g., 20mg / L), or > about 30mg / L (e.g., CRP levels, if assessed at baseline (BSL), can be is called "baseline CRP." The disclosed methods, regimens, uses, kits and pharmaceutical compositions In some embodiments of the composition, the patient has elevated baseline CRP or hsCRP. do.

[0062] IL-17 antagonist The various processes, kits, uses, and methods disclosed include IL-17 antagonists, For example, an IL-17 binding molecule (e.g., a soluble IL-17 receptor, an IL-17 antibody, or the like) an antigen-binding fragment of IL-17, e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., IL- In some embodiments, IL-1 receptor antibodies or antigen-binding fragments thereof are used. 7. The antagonist is an IL-17 binding molecule, preferably an IL-17 antibody or its antigen-binding It is a fragment.

[0063] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises the hypervariable region CDR1, at least one immunoglobulin heavy chain variable domain (V) comprising CDR2 and CDR3; H ) wherein said CDR1 has the amino acid sequence SEQ ID NO: 1 and said CDR2 has the amino acid sequence In one embodiment, the CDR3 has the amino acid sequence SEQ ID NO:3. The IL-17 antibody or antigen-binding fragment thereof comprises hypervariable regions CDR1', CDR2' and and at least one immunoglobulin light chain variable domain (V) comprising CDR3' and CDR4'. L’ ) , wherein the CDR1' has the amino acid sequence SEQ ID NO: 4, and the CDR2' has the amino acid sequence In one embodiment, the CDR3′ has the amino acid sequence SEQ ID NO: 6. The IL-17 antibody or antigen-binding fragment thereof has hypervariable regions CDR1-x, CDR2- at least one immunoglobulin heavy chain variable domain (V) comprising CDR3-x and CDR4-x H )of wherein the CDR1-x has the amino acid sequence SEQ ID NO: 11, and the CDR2-x has the amino acid sequence SEQ ID NO: The CDR3-x has the amino acid sequence SEQ ID NO: 13. do.

[0064] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof is Brin V Hdomain and at least one immunoglobulin V L and a domain, where: a) Immunoglobulin V H The domains may be (e.g., in order): i) hypervariable region CDR1; CDR2 and CDR3 (the CDR1 has the amino acid sequence SEQ ID NO: 1 and the CDR2 has the amino acid sequence SEQ ID NO: , having the amino acid sequence SEQ ID NO:2, and said CDR3 having the amino acid sequence SEQ ID NO:3) or ii) hypervariable regions CDR1-x, CDR2-x and CDR3-x (the CDRs 1-x has the amino acid sequence SEQ ID NO: 11, and said CDR2-x has the amino acid sequence SEQ ID NO: SEQ ID NO: 12, and said CDR3-x has the amino acid sequence SEQ ID NO: 13), and b) Immunoglobulin V L The domains may be (e.g., in order): hypervariable region CDR1', CD4 CDR1' has the amino acid sequence SEQ ID NO: 4, and CDR2' and CDR3' 2' has the amino acid sequence SEQ ID NO:5, and the CDR3' has the amino acid sequence SEQ ID NO:6. (including those having

[0065] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof is a) an IL-17 antibody or antigen-binding fragment thereof having the sequence shown as SEQ ID NO: 8. The immunoglobulin heavy chain variable domain (V) contains the amino acid sequence H ), b) SEQ ID NO: 10 and An immunoglobulin light chain variable domain (V) comprising the amino acid sequence shown L ), c) Sequence number Immunoglobulin V containing the amino acid sequence shown as No. 8 H Domain and SEQ ID NO: 10 Immunoglobulin V containing the amino acid sequence shown L domain, d) SEQ ID NO: 1, SEQ ID NO: Immunoglobulin V comprising the hypervariable region shown as SEQ ID NO: 2 and SEQ ID NO: 3 H domain, e) an immunoglobulin containing the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; Roblin V L f) domains shown as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 Immunoglobulin V containing a hypervariable region H domain, g) SEQ ID NO: 1, SEQ ID NO: 2, and Immunoglobulin V comprising the hypervariable region shown as SEQ ID NO:3 H Domains and sequences Immunoglobulins comprising hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 V L domain, or h) the high-molecular-weight peptides shown as SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 Immunoglobulin V containing frequency variable region H Domains and SEQ ID NO: 4, SEQ ID NO: 5 and sequences Immunoglobulin V containing the hypervariable region designated as number 6 L Includes the domain.

[0066] For ease of reference, the values ​​are based on the Kabat definition and determined by X-ray analysis. and secukinumab monoclonal antibody using the methodology of Chothia and collaborators. The amino acid sequences of the hypervariable regions of the antibody are provided in Table 1 below.

[0067] [Table 1]

[0068] Secukinumab CDRs by IMGT are as follows: Light chain CDR1 (QSVSSS Y; SEQ ID NO: 16), CDR2 (GAS; SEQ ID NO: 17), CDR3 (QQYGSSPC T; SEQ ID NO: 18); and heavy chain CDR1 (GFTFSNYW; SEQ ID NO: 19), CDR2 (INQDGSEK; SEQ ID NO: 20), (VRDYYDILTDYYIHYWYFDL; SEQ ID NO: 21).

[0069] In a preferred embodiment, the constant region domain is preferably also es of Proteins of Immunological Interest ”,Kabat EAet al,US Department of Healt h and Human Services,Public Health Service ce, as described by the National Institute of Health The V of secukinumab contains a suitable human constant region domain. L The DNA encoding Set forth in SEQ ID NO: 9. V of Secukinumab H The DNA encoding the will be done.

[0070] In some embodiments, an IL-17 antibody or antigen-binding fragment thereof (e.g., Seckinumab) is The IL-17 antibody or antibody thereof comprises the three CDRs of SEQ ID NO: 10. The antigen-binding fragment of comprises the three CDRs of SEQ ID NO: 8. The antibody or antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 10 and three CDRs of SEQ ID NO: 8. The CDRs of SEQ ID NO: 8 and SEQ ID NO: 10 can be found in Table 1. The free cysteine ​​in the chain (CysL97) can be seen in SEQ ID NO:6.

[0071] In some embodiments, the IL-17 antibody or antigen-binding fragment thereof is a light chain of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises a chain of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises a heavy chain. and a heavy domain of SEQ ID NO: 15. In some embodiments, the IL-17 antibody or an antigen-binding fragment thereof comprising the three CDRs of SEQ ID NO: 14. The -17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 15. In the above, the IL-17 antibody or antigen-binding fragment thereof has three CDRs of SEQ ID NO: 14 and SEQ ID NO: The CDRs of SEQ ID NO: 14 and SEQ ID NO: 15 are shown in Table 1. You can refer to it.

[0072] The hypervariable regions can be associated with any type of framework region, but are not necessarily of human origin. Suitable framework regions are those of the source, as described in Kabat EA et al. Preferred heavy chain frameworks are human heavy chain frameworks, For example, the heavy chain framework of the secukinumab antibody. FR1 (amino acids 1 to 30 of SEQ ID NO: 8), FR2 (amino acids 36 to 49 of SEQ ID NO: 8), FR3 ( FR4 (amino acids 67 to 98 of SEQ ID NO: 8) and FR5 (amino acids 117 to 127 of SEQ ID NO: 8) Considering the hypervariable regions of secukinumab determined by X-ray analysis, Another preferred heavy chain framework is FR1-x (amino acids 1-25 of SEQ ID NO: 8), in order. ), FR2-x (amino acids 36 to 49 of SEQ ID NO: 8), FR3-x (amino acids 37 to 49 of SEQ ID NO: 8) FR1 (amino acids 61-95 of SEQ ID NO: 8) and FR2 (amino acids 119-127 of SEQ ID NO: 8) regions. The light chain framework is composed of, in order, FR1' (amino acids 1 to 23 of SEQ ID NO: 10), FR FR2' (amino acids 36 to 50 of SEQ ID NO: 10), FR3' (amino acids 58 to 59 of SEQ ID NO: 10) 89) and FR4' (amino acids 99 to 109 of SEQ ID NO: 10) regions.

[0073] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) at least a) a variable domain comprising, in order, hypervariable regions CDR1, CDR2 and CDR3; and an immunoglobulin heavy chain or a fragment thereof (as described above) comprising a constant region of a human heavy chain or a fragment thereof. CDR1 has the amino acid sequence SEQ ID NO: 1, and CDR2 has the amino acid sequence SEQ ID NO: 2 wherein said CDR3 has the amino acid sequence SEQ ID NO: 3), and b) in turn a hypervariable a variable domain comprising the regions CDR1', CDR2' and CDR3' and a constant region of a human light chain or and an immunoglobulin light chain or a fragment thereof comprising the CDR1', SEQ ID NO: 4, said CDR2' having the amino acid sequence SEQ ID NO: 5, said CDR3' has the amino acid sequence SEQ ID NO:6).

[0074] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises: a) a hypervariable region a first domain comprising CDR1, CDR2 and CDR3, wherein CDR1 has the amino acid sequence SEQ ID NO: 1, said CDR2 having the amino acid sequence SEQ ID NO: 2, and said CDR3 having having the amino acid sequence SEQ ID NO: 3), and b) hypervariable regions CDR1', CDR2, a second domain comprising CDR1' and CDR3' (said CDR1' having the amino acid sequence SEQ ID NO: 4); wherein the CDR2' has the amino acid sequence SEQ ID NO:5 and the CDR3' has the amino acid sequence having the sequence SEQ ID NO: 6), and c) the N-terminus of the first domain and the C-terminus of the second domain; or a peptide linker connecting the C-terminus of the first domain to the N-terminus of the second domain and

[0075] Alternatively, the IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may comprise the sequence Thus, derivatives of the IL-17 antibodies described herein (e.g., pegylated variants of secukinumab) may be used. Alternatively, the disclosed methods may include the use of an IL-17 antibody or its V of antigen-binding fragment H or V L The domains are V as described herein. H or V L Domain and Real Qualitatively identical V H or V L Domains (e.g., those set forth in SEQ ID NOs: 8 and 10) The human IL-17 antibody disclosed herein can have the sequence shown in SEQ ID NO: 15. a heavy chain substantially identical to that shown as SEQ ID NO: 14 and / or a heavy chain substantially identical to that shown as SEQ ID NO: 15 The human IL-17 antibodies disclosed herein may comprise a light chain that is substantially identical to the human IL-17 antibody. can comprise a heavy chain comprising SEQ ID NO: 15 and a light chain comprising SEQ ID NO: 14. The human IL-17 antibody disclosed therein comprises: a) an amino acid sequence substantially identical to that set forth in SEQ ID NO:8; a) one heavy chain comprising a variable domain having the sequence of SEQ ID NO: 1 and a constant region of a human heavy chain; a variable domain having an amino acid sequence substantially identical to that shown in No. 10 and a human light chain The antibody may comprise one light chain comprising a constant region and one light chain comprising a constant region.

[0076] Alternatively, the IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may be The amino acid sequence of the reference IL-17 antibody set forth herein is the same as that of the reference IL-17 antibody set forth herein, as long as it contains CysL97. The present disclosure includes V-type variants of secukinumab. H or V L Amino acids in the domain One or more, typically only a few (e.g., 1-10) of the residues (other than CysL97) ) are changed, for example, by mutation of the corresponding DNA sequence, for example, by site-directed mutagenesis. Also included are IL-17 antibodies or antigen-binding fragments thereof (e.g., secukinumab). In all such cases of variants, the IL-17 antibody or antigen-binding fragment thereof may be About 50 nM or less, about 20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nM or less or better More preferably, the concentration of said molecule is about 1 nM or less, and about 1 nM (=30 ng / ml) human IL- 17 by 50%, and the inhibitory activity was as described in WO 2006 / 023494. As described in Example 1 of the pamphlet of No. 013107, human skin fibroblasts were The results are measured against IL-6 production induced by hu-IL-17.

[0077] In some embodiments, an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab are Leu74, Tyr85, His86, Met87, Asn88, Val124, and T Mature nucleotides containing hr125, Pro126, Ile127, Val128, and His129 In some embodiments, an IL-17 antibody, e.g., For example, secukinumab binds to Tyr43, Tyr44, Arg46, Ala79, and Asp80. In some embodiments, the IL-17 epitope comprises a nucleotide sequence that binds to an epitope of mature human IL-17. 17 antibodies, such as secukinumab, are IL-17 antibodies that contain two mature human IL-17 chains. A homodimeric epitope (the epitope is located at Leu74, Tyr85, H on one chain) is86, Met87, Asn88, Val124, Thr125, Pro126, Il e127, Val128, His129 on the other chain and Tyr43, Tyr44, Ar These epitopes are defined as binding to the nucleotides α, β, and β. The residue numbering scheme used for this is that residue 1 is the first residue in the mature protein. (i.e., IL-17A has a 23 amino acid N-terminal signal peptide. The sequence of immature IL-17A is based on the lack of a nucleotide and starting with glycine. The columns are described in Swiss-Prot entry Q16552. In embodiments, the IL-17 antibody has a K of about 100-200 pM. D Some real In one embodiment, the IL-17 antibody has an inhibitory effect on the biological activity of human IL-17A of about 0.67 nM. IC of approximately 0.4 nM for in vitro neutralization 50 In some embodiments, The absolute bioavailability of subcutaneously (SC) administered IL-17 antibodies is approximately 60-70%. In some embodiments, the antibody is in the range of about 80%, for example about 76%. The IL-17 antibody is administered for about 4 weeks (e.g., about 23 to about 35 days, about 23 to about 30 days, for example, about 3 In some embodiments, the IL-17 antibody (secukinumab etc.) will take about 7-8 days to arrive. max It has.

[0078] Particularly preferred IL-17 antibodies or antigen-binding fragments thereof for use in the disclosed methods are human IL-17 antibodies or antigen-binding fragments thereof. In particular, the antibodies described in Examples 1 and 2 of WO 2006 / 013107 Secukinumab is a IgG1 / kappa isotype inhibitor. Recombinant high-affinity, fully human monoclonal anti-human interleukin-17A (IL-17 A, IL-17) antibody. (See brochure no. 2007 / 117749) is based on IL-17 It has a very high affinity for D is approximately 100-200 pM, and IC 50 teeth, Approximately 0.4 nM for in vitro neutralization of the biological activity of approximately 0.67 nM human IL-17A Therefore, secukinumab inhibits the antigen at a molar ratio of approximately 1:1. This affinity makes the secukinumab antibody particularly suitable for therapeutic applications. It has been demonstrated to have a very long reduction period, i.e., approximately 4 weeks, which makes it suitable for the treatment of PsA and axSpA (i.e., nr-axSpA and AS, e.g., nr-axSpA, e.g., AS) Extending the time between doses when treating any chronic, lifelong disorder This is an extremely excellent characteristic.

[0079] Other Preferred IL-17 Antibodies for Use in the Disclosed Methods, Kits, and Regimens No. 8,057,799, the entire contents of which are incorporated herein by reference. No. 4; U.S. Patent No. 8,003,099; U.S. Patent No. 8,110,191 and U.S. Patent No. 7,838,638, and U.S. Patent Application Publication No. 201 No. 20034656 and U.S. Patent Application Publication No. 20110027290 It is what is stated.

[0080] Methods of Treatment and Use of IL-17 Antagonists Disclosed IL-17 antagonists, such as IL-17 binding molecules (e.g., IL-17 an antibody or antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., The antibodies (e.g., IL-17 receptor antibodies or antigen-binding fragments thereof) can be used in vitro or ex vivo. and can be incorporated into pharmaceutical compositions to treat PsA or axSpA (i.e., nr-axSpA and AS, e.g., nr-axSpA, e.g., AS) patients (e.g., human patients). and / or PsA or axSpA (i.e., nr-axSpA and AS, e.g., nr - axSpA (e.g., AS) patients who have been previously treated with, for example, a TNF-alpha inhibitor Patients with no PsA or axSpA (TNF-naive patients), previously treated with TNF-alpha inhibitors Patients with PsA or axSpA who have been previously treated, e.g., those treated with TNF-alpha inhibitors have been given treatment but responded inadequately (e.g., were unable to respond or PsA or axSpA patients (TNF-IR patients) and NSA Previously treated with ID but did not respond adequately (e.g., In patients with PsA or axSpA, where the The compounds may be administered in vivo to inhibit the progression of cardiac injury.

[0081] Disclosed IL-17 antagonists, such as IL-17 binding molecules (e.g., IL-17 an antibody or antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., The disclosed IV regimens utilize IL-17 receptor antibodies or antigen-binding fragments thereof. (e.g., initial dose of 6 mg / kg and then 3 mg / kg thereafter) is used to treat psoriasis (e.g., abscesses, ulcers, ulcers, psoriasi ...) vesicular or plaque psoriasis), asthma, acne, tendon disorders (e.g., plantar fasciitis, Achilles tendinopathy, patellar tendinopathy) Tendinopathy (tendonitis), rotator cuff tendinopathy, jumper's knee, lateral epicondylitis, medial epicondylitis, supraspinatus syndrome group or any combination thereof), Graves' orbital disease (thyroid eye disease, Graves' eye disorders, Graves' eye disease), hidradenitis suppurativa, uveitis (including pediatric uveitis), JIA (including JIA associated with uveitis) or vasculitis (e.g. , Behcet's syndrome, Buerger's disease (thromboangiitis obliterans), peripheral spondyloarthritis, antineutrophils Autoantibody-cytoplasmic vasculitis (ANCA)-associated systemic vasculitis (AASV) (AAV-ANCA-associated vasculitis) Wegener's granuloma (WG) (granulomatosis with large vessel vasculitis, polyangiitis) eosinophilic polyangiitis (MPA), Churg-Strauss syndrome (CSS) (oxygen-induced Granulomatosis with polyangiitis bulbar (EPGA)), cryoglobulinemia, giant cell arteritis (GC) A), Henoch-Schönlein purpura, hypersensitivity vasculitis, Kawasaki disease (mucocutaneous lymph node syndrome) group), polyarteritis nodosa, rheumatoid vasculitis, Takayasu's arteritis and polymyalgia rheumatica (P MR)), CRMO (chronic relapsing multifocal osteomyelitis), CNO (chronic non-bacterial osteomyelitis), SA IBD with PHO syndrome, peripheral arthritis, reactive arthritis, unclassified peripheral arthritis, and PsA It is also contemplated that the compounds may be administered to treat patients with

[0082] The disclosed total intravenous regimen, which uses weight-based (rather than flat) dosing, is currently Approved completely subcutaneous secukinumab regimens (i.e., initial doses at weeks 0, 1, 2, 3, and 4) 150 mg or 300 mg secukinumab administered SC at baseline, followed by monthly maintenance doses) provides more consistent secukinumab concentrations, and therefore efficacy, regardless of body weight when compared with placebo This is expected to be a significant benefit to patients.

[0083] In the treatment of various disorders, particularly PsA or axSpA, e.g., AS or nr-axSpA The effectiveness of the disclosed methods, kits, uses and compositions in the treatment of spondyloarthritis has been confirmed by the ASAS (Spondyloarthritis International Society). Assessment in SpondyloArthritis Intervention Ankylosing Spondylitis Disease Activity Index (Bath Ankylosing Spondylitis Disease Activity Index) Bath Ankylosing Spondylitis Disease Acti vity Index), Ankylosing Spondylitis Quality of Life Spondylitis Quality of Life (ASQoL) Scale , American College of Rheumatology Tology 20 (ACR20), 40 (ACR40), or 50 (ACR5) response , van der Heijde modified total Sharpe score (van der Heijde -modified total Sharp score)(vdH-mTSS), dry Psoriatic Area and Severity Ind Ex) Score (e.g. PASI75, PASI90, PASI100), Health Assessment Questionnaire -Disability Index (Health Assessment Questionnaire-Di Sability Index) (HAQ-DI score range of 0-3, higher scores are 28-joint disease activity score using C-reactive protein; Change from baseline in activity (DAS28-CRP, higher scores indicate higher activity) and resolution of enthesitis and dactylitis (e.g., PsA scale). For a discussion of the above, see Mease P, et al. (2018) Ann Rheum Di s 77:890-897; Regarding the consideration of axSpA scales, Baeten et al. (See also: I. (2015) N Engl J Med 373:2534-48) Efficacy can be measured by a variety of criteria known in the art. Additional efficacy criteria can be found in the Examples. Details of some representative criteria are found below and should not be construed as limiting. It should not be interpreted.

[0084] ASAS (Assessment in Spondyloarthritis International Society) Arthritis International Society) Evaluation Criteria (1~ 6) consisted of the following assessment domains: (1) 100 mm visual analog scale (VAS); (2) patient global assessment of disease activity as assessed by the VAS pain score (0-100 scale); (3) Pain assessed by the BASFI score (0-10) or NRS (0-10) (4) physical function assessed by a 10-point scale or 100mm VAS scale; By averaging the two morning stiffness BASDAI questions No. 5 and No. 6 on the core Inflammation assessed; (5) Bath Ankylosing Spondylitis Metric Index BASMI score (cervical rotation, thoracic expansion, lumbar lateral flexion, modified Schober index, distance from occipital to wall); (6) C-reactive protein (acute phase reactant).

[0085] Definition of ASAS20 Responders A subject is defined as an ASAS20 responder if they possess the following: 1. ≥ 20% improvement in the following four core ASAS domains: Patient Global Assessment (0-ai) Measured on a VAS (0-100 mm VAS) as total back pain or nighttime back pain ); physical function (BASFI, as measured by 0-10); inflammation (BASDAI, 0 Measured by the average of two morning stiffness questions, number 5 and number 6, out of 10 ≥ 3 of the cases have an absolute improvement of ≥ 1 unit; 2. No exacerbation in the remaining available domains (exacerbation is defined as ≥ 20% worsening and baseline (defined as an absolute worsening of ≥ 1 unit from

[0086] Definition of ASAS40 Responders A subject is defined as an ASAS40 responder if they hold the following conditions: 1. ≥ 40% improvement in the following four domains: Patient Global Assessment (VA 0-100mm) back pain (measured as total back pain or nighttime back pain on a VAS ranging from 0 to 100 mm) ); physical function (BASFI, as measured by 0-10); inflammation (BASDAI, 0 Measured by the average of two morning stiffness questions, number 5 and number 6, out of 10 Absolute improvement ≥ 2 units in 3 of the cases; 2. No deterioration from baseline in any remaining available domain (>0% or >0%) unit).

[0087] Definition of ASAS5 / 6 responders Subjects were assessed on the following six ASAS domains: Patient Global Assessment (measured on a VAS ranging from 0 to 100 mm); back pain (measured as total back pain or nighttime back pain on a VAS scale of 0 to 100 mm); Function (BASFI, as measured by 0-10); inflammation (BASDAI, as measured by 0-10) (as measured by the average of two morning stiffness questions, number 5 and number 6). Bath Ankylosing Spondylitis Measurement Index s Metrology Index) (BASMI); score (neck rotation, chest expansion, Lumbar lateral bending, modified Schober index, distance from occipital wall); (6) C-reactive protein If there is a ≥ 20% improvement in five of the following substances (acute phase reactants), the ASAS5 score is defined as a / 6 responder.

[0088] Definition of ASAS partial response Subjects are considered to have a score of <2 units in each of the following four core ASAS domains: Partial remission was defined as achieved if: Patient Global Assessment (measured on a VAS ranging from 0 to 100 mm) back pain (measured as total back pain or nighttime back pain on a 0-100 mm VAS); physical function activity (BASFI, as measured by 0 to 10); inflammation (BASDAI, as measured by 0 to 10); (as measured by the average of the two morning stiffness questions number 5 and number 6).

[0089] Bath Ankylosing Spondylitis Functional Index Body Functional Index (BASFI) BASFI is a tool to measure functional control in patients with axSpA, e.g., AS or non-r-axSpA. It is a set of 10 questions designed to determine the degree of For example, major input from patients with AS or non-r-axSpA is 1 0 questions were selected. The first 8 questions consider functional anatomy activities. The latter two questions assess the patient's ability to cope with daily activities. Answer the questions using a scale. The average of the 10 scales is the BASFI score -0 to gives a value of 10.

[0090] Bath Ankylosing Spondyl Disease Activity Index itis Disease Activity Index)(BASDAI) BASDAI is a scale of 0 to 10 (0 being no problems and 10 being the worst problems). This relates to the five major symptoms of axSpA, such as AS or nr-axSpA. Six questions: 1. Fatigue; 2. Spinal pain; 3. Joint pain / swelling; 4. Area of ​​localized tenderness (tendon-related) 5. Duration of morning stiffness; 6. Morning stiffness To give equal weight to each symptom, the morning The average (mean) of the two scores for stiffness is added to the scores for the other four questions. The resulting score of 0-50 is divided by 5 to give a final BASDAI score of 0-10. A BASDAI score of 4 or greater suggests suboptimal disease control, and patients with a score of 4 or greater usually involves a change in their medical treatment or the development of axSpA, e.g., AS or nr-axSpA. are good candidates for enrollment in clinical trials evaluating new drug therapies directed at be.

[0091] Bath Ankylosing Spondyl Disease Activity Index itis Disease Activity Index)(BASDAI50) BASDAI50 is defined as at least a 50% improvement in BASDAI compared to baseline. Defined as good.

[0092] Patient Global Assessment of Disease Activity Patient Global Assessment of Disease Activity is a measure of the broad range of ways your arthritis affects you. Consider this and draw a line on the scale to indicate how well you are doing. (Considering all the ways your arthriti s affects you,draw a line on the scale f or how well you are doing) A 100mm visual analogue scale (VAS) ranging from no activity to maximum disease activity was used. This can be done using

[0093] Patient assessment of pain intensity Patient assessment of back pain should include the following when assessed individually for total back pain or nighttime back pain: This can be done using a 100mm VAS ranging from no pain to intolerable pain.

[0094] Bath Ankylosing Spondylitis Measurement Index Base Assurance Metrology Index (BASMI) BASMI aims to define clinically meaningful changes in spinal motion. It is a validated instrument that uses a minimum number of clinically relevant measurements to accurately assess axial status. The parameters are: 1. Cervical rotation; 2. Tragus to wall distance; 3. Lumbar lateral flexion; 4. Modified Schober's; 5. Includes inter-ankle distance. Two additional parameters: 6. Chest expansion and 7. distance from occiput to wall are also assessed.

[0095] Maastricht Ankylosing Spondylitis Enthesitis Score ng Spondylitis Enthesitis Score)(MASES) Maastricht Ankylosing Spondylitis Enthesitis Score ing Spondylitis Enthesitis Score)(MASES) The MASE was developed from the Mander index and includes the assessment of 13 areas. The areas of enthesitis included in the S index are: 1st costal cartilage, 7th costal cartilage, posterior superior iliac spine, and anterior superior iliac spine. , iliac crest (all of the above evaluated bilaterally), fifth lumbar spinous process, proximal Achilles tendon (proximal al Achilles) (both sides).

[0096] Leeds enthesis index (LEI) The LEI uses six sites for evaluation of tendon attachment: lateral epicondyle, humerus (L+R), proximal Achilles tendon, and tendon insertion. (proximal achilles) Use only L+R ​​and lateral condyle femur The LEI is a validated enthesitis index. While agreement was demonstrated to be adequate to excellent, LEI was not associated with ankylosing spondylitis. demonstrated lower agreement with MASES and therefore further information is needed in this index. This can result.

[0097] MRI Magnetic resonance imaging (MRI) of the spine may be useful in patients treated with IL-17 antibodies (e.g., secukinumab). To investigate whether these changes were affected by the MRI can be obtained locally in a clinical setting. The images are transmitted, quality controlled, anonymized (if necessary), and stored centrally. MRI scans will be performed at baseline (preferably the first The patients may be collected within 2 weeks before treatment, at week 6 (± 1 week), and at week 28 (± 1 week). MRI scans were performed using gadolinium-enhanced MR imaging before and after intravenous injection to assess inflammation. Fat saturation techniques such as short tau inversion recovery (STIR) to monitor I and bone marrow edema The analysis method used was the ASspiMRI-a Berlin Modification. in modification of ASspiMRI-a)” (Lukas C et al(2007)J Rheumatol;34(4):862-70 and Rud waleit et al(2005)[abstract]Arthritis Rh eum 50:S211), which is inflammation in almost the entire spine (C2-S1). The ASspiMRI-a Berlin Modified score (ASpMRI-a) was used to score the sexual changes. SspiMRI-a Berlin modification score) and Berlin The Berlin SIJ edema score is a measure of SIJ edema. MRI evaluation is preferred.

[0098] ASDAS-CRP and ASDAS Response Categories Ankylosing Spondylitis Disease Activity Score (ANSDS) The AS Disease Activity Score (ASDAS) is a measure of disease activity in AS. It is a composite index for assessing dynamics.

[0099] ASDAS-CRP is used to assess the state of disease activity. The parameters used for this included total back pain (BASDAI question 2), disease activity, and peripheral Patient Global Assessment of Pain / Swelling (BASDAI Question 3), duration of morning stiffness (BASD AI question 6) and C-reactive protein (CRP) in mg / L.

[0100] Disease activity status: inactive disease, moderate disease activity, high disease activity and very high disease activity Disease activity. The three values ​​chosen to separate these states are <1.3 inactive disease Severe to moderate disease activity; <2.1 moderate to high disease activity; and >3. 5 High to very high disease activity. Selected cups for improvement scores The study outlined a change of ≥ 1.1 units for a "minimal clinically important improvement" and a "substantial improvement." A "significant improvement" is a change of ≥ 2.0 units.

[0101] ASQoL The quality of life of axSpA patients is evaluated by Doward et al. (2003 ) Ann Rheum Dis 2003;62:20-26 AS-specific qualifier It can be assessed using the Tea of ​​Life instrument.

[0102] Tender and swollen joints (44 joints) The following 44 joints are assessed for tenderness and swelling: 2 sternoclavicular joints (L+R) 2 acromioclavicular joints (L+R) 2 shoulder joints (L+R) 2 elbows (L+R) 2 wrists (L+R) 10 metacarpophalangeal joints (L+R) 10 proximal interphalangeal joints (L+R) (hand) 2 knees (L+R) 2 ankles (L+R) 10 metatarsophalangeal joints (L+R)

[0103] The tender joint count (44 joints) was determined by scoring several different points of tenderness. It is performed by pressure and joint manipulation during physical examination. The information for each should then be collapsed into a single dichotomy of "tender" vs. "non-tender." is.

[0104] The presence of synovial fluid and / or soft tissue swelling but no bone overgrowth was associated with a higher incidence of swollen joints. corresponds to a positive result.

[0105] sleep improvement Combined with data from wearable devices (e.g., wrist-worn actigraphs), By using subjective patient-reported sleep outcomes (i.e., ESS and PSQI) Measure improvements in sleep (e.g., improved sleep quality, improved sleep disturbances, etc.) and reduction in nighttime awakenings Important endpoints include the cumulative number of night-time awakenings after sleep onset (WASO). Number and number of arousal events per sleep period (e.g., minutes), nighttime awakenings, sleep efficiency (percentage) , sleep latency (min), and total sleep time (min).

[0106] American College of Rheumatology ogy)(ACR) reaction ACR responses (Appendix 4) are used to determine efficacy (Felson et al. 1995). An elephant can be ACR if and only if the following three conditions are met: 50 Responders are defined as: ≥ 50% improvement in tender joint count (based on 78 joints) ≥ 50% improvement in swollen joint count (based on 76 joints) ≥ 50% improvement in three of the following five domains: Patient global assessment of disease activity (measured on a VAS scale, 0-100) Physician global assessment of disease activity (measured on a VAS scale, 0-100) Patient assessment of PsA pain (measured on a VAS scale, 0–100) Health Assessment Questionnaire e) (HAQ (Copyright)) score Acute phase reactants (hsCRP or ESR)

[0107] ACR20 = 20% improvement in at least 3 of 5 measurements and a 20% improvement in the number of swollen and tender joints 20% improvement.

[0108] ACR50 = 50% improvement in at least 3 of 5 measurements and the number of swollen and tender joints 50% improvement.

[0109] ACR70 = 70% improvement in at least 3 of 5 measurements and the number of swollen and tender joints 70% improvement.

[0110] Psoriasis Area and Severity In dex)(PASI) PASI measures the severity of psoriasis in four body surface areas (head, trunk, and upper and lower limbs). The PASI score is calculated by assessing the degree of plaque-like erythema, scaling, and thickening. Weisman et al 2003 J Dermatolog Treat p 158-65. Briefly, erythema, thickening (plaque) Evaluate the head, trunk, and upper and lower extremities separately for swelling, induration, and scaling (scaling). The average severity of each symptom in each of the four body areas is assigned a score of 0 to 4. The area affected by the lesions on each body region as a percentage of the total area of ​​the particular body region. Estimate the area that will be covered.

[0111] Further efficacy studies commonly used to evaluate the effectiveness of treatments for PsA patients Outcomes included swollen joint count (SJC) / tender joint count (TJC); patients with disease activity Global assessment (VAS); Physician global assessment of disease activity (VAS); Patient assessment of PsA pain intensity Visual Analogue Scale (VAS); Health Assessment Questionnaire-Disability Index (Health Assessment Questionnaire-Disability Index) estionnaire-Disability Index) (HAQ-DI (Copyright )); high-sensitivity C-reactive protein (hsCRP); erythrocyte sedimentation rate (ESR); psoriatic Psoriatic arthritis response criteria teria) (PsARC) response; Disease Activity Score-CRP (Disease Act DAS28-CRP) and EULAR response criteria; Psoriatic Arthritis Disease Activity Score Patient Activity Score (PASDAS); a measure of psoriasis and arthritis disease activity. Patient global assessment (VAS); Minimal disease activity (Minimum disease activity ity);Leeds Dactylitis Index (LD I) and dactylitis count; Leeds Enthesitis Index (LEES) ex)(LEI); Canadian Spondyloarthritis Research Consortium itis Research Consortium of Canada)(SPAR Novartis Investigator Global Assessment 2011 Revised (Novartis I nvestigator's Global Assessment modified 2011) (IGA mod 2011; Modified Nail Psoriasis Severity Index Nail Psoriasis Severity Index)(mNAPSI) The nurse's overall fingernail disease severity rating (VAS) was included.

[0112] As used herein, the phrase "patient population" refers to a patient population, e.g., ACR20, ACR 40, PASI75, PASI90, ASAS20, ASAS40, BASDI, etc. PsA or axS of sufficient size to perform statistical analysis for a given disease score Patients with SpA (i.e., non-rxSpA and AS, e.g., non-rxSpA, e.g., AS) This refers to the .

[0113] In some embodiments, the claimed methods (e.g., a loading dose of 6 mg / kg at week 0, followed by monthly administration of 3 mg / kg secukinumab in patients with TNF-naive PsA When the population is treated, the population has at least about 55%, 32%, and 14% A Achieve CR20 / 50 / 70 (week 16, not subtracting placebo). In embodiments, the claimed methods (e.g., a loading dose of 6 mg / kg at week 0, followed by a 3 mg / kg A group of TNF-naive PsA patients was treated according to the When administered, this population achieved ACR20 / 50 scores of at least approximately 58%, 37%, and 18%, respectively. / 70 (week 16, not subtracting placebo).

[0114] In some embodiments, the claimed methods (e.g., a loading dose of 6 mg / kg at week 0, Subsequently, monthly administration of 3 mg / kg secukinumab was used) according to TNF-IR in PsA patients When a population is treated, the population should have at least about 40%, 20%, and 10% A Achieve CR20 / 50 / 70 (week 16, not subtracting placebo). In embodiments, the claimed methods (e.g., a loading dose of 6 mg / kg at week 0, followed by a 3 mg / kg A population of PsA patients treated according to TNF-IR (using monthly doses of 1 kg secukinumab) When administered, this population had an ACR20 / 50 response rate of at least approximately 45%, 23%, and 12%, respectively. / 70 (week 16, not subtracting placebo).

[0115] In some embodiments, the claimed methods (e.g., a loading dose of 6 mg / kg at week 0, A group of PsA patients was subsequently treated according to the 3 mg / kg monthly dose of secukinumab. If this population is treated, PASI75 / 90 (secondary) scores of at least about 57% and 35%, respectively, are achieved. In some embodiments, the claimed method (e.g., 6 mg at week 0) achieves 16 weeks. secukinumab monthly doses of 3 mg / kg (using a loading dose of 3 mg / kg). When a population of patients is treated, this population has a PA of at least about 70% and 47%, respectively. Achieve SI75 / 90 (week 16).

[0116] In some embodiments, the claimed methods (e.g., a loading dose of 6 mg / kg at week 0, A cohort of ax-SpA patients was subsequently treated with secukinumab (using monthly doses of 3 mg / kg). When treated, this population has an ASAS40 of at least about 37% or 39% (week 16; In some embodiments, the claimed method (e.g., placebo) is achieved. For example, a loading dose of 6 mg / kg at week 0 followed by monthly doses of 3 mg / kg secukinumab If a population of ax-SpA patients is treated according to Achieve a significant improvement in ASDAS-CRP (Week 16). The method of administration (e.g., a loading dose of 6 mg / kg at week 0 followed by 3 mg / kg secukinumab) If a population of ax-SpA patients is treated according to the Achieve at least approximately 14% or 17% ASDAS-CRP inactive disease (week 16) In some embodiments, the claimed methods (e.g., a loading dose of 6 mg / kg at week 0, A cohort of ax-SpA patients was subsequently treated with secukinumab (using monthly doses of 3 mg / kg). When treated, this population has an ASAS20 score of at least about 53% or 56% (week 16; In some embodiments, the claimed method (e.g., placebo) is achieved. For example, a loading dose of 6 mg / kg at week 0 followed by monthly doses of 3 mg / kg secukinumab If a population of ax-SpA patients is treated according to achieves 50% ASAS40 (week 52).

[0117] IL-17 antagonists, such as IL-17 binding molecules (e.g., IL-17 antibodies or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., IL The medicament for treating rheumatoid arthritis (antibody or antigen-binding fragment thereof) when combined with a pharmaceutically acceptable carrier is Such compositions can be used as pharmaceutical compositions containing IL-17 antagonists. In addition, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers and other agents known in the art. It may contain other well-known materials. The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition for use in the method may be an additional therapeutic agent for the treatment of the particular disorder being targeted. For example, the pharmaceutical composition may also include an anti-inflammatory agent. Including such additional factors and / or agents in the pharmaceutical composition may promote synergy with the IL-17 binding molecule. or to produce an IL-17 antagonist, such as an IL-17 binding molecule (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) or IL-17 receptor-binding and preventing side effects caused by a molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof). can be minimized.

[0118] Pharmaceutical compositions for use in the disclosed methods can be prepared in a conventional manner. In one embodiment, the pharmaceutical composition is provided in lyophilized form. For immediate administration, this , dissolved in a suitable aqueous carrier, such as sterile water for injection or sterile buffered saline. To compose a larger volume of solution for administration by infusion rather than bolus injection. If this is considered desirable, human serum albumin or the patient's own heparinization should be used at the time of formulation. It may be advantageous to incorporate the extracted blood into saline. The presence of physiologically inactive proteins can lead to absorption to the walls of containers and tubing used with the infusion solution. When albumin is used, the preferred concentration is 100 mg / mL saline. The concentration is 0.5 to 4.5% by weight of the solution. Other formulations are liquid or freeze-dried. Contains agents.

[0119] Antibodies, such as antibodies against IL-17, are typically formulated in aqueous, ready-to-administer parenteral formulations. or as a lyophilizate for reconstitution with a suitable diluent prior to administration. In some embodiments of the disclosed methods and uses, an IL-17 antagonist, e.g. For example, an IL-17 antibody, such as secukinumab, is formulated as a lyophilizate. The lysed dry product can be reconstituted into a small volume of liquid (e.g., 2 ml or less) to allow subcutaneous administration. This can produce a solution with low levels of antibody aggregation. The use of antibodies as components is well known in the art, including HERCEPTIN™ (trastuzumab), RITU XAN™ (rituximab) and SYNAGIS™ (palivizumab) products Currently, there are many different techniques for purifying antibodies to pharmaceutical grade, including: A therapeutically effective amount of an IL-17 antagonist, e.g., an IL-17 inhibitor, is well known in the art. a synthetic molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 IL-17 receptor-binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof) are administered intravenously or subcutaneously. or when administered by subcutaneous injection, the IL-17 antagonist is pyrogen-free. For intravenous, cutaneous or subcutaneous injection, The pharmaceutical composition of the present invention contains, in addition to the IL-17 antagonist, sodium chloride, Ringer's solution, Isotonic vehicles such as dextrose, dextrose and sodium chloride, and lactated Ringer's solution or may contain other vehicles known in the art.

[0120] The appropriate dosage will depend on the particular IL-17 antagonist to be used, e.g. an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab ) or an IL-17 receptor-binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof), a host , the mode of administration and the nature and severity of the condition being treated, and the nature of previous treatments the patient has received. Ultimately, the healthcare provider in charge will have the resources to treat each individual patient. The amount of IL-17 antagonist is determined. In some embodiments, the patient's healthcare provider Alternatively, a low dose of the IL-17 antagonist may be administered and the patient's response monitored. In this setting, patients are given a high initial dose of IL-17 antagonist, followed by a flare-up. Titrate downward until a higher dose is achieved until optimal therapeutic effect is achieved for the patient. of IL-17 antagonist may be administered, but the dosage is generally not increased further.

[0121] In practicing some of the methods of treatment or use of the present disclosure, a therapeutically effective amount of IL-17 antagonist is administered. agonists, such as IL-17 binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof, secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or its The antigen-binding fragment is administered to a patient, e.g., a mammal (e.g., a human). , the use of IL-17 antagonists (e.g., secukinumab) to treat PsA or axSpA (i.e., non-rx-SpA and AS, e.g., non-rx-SpA, e.g., AS) It is understood that this provides a therapeutic benefit to patients ultimately treated with an IL-17 antagonist. If this is the case, it is important to understand that such IL-17 antagonist therapy is necessarily a monotherapy. In fact, if a patient is selected for treatment with an IL-17 antagonist, alone or in combination with PsA or axSpA (i.e., nr-axSpA and AS, e.g., nr- in combination with other drugs and therapeutic agents for treating patients with axSpA, e.g., AS, e.g. For example, immunosuppressants, disease-modifying antirheumatic drugs (DMARDs) (e.g., sulfasalazine), Pain-modulating drugs, steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), cytokine antagonists anti-resorptive drugs and their combinations (e.g., dual and triple therapy), at least one additional PsA or axSp treatment, such as an NF-alpha antagonist In combination with agent A, an IL-17 antagonist (e.g., secukinumab) It may be administered according to the methods of the present disclosure. When administered, the IL-17 antagonist may be administered either simultaneously or sequentially with other agents. If administered sequentially, the attending physician will review the other medications and appropriate medications for co-delivery. Determine the appropriate sequence of administering IL-17 antagonists in combination with appropriate doses. do.

[0122] PsA or axSpA (i.e., nr-axSpA and AS, e.g., nr-axSpA, e.g., Non-steroidal anti-inflammatory drugs useful in combination with secukinumab for the treatment of patients with AS Anti-inflammatory drugs (NSAIDs) and pain control agents include propionic acid derivatives, acetic acid derivatives, and ethoxylated enolic acid derivatives, fenamic acid derivatives, Cox inhibitors, e.g. Lumiracoxib, ibuprofen, fenoprofen, ketoprofen, flurbiprofen phenanthrene, oxaprozin, indomethacin, sulindac, etodolac, ketorolac, nabume Ton, aspirin, naproxen, valdecoxib, etoricoxib, MK0966, Fecoxib, acetaminophen, celecoxib, diclofenac, tramadol, Roxicam, Meloxicam, Tenoxicam, Droxicam, Lornoxicam, Isoxicam mefanamic acid, meclofenamic acid, flufenamic acid These include, but are not limited to, benzodiazepine, tolfenamic acid, parecoxib, and firocoxib. sA or axSpA (i.e., nr-axSpA and AS, e.g., nr-axSpA, e.g., in combination with IL-17 antagonists, e.g., secukinumab, for the treatment of patients with AS DMARDs useful in this regard include methotrexate (MTX), antimalarials (e.g., (e.g., hydroxychloroquine and chloroquine), sulfasalazine, leflunomide, azathioprine Oprin, cyclosporine, gold salts, minocycline, cyclophosphamide, D-penicilla Min, minocycline, auranofin, tacrolimus, myocrisin, chlorambucil These include, but are not limited to, PsA or axSpA (i.e., nr-axSpA and AS, IL-17 antagonists for the treatment of patients with non-rx-SpA, e.g., AS; For example, steroids (e.g., glucocorticoids) useful in combination with secukinumab Prednisolone, prednisone, dexamethasone, cortisol, corticosteroids betamethasone, triamcinolone, methylprednisolone, hydrocortisone, methylprednisolone, Examples include clomethasone, fludrocortisone, deoxycorticosterone, and aldosterone. This may be, but is not limited to:

[0123] PsA or axSpA (i.e., nr-axSpA and AS, e.g., nr-axSpA, e.g., In combination with IL-17 antagonists, e.g., secukinumab, for the treatment of patients with AS Biologics that may be useful in combination include adalimumab (Humira®). (registered trademark), etanercept (Enbrel (registered trademark)), infliximab (Remicad (registered trademark) TA-650), certolizumab pegol (Cimzia®; CDP87 0), golimumab (Simponi®; CNTO148), rituximab (Ritux) San (registered trademark); MabThera (registered trademark), abatacept (Orencia (registered trademark)) , tocilizumab (RoActemAS / Actemra®), integrin antagonist agonist (TYSABRI® (natalizumab)), IL-1 antagonist ( ACZ885, canakinumab (Ilaris®), anakinra (Kinere®) t®), CD4 antagonists, other IL-17 antagonists (LY24 39821, ixekizumab, RG4934, AMG827, brodalumab, SCH90 0117, R05310074, MEDI-571, CAT-2200), IL-23A antagonists, IL-20 antagonists, IL-6 antagonists, other TNF antagonists TNF alpha antagonists (e.g., other TNF alpha antagonists or TNF alpha receptor antagonists) antagonists (e.g., pegsunercept), BLyS antagonists (e.g., ata Sicept, Benlysta® / LymphoStat-B® (Belima) P38 inhibitors, CD20 antagonists (ocrelizumab, ofatumumab (anticoagulant)), -Zera (registered trademark), interferon gamma antagonist (fontolizumab) or biosimilar versions of these biologics.

[0124] IL-17 antagonists, such as IL-17 binding molecules (e.g., IL-17 antibodies or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., IL The IFN-17 receptor antibody or antigen-binding fragment thereof is conveniently administered intravenously (e.g., intracubital or other peripheral The duration of intravenous (IV) therapy using the pharmaceutical compositions of the present disclosure is determined by the therapeutic Varies depending on the severity of the disease and condition being treated and the individual response of each individual patient. A healthcare provider may administer IV therapy using the pharmaceutical compositions of the present disclosure, as well as the appropriate duration and duration of this therapy. Determine the timing of administration.

[0125] Infusion durations of 15 minutes, 30 minutes, 45 minutes or 1 hour are preferred.

[0126] IL-17 antagonists, such as IL-17 binding molecules (e.g., IL-17 antibodies or the like) antigen-binding fragment of IL-17 receptor (e.g., secukinumab) or IL-17 receptor-binding molecule (e.g., IL-1 7 receptor antibody or its antigen-binding fragment) is administered at a dose of about 4 mg / kg to about 9 mg once during week 0. / kg (preferably about 6 mg / kg) and in patients with hidradenitis suppurativa, psoriasis (i.e., pustular or plaque psoriasis), PsA or axSpA (i.e., nr-axSpA or AS, e.g., nr - patients with axSpA (e.g. AS), preferably patients with PsA or axSpA administered intravenously (IV) to a patient (e.g., as part of a loading regimen) first, followed by a fourth Starting midweek, monthly (every 4 weeks) doses of about 2 mg / kg to about 4 mg / kg (preferably about 3 mg / kg) g / kg) is administered IV to patients (e.g., as part of a maintenance regimen). During week 0, the patient receives about 4 mg / kg to about 9 mg / kg (preferably about 6 mg / kg). IV, then at about 2 mg / kg to about 4 mg / kg (preferably at 4, 8, 12 weeks) or about 3 mg / kg) of an IL-17 antagonist (e.g., preferably secukinumab) is administered IV to the patient.

[0127] The disclosed methods for treating PsA or axSpA (e.g., nr-axSpA or AS) Preferred regimens (doses and administration schemes) for use with IL-17 antagonists ) are provided in Table 2.

[0128] [Table 2]

[0129] Other autoimmune diseases, such as psoriasis (e.g., pustular or plaque psoriasis), asthma, acne, tendonitis Disorders (e.g., plantar fasciitis, Achilles tendinopathy, patellar tendinopathy (tendinitis), rotator cuff tendinopathy, Knee Jumper, Lateral Epicondylitis, Medial Epicondylitis, Supraspinatus Syndrome, or any combination thereof) , Graves' orbital disease (thyroid eye disease, Graves' ophthalmopathy, Graves' eye disease), suppurative Hidradenitis, uveitis (including pediatric uveitis), juvenile idiopathic arthritis (JIA) (grape JIA with meningitis) or vasculitis (e.g., Behçet's syndrome, Buerger's disease (obstructive) thromboangiitis), peripheral spondyloarthritis, antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vascular AAV-ANCA-associated vasculitis (AASV) (also known as AAV-ANCA-associated vasculitis), Wegener's granulomatosis (W G) (large vessel vasculitis, granulomatosis with polyangiitis), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS) (eosinophilic granulomatosis with polyangiitis (EPGA)), Cryoglobulinemia, giant cell arteritis (GCA), Henoch-Schönlein purpura, hypertension Irritable vasculitis, Kawasaki disease (mucocutaneous lymph node syndrome), polyarteritis nodosa, rheumatoid vasculitis , Takayasu's arteritis and polymyalgia rheumatica (PMR), CRMO (chronic relapsing multifocal myeloma) inflammation), CNO (chronic non-bacterial osteomyelitis), SAPHO syndrome, peripheral arthritis, reactive arthritis, The disclosed IL-17 antibodies are also useful for treating IBD associated with undifferentiated peripheral arthritis and PsA. The dosing regimens disclosed in Table 2 with the antagonists can be used.

[0130] In a most preferred embodiment, an IL-17 antagonist (e.g., most preferably a secukinumab antagonist) is used. The initial dose of IMAB (Immunostat) is approximately 6 mg / kg (e.g., 6 mg / kg), and the IL-17 antagonist The maintenance dose of the antagonist (e.g., most preferably secukinumab) is about 3 mg / kg (e.g., 3mg / kg).

[0131] Alternatively, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody) may be used. or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., IL-17 receptor antibody or antigen-binding fragment thereof) is administered to patients without a loading regimen. For example, antagonists (e.g., secukinumab) are administered at approximately 2 mg / kg every 4 weeks (monthly). The dose can be administered IV to a patient at a dose of between about 100 mg / kg and about 4 mg / kg (preferably about 3 mg / kg). In embodiments, the patient is administered an IL-17 antagonist (e.g., IL-17 inhibitor) during weeks 0, 4, 8, 12, etc. For example, secukinumab) is administered intravenously at approximately 3 mg / kg.

[0132] Certain patients may be treated with an IL-17 antagonist, such as an IL-17 binding molecule (e.g., (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding Inadequate response to treatment with a combination molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof) Dose escalation may be required for responding patients (e.g., during induction and / or maintenance phases) Therefore, it is understood that IL-17 antagonists (e.g., IL-17 antibodies or The dose (e.g., delivered IV) of the antigen-binding fragment, e.g., secukinumab, is about 6 mg / kg (preferred loading dose) or greater than 3 mg / kg (preferred maintenance dose), e.g., about 7 m g / kg, 8mg / kg, 9mg / kg, 10mg / kg, 4mg / kg, 5mg / kg Certain patients may be at increased risk of developing IL-17 antagonists (e.g., IL-17 Adverse events or adverse reactions to treatment with an antibody or antigen-binding fragment thereof, e.g., secukinumab Dose reductions may also be required for responding patients (e.g., during induction and / or maintenance phases). Therefore, it is understood that an IL-17 antagonist (e.g., an IL-17 antibody or its anti-IL-17 antibody) The dosage (e.g., delivered IV) of the original binding fragment, e.g., secukinumab, is about 6 mg / kg. g (preferred loading / initial dose) or less than 3 mg / kg (preferred maintenance dose), e.g., about 5 Some examples include: In embodiments, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., IL-17 an antibody or antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor-binding molecule (e.g., For example, an IL-17 receptor antibody or an antigen-binding fragment thereof) is administered at a dose of about 6 mg / kg (loading dose) or 3 mg / kg. The patient may be administered an initial dose (e.g., delivered IV) of 1 mg / kg (maintenance doses), followed by The dose may be titrated up as needed, as determined by a physician.

[0133] The timing of dosing generally begins on the day of the first dose of secukinumab (referred to as "baseline"). However, healthcare providers often use the following methods, as shown in Table 3: Use different naming conventions to clarify dosing schedules.

[0134] [Table 3]

[0135] In particular, week 0 may be considered week 1 by some healthcare providers, while week Day 0 may be considered day 1 by some healthcare providers. The nurse may refer to the same medication schedule, for example, for 3 weeks / day 21 and for 3 weeks / day 22. A dose is said to be given on day 22 for 4 weeks / day 21 for 4 weeks / day 22. For consistency, the first week of dosing is referred to herein as the first week. The first day of dosing will be considered as day 1, whereas the first day of dosing will be considered as week 0. However, this naming convention is used solely for consistency and should not be construed as restrictive. It is not possible to distinguish between whether a physician refers to a particular week as "week 1" or "week 2." Regardless, it will be appreciated by those skilled in the art that weekly dosing is a definition of a weekly dose of IL-17 antibody. Furthermore, in a preferred administration regimen, the antibody is administered at doses 0, 4, 8, It is administered at 12, 16, 20, etc. weeks. Some providers may administer this regimen monthly. Some may refer to this regimen as every four weeks, others may refer to this regimen as every four weeks.

[0136] As used herein, the term "monthly" is interchangeable with "every four weeks" and "q4w". are used interchangeably with.

[0137] Psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) (i.e., nr-axSpA) and methods of treating patients with AS, e.g., nr-axSpA, e.g., AS, are provided herein. The method disclosed therein includes administering IL-17 antagonist at a dose of about 6 mg / kg once during week 0. agonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) to the patient. IV, followed by a dose of approximately 3 mg / kg every 4 weeks (monthly) starting during the 4th week and administering to the patient intravenously an IL-17 antagonist (e.g., an IL-17 antibody or Its antigen-binding fragments, e.g., secukinumab, contain two mature IL-17 protein chains. The epitope of the IL-17 homodimer is located on one of the chains of the Le u74, Tyr85, His86, Met87, Asn88, Val124, Thr12 5, Pro126, Ile127, Val128, His129, and a T on the other strand. This IL-17 antigen contains yr43, Tyr44, Arg46, Ala79, and Asp80. K of an IL-17 antagonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) D The IL-17 antagonist (e.g., IL-17 antibody) The in vivo half-life of the antibody or antigen-binding fragment thereof, e.g., secukinumab, is approximately 4 weeks.

[0138] Further disclosed herein are methods of treating patients with psoriatic arthritis (PsA). This method involves administering a dose of about 4 mg / kg to about 9 mg / kg (preferably about 6 mg / kg) Patients will receive an IL-17 antagonist (e.g., secukinumab) intravenously (IV) once during week 0. ) and then every 4 weeks (monthly) starting during the 4th week, at about 2 to about 4 mg / kg (preferably Preferably, the patient is administered an IL-17 antagonist (e.g., secukinumab) at a dose of about 3 mg / kg. This includes administering.

[0139] Additionally, axial spondyloarthritis (axSpA) (i.e., nr-axSpA and AS, e.g., n Disclosed herein are methods for treating patients with r-axSpA (e.g., AS), The method involves administering IL-1 at a dose of about 4 mg / kg to about 9 mg / kg (preferably about 6 mg / kg). Patients will receive a single intravenous (IV) injection of a -17 antagonist (e.g., secukinumab) during week 0. Then, starting during the fourth week, approximately 2 mg / kg to approximately 4 mg / kg every four weeks (monthly) kg (preferably about 3 mg / kg) of an IL-17 antagonist (e.g., secukinumab) to the patient.

[0140] Furthermore, psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) (i.e., nr-a Structural changes in patients with xSpA and AS (e.g., nr-axSpA, e.g., AS) Disclosed herein is a method of inhibiting the progression of damage, the method comprising administering a dose of about 6 mg / kg of IL-17 antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., sec- Patients will receive 1 dose of NIH-Numab (Numab) once during week 0, then every 4 weeks (every 4 weeks) starting during week 4. a dose of about 3 mg / kg (monthly) of an IL-17 antagonist, The antibody (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) is composed of two components. Binds to an epitope of the IL-17 homodimer having a mature IL-17 protein chain, and The pitope is located at Leu74, Tyr85, His86, Met87, and Asn8 on one strand. 8, Val124, Thr125, Pro126, Ile127, Val128, His 129, and on the other strand Tyr43, Tyr44, Arg46, Ala79, Asp 80, and the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof) K of the fragment (e.g., secukinumab) DThe IL-17 antagonist is approximately 100-200 pM. In vivo administration of an IL-17 agonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) The half-life is approximately 4 weeks.

[0141] Additionally, axial spondyloarthritis (axSpA) (i.e., nr-axSpA and AS, e.g., n IL-17 Antagonists for Use in Treating Patients with r-axSpA (e.g., AS) The compounds described herein (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) are also disclosed. and the IL-17 antagonist (e.g., an IL-17 antibody or its antigen-binding The fragment (e.g., secukinumab) is administered intravenously to patients at a dose of approximately 6 mg / kg once during week 0. The patient will then receive approximately 3 mg / kg every 4 weeks (monthly) starting during the 4th week. The IL-17 antagonist (e.g., an IL-17 antibody) should be administered intravenously to or an antigen-binding fragment thereof, e.g., secukinumab), which binds two mature IL-17 protein chains The epitope of the IL-17 homodimer is located on one chain of the L eu74, Tyr85, His86, Met87, Asn88, Val124, Thr1 25, Pro126, Ile127, Val128, His129, and on the other strand This IL-17 contains Tyr43, Tyr44, Arg46, Ala79, and Asp80. antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) K D is about 100 to 200 pM, and this IL-17 antagonist (e.g., IL-17 The in vivo half-life of the antibody or antigen-binding fragment thereof, such as secukinumab, is approximately 4 weeks.

[0142] Additionally, axial spondyloarthritis (axSpA) (i.e., nr-axSpA and AS, e.g., n for use in inhibiting the progression of structural damage in patients with r-axSpA (e.g., AS) IL-17 antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab Mabs) are disclosed herein, and the IL-17 antagonists (e.g., IL-17 antibodies) or an antigen-binding fragment thereof, e.g., secukinumab) at a dose of about 6 mg / kg once during week 0 It is administered intravenously to patients at approximately 3 mg / month every 4 weeks (monthly) starting during the 4th week. The IL-17 antagonist (e.g., For example, IL-17 antibodies or antigen-binding fragments thereof, such as secukinumab, bind to two mature IL-1 Binds to an epitope on the IL-17 homodimer, which has seven protein chains. , Leu74, Tyr85, His86, Met87, Asn88, Val on one strand Includes 124, Thr125, Pro126, Ile127, Val128, His129 and on the other chain contains Tyr43, Tyr44, Arg46, Ala79, and Asp80. , the IL-17 antagonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., Secukinumab) K D is about 100 to 200 pM, and the IL-17 antibody or its antigen binding The in vivo half-life of the fragment is approximately 4 weeks.

[0143] Additionally, axial spondyloarthritis (axSpA) (i.e., nr-axSpA and AS, e.g., n For use in the manufacture of a medicament for treating patients with r-axSpA (e.g., AS) IL-17 antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., sec- kinumab) are disclosed herein, and this IL-17 antagonist (e.g., IL-17 The antibody or antigen-binding fragment thereof, e.g., secukinumab, is administered once during week 0 at a dose of approximately 6 mg / kg. The dose is administered intravenously to patients at approximately 3 mg every four weeks (monthly) starting during the fourth week. should be administered intravenously to patients at a dose of 1 / kg and an IL-17 antagonist (e.g. IL-17 antibodies or antigen-binding fragments thereof, such as secukinumab, bind to two mature IL-17 proteins. It binds to an epitope on the IL-17 homodimer containing the protein chain, and this epitope is Leu74, Tyr85, His86, Met87, Asn88, Val12 on one strand 4, including Thr125, Pro126, Ile127, Val128, and His129; On the other chain, it contains Tyr43, Tyr44, Arg46, Ala79, and Asp80. IL-17 antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., sec- K in kinumab D is approximately 100-200 pM, and IL-17 antagonists (e.g., I The in vivo half-life of the L-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, is approximately 4 weeks. is.

[0144] Additionally, axial spondyloarthritis (axSpA) (i.e., nr-axSpA and AS, e.g., n Preparation of drugs to inhibit the progression of structural damage in patients with r-axSpA (e.g., AS) IL-17 antagonists (e.g., IL-17 antibodies or antigen-binding Fragments, such as secukinumab, are disclosed herein, and this IL-17 antagonist ( For example, an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, is administered once during week 0. , administered intravenously to patients at a dose of approximately 6 mg / kg, and then every 4 weeks starting during the 4th week. This IL-17 should be administered intravenously to patients at a dose of approximately 3 mg / kg every month. Antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) Binds to an epitope on the IL-17 homodimer containing two mature IL-17 protein chains This epitope is located at Leu74, Tyr85, His86, Met87, and Asn88, Val124, Thr125, Pro126, Ile127, Val128 , His129, and on the other chain Tyr43, Tyr44, Arg46, Ala79 , Asp80, and this IL-17 antagonist (e.g., IL-17 antibody or its antibody K of the original binding fragment (e.g., secukinumab) D The IL-17 activity was approximately 100-200 pM. antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) The in vivo half-life is approximately 4 weeks.

[0145] Furthermore, psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) (i.e., nr-a To treat patients with xSpA and AS, e.g., nr-axSpA, e.g., AS IL-17 antagonists (e.g., IL-17 antibodies or the like) for use in the manufacture of medicaments for Disclosed herein is an antigen-binding fragment of secukinumab, which comprises a container. Each container contains at least about 6 mg / kg of IL-17 antagonist ( For example, an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) / unit dose delivery ( and administering a sufficient amount of IL-17 antagonist (e.g., IV delivery) to allow for IV delivery. and (ii) a IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab, and antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) binds to an epitope on the IL-17 homodimer containing two mature IL-17 protein chains; This epitope is located on one chain at Leu74, Tyr85, His86, Met87, and A sn88, Val124, Thr125, Pro126, Ile127, Val128, His129, and Tyr43, Tyr44, Arg46, Ala79, on the other chain. Asp80, and this IL-17 antagonist (e.g., IL-17 antibody or its antigen) K of binding fragments, e.g., secukinumab) D The IL-17 antagonist was approximately 100-200 pM. agonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) The in vivo half-life is approximately 4 weeks.

[0146] Furthermore, psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) (i.e., nr-a To treat patients with xSpA and AS, e.g., nr-axSpA, e.g., AS IL-17 antagonists (e.g., IL-17 antibodies or the like) for use in the manufacture of medicaments for Disclosed herein is an antigen-binding fragment of Each container contains a unit dose of an IL-17 antagonist (e.g., IL- 17) delivery of at least about 3 mg / kg of an antibody or antigen-binding fragment thereof, e.g., secukinumab and administering a sufficient amount of an IL-17 antagonist (e.g., IL-17 antagonist) to allow for delivery (preferably IV delivery). and (b) an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab, and 7 antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) binds to an epitope on the IL-17 homodimer, which contains two mature IL-17 protein chains This epitope is located at Leu74, Tyr85, His86, and Met87 on one chain. , Asn88, Val124, Thr125, Pro126, Ile127, Val12 8, containing His129 and Tyr43, Tyr44, Arg46, and Ala7 on the other strand. 9. Asp80, and the IL-17 antagonist (e.g., IL-17 antibody or its K of antigen-binding fragments (e.g., secukinumab) D The IL- IL-17 antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) ) has an in vivo half-life of approximately 4 weeks.

[0147] Furthermore, psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) (i.e., nr-a Progression of structural damage in patients with xSpA and AS, e.g., non-rxSpA, e.g., AS IL-17 antagonists (e.g., IL-17 antagonists) for use in the manufacture of a medicament for inhibiting IL-17 proliferation. Disclosed herein is a .DELTA.-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, The drug is formulated to contain containers, each container containing at least about 6 mg / kg per unit dose. IL-17 antagonists (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., sec- a sufficient amount of IL-17 antagonist to allow delivery (preferably IV delivery) of IL-17 antagonist (kinumab) an IL-17 agonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab); Furthermore, this IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., Secukinumab (e.g., secukinumab) is an IL-17 homodimer containing two mature IL-17 protein chains. This epitope is located on one chain at Leu74, Tyr85, and Hi s86, Met87, Asn88, Val124, Thr125, Pro126, Ile 127, Val128, His129 on the other strand, and Tyr43, Tyr44, A rg46, Ala79, and Asp80, K D is about 100 to 200 pM, and this IL-17 antagonist (e.g., IL-17 The in vivo half-life of the antibody or antigen-binding fragment thereof, such as secukinumab, is approximately 4 weeks.

[0148] Furthermore, psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) (i.e., nr-a Progression of structural damage in patients with xSpA and AS, e.g., non-rxSpA, e.g., AS IL-17 antagonists for use in the manufacture of a medicament for inhibiting IL-17 proliferation (e.g., Disclosed herein are IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab, The drug is formulated to contain containers, each container containing at least about 3 mg / unit dose. kg of an IL-17 antagonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., a sufficient amount of IL-17 antibody to allow delivery (preferably IV delivery) of secukinumab antagonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) Furthermore, this IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof) , e.g., secukinumab), which is an IL-17 homodimer containing two mature IL-17 protein chains. The epitope is located at Leu74, Tyr85, and His86, Met87, Asn88, Val124, Thr125, Pro126, I It contains Ile127, Val128, and His129, and Tyr43 and Tyr44 on the other strand. , Arg46, Ala79, Asp80, and this IL-17 antagonist (e.g. K of an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab D is about 100 to 200 pM, and the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof) The in vivo half-life of one antibody (e.g., secukinumab) is approximately 4 weeks.

[0149] Furthermore, psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) (i.e., nr-a Sleep in patients with xSpA and AS (e.g., nr-axSpA, e.g., AS) Disclosed herein are methods for improving (e.g., improving sleep quality, reducing sleep disorders) This method involves administering a dose of about 4 mg / kg to about 9 mg / kg (preferably about 6 mg / kg). Patients will receive an IL-17 antagonist (e.g., secukinumab) intravenously (IV) once during week 0 Administered at approximately 2 mg / kg to approximately 4 mg / kg every 4 weeks (monthly) starting during the 4th week. g (preferably about 3 mg / kg) of an IL-17 antagonist (e.g., secukinumab) administering the compound to a patient.

[0150] Furthermore, psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) (i.e., nr-a Night vision loss in patients with xSpA and AS, e.g., nr-axSpA (e.g., AS) Disclosed herein is a method for reducing wakefulness, the method comprising administering a dose of about 4 mg / kg to about 9 mg / kg. g (preferably about 6 mg / kg) of an IL-17 antagonist (e.g., Seckinumab) Patients will receive intravenous (IV) therapy once during week 0, then every 4 weeks starting during week 4. (monthly) about 2 mg / kg to about 4 mg / kg (preferably about 3 mg / kg) of IL-17 This involves administering an antagonist (e.g., secukinumab) to the patient.

[0151] Furthermore, psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) (i.e., nr-a Morning sickness in patients with xSpA and AS (e.g., nr-axSpA, e.g., AS) Disclosed herein is a method for reducing stinging, the method comprising administering a dose of about 4 mg / kg to about 9 mg an IL-17 antagonist (e.g., secukinumab) at a dose of about 1 mg / kg (preferably about 6 mg / kg); Patients will receive intravenous (IV) administration of numab once during week 0, followed by a 4-week Every month (monthly) about 2 mg / kg to about 4 mg / kg (preferably about 3 mg / kg) of IL- The method involves administering to the patient a rheumatoid arthritis inhibitor (e.g., secukinumab).

[0152] Furthermore, psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) (i.e., nr-a Mobility in patients with xSpA and AS, e.g., nr-axSpA, e.g., AS Disclosed herein is a method for improving the condition of a patient suffering from atopic dermatitis, the method comprising administering about 4 mg / kg to about 100 mg / kg of niacin-3-one once a week for 24 hours. A dose of about 9 mg / kg (preferably about 6 mg / kg) of an IL-17 antagonist (e.g., Patients will receive intravenous (IV) therapy (e.g., secukinumab) and then every four weeks starting during week four. (monthly) about 2 mg / kg to about 4 mg / kg (preferably about 3 mg / kg) of IL-17 This involves administering an antagonist (e.g., secukinumab) to the patient.

[0153] As used herein, "a compound capable of delivering a specified dose by a specified route of administration" means a compound capable of delivering a specified dose by a specified route of administration. The phrase "prescribed at a dose" refers to a dose administered via a specified route of administration (e.g., preferably IV). and a desired dose of an IL-17 antagonist, e.g., an IL-17 antibody, e.g., secukinumab. The term "pharmaceutical composition" is used to mean that certain pharmaceutical compositions can be used to provide As an example, if the desired IV dose is 6 mg / kg and the patient weighs 60 kg, The floor is equipped with 14.4 ml of ... As another example, if the desired IV dose is 3 mg / kg, a 100 mg / kg IL-17 antibody formulation may be used. and the patient weighs 60 kg, the clinician delivers a 180 mg dose to the patient For this purpose, 17.2 ml of an IL-17 antibody formulation having a concentration of 25 mg / ml may be used. In this case, the 25 mg / ml formulation had a 6 mg / kg loading dose and a 3 mg / kg maintenance dose. A sustained dose route is sufficient to deliver the dose.

[0154] Most preferably, the IL-17 antagonist (e.g., secukinumab) is administered in a liquid composition. Liquid pharmaceutical compositions of secukinumab are provided herein by reference in their entirety. and WO 2016103153, which is incorporated herein by reference. The new liquid formulation comprises about 25 mg / mL to about 150 mg / mL secukinumab, about 10 mM to about 2 ... Approximately 30 mM histidine pH 5.8, approximately 200 mM to approximately 225 mM trehalose, approximately 0. 0.2% polysorbate 80 and about 2.5 mM to about 20 mM methionine. The most preferred compositions for use in the methods, medicaments, uses, kits, etc., are about 25 mg / m L Secukinumab, approximately 225 mM trehalose, approximately 0.02% polysorbate 80, approximately 5 mM A liquid pharmaceutical composition comprising M L-methionine and about 20 mM histidine buffer, pH about 5.8. The preferred liquid formulations have a volume size of 2 ml to 10 ml, preferably 5 ml or It is supplied in a container (e.g., a vial) containing 8 ml. Most preferably, the IL-17 antibody is The antagonist (e.g., secukinumab) is provided as a liquid composition in an 8 ml vial. do.

[0155] As used herein, "IL-17 administration to enable delivery of [specified dose]" means administration of an IL-17 antibody to a mammalian subject. The phrase "a container having a sufficient amount of the antagonist" refers to a container of some kind (e.g., a vial). When the combination is fully or partially combined, use The volume of the IL-17 antagonist (e.g., secukinumab) that can be administered is determined, for example, by administering the pharmaceutical composition It is used to mean placing something inside it (as part of something). For example, the desired I If the V dose is 6 mg / kg and the patient weighs 60 kg, the clinician should administer the 36 mg / kg dose to the patient. of an IL-17 antibody formulation at a concentration of 25 mg / ml to deliver a 1.8 mg dose. x 8 ml vials (total 14.4 ml) may be used. In this case, The vessel contains 100 mg of IL-17 antagonist to allow delivery of the desired 6 mg / kg loading dose. As another example, if the desired IV dose is 3 mg / kg and the patient weighs If the patient weighs 60 kg, the clinician may need a 25 mg concentration to deliver a 180 mg dose to the patient. 17.2 ml of an IL-17 antibody formulation at 1 / ml can be used. The device contains a sufficient amount of IL-17 antagonist to allow delivery of the desired 3 mg / kg maintenance dose. It has an agonist.

[0156] In some embodiments of the disclosed uses, methods and kits, the patient is administered ASAS ax Some embodiments of the disclosed uses, methods and kits include: In embodiments, a) the patient has been suffering from an inflammatory back pain for at least 3 months, preferably at least 6 months. b) the onset of the inflammatory back pain occurred before the patient reached age 45; ) the patient has active axial SpA, and / or d) the patient has been on steroids for a minimum total of 4 weeks had an inadequate or failed response to at least two NSAIDs Additionally, in some embodiments for patients with AS, the patient is treated with revision neuroleptic malignant tumor suppressant therapy for AS. Moderate to severe AS with previous substantiated radiological evidence meeting York criteria Further, in some embodiments for patients with nr-axSpA, the patient had sacroiliitis on MRI and ≥1 SpA trait or HLA-B-27 positive and ≥2 SpA characteristics. In some embodiments, patients are identified as having SIJ inflammation as determined by MRI and / or hsCRP>ULN (in practice). have objective signs of inflammation as evidenced by either:

[0157] In some embodiments of the disclosed uses, methods and kits, the patient is treated with C-reactive protein. Elevated protein (CRP) and / or magnetic resonance imaging (MRI) evidence of sacroiliac joint inflammation Some of the disclosed uses, methods and kits have objective signs of inflammation as indicated by In some embodiments, the patient is evaluated for sacroiliac joint (SIJ) scoring using the Berlin sacroiliac joint (SIJ) scoring method. According to the sacroiliac joint (SIJ) scoring method Objective signs of inflammation as shown by MRI evidence of sacroiliac joint inflammation as determined by In some embodiments of the disclosed uses, methods and kits, the patient has spinal inflammation. have objective signs of inflammation as demonstrated by MRI evidence of the disease.

[0158] In some embodiments of the disclosed uses, methods and kits, the patient has ankylosing spondylitis. does not meet the radiological criteria according to the revised New York diagnostic criteria for glaucoma.

[0159] In some embodiments of the disclosed uses, methods and kits, the patient has active SpA ( For example, active nr-axSpA, e.g., active AS). "Active" SpA is defined as a total BASDAI of ≥ 4 on a scale of 0 to 10, a BASDAI of ≥ 4, or Spinal pain as measured by question number 2 ≥ 4 (0-10) and visual analogue scale Patients with total back pain as measured by (VAS) ≥ 40 mm (0-100 mm) In other embodiments of the disclosed uses, methods and kits, the patient has a total BAS of ≧4. In some embodiments of the disclosed uses, methods and kits, the patient has: Measured by BASDAI question number 2 being ≥ 4 cm (0-10 cm) at baseline Some embodiments of the disclosed uses, methods, and kits In this study, patients were considered to have a VAS score of ≥ 40 mm (0–100 mm) at baseline. The patient has pain in the entire back.

[0160] In some embodiments of the disclosed uses, methods and kits, the patient has active AS. In some embodiments of the disclosed uses, methods and kits, the patient has active PsA. In some embodiments of the disclosed uses, methods and kits, the patient has an active nr In some embodiments of the disclosed uses, methods and kits, the patient has α-axSpA. The patient has active axSpA.

[0161] In some embodiments of the disclosed uses, methods and kits, the patient has moderate to severe P In some embodiments of the disclosed uses, methods and kits, the patient has moderate to severe sA. In some embodiments of the disclosed uses, methods, and kits, The patient has moderate AS. In some embodiments of the disclosed uses, methods and kits In some embodiments of the disclosed uses, methods, and kits, the patient has severe AS. In this case, the patient has moderate to severe nr-axSpA. In some embodiments, the patient has severe non-r-axSpA. In some embodiments of the methods and kits, the patient has active nr-axSpA.

[0162] In some embodiments of the disclosed uses, methods and kits, a patient, e.g., axSpA The patient may have concomitant uveitis, e.g., chronic uveitis, e.g., inflammatory non-infectious uveitis. , for example, chronic inflammatory non-infectious uveitis, for example, non-infectious acute anterior uveitis. Ideally, treatment will result in an improvement in the frequency of erythema / uveitis episodes, as well as a Reduces episodes of xSpA.

[0163] In some embodiments of the disclosed uses, methods and kits, the patient has previously been on non-steroidal anti-inflammatory drugs (NSAIDs). have failed to respond to or responded inadequately to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) In some embodiments of the disclosed uses, methods and kits, the patient previously had T Failure to respond to or intolerance to treatment with NF-alpha inhibitors (TNF-IR) In some embodiments of the disclosed uses, methods and kits, the patient Subjects were not previously treated with a TNF-alpha antagonist (TNF-naive).

[0164] In some embodiments of the disclosed uses, methods and kits, the patient further receives cyclosporine. Porin, hydroxychloroquine, methotrexate, NSAIDs, sulfasalazine, Flunomide, prednisolone, prednisone, or methylprednisolone is administered.

[0165] In some embodiments of the disclosed uses, methods and kits, a single loading dose is administered to the patient. Subjects will receive 6 mg / kg of IL-17 antibody or its antigen-binding fragment (e.g., secukinumab) intravenously. In some embodiments of the disclosed uses, methods and kits, Patients receive 3 mg / kg of IL-17 antibody or its antigen-binding fragment (e.g., secukinumab) intravenously. It is administered monthly (every 4 weeks) by intravenous injection. In a preferred embodiment, about 6 mg / kg of an IL-17 antibody or its antigen is administered once during week 0. The binding fragment (e.g., secukinumab) is administered to the patient by intravenous injection, followed by subsequent It is given intravenously monthly (every 4 weeks) starting at 4 weeks.

[0166] In some embodiments of the disclosed uses, methods and kits, an IL-17 antagonist The antibody (e.g., an IL-17 antibody or antigen-binding fragment thereof) is secukinumab.

[0167] The patient is administered a dose of secukinumab of about 2 mg / kg to about 4 mg / kg (preferably about 3 mg / kg). In patients with autoimmune diseases (e.g., Psoriasis), including administering the drug intravenously every four weeks to A, axSpA (nr-axSpA, AS), psoriasis (e.g., pustular or plaque psoriasis), asthma Breath, acne, tendon disorders (e.g. plantar fasciitis, Achilles tendinopathy, patellar tendinopathy (tendinitis), rotator cuff Tendinopathy, jumper's knee, lateral epicondylitis, medial epicondylitis, supraspinatus syndrome, or any combination thereof combination), Graves' orbital disease (thyroid eye disease, Graves' ophthalmopathy, Graves' eye disease ), hidradenitis suppurativa, uveitis (including pediatric uveitis), juvenile idiopathic arthritis (JIA) ) (JIA with uveitis) or vasculitis (e.g., Behçet's syndrome, Buerger's disease ( Thromboangiitis obliterans), peripheral spondyloarthritis, antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic AAV-ANCA-associated vasculitis (AASV), Wegener's granulomatosis (WG) (large vessel vasculitis, granulomatosis with polyangiitis), microscopic polyangiitis (MPA ), Churg-Strauss syndrome (CSS) (eosinophilic granulomatosis with polyangiitis (EPGA)) ), cryoglobulinemia, giant cell arteritis (GCA), Henoch-Schönlein purpura , hypersensitivity vasculitis, Kawasaki disease (mucocutaneous lymph node syndrome), polyarteritis nodosa, rheumatic hematoma arteritis, Takayasu's arteritis and polymyalgia rheumatica (PMR), CRMO (chronic relapsing multifocal osteomyelitis), CNO (chronic non-bacterial osteomyelitis), SAPHO syndrome, peripheral arthritis, reactive joints Compositions, uses, kits and methods for treating IBD associated with PsA, including inflammatory bowel disease, undifferentiated peripheral arthritis, and PsA In a preferred embodiment, a patient receives about 4 mg / kg of steroids during week 0. An initial dose of secukinumab of 10 mg / kg to about 9 mg / kg (preferably about 6 mg / kg) is administered. Administer.

[0168] Compositions, uses, kits and methods for treating psoriatic arthritis (PsA) in patients are disclosed herein. The present disclosure provides a dose of about 4 mg / kg to about 9 mg / kg (preferably 10 mg / kg) during week 0. Patients will receive an initial dose of secukinumab (approximately 6 mg / kg) intravenously, followed by a 4-week Starting at about 2 mg / kg to about 4 mg / kg (preferably about 3 mg / kg) every 4 weeks This includes administering an amount.

[0169] Compositions, uses, kits and methods for treating axial spondyloarthritis (axSpA) in patients A method is disclosed herein, which involves administering about 4 mg / kg to about 9 mg / kg (preferably 10 mg / kg) of steroids during week 0. The first dose of secukinumab (preferably about 6 mg / kg) is administered starting during week 4 and continuing for 4 weeks thereafter. The patient is given an intravenous dose of about 2 mg / kg to about 4 mg / kg (preferably about 3 mg / kg) every 2 weeks. This includes intravenous administration.

[0170] Disclosed herein are compositions, uses, kits and methods for treating AS in a patient, This is achieved by administering about 4 mg / kg to about 9 mg / kg (preferably about 6 mg / kg) of cerebrospinal fluid during week 0. The initial dose of cukinumab is approximately 2 mg / kg to approximately 10 mg / kg every 4 weeks, starting during week 4. This involves administering a dose of 4 mg / kg (preferably about 3 mg / kg) intravenously to the patient.

[0171] Compositions, uses, kits and methods for treating nr-axSpA in patients are described herein. and which is disclosed in the literature as a dose of about 4 mg / kg to about 9 mg / kg (preferably about 6 mg / kg) during week 0. g / kg) of secukinumab at the initial dose, and then every 4 weeks starting during week 4 A dose of about 2 mg / kg to about 4 mg / kg (preferably about 3 mg / kg) is administered intravenously to the patient. This includes:

[0172] Compositions, uses, kits and methods for treating hidradenitis suppurativa in a patient are described herein. This is disclosed as a dose of about 4 mg / kg to about 9 mg / kg (preferably about 6 mg / kg) during week 0. kg) of secukinumab as an initial dose, and then approximately 2 doses every 4 weeks starting during week 4. A dose of 100 mg / kg to about 4 mg / kg (preferably about 3 mg / kg) is administered intravenously to the patient. This includes:

[0173] Disclosed herein are compositions, uses, kits and methods for treating psoriasis in a patient. This means that during week 0, the dose is about 4 mg / kg to about 9 mg / kg (preferably about 6 mg / kg). The initial dose of secukinumab was approximately 2 mg / kg every 4 weeks starting during week 4. The method includes intravenously administering to a patient a dose of about 100 mg / kg to about 4 mg / kg (preferably about 3 mg / kg). nothing.

[0174] In some embodiments, the disclosed compositions, uses, kits and methods are administered every four weeks. It involves administering a dose of approximately 3 mg / kg of secukinumab intravenously to a patient.

[0175] In some embodiments, the disclosed compositions, uses, kits and methods comprise administering to a subject at least about 10 days prior to the start of treatment. An initial dose of secukinumab of 4 mg / kg to about 9 mg / kg (preferably about 6 mg / kg) and then about 2 mg / kg to about 4 mg / kg (preferably every 4 weeks) starting during the 4th week. Preferably, the dose comprises administering a dose of about 3 mg / kg intravenously to the patient.

[0176] In some embodiments, the disclosed compositions, uses, kits and methods comprise administering to a subject at least about 10 days prior to the start of treatment. An initial dose of 6 mg / kg secukinumab and then every 4 weeks starting during week 4 This involves administering a dose of about 3 mg / kg intravenously to a patient.

[0177] In some embodiments of the disclosed compositions, uses, kits and methods, the patient is Patients with axSpA that does not satisfy the above criteria (nr-axSpA).

[0178] In some embodiments of the disclosed compositions, uses, kits and methods, the patient is in moderate to severe pulmonary embolism. I have severe non-rx SpA.

[0179] In some embodiments of the disclosed compositions, uses, kits and methods, the patient has severe n I have r-axSpA.

[0180] In some embodiments of the disclosed compositions, uses, kits and methods, the patient has active n I have r-axSpA.

[0181] In some embodiments of the disclosed compositions, uses, kits and methods, the patient is Activity nr- when assessed by total BASDAI ≥ 4cm (0-10cm) on the line axSpA, measured at baseline by BASDAI question number 2 ≥ 4 cm (0–10 cm) Spinal pain as determined by VAS ≥ 40 mm (0-100 mm) at baseline Patients have full back pain when the condition is specified.

[0182] In some embodiments of the disclosed compositions, uses, kits and methods, the patient is Patients have non-recurrent axSpA according to axSpA criteria.

[0183] In some embodiments of the disclosed compositions, uses, kits and methods, a) the patient is Inflammatory back pain for at least 3 months, preferably at least 6 months, before treatment with cukinumab b) the onset of inflammatory back pain in a) occurred before the patient reached age 45; and c) Patients had MRI evidence of sacroiliac joint (SIJ) inflammation and at least one SpA characteristic or the patient is HLA-B27 positive and has at least two SpA characteristics. do.

[0184] In some embodiments of the disclosed compositions, uses, kits and methods, the patient is Elevated reactive protein (CRP) and / or magnetic resonance imaging (MRI) evidence of SIJ inflammation have objective signs of inflammation as demonstrated by irritation.

[0185] In some embodiments of the disclosed compositions, uses, kits and methods, the patient is The results were determined according to the Berlin SIJ scoring method. Have objective signs of inflammation as demonstrated by MRI evidence of SIJ inflammation .

[0186] In some embodiments of the disclosed compositions, uses, kits and methods, the patient is Have objective signs of inflammation as demonstrated by MRI evidence of inflammation.

[0187] In some embodiments of the disclosed compositions, uses, kits and methods, the patient has a total BA Have active nr-axSpA as assessed by SDAI ≥ 4.

[0188] In some embodiments of the disclosed compositions, uses, kits and methods, the patient has a rigid Does not meet radiological criteria according to the revised New York diagnostic criteria for spondylitis.

[0189] In some embodiments of the disclosed compositions, uses, kits and methods, nr-axSp When a population of patients with A is treated as described, at least 30% of the patients, preferably At least 37%, more preferably at least 39%, of patients with spinal cord injury by the 16th week of treatment Assessment of Spondyloarthritis Achieve ASAS 40.

[0190] In some embodiments of the disclosed compositions, uses, kits and methods, nr-axSp When a population of patients with A is treated as described, at least 20% of the patients, preferably At least 28% achieved a significant improvement response on ASDAS-CRP by week 16 of treatment. Complete.

[0191] In some embodiments of the disclosed compositions, uses, kits and methods, nr-axSp When a population of patients with A is treated as described, at least 50% of the patients, preferably At least 53%, more preferably at least 56%, of patients with ASA by week 16 of treatment Achieve S20.

[0192] In some embodiments of the disclosed compositions, uses, kits and methods, the patient has PsA. Has.

[0193] In some embodiments of the disclosed compositions, uses, kits and methods, the patient has active P Has sA.

[0194] In some embodiments of the disclosed compositions, uses, kits and methods, the patient has a concomitant Patients with moderate to severe plaque psoriasis.

[0195] In some embodiments of the disclosed compositions, uses, kits and methods, a subject with PsA may When a patient population is treated as described, at least 20% of the patients, preferably at least 30% of patients had a history of rheumatoid arthritis by the 16th week of treatment (American College of Rheumatology). Achieve American College of Rheumatology (ACR) criteria 50.

[0196] In some embodiments of the disclosed compositions, uses, kits and methods, a subject with PsA may When a patient population is treated as described, at least 40% of the patients, preferably at least 50% of patients achieved ACR20 by week 16 of treatment.

[0197] In some embodiments of the disclosed compositions, uses, kits and methods, a subject with PsA may When a patient population is treated as described, at least 50% of the patients, preferably at least 70% of patients had a Psoriasis Area Severity Index score by the 16th week of treatment. Achieve a PASI (Passive Acute Immunodeficiency and Severity Index) of 75.

[0198] In some embodiments of the disclosed compositions, uses, kits and methods, a subject with PsA may When a patient population is treated as described, at least 30% of the patients, preferably at least 40% of patients achieved PASI90 by the 16th week of treatment.

[0199] In some embodiments of the disclosed compositions, uses, kits and methods, the patient has ankylosed spinal cord. He has spondylitis (AS).

[0200] In some embodiments of the disclosed compositions, uses, kits and methods, the patient has active A It has S.

[0201] In some embodiments of the disclosed compositions, uses, kits and methods, the patient is in moderate to severe pulmonary embolism. Has severe AS.

[0202] In some embodiments of the disclosed compositions, uses, kits and methods, a patient with AS is treated with When a population of patients is treated as described, at least 40% of the patients, preferably at least 42% of patients had a Spondyloarthritis Assessment of Spondyloarthritis (SAAS) score by week 16. ondyloArthritis International Society)(A Achieve SAS 40.

[0203] In some embodiments of the disclosed compositions, uses, kits and methods, a patient with AS is treated with When a population of patients is treated as described, at least 20% of patients, preferably at least 28% of patients had ankylosing spondylitis disease activity scores by week 16 of treatment. Spondylitis Disease Activity Score)(ASD Achieve a significant improvement response in AS)-C-reactive protein (CRP).

[0204] In some embodiments of the disclosed compositions, uses, kits and methods, a patient with AS is treated with When a population of patients is treated as described, at least 15% of patients, preferably at least 20% achieve an ASDAS-CRP inactive disease response by week 16 of treatment.

[0205] In some embodiments of the disclosed compositions, uses, kits and methods, a patient with AS is treated with When a population of patients is treated as described, at least 60% of the patients, preferably at least 61% achieved ASAS20 by the 16th week of treatment.

[0206] In some embodiments of the disclosed compositions, uses, kits and methods, a patient with AS is treated with When a population of patients is treated as described, at least 70% of the patients, preferably at least 72% achieved ASAS20 by week 104 of treatment.

[0207] In some embodiments of the disclosed compositions, uses, kits and methods, When a patient population with this condition is treated as described, at least 35% of the patients, preferably at least At least 37%, more preferably at least 39%, of patients with spondyloarthritis by week 16 of treatment Assessment of SpondyloArthritis Infection International Society (ASAS) 40.

[0208] In some embodiments of the disclosed compositions, uses, kits and methods, When a patient population with this condition is treated as described, at least 25% of the patients, preferably at least At least 28% will achieve a significant improvement response in ASDAS-CRP by week 16 of treatment .

[0209] In some embodiments of the disclosed compositions, uses, kits and methods, When a patient population with this condition is treated as described, at least 10% of the patients, preferably at least At least 14%, and more preferably at least 17%, of patients with an ASDAS score by week 16 of treatment - Achieve a CRP inactive disease response.

[0210] In some embodiments of the disclosed compositions, uses, kits and methods, When a patient population with this condition is treated as described, at least 50% of the patients, preferably at least At least 53%, more preferably at least 56%, of the subjects will achieve an ASAS20 score by week 16 of treatment. Achieve this.

[0211] In some embodiments of the disclosed compositions, uses, kits and methods, When a patient population with this condition is treated as described, at least 30% of the patients, preferably at least At least 36%, more preferably at least 50%, have an ASAS 40 response rate by week 52 of treatment Achieve this.

[0212] In some embodiments of the disclosed compositions, uses, kits and methods, the patient has previously had non-steroidal anti-inflammatory drugs (NSAIDs). have failed to respond to or have responded poorly to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) It was insufficient.

[0213] In some embodiments of the disclosed compositions, uses, kits and methods, the patient has previously have failed to respond or responded inadequately to treatment with biologic DMARDs Ta.

[0214] In some embodiments of the disclosed compositions, uses, kits and methods, the patient has previously had T Failure to respond to or intolerance to treatment with NF-alpha inhibitors (TNF-IR) The response was insufficient.

[0215] In some embodiments of the disclosed compositions, uses, kits and methods, the patient is TNF- No previous treatment with alpha inhibitors (TNF-naive).

[0216] In some embodiments of the disclosed compositions, uses, kits and methods, cyclosporine , hydroxychloroquine, methotrexate, NSAIDs, sulfasalazine, lefluno Administering methylprednisolone, prednisolone, prednisone, or methylprednisolone to patients Further includes:

[0217] In some embodiments of the disclosed compositions, uses, kits and methods, secukinumab It is supplied in a vial, for example an 8 ml vial.

[0218] In some embodiments of the disclosed compositions, uses, kits and methods, secukinumab , is supplied in a liquid composition containing about 25 mg / mL of secukinumab.

[0219] In some embodiments of the disclosed compositions, uses, kits and methods, secukinumab , approximately 25 mg / mL secukinumab, approximately 225 mM trehalose, approximately 0.02% polysorbate 80, about 5 mM L-methionine and about 20 mM histidine buffer, pH about 5.8 The composition is provided in a liquid form comprising:

[0220] In some embodiments of the disclosed compositions, uses, kits and methods, secukinumab , is administered to the patient over an infusion duration of approximately 30 minutes.

[0221] In some embodiments of the disclosed compositions, uses, kits and methods, the patient receives concurrent Patients have inflammatory non-infectious uveitis.

[0222] kit The present disclosure relates to the treatment of autoimmune diseases, such as PsA or axSpA (i.e., nr-axSpA and to treat AS, e.g., non-rx-SpA, e.g., AS), and / or in these patients The present invention also includes kits for preventing structural damage (e.g., bone and / or joint damage) in the Such kits may include an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., IL-1 7 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor-binding molecule (e.g., For example, an IL-17 antibody or antigen-binding fragment thereof (e.g., in liquid form) or an IL-17 antagonist. Additionally, such kits include pharmaceutical compositions containing an IL-17 agonist (as described above). The container includes a means for containing the antagonist (e.g., an infusion bag, vial) and instructions for use. These kits are designed to detect PsA or axSpA (i.e., nr-axSpA and AS, e.g., and the like. For example, encapsulated IL-17 antibodies for treating non-small cell lung axonal spastic encephalopathy (nr-axonal spastic encephalopathy, e.g., AS). antagonists, e.g., IL-17 binding molecules, e.g., IL-17 antibodies, e.g., Seckinumab Such kits may contain additional therapeutic agents (described above) for delivery in combination with the antibody. is an autoimmune disease, such as PsA or axSpA (i.e., nr-axSpA and AS, e.g., for treating non-rx-SpA, e.g., AS) and / or for treating these patients (e.g., T structurally in NF-naive and / or TNF-IR patients, NSAID-refractory patients, etc. IL-17 antagonists (e.g., IL-17 antibodies, e.g., Such instructions may also include instructions for administration of the encapsulated IL (secukinumab). IL-17 antagonists, e.g., IL-17 binding molecules, e.g., IL-17 antibodies, e.g., For use with kinumab, dose (e.g., 6 mg / kg and / or 3 mg / kg), administration The route (e.g., IV) and dosing regimen (e.g., about 6 mg / kg once during week 0, then Monthly [3 mg / kg IV every 4 weeks] for weeks 4, 8, 12, etc. may be provided.

[0223] The phrase "means for containing" includes pre-filled syringes, vials and syringes, Including but not limited to injection pens, auto-injectors, IV drips and bags, vials, pumps, etc. Used to indicate any available device for containing an unspecified drug. The filled vial contains an encapsulated IL-17 antagonist, e.g., an IL-17 binding molecule. , for example, an IL-17 antibody, such as secukinumab.

[0224] IL-17 antagonists (e.g., IL-17 binding molecules, e.g., IL-17 antibodies or PsA or axSpA (i.e., nr-axSpA), including an antigen-binding fragment of Treating patients with SpA and AS, e.g., nr-axSpA, e.g., AS) and / or or kits for use in inhibiting the progression of structural damage in such patients. In some embodiments, the kit comprises an IL-17 antagonist. In some embodiments, the kit further comprises a means for administering the agonist to the patient. The method further includes instructions for administration of the IL-17 antagonist, the instructions comprising administering an IL-17 antagonist to a patient. -17 antagonists (e.g., IL-17 binding molecules, e.g., IL-17 antibodies or their antigens) Binding fragment, e.g., secukinumab) at approximately 6 mg / kg (loading dose) once during week 0 and then every 4 weeks (monthly) during weeks 4, 8, 12, etc. at 3 mg / kg per patient (e.g. It should be administered intravenously (IV) to patients (TNF-naive and / or TNF-experienced). In some embodiments, the kit includes an IL-17 antagonist. and further comprising instructions for administration of an IL-17 antagonist (e.g., IL-17 binding molecules, such as IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab ) is administered IV to patients at approximately 3 mg / kg every 4 weeks (monthly) without a loading regimen. In some embodiments, the instructions include instructions for dose escalation. (e.g., a maintenance dose of about 3 mg / kg, or higher doses as needed, as determined by a physician) or dose reduction (e.g., from a maintenance dose of about 3 mg / kg to a lower dose if necessary). dosage, which should be determined by a physician).

[0225] General In some embodiments of the disclosed methods, treatments, medicaments, regimens, uses and kits, The IL-17 antagonist is an IL-17 binding molecule. The IL-17 binding molecule is an IL-17 antibody or an antigen-binding fragment thereof. In a more preferred embodiment of the regimen, use and kit, an IL-17 antibody or its antigen binding agent is administered. The fusion fragment is selected from the group consisting of: a) Leu74, Tyr85, His8 6, Met87, Asn88, Val124, Thr125, Pro126, Ile12 7, IL-17 antibody that binds to IL-17 epitopes including Val128 and His129 a) a polypeptide or an antigen-binding fragment thereof; b) a polypeptide comprising Tyr43, Tyr44, Arg46, Ala79, As an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of IL-17, including p80; c) Binds to an epitope of the IL-17 homodimer containing two mature IL-17 protein chains an IL-17 antibody or antigen-binding fragment thereof that binds to IL-17, wherein the epitope is located on one chain of the antibody or antigen-binding fragment thereof; Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr 125, Pro126, Ile127, Val128, His129, and on the other strand and d) those containing Tyr43, Tyr44, Arg46, Ala79, and Asp80. Binds to an epitope on the IL-17 homodimer, which contains two mature IL-17 protein chains. an IL-17 antibody or antigen-binding fragment thereof, wherein the epitope is located on one chain of Le u74, Tyr85, His86, Met87, Asn88, Val124, Thr12 5, Pro126, Ile127, Val128, His129, and a T on the other strand. Contains yr43, Tyr44, Arg46, Ala79, and Asp80, and contains IL-17 binding domains Child K D and the in vivo half-life of the IL-17 binding molecule is approximately 23 ~About 35 days.

[0226] In even more preferred embodiments of the disclosed methods, treatments, regimens, uses and kits The IL-17 antibody or antigen-binding fragment thereof includes: i) the antibody set forth as SEQ ID NO: 8 The immunoglobulin heavy chain variable domain (V) containing the amino acid sequence H ii) SEQ ID NO: 10 The immunoglobulin light chain variable domain (V) contains the amino acid sequence described above. L );iii) Array Immunoglobulin V containing the amino acid sequence set forth as number 8 H domain and SEQ ID NO: 10 Immunoglobulin V containing the amino acid sequence described as L domain; iv) SEQ ID NO: 1, Immunoglobulin V containing the hypervariable region set forth as SEQ ID NO: 2 and SEQ ID NO: 3 H Domestic v) containing the hypervariable regions set forth as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 Immunoglobulin V L domains; vi) SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 Immunoglobulin V containing a hypervariable region described as H domain; vii) SEQ ID NO: 1 , SEQ ID NO: 2, and an immunoglobulin V comprising the hypervariable regions set forth as SEQ ID NO: 3. H domains and the hypervariable regions set forth as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6. Contains immunoglobulin V L domain; viii) SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: Immunoglobulin V containing the hypervariable region described as No. 13 H domain and SEQ ID NO: 4 , SEQ ID NO: 5, and SEQ ID NO: 6. L Domain; ix) an immunoglobulin light chain comprising the amino acid sequence set forth as SEQ ID NO: 14; x) an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 15; or xi) an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 16. an immunoglobulin light chain comprising the amino acid sequence set forth as SEQ ID NO: 14; An immunoglobulin heavy chain comprising an amino acid sequence described above.

[0227] In even more preferred embodiments of the disclosed methods, treatments, regimens, uses and kits The IL-17 antibody or antigen-binding fragment thereof is a human antibody of the IgG1 isotype.

[0228] In the most preferred embodiments of the disclosed methods, treatments, regimens, uses and kits, IL The -17 antibody or antigen-binding fragment thereof is secukinumab.

[0229] In the most preferred embodiments of the disclosed methods, treatments, regimens, uses and kits, treatment The patient (preferably an adult) to be treated is a patient with PsA or non-rapid-acting axSpA, e.g., active non-rapid-acting axSpA. The disclosed methods, treatments, and methods for treating rhesus macular degeneration (nr-axSpA) include those for treating rhesus macular degeneration (nr-axSpA), such as moderate to severe nonr-axSpA. In some embodiments of the treatments, regimens, uses and kits, the patient is diagnosed with psoriasis (e.g., plaques). Patients with psoriasis (e.g., pustular psoriasis or pustular psoriasis) or hidradenitis suppurativa.

[0230] The details of one or more embodiments of the present disclosure are set forth above in the accompanying description. Any methods and materials similar or equivalent to those described herein may be used in the practice or testing of this disclosure. Although any method or material may be used in the present disclosure, preferred methods and materials are described herein. Features, objects, and advantages will be apparent from the description and claims. In the appended claims, the singular forms "a," "an," and "the" refer to plural forms unless the context clearly dictates otherwise. Unless otherwise defined, all technologies and All scientific and technical terms have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference. The examples are provided to more fully illustrate the preferred embodiments of the present disclosure. The examples do not limit the scope of the disclosed subject matter, which is defined by the appended claims. should never be construed as [Example]

[0231] Example 1: Efficacy of Secukinumab in Patients with Axial Spondyloarthritis Not Meeting Radiographic Criteria Efficacy and safety study (CAIN457H2315) The purpose of this study was to evaluate the efficacy and safety of steroids in patients with non-rx-SpA at 16 and 52 weeks. Two different regimens of secukinumab, with and without a loading dose, compared with sebo The objective of this study is to demonstrate the clinical efficacy, safety, and tolerability of the drug. The one-year progression of structural changes as a function of secukinumab will be assessed at week 52. Long-term efficacy, safety, and tolerability, and inflammation based on MRI and X-ray results up to 104 weeks and the evolution of radiological correlates of structural progression.

[0232] At the end of the core phase, an optional 16-week randomized dose-escalation treatment period will involve a 150 mg to 3 mg Treatment escalation to 100 mg secukinumab compared with continuous treatment with 150 mg secukinumab Furthermore, in the treatment follow-up phase, To evaluate the long-term efficacy, safety, and tolerability of the 300 mg dose.

[0233] This is a randomized, double-blind, placebo-controlled study with three treatment arms (1:1:1 ratio) Ratio of secukinumab 150 mg loading, secukinumab 150 mg no loading, or placebo Patients will be randomly assigned to one of: Group 1 (secukinumab 150 mg loading): Baseline (BSL), Weeks 1, 2, and 3 followed by secukinumab 150 mg (1 mL, 150 ml) every 4 weeks starting at week 4. g / mL) sc prefilled syringe (PFS) administration Group 2 (no secukinumab 150 mg loading): Secukinumab 150 mg (1 mL, 150 mg / mL) scPFS, placebo at weeks 1, 2, and 3, followed by week 4 Secukinumab 150 mg PFS every 4 weeks starting at Group 3 (placebo): BSL, placebo (1 mL) scPFS at weeks 1, 2, and 3; Then every 4 weeks starting at week 4

[0234] At Week 104, patients may continue in the optional randomized dose escalation treatment extension phase. will be assessed based on their ASAS20 response at week 104.

[0235] Responders to secukinumab 150 mg at week 104 (core phase responders) were randomized to the next treatment in a blinded fashion. Randomize to groups: Group 4 (core phase responders 150 mg): Secukinumab 150 mg (1 mL, 150 mg / mL) sc prefilled syringe (PFS) and placebo (1 mL) scPFS , every 4 weeks Group 5 (core phase responders 300 mg): Secukinumab 150 mg (1 mL, 150 mg / mL) scPFS for two injections, every 4 weeks

[0236] Incomplete responders to secukinumab 150 mg at week 104 (core phase non-responders) were included in the open Increase the dose to secukinumab 300 mg per label. Group 6 (core phase non-responders 300 mg): Open-label secukinumab every 4 weeks Two injections of 150 mg (1 mL, 150 mg / mL) scPFS

[0237] Based on clinical judgment of disease activity by the investigator and patient, from week 16 onwards, nr-a Background medications such as NSAIDs and DMARDs are used to treat the signs and symptoms of xSpA. Additionally, investigator and patient assessment of disease activity may be performed. Patients who are repeatedly (e.g., on 2 or more consecutive visits) deemed to be poor responders based on the clinical judgment of the Patients receiving secukinumab 150 mg sc or other standard of care starting at week 20 A biologic may be administered.

[0238] Changes in concomitant medications used to treat nr-axSpA were reported in all 16 Efficacy will be assessed in detail at all study visits and safety assessments will not be permitted prior to the completion of the weekly assessments. for use either from the study treatment or on their own accord based on safety and efficacy assessments Patients who are not deemed to be benefiting are free to discontinue participation in the study at any time. do.

[0239] Patients were stratified at randomization according to the subgroup of objective signs of inflammation to which they belonged. (based on patient's CRP and MRI status at screening) The only condition was that 15% or more of the patients had one of three subgroups of objective signs of inflammation: CRP+ and and MRI+, CRP+ and MRI-, or CRP- and MRI+. That is what I mean.

[0240] Additionally, the study plans to enroll no more than approximately 20% of patients with TNF-IR. Some TNF-IR patients require a long-term drug holiday, so Enrollment of R patients will end two months prior to the planned end of the screening period.

[0241] Beginning at week 52, blinded study treatment (secukinumab 150 mg / kg) was administered during the first 52 weeks of the study. All patients were sex-matched in an open-label manner, except for those who discontinued treatment (mg or placebo). Patients will be assigned to receive numab 150 mg sc.

[0242] The originally randomized treatment assignment (section) was maintained until all patients completed the 52-week visit. The treatment group (kinumab 150 mg or placebo) will remain blinded. All patients will receive treatment in Treatment Period 2 (Week 52). After the 52-week database lock was completed, field staff and patients were All patients will be unblinded to their original randomized treatment assignment in the study. Patients will continue to receive secukinumab as open-label treatment through week 100 unless otherwise advised.

[0243] All patients completing the core phase per protocol on study medication, starting at week 104 Core phase responders (i.e., ASAS 400 at week 104) will be asked to continue in the extension phase. 20) or core phase non-responders (i.e., did not achieve ASAS20 at week 104). Core phase responders were evaluated as patients who continued treatment with secukinumab at 150 mg or 300 mg. Non-responders to the core phase will be randomized 1:1 to 300 mg treatment. Receive the label.

[0244] At the end of the 16-week dose-escalation treatment period, all patients were treated with the last patient in the 16-week dose-escalation treatment period ( Their current treatment will continue until the end of the treatment period (i.e., the continuation treatment period).

[0245] Beginning at week 156, patients were randomized to receive 100 mg / kg / day of treatment based on clinical judgment of disease activity by the investigator. The original dose for the extension phase is: If available, extensions should be provided to each patient to allow continued treatment at the same dose. Unblinding will occur only at the individual patient level at the end of the phase.

[0246] Follow-up visits are conducted based on planned completion of the entire study (either core or extension phase) or The study was conducted 12 weeks after the last dose of study treatment for all patients, regardless of early discontinuation. It shall be possible.

[0247] Subjects who complete the 2-year core phase are eligible to enter the extension phase.

[0248] A detailed protocol summary is provided below.

[0249] [Table 4]

[0250] [Table 5]

[0251] [Table 6]

[0252] [Table 7]

[0253] [Table 8]

[0254] [Table 9]

[0255] [Table 10]

[0256] [Table 11]

[0257] result: The study included patients with active non-rx-axSpA (onset before age 45 years, spinal pain manifested by visual analogues) ≥ 40 / 100 on the Visual Analogue Scale (VAS) and the Bath Ankylosing Spondylitis Disease Activity Index Mark (Bath Ankylosing Spondylitis Disease Ac Patients with a BASDAI (Body Activity Index) ≥ 4) who had a maximum of 4 weeks before the start of the study Taking at least two different nonsteroidal anti-inflammatory drugs (NSAIDs) at maximum doses 555 adult patients, both male and female, were enrolled. Patients had not previously taken TNF inhibitors (but not multiple inhibitors). The 555 patients enrolled in this study may have had a history of steroid use but had an inadequate response. Of the patients, 501 (90%) were biologic-naive.

[0258] The ongoing Phase III trial met its ASAS40 primary endpoint at week 16, This is a disease progression profile in patients with non-r-axSpA treated with secukinumab compared to placebo. demonstrated a significant and clinically meaningful reduction in disease activity. All secondary endpoints were also met. did.

[0259] The primary endpoint was achieving an ASAS40 response with secukinumab 150 mg at weeks 16 and 52. Secondary endpoints included the change in BASDAI over time and the percentage of patients who achieved CRP. Ankylosing Spondylitis Disease Activity Score Changes in the ASDAS-CRP (Associated Severe Disease Activity Score) were included. can be.

[0260] The findings demonstrate a favorable safety profile consistent with previous clinical trials.

[0261] Example 2: Pharmacokinetic Modeling and Pharmacokinetic Analysis of a Sec- tion for Treating Patients with PsA and axSpA Simulation of Kinuma regimen method: The decision on the iv regimen was based on the following considerations: dose should be determined based on the mean sec- ondary dose at steady state. The approximate concentration of secukinumab in the sc regimen considered safe and effective The range was chosen to be within the peak-to-trajectory range while avoiding too frequent administration visits. A q4w dosing interval was chosen to limit the dose-to-dose ratio. The idea of ​​using a higher initial dose was explored. We investigated the IV regimens of PK simulation to explore their characteristics and They were compared with appropriate sc regimens using weight distributions from a phase 3 registration study. Simulation was performed. The secukinumab PsA and AS registration trials were developed, but the Two closed population PK models with similar characteristics to the open model (Bruin et al. (2017) Clin Pharmacol. 57(7):876-885), i.e., subcutaneous Intravenous administration has first-order absorption, whereas intravenous administration has zero-order infusion, which affects clearance. A two-compartment PK model in which the only covariates studied were linear elimination and body weight was used for this study. NONMEM software version 7.2 and 7.3 Beal were used for this purpose. , S., Sheiner, L.B., Boeckmann, A., & Bauer, R. J.,NONMEM User's Guides.(1989-2009),Icon Development Solutions,Ellicott City,MD, We fitted this model using the IEEE Transactions on Pharmacology and Life Sciences (2009). Next, we performed simulations. For this purpose, we use Monolix Model Coding Language (Mlxt ran) and recoded this model in the mlxR package version 3.3.0. The simulation given here was performed in R version 3.4.3 using (R Core Team (2017). R: A language and vironment for statistical computing.R Fo undation for Statistical Computing,Vienn a,Available at Austria.worldwideweb.R-project.org / possible).

[0262] result: Three high initial (loading / induction) doses (4 mg / kg, 6 mg / kg, and 9 mg / kg) followed by three maintenance doses (2 mg / kg, 3 mg / kg) every four weeks from week four onwards. The authors characterized nine regimens defined as combinations of 4 mg / kg and 4 mg / kg of vasopressin. Two registered sc regimens were used: 150 mg q1w until week 4, then 8 300m from week to Q4W (weeks 0, 1, 2, 3, 4, 8, 12, 16, etc.) and up to week 4 g q1w, then q4w from week 8 (weeks 0, 1, 2, 3, 4, 8, 12, 16, etc.) The median secukinumab doses for these nine regimens were compared with the corresponding profiles from The time-concentration profiles are shown in Figure 1 (AS) and Figure 2 (PSA). .The dose is consistent with a steady trough concentration of at least 150 s.c. regimen, while 6 mg / Test CAIN457P12301 and CAIN457P12301 in combination with a kg initial (loading) dose For 57P12302, 3m approximately corresponds to the mean steady-state concentration of the 300 s.c. regimen. A maintenance dose of 100 mg / kg iv was selected. Of note, the iv regimen Steady state was reached at approximately week 4, while both sc regimens required 100 mg / kg of steroids to reach steady state. It takes 16 to 20 weeks. Therefore, it is recommended that the patient be given a dose proportional to their weight. IV regimens are more consistent across a range of weights than SC regimens. Ensure adequate exposure (Figures 3A-C and 4A-C).

[0263] Example 3: Pharmacodynamic Modeling and Simulation of Secukinumab Regimen (In Patients) Secukinumab 150 mg and 300 mg SC to secukinumab 6 mg / kg / 3 mg / kg IV dose does not affect efficacy) The efficacy of the IV regimen administered in this study may be compared with the SC regimen administered in other studies. The use of meta-analysis to assess how comparable Zymen is to other drugs is a key consideration in determining drug efficacy. Conversely, from a pharmacodynamic perspective, it is difficult to predict the effectiveness of iv The difference in efficacy between the . and s.c. regimens depends on how directly the drug's effect is. In fact, if the effect is direct, i.e., plasma drug If the concentration can be seen to have a direct effect, the iv regimen may be more effective than the lower The effect should diminish by the end of the dosing interval when the α- concentration is given; If there is a delay in the observed effect on plasma drug concentrations, The efficacy of the IV regimen in this setting remains unclear from the higher peak that occurs after IV administration. Preliminary internal experiments with data from registration studies have demonstrated that the concentration-effect relationship Therefore, the inventors' objective is to obtain this delay with sufficient accuracy. and ultimately, the sc regimen to be enrolled (phases 0, 1, 2, 3 and 4 weeks and then monthly thereafter (q4w) starting during week 8, 150 mg or 300 mg sc) used in CAIN457P12301 and CAIN457P12302 The benefits patients can expect when switching to a recommended iv secukinumab regimen To this end, the inventors performed time-varying secukinumab concentration and To estimate the relationship between the efficacy outcome measures and related efficacy endpoints (e.g., BASDAI in AS) A nonlinear mixed-effects model approach was used to develop a pharmacometric PK / PD approach. To ensure robustness of predictions with respect to such variability, The analysis was performed on a pool of phase 3 trials and included differences between trials in all relevant parameters. Account for variability.

[0264] Example 4: Clinical Trial CAIN457P12302 This multicenter study evaluated the efficacy of intravenous secukinumab (baseline ( A loading dose of iv secukinumab 6 mg / kg (BSL) was administered, followed by a 4-week The efficacy, safety, and safety of treatment with secukinumab 3 mg / kg every 4 weeks starting at 1 mg / kg A randomized, double-blind, placebo-controlled, parallel-group design to study efficacy and tolerability The study population will be those with current or prior NSAIDs, DMARDs and / or TNF inhibitors. Patients with active PsA despite drug therapy or who are intolerant to these treatments This includes those who:

[0265] Study design: At baseline, patients with active PsA were randomized in a 1:1 ratio to one of two treatment groups. Assign to: Group 1: Secukinumab iv (6 mg / kg) at BSL followed by 4 weeks starting at week 4 Secukinumab 3 mg / kg iv every 2 weeks until week 48 (exposure until week 52). Group 2: BSL, placebo iv at weeks 4, 8, and 12, followed by 4 starting at week 16 Secukinumab 3 mg / kg iv weekly until week 48 (exposure until week 52).

[0266] This study consists of four periods: Screening Period (up to 10 weeks), Treatment Period 1 ( Treatment period 1 (total duration of 16 weeks) and treatment period 2 (total duration of 32 weeks), followed by treatment Safety follow-up period 8 weeks after the end of the visit (i.e., Week 52). The primary endpoint is at Week 16 data (last patient completed Treatment Period 1) The primary endpoint will be analyzed using the )) Long-term efficacy and safety will be evaluated up to week 52 .

[0267] According to the response to TNF-inhibitor therapy, TNF-inhibitor naive (TNF-naive) randomized to evaluate efficacy and safety in both the TNF-IR and TNF-FR populations Patients will be stratified at times. Starting at week 16, all patients, including all placebo patients, will receive The study design is shown in Figure 5A.

[0268] Rationale for dose, regimen, and duration of treatment Phase 3 study in subjects with active PsA (CAIN457F2312, CAIN457F 2318 and CAIN457F2342) demonstrated superior efficacy of secukinumab 15% over placebo Demonstrate efficacy of 0 mg sc and 300 mg sc regimens. The 150 mg sc and 300 mg sc regimens performed well across several endpoints. and have a rapid response onset and similar magnitude of efficacy.

[0269] Both secukinumab 150 mg sc and 300 mg sc regimens were effective in preventing TN. While it was more effective than placebo regardless of F-naive or TNF-IR status, The 0 mg sc regimen was effective in resolving dactylitis and enthesitis, as well as in preventing structural progression. In the inhibition of ACR20, ACR50, ACR70, HAQ-DI, PASI75, Greatest efficacy across multiple PsA domains, including PASI90 and SF-36 PCS This resulted in...

[0270] In a pooled analysis of 2049 PsA patients in the Phase III program, There is limited evidence of efficacy in the overall population and in patients with TNF-IR and those not receiving concomitant MTX. It has been shown to be effective in several subsets of PsA patients, including but not limited to those with At week 6, several endpoints were assessed by secukinumab 300 mg sc at 150 mg / day. mg sc was preferred over 1 mg sc, and this trend was maintained through week 52.

[0271] Furthermore, secukinumab 300 mg sc was effective in moderate to severe psoriasis (≥10% BSA In subjects with rash clear / almost clear skin (PASI 9), 0, IGA mod 2011 0 / 1), achieving clinically meaningful improvement in skin disease was more effective than 150 mg sc in achieving a higher threshold for skin rash clearance. There was a clear dose response in favor of secukinumab 300 mg sc. The difference between the 150 mg sc and 150 mg sc regimens is more difficult to achieve. It was more pronounced in I90 and IGA mod 2011 0 / 1 evaluation items, ≥ 10 21.9% and 27.4% more patients with %BSA compared with <10%BSA In the case of A, 8.2% and 3.3% more patients had PASI90 and IGA mod 2011 achieved 0 / 1 response at week 24, respectively. Therefore, the clinical significance of psoriasis, especially at baseline, was unclear. In subjects with secukinumab 300mg s., achieving rash clearance / almost rash clearance was c. produced greater improvement in psoriasis than 150 mg sc.

[0272] Furthermore, in relation to safety evaluation, the Phase III study in PsA patients showed that , exposure-adjusted incidence of major risks at 300 mg and 150 mg secukinumab doses There were no clinically meaningful differences between

[0273] Overall safety data in the PsA population were consistent with previous extensive experience in psoriasis, Secukinumab 300 mg and 150 mg are effective for chronic use in adult patients with active PsA. However, the results show that 150 mg sc and 300 mg sc are acceptable. Despite the demonstrated clinical efficacy of these drugs, the fixed-dose nature of these regimens These limitations are imposed on certain patient populations. To provide weight-based dosing with the flexibility to A new formulation is being developed at BSL, at 6 mg / kg and then 3 mg / kg every 4 weeks. The iv regimens of secukinumab are 150 mg sc and 300 mg sc As a result of extensive database-based PK analysis and modeling of secukinumab To be designed.

[0274] Secukinumab at 6 mg / kg in BSL and then 3 mg / kg q4wkly This iv regimen consistently achieved Cmins greater than those achieved with 150 mg sc. The Cavg and Cmax were modeled to target 30 as illustrated in Figure 6. Therefore, the proposed intravenous regimen of secukinumab is The men are expected to deliver an exposure approximating 300 mg sc. The amount of data collected and the PK profile for secukinumab in PsA Considering the understanding achieved in the IV regimen, clinical response to the proposed IV regimen is expected to be significantly higher than that achieved in the SC regimen. .These findings are expected to be similar to those observed with the regimen.

[0275] A detailed protocol summary follows:

[0276] [Table 12]

[0277] [Table 13]

[0278] [Table 14]

[0279] [Table 15]

[0280] [Table 16]

[0281] Example 5: Clinical Trial CAIN457P12301 This multicenter study evaluated the efficacy and safety of intravenous secukinumab (6 mg / mL) in subjects with active ax-SpA. kg initial dose followed by 3 mg / kg every 4 weeks thereafter) Randomized, double-blind, placebo-controlled, parallel-group study to test safety and tolerability The study population will be those taking current or previous NSAIDs, DMARDs and / or have active AS despite TNF inhibitor therapy or intolerant to both. The study consisted of subjects with SpA and subjects with non-SpA.

[0282] Study design: At baseline, subjects with active AS and non-rxSpA were assigned to one of two treatment arms. Randomize: Group 1: AS and nr-axSpA subjects; these subjects received secukinumab at BSL. 6 mg / kg iv, followed by sex every 4 weeks starting at week 4 until week 48 Kinumab 3 mg / kg was administered i.v. Group 2: AS subjects and non-r-axSpA subjects; these subjects were randomized and Secukinumab 6 mg / kg iv and matching placebo were administered iv at weeks 8 and 12. followed by secukinumab 3 mg / kg iv at week 16 and every 4 weeks until week 48. .Administer.

[0283] The study will have four periods: screening period (up to 10 weeks), treatment period 1 (total 1 6 weeks duration) and Treatment Period 2 (total duration of 32 weeks), followed by the End of Treatment Visit and a safety follow-up period of 8 weeks after treatment (i.e., Week 52).

[0284] According to response to TNF inhibitor therapy and disease status (i.e., AS or nr-ax-SpA), Subjects will be stratified at randomization. Starting at week 16, all placebo subjects will be included. All subjects will be switched to open-label intravenous secukinumab. The End of Visit (Week 52) should occur 4 weeks after the last study treatment administration and should be followed by a post-treatment follow-up visit. A follow-up visit (Week 60) should occur 12 weeks after the last study treatment administration ( (regardless of whether the subject completed the entire study as planned or discontinued earlier than normal).

[0285] This study has a primary endpoint analysis at week 16. Therefore, the primary analysis will be conducted at the time when the last subject is cured. After completing the treatment period, data from week 16 will be used. The study design is shown in Figure 5B.

[0286] Rationale for dose, regimen, and duration of treatment This iv secukinumab dose was 6 mg / kg at BSL and 3 mg / kg every 4 weeks. The regimen aims for a Cmin consistently above that achieved with 150 mg sc. The Cavg and Cmax were modeled to be 300 mg, as illustrated in Figure 7. Therefore, the proposed IV regimen is similar to that achieved with secukinumab. It is expected to deliver exposure within the approved sc dose. Considering the amount of clinical data and understanding the PK profile of secukinumab in AS, Clinical responses with the proposed IV regimen are comparable to those observed with the currently approved SC regimen. It is expected to be similar to that

[0287] A detailed protocol summary follows:

[0288] [Table 17]

[0289] [Table 18]

[0290] [Table 19]

[0291] [Table 20]

[0292] [Table 21]

[0293] [Table 22]

[0294] [Table 23]

[0295] Sequence Listing [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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Claims

1. Treating psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA) in patients 1. The method of claim 1, wherein the initial dose of about 4 mg / kg to about 9 mg / kg secukinumab is administered during week 0 and and every four weeks thereafter starting during the fourth week at a dose of about 2 mg / kg to about 4 mg / kg. administering the compound intravenously to the patient.

2. An initial dose of secukinumab of approximately 6 mg / kg was administered during week 0 and then starting during week 4.

10. The method of claim 1, comprising administering to said patient a dose of about 3 mg / kg intravenously every four weeks. The method described.

3. 1. A method of treating PsA or axSpA in a patient, comprising administering about 2 mg / mL of benzodiazepine every 4 weeks. administering to said patient intravenously secukinumab at a dose of 1 mg / kg to about 4 mg / kg. Law.

4. administering secukinumab intravenously to said patient at a dose of about 3 mg / kg every four weeks; The method of claim 3, comprising:

5. 10. The patient has non-radiographic axSpA (nr-axSpA).

5. The method according to any one of claims 1 to 4.

6. 6. The method according to claim 1, wherein the patient has moderate to severe non-rx-axSpA. How to post.

7. 7. The method of any one of claims 1 to 6, wherein the patient has severe nr-axSpA. 。

8. 8. The method of any one of claims 1 to 7, wherein the patient has active nr-axSpA. 。

9. The patient is assessed by a total BASDAI score of ≥ 4 cm (0-10 cm) at baseline. Active nr-axSpA if present, BASDAI Question 2 ≥ 4 cm (0 spinal pain as measured by VAS ≥ 40 mm (0-10 cm) at baseline 9. The method according to claim 1, wherein the patient has total back pain as measured by a 100 mm (100 mm) or 100 mm (100 mm) measurement. How to post.

10. 1 to 3, wherein the patient has nr-axSpA according to the ASAS axSpA criteria.

10. The method according to any one of claims 9 to 9.

11. a) said patient has had 2 or more steroid hormones for at least 3 months, preferably at least 1 month, prior to treatment with secukinumab He has had inflammatory back pain for six months, b) the onset of the inflammatory back pain of a) occurs before the patient reaches age 45; c) the patient has MRI evidence of sacroiliac joint (SIJ) inflammation and at least one or the patient is HLA-B27 positive and has at least two SpA characteristics. The method according to any one of claims 5 to 10, wherein the method has SpA characteristics of

12. The patient is evaluated for elevated C-reactive protein (CRP) and / or SIJ inflammation by magnetic resonance imaging.

5. The patient has objective signs of inflammation as shown by imaging (MRI) evidence.

12. The method according to any one of claims 1 to 11.

13. The patient had a SIJ score according to the Berlin SIJ scoring method. Inflammation as shown by MRI evidence of SIJ inflammation as determined according to the have objective signs of The method according to any one of claims 5 to 12.

14. The patient has objective signs of inflammation as shown by MRI evidence of inflammation of the spine. The method according to any one of claims 5 to 13, comprising:

15. The patient has active non-rx-SpA as assessed by a total BASDAI score of ≥ 4. The method according to any one of claims 5 to 14,

16. The patient meets the radiological criteria of the revised New York diagnostic criteria for ankylosing spondylitis. The method according to any one of claims 5 to 15, wherein the above condition is not satisfied.

17. When a population of patients with nr-axSpA are treated as described, a small proportion of those patients At least 30%, preferably at least 37%, more preferably at least 39% of the therapeutic By the 16th week, the Spondyloarthritis International Society Assessment oArthritis International Society (ASAS)4 17. The method according to any one of claims 5 to 16, wherein the method achieves 0.

18. When a population of patients with nr-axSpA are treated as described, a small proportion of those patients At least 20%, preferably at least 28%, of the ASDAS-CRP score should be improved by the 16th week of treatment. The method according to any one of claims 5 to 16, wherein a significantly improved response of

19. When a population of patients with nr-axSpA are treated as described, a small proportion of those patients At least 50%, preferably at least 53%, more preferably at least 56% of the therapeutic The method of any one of claims 5 to 16, wherein ASAS 20 is achieved by the 16th week.

20. The method of any one of claims 1 to 4, wherein the patient has PsA.

21. 21. The method of any one of claims 1 to 4 or 20, wherein the patient has active PsA.

22. Claims 1 to 4 or 20 to 21, wherein the patient has concomitant moderate to severe plaque psoriasis 10. The method according to any one of the preceding claims.

23. When a population of patients with PsA is treated as described, at least 20% of said patients % of patients, preferably at least 30%, achieved the American College of Rheumatology (ACR) standard by the 16th week of treatment. American College of Rheumatology (ACR) Standard 50 The method according to any one of claims 1 to 4 or 20 to 22, wherein

24. When a population of patients with PsA is treated as described, at least 40% of said patients %, preferably at least 50%, achieve ACR20 by week 16 of treatment.

24. The method according to any one of 1 to 4 or 20 to 23.

25. When a population of patients with PsA are treated as described, at least 50% of said patients %, preferably at least 70% of patients with Psoriasis Area and Severity Index (Psor) by week 16 of treatment. Achieved a PASI Area and Severity Index (PASI) of 75 The method according to any one of claims 1 to 4 or 20 to 24, comprising:

26. When a population of patients with PsA is treated as described, at least 30% of said patients %, preferably at least 40% achieve PASI 90 by the 16th week of treatment. Item 26. The method according to any one of Items 1 to 4 or 20 to 25.

27. The method of any one of claims 1 to 4, wherein the patient has ankylosing spondylitis (AS).

28. 30. The method of any one of claims 1 to 4 or 27, wherein the patient has active AS.

29. 29. The method of any one of claims 1 to 4 or 27 to 28, wherein the patient has moderate to severe AS. The method described.

30. When a population of patients with AS are treated as described, at least 40% of said patients Preferably, at least 42% of patients achieve the Spondyloarthritis International Society Assessment by Week 16. ment of SpondyloArthritis International Any one of claims 1 to 4 or 27 to 29, achieving ASAS 40. The method described in paragraph .

31. When a population of patients with AS are treated as described, at least 20% of said patients , preferably at least 28% have an ankylosing spondylitis disease activity score ( Ankylosing Spondylitis Disease Activity Achieving a significant improvement in ASDAS (Advanced Systemic Dosage and Assessment Score)-C-reactive protein (CRP) response The method according to any one of claims 1 to 4 or 27 to 30,

32. When a population of patients with AS are treated as described, at least 15% of said patients , preferably at least 20% have ASDAS-CRP inactive disease by week 16 of treatment 32. The method of any one of claims 1 to 4 or 27 to 31, wherein the reaction is effected by

33. When a population of patients with AS are treated as described, at least 60% of said patients , preferably at least 61% achieve ASAS 20 by the 16th week of treatment.

33. The method of any one of 1 to 4 or 27 to 32.

34. When a population of patients with AS are treated as described, at least 70% of said patients , preferably at least 72% achieve ASAS 20 by week 104 of treatment. Item 34. The method according to any one of Items 1 to 4 or 27 to 33.

35. 1. A method of treating axial spondyloarthritis (axSpA) in a patient, comprising administering about 20 mg of acetaminophen during week 0. An initial dose of 6 mg / kg secukinumab followed by approximately 3 doses every 4 weeks starting during week 4 m / kg of a dose of the compound of formula (I) or (II) to said patient.

36. 1. A method of treating axial spondyloarthritis (axSpA) in a patient, comprising administering a dose of 20 mg of acetaminophen every four weeks. administering intravenously to said patient a dose of about 3 m / kg secukinumab.

37. The patient has non-radiographic criteria for axial spondyloarthritis (nr-axSpA).

37. The method according to claim 35 or 36.

38. 37. The method of claim 35 or 36, wherein the patient has ankylosing spondylitis (AS).

39. When a population of patients with axSpA are treated as described, at least one of said patients 35%, preferably at least 37%, more preferably at least 39% of the time Assessment of Spondyloarthritis International Society by week thritis International Society (ASAS) 40 The method according to any one of claims 35 to 37, comprising:

40. When a population of patients with axSpA are treated as described, at least one of said patients 25%, preferably at least 28%, have a significant improvement in ASDAS-CRP by week 16 of treatment 40. The method of any one of claims 35 to 39, wherein a significantly improved response is achieved.

41. When a population of patients with axSpA are treated as described, at least one of said patients 10%, preferably at least 14%, more preferably at least 17% of the time 41. The method of claim 35, wherein the patient achieves an ASDAS-CRP inactive disease response by 1 week. The method described in paragraph .

42. When a population of patients with axSpA are treated as described, at least one of said patients 50%, preferably at least 53%, more preferably at least 56% of patients undergoing treatment 42. The method of any one of claims 35 to 41, wherein the method achieves an ASAS 20 by week.

43. When a population of patients with axSpA are treated as described, at least one of said patients 30%, preferably at least 36%, more preferably at least 50% of the time 43. The method of any one of claims 35 to 42, wherein an ASAS score of 40 is achieved within a week.

44. Whether the patient has previously failed to respond to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or claims that there has been an inadequate response to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). Item 44. The method according to any one of Items 1 to 43.

45. The patient has previously failed to respond to a non-biologic DMARD or 45. The method of any one of claims 1 to 44, wherein the response to D was inadequate.

46. The patient had previously failed to respond to treatment with a TNF-alpha inhibitor (TNF-IR). or had an inadequate response to treatment with TNF-alpha inhibitors (TNF-IR). Also, the method according to any one of claims 1 to 45.

47. The patient has not been previously treated with a TNF-alpha inhibitor (TNF-naive).

47. The method according to any one of claims 1 to 46.

48. Cyclosporine, hydroxychloroquine, methotrexate, NSAIDs, sulfasalazine tetracycline, leflunomide, prednisolone, prednisone or methylprednisolone 48. The method of any one of claims 1 to 47, further comprising administering to a patient.

49. Any of claims 1 to 48, wherein secukinumab is supplied in a vial, for example an 8 ml vial. The method according to any one of claims 1 to 10.

50. The secukinumab is provided in a liquid composition containing about 25 mg / mL secukinumab.

50. The method of any one of claims 1 to 49.

51. Secukinumab is about 25 mg / mL secukinumab, about 225 mM trehalose, about 0. 0.2% polysorbate 80, about 5 mM L-methionine and about 20 mM histidine buffer 51. The method of claim 1, wherein the composition is provided in a liquid composition comprising: method.

52. 52. The method of claim 1, wherein secukinumab is administered to the patient over an infusion duration of about 30 minutes.

10. The method according to any one of claims 1 to 9.

53. 53. Any one of claims 1 to 52, wherein the patient has concurrent inflammatory non-infectious uveitis. The method described below.

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