Use of il-17 antagonists for inhibiting progression of structural damage in psoriatic arthritis patients

Abstract

To provide novel therapies to prevent progression of structural damage associated with psoriatic arthritis (PsA) in PsA patients being TNF inadequate responders (TNF-IR) whose response to previous treatment with a TNF alpha antagonist was inadequate.SOLUTION: The disclosure provides methods, uses, medicaments, pharmaceutical formulations, dosage forms, and kits for inhibiting the progression of structural damage in psoriatic arthritis (PsA) patients using IL-17 antagonists, e.g., IL-17 antibodies and antigen-binding fragments thereof, e.g., secukinumab.SELECTED DRAWING: None

Description

[Technical field]

[0001] This disclosure is incorporated by reference in its entirety. This application claims priority to U.S. Provisional Patent Application No. 62 / 048,512, filed on do.

[0002] Technical Field The present disclosure provides a method for the treatment of psoriatic arthritis (PS) using an IL-17 antagonist, e.g., secukinumab. Patients with psoriatic arthritis (PsA) (e.g., those taking biologics, e.g., TNF-alpha inhibitors) (Patients previously treated with harmful drugs and patients not previously treated with biologics) The present invention relates to a method for inhibiting the progression of structural damage in a subject. [Background technology]

[0003] PsA is a chronic, systemic inflammatory disease affecting the peripheral joints, connective tissue, and axial skeleton. May be associated with skin and nail psoriasis (Boehncke and Menter (2013), Am J Clin Derm atol;14:377-88; Gladman et al. (2005) Ann Rheum Dis;64(Suppl 2):ii14-17). Ps A is a multifaceted disease that includes synovitis, enthesitis, dactylitis, spondylitis, uveitis, and inflammatory bowel disease. Traditional disease-modifying antirheumatic drugs (DMARDs) are methotrexate (MTX ), sulfasalazine, cyclosporine, and leflunomide, which are inadequate for many patients. is sufficient because these drugs only partially control established disease. (Mease PJ (2008) Psoriatic Arthritis. In: Klippel et al, eds. Primer on R heumatic diseases. 13th ed. New York: Springer Science, p. 170-192). Cause of tumor necrosis Tumor necrosis factor (TNF) inhibitors have improved the management of PsA in recent years (Mease (2013) Curr Opin Rheumat ol.;25:287-96; Mease and Armstrong (2014)Drugs 2014a; 74:423-41; Gossec et al. (2012) Ann Rheum Dis; 71:4-12; Menter et al. (2011) J Am Acad Dermatol 2011;65:1 37-74), but not all patients responded to or tolerated these drugs (i.e., PsA Approximately 40% of patients continue to experience significant impairment in physical function, disability, and reduced quality of life. (Boehncke and Menter (2013) Am J Clin Dermatol 2013;14:377-88; Gladman et al. (2005) Ann Rheum Dis.;64(Suppl 2):ii14-7).

[0004] Approximately two-thirds of patients with PsA have progressive and reversible structural lesions with varying degrees of disability. They experience damage (e.g., erosions, joint space narrowing (JSN), osteolysis, ankylosis, etc.). Within 2 years of onset of PsA, nearly 50% of patients had ≥1 erosion and were followed up for 10 years. 55% develop deformity in ≥5 joints after surgery (Kavanaugh et al (2014) Ann. Rheum. D 73:1000-1006). Several therapies have been shown to reduce the incidence of TNF-associated leukemia in TNF-naive patients. (e.g., ustekinumab, Kavanaugh et al. 2014), supra), but currently, no studies have investigated the efficacy of TNF in PsA patients with prior TNF exposure (i.e., There are no biologics that can prevent the progression of structural damage in tumor necrosis factor-ineffective responders (TNF-IR). do not have. Summary of the Invention [Problem to be solved by the invention]

[0005] In light of the above, we would like to consider the following points regarding the possible causes of PsA, especially for PsA patients with TNF-IR: There is a need to develop new therapies that can inhibit the progression of structural damage associated with glaucoma. [Means for solving the problem]

[0006] Increasing evidence suggests the involvement of interleukin-17A in the pathogenesis of PsA. Increased levels of interleukin-17A-producing cells have been shown to improve circulation and joint function in patients with dry skin. It has been found in psoriatic skin plaques (Jandus (2008) Arthritis Rheum;58:2307-17; Kagami ( 2010) J Invest Dermatol;130:1373-83; Lin (2011) J Immunol;187:490-500; s (2012) Arthritis Rheum;64:99-109), and was correlated with measures of disease activity and structural damage. It was shown that the structure The effect of interleukin-17A inhibition on vascular injury has not been shown previously, but In a phase 2 trial, interleukin-17A ligand (McInnes et al. (2014) Ann Rheum Dis 20 14;73:349-56) or receptor (Mease et al. (2014) N Engl J Med; 370:2295-306) inhibition has been demonstrated to improve the signs and symptoms of PsA.

[0007] Secukinumab (AIN457) is a high-affinity complete inhibitor of interleukin-17A activity. It is a fully human monoclonal anti-human antibody. Recent PsA proof-of-concept (PoC) trials (AIN 457A2206) (Example 1), secukinumab demonstrated a The objective of the study was not met (proportion of ACR20 responders at week 6 for active vs placebo). However, a larger study (Example 2) using an improved dosing regimen demonstrated that secukinumab The results now show that cyclosporine is highly effective in treating both the signs and symptoms of PsA. Furthermore, the radiographic data (Examples 3-4) were consistent with the prior TNF inhibitor therapy status (TNF Drug-naive vs. prior TNF treatment) or concomitant methotrexate administration First and foremost, it is the first biologic to demonstrate significant inhibition of the progression of structural damage in patients with PsA. To our knowledge, secukinumab has been shown to be effective against TNF-alpha antagonists. Structural damage in PsA patients previously treated with It is the first biologic to show inhibition of progression. For example, antagonistic anti-IL-12 / 23 In a PsA trial using the p40 monoclonal antibody ustekinumab, Inhibition of radiographic progression of joint damage in patients with F alpha antagonist exposure IL-23 inhibits the expression of IL-17-producing, highly pathogenic T helper cells. Induce differentiation of naive CD4(+) T cells into Th17 / Th(IL-17) Therefore, we have assessed the association of secukinumab with TNF-alpha antagonists in patients with prior exposure to TNF-alpha antagonists. In contrast, ustekinumab did not inhibit radiographic progression of nodal damage. This fact is unexpected.

[0008] Thus, disclosed herein is an IL-17 antagonist for use in treating patients in need thereof. The present invention relates to a method for inhibiting the progression of structural damage in a patient with PsA, the method comprising administering to a patient having Also disclosed herein are methods for administering IL-17 antagonists to patients in need thereof. and reducing the signs and symptoms of active PsA in PsA patients, including administering inhibiting the progression of structural (e.g., bone and / or joint) damage in patients with Ps A method for improving physical function in a patient. In some embodiments, the patient is biologic-naive. In some embodiments of the disclosed uses, methods and kits, the patient is biologic-experienced. Some of the disclosed uses, methods and kits are biologic-experienced. In this embodiment, the patient has not previously been treated with a TNF alpha antagonist. In some embodiments of the disclosed uses, methods and kits, the patient is Some of the disclosed uses, methods and kits In one embodiment, the patient has a history of relapse to prior treatment with a TNF alpha antagonist. The disclosed uses, methods and In some embodiments of the method, the inhibition of progression of structural damage is Heijde psoriatic arthritis modified total Sharp score (mT In some embodiments of the disclosed uses, methods and kits, Inhibition of progression of structural damage was measured by erosion and joint space narrowing (JSN) scores. In some embodiments of the disclosed uses, methods and kits, erosions, joint space narrowing, pencil-in-cup phenomenon, joint widening, joint narrowing ing), subluxation, bone proliferation, osteolysis and / or the progression of ankylosis are inhibited. In an embodiment, the disclosed method comprises administering a DMARD, such as methotrexate (MTX), to a patient. and administering to a patient. In this study, IL-17 antagonist was administered at approximately 10 mg / kg every other week at weeks 0, 2, and 4. The drug was administered intravenously (iv) to 112 subjects, followed by monthly (every 4 weeks) administration starting in the 8th week for approximately 75 minutes. The compound is administered subcutaneously (sc) to a patient at about 150 mg, about 150 mg or about 300 mg. In some embodiments of the methods and kits, the IL-17 antagonist is administered at 0, 1, Patients will receive sc doses of approximately 75 mg, 150 mg, or 300 mg once weekly during weeks 2 and 3. Then, starting in the 4th week, take about 75 mg, about 150 mg, or about 3 mg once a month (every 4 weeks). 00 mg is administered sc to patients. In some cases, the patient has concomitant psoriasis (e.g., concomitant moderate to severe plaque psoriasis). In some embodiments of the disclosed uses, methods and kits, progression of structural damage is Inhibition of is defined as a change from baseline in mTSS of ≦0.5. In some embodiments of the methods and kits, the inhibition of progression of structural damage is ≦0.3 The change from baseline in erosion score is defined as the change from baseline in erosion score. In some embodiments, inhibition of progression of structural damage is characterized by a baseline JSN score of ≦0.2. Some embodiments of the disclosed uses, methods and kits In this embodiment, the patient is notified that the patient has previously received a TNF alpha antagonist. In some embodiments of the disclosed uses, methods and kits, The IL-17 antibody, e.g., secukinumab, is then formulated into a liquid pharmaceutical composition (e.g., from a lyophilized form). Reconstituted or not reconstituted from a lyophilized form, preferably reconstituted from a lyophilized form The patient will be administered the same treatment as if the patient had not been administered the same dose.

[0009] 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 comprises: a) Leu74 ,Tyr85,His86,Met87,Asn88,Val124,Thr125,P Epitopes of IL-17 including ro126, Ile127, Val128, and His129 b) an IL-17 antibody or an antigen-binding fragment thereof that binds to Tyr43, Tyr44, Arg; IL-17 antibody that binds to epitopes of IL-17 including 46, Ala79, and Asp80 or an antigen-binding fragment thereof, c) an IL-17 homozygote having two mature IL-17 protein chains. Binds to a dimeric epitope, which is located at Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, I Le127, Val128, His129 and Tyr43, Tyr44, Ar on the other chain IL-17 antibody or antigen-binding fragment thereof, comprising g46, Ala79, and Asp80; d) 2 Binds to an epitope on the IL-17 homodimer having two mature IL-17 protein chains, The epitope is located at Leu74, Tyr85, His86, Met87, As on one chain. n88, Val124, Thr125, Pro126, Ile127, Val128, H Tyr43, Tyr44, Arg46, Ala79, Asp8 on is129 and other strands K of approximately 100-200 pM, including 0 D It has an in vivo half-life of about 23 to about 35 days. and e) an IL-17 antibody or antigen-binding fragment thereof having the structure shown as SEQ ID NO: 8. The immunoglobulin heavy chain variable domain (V H ), ii) SEQ ID NO: 1 The immunoglobulin light chain variable domain (V L ), iii ) Immunoglobulin V comprising the amino acid sequence shown as SEQ ID NO:8 H Domain and sequence number Immunoglobulin V containing the amino acid sequence shown as No. 10 L domain, iv) sequence number 1, an immunoglobulin V comprising a hypervariable region shown as SEQ ID NO:2 and SEQ ID NO:3 H Domestic v) an immunological compound comprising the hypervariable regions shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; Globulin V L vi) domains shown as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 Immunoglobulin V containing the hypervariable region H domain, vii) SEQ ID NO:1, SEQ ID NO:2 and an immunoglobulin V comprising a hypervariable region as shown in SEQ ID NO:3 HDomains and sequences Immunoglobulin V comprising the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L domain, viii) the hyperpolymerization domains shown as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13; Immunoglobulin V containing variable regions H Domains and SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 Immunoglobulin V containing a hypervariable region designated as L Domain, ix) SEQ ID NO: 14 x) an immunoglobulin light chain comprising the amino acid sequence shown as SEQ ID NO: 15; or xi) an immunoglobulin heavy chain comprising the amino acid sequence shown as SEQ ID NO: 14. and an immunoglobulin light chain comprising the amino acid sequence shown as SEQ ID NO: 15. The antibody is selected from the group consisting of an IL-17 antibody or an antigen-binding fragment thereof that comprises a globulin heavy chain. In some embodiments of the disclosed uses, methods and kits, an IL-17 antibody or its The antigen-binding fragment is secukinumab.

[0010] Further disclosed herein is a pharmaceutical composition comprising about 75 mg to about 300 mg of secukinumab (e.g., About 150 mg to about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) per month This includes administering the drug once to patients who have not previously been treated with a TNF-alpha antagonist. and a method of inhibiting the progression of structural damage in PsA patients.

[0011] Further disclosed herein is a method for treating a chronic bronchitis, comprising administering to a patient a therapeutically effective amount of from about 75 mg to about 300 mg (e.g., from about 150 mg to about 300 mg). Approximately 300 mg, e.g., approximately 75 mg, approximately 150 mg, approximately 300 mg) of secukinumab per month The study involves administering a single dose to patients who have not previously been treated with a TNF-alpha antagonist. and a method of inhibiting the progression of structural damage in PsA patients.

[0012] Further disclosed herein is a method for treating a chronic bronchitis, comprising administering to a patient a therapeutically effective amount of from about 75 mg to about 300 mg (e.g., from about 150 mg to about 300 mg). Approximately 300 mg, e.g., approximately 75 mg, approximately 150 mg, approximately 300 mg) of secukinumab per month The study involves administering a single dose to patients who have not previously been treated with a TNF-alpha antagonist. Based on these findings, treatment options are based on methods that inhibit the progression of structural damage in PsA patients. It is law.

[0013] Further disclosed herein is a method for treating a patient suffering from a TNF alpha antagonist treatment. Approximately 75 mg to approximately 300 mg (e.g., approximately 150 mg to approximately 300 mg) based on previous intake. mg (e.g., about 75 mg, about 150 mg, about 300 mg) of secukinumab once a month and a method for inhibiting the progression of structural damage in a patient with PsA, the method comprising selectively administering be.

[0014] Further disclosed herein is an initial administration at weeks 0, 1, 2 and 3 followed by 4 Approximately 150 mg to approximately 300 mg (e.g., approximately 150 mg) is administered once a month starting on the 2nd week of the month. g to about 300 mg, e.g., about 75 mg, about 150 mg, about 300 mg) of secukinumab The study involves administering a subcutaneous injection of 5-HT2 inhibitors to patients with PsA to slow the progression of structural damage. In some embodiments, the patient is treated with a TNF alpha antagonist. Previously treated with

[0015] Further disclosed herein is a method for administering about 10 mg / kg of cerebrospinal fluid by intravenous injection at weeks 0, 2 and 4. Patients were administered 15 kg of secukinumab followed by approximately 15 mg of secukinumab by subcutaneous injection starting at week 8. In patients with PsA, the study included administering 0 mg or approximately 300 mg of secukinumab to patients. In some embodiments, the patient is diagnosed with TN. Previous treatment with an F alpha antagonist. [Brief description of the drawings]

[0016] [Figure 1] FIG. 1 shows the AIN457F2306 study design. [Figure 2A] Figure 1: American College of Rheumatology (ACR) response over time from baseline to week 24 (placebo-controlled period), and for subjects randomized to secukinumab at baseline, to week 52. Proportion of subjects with a 20% improvement in ACR response criteria (ACR20) over time is shown. Missing data were imputed as non-responders through week 24, and observed data are reported from week 24 to week 52. *P<0.05, **P<0.01, and ***P<0.001 vs. placebo. [Figure 2B] Figure 1: American College of Rheumatology (ACR) response over time from baseline to week 24 (placebo-controlled period), and for subjects randomized to secukinumab at baseline, to week 52. Proportion of subjects with a 50% improvement in ACR response criteria (ACR50) over time is shown. Missing data were imputed as non-responders through week 24, and observed data are reported from week 24 to week 52. *P<0.05, **P<0.01, and ***P<0.001 vs. placebo. [Figure 2C] Figure 1: American College of Rheumatology (ACR) response over time from baseline to week 24 (placebo-controlled period), and for subjects randomized to secukinumab at baseline, to week 52. Proportion of subjects with 70% improvement in ACR response criteria (ACR70) over time is shown. Missing data were imputed as non-responders through week 24, and observed data are reported from week 24 to week 52. *P<0.05, **P<0.01, and ***P<0.001 vs. placebo. [Diagram 3]3A-B show the mean change in modified total Sharpe score (vdH-mTSS) from baseline to week 24 (placebo-controlled period) and from baseline to week 52 for subjects randomized to secukinumab at baseline. Mean change from baseline in vdH-mTSS at week 24 (FIG. 3A) and week 52 (FIG. 3B) are shown. Statistical analysis at week 24 was assessed using a nonparametric ANCOVA model with linear extrapolation of missing data. Data through week 52 represent subjects randomized to secukinumab at baseline only. *P<0.05 vs. placebo. [Figure 4A] Figure 4: ACR response through week 24 in biologic-naive and biologic-experienced subjects (non-responder imputation analysis). The proportion of subjects with 20%, 50% and 70% improvement in ACR response criteria (ACR20, ACR50 and ACR70, respectively) over time is shown for a) biologic-naive (Figure 4A) and b) biologic-experienced (Figure 4B) subjects. Missing data were imputed as non-responders. *P<0.05, **P<0.01, ***P<0.001 vs. placebo. Statistical comparison of ACR70 response at week 24 in biologic-experienced subjects with placebo was not possible due to the absence of responders in the placebo group. [Figure 4B] Figure 4: ACR response through week 24 in biologic-naive and biologic-experienced subjects (non-responder imputation analysis). The proportion of subjects with 20%, 50% and 70% improvement in ACR response criteria (ACR20, ACR50 and ACR70, respectively) over time is shown for a) biologic-naive (Figure 4A) and b) biologic-experienced (Figure 4B) subjects. Missing data were imputed as non-responders. *P<0.05, **P<0.01, ***P<0.001 vs. placebo. Statistical comparison of ACR70 response at week 24 in biologic-experienced subjects with placebo was not possible due to the absence of responders in the placebo group. [Figure 5A]Figure 5: Time course of ACR response through week 24 in subjects with and without concomitant MTX (non-responder imputation analysis). The time course of the proportion of subjects with 20%, 50% and 70% improvement in ACR response criteria (ACR20, ACR50 and ACR70, respectively) through week 24 is shown for subjects who received concomitant methotrexate treatment (Figure 5A) and those who did not receive concomitant MTX (Figure 5B). Missing data were imputed as non-response. *P<0.05, **P<0.01, ***P<0.001 vs. placebo. [Figure 5B] Figure 5: Time course of ACR response through week 24 in subjects with and without concomitant MTX (non-responder imputation analysis). The time course of the proportion of subjects with 20%, 50% and 70% improvement in ACR response criteria (ACR20, ACR50 and ACR70, respectively) through week 24 is shown for subjects who received concomitant methotrexate treatment (Figure 5A) and those who did not receive concomitant MTX (Figure 5B). Missing data were imputed as non-response. *P<0.05, **P<0.01, ***P<0.001 vs. placebo. [Figure 6] Figure 1: Secukinumab 75 mg and 150 mg are superior to placebo in inhibiting progression of structural joint damage measured by vdH-mTSS at week 24. Total population (FAS). ‡P<0.05 vs placebo. Missing values ​​at week 24 were imputed by linear extrapolation. [Figure 7] FIG. 13 shows cumulative distribution plots of total vdH-mTSS scores at week 24. [Figure 8] FIG. 1 shows the time course of total vdH-mTSS progression. [Figure 9] 9A-B show that secukinumab demonstrates significant inhibition of structural damage in both TNF-naive responders (FIG. 9A) and TNF-inadequate responders (FIG. 9B) as measured by vdH-mTSS. [Figure 10]Figures 10A-B show the mean (+standard deviation) change in mTSS for x-ray completers (i.e., patients who had x-ray measurements at baseline, weeks 16 / 24, and week 52) during two time periods: from baseline to week 24 (Figure 10A) and from weeks 24 to 52 (Figure 10B). IV, intravenous; mTSS, modified total Sharp score; SC, subcutaneous; SD, standard deviation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] Detailed Description of the Invention IL-17 antagonists, such as secukinumab, are used to treat psoriatic arthritis (PsA) patients. The present invention provides a method for inhibiting structural damage (e.g., bone and / or joint) in a subject. This is the purpose of the disclosure.

[0018] The term "comprising" includes both "including" and "consisting of" ", for example, a composition "comprising" X may consist exclusively of X. It may also include another, for example X+Y.

[0019] As used herein, the phrase "inhibits the progression of structural damage" means "inhibits the progression of structural damage" or "inhibits the progression of structural damage." "Prevents the progression of bone and / or joint damage associated with PsA" is synonymous with "prevents the progression of bone and joint damage" It is used to mean to cause, eliminate, or slow the progression of something. Various bone and / or joint damage may occur, such as erosions, joint space narrowing (JSN), pencil indentation, etc. These include joint popping, widening, narrowing, subluxation, osteophytes, osteolysis and / or ankylosis. Various radiographic scoring methods for measuring the progression of structural damage in the Inbrocker Sharp scoring system, mTSS (also called vdH-mTSS) and R There exists an Atingen score (e.g., van der Heijde (2005) Ann. Rheum. Dis. 6 4:ii61-ii64). In some embodiments, the mTSS (also referred to as vdH-mTSS) The MRI scan is used to assess the progression of structural damage in patients with PsA. In some embodiments, the inhibition of progression of structural damage is <0.57, ≦0.5, ≦0.3, ≦0.25, ≦0.20, ≦0.15, ≦0.13, ≦0.10, ≦0.05 or ≦0. The effect was defined as the change from baseline in vdH-mTSS at baseline of 02, and the long-term maintenance of this effect The change from baseline can include any given time point, for example, 2 hours after the start of treatment. Measurements can be taken at 4 weeks and 52 weeks after initiation of treatment. Inhibition of objective progression is defined as a change in mTSS of ≦0.5 from baseline.

[0020] Inhibition of progression of structural damage may be beneficial in preventing certain types of bone and joint damage (e.g., erosions, joint space narrowing, etc.) Smaller joints (JSN), pencil-in-cup phenomenon, enlargement, narrowing, subluxation, osteophytosis, osteolysis and / or In some embodiments, the evaluation may also be performed by analyzing the joint stiffness (ankylosis or joint stiffness). Objective: To assess the progression of structural damage in patients with PsA using radiographic imaging of erosions. In some embodiments, the inhibition of progression of structural damage is <0.35, ≦0.30, ≦ 0.25, ≦0.2, ≦0.15, ≦0.1, ≦0.08, ≦0.05, ≦0.03 Elongation In some embodiments, the change from baseline in JS score is defined as the change from baseline in JS score. Radiographic imaging of N is used to assess the progression of structural damage in patients with PsA. In embodiments, the inhibition of progression of structural damage is <0.23, ≦0.20, ≦0.15, ≦ was defined as a change from baseline in the JSN score of 0.10, ≤0.05, or ≤0.02. can be.

[0021] In addition to radiographic imaging, other methods useful for visualizing changes in bone and / or joint structure include , MRI and ultrasound, including power Doppler grayscale ultrasound (PDUS) The scoring system used to evaluate changes in bone and / or joint structure is determined by the physician. Dependent on the visualization mode selected, if PDUS is applied, e.g. OMERACT -The EULAR composite PDUS score can be used to assess synovial activity.

[0022] The term "about" in reference to a numerical value x means, for example, + / - 10%. When used before a list of numbers, the term "about" applies to every number in the series. For example, the phrase "about 1 to 5" should be interpreted as "about 1 to about 5" or For example, the phrase "about 1, 2, 3, 4" should be interpreted as "about 1, about 2, about 3, about 4, etc." It is.

[0023] The term "substantially" does not exclude "completely." For example, "substantially does not contain Y" means The composition may be completely free of Y. Where necessary, the word "substantially" may be used to , may be excluded from the definition of this disclosure.

[0024] The term "antibody" as used herein refers to a whole antibody. An "antibody" is a molecule that comprises at least two heavy (H) chains interconnected by disulfide bonds and Each heavy chain is a glycoprotein that contains two light (L) chains. TE V HThe heavy chain constant region consists of three domains: Each light chain is composed of a light chain variable region (herein defined as CH1, CH2, and CH3). The light chain constant region is composed of one It is composed of domains CL. V H and V L The region is the framework region (FR). The hypervariable or complementarity determining regions are interspersed with more conserved regions called Each V can be further subdivided into regions of hypervariability called constant region (CDR). H Reach BiV L has three CDRs and a CDR1 arranged from amino terminus to carboxy terminus in the following order: It is composed of four FRs: FR1, CDR1, FR2, CDR2, FR3, CDR 3, FR4. The variable regions of the heavy and light chains contain the binding domains that interact with an antigen. The constant region is involved in the regulation of various cells of the immune system (e.g., effector cells) and the first step of the classical complement system. The disclosed method can mediate the binding of immunoglobulins to host tissues or factors that contain the component (C1q). In some embodiments of the methods, regimens, kits, processes, uses and compositions, IL -17 or an antibody against the IL-17 receptor, preferably an antibody against IL-17, e.g. , secukinumab is used.

[0025] The term "antigen-binding fragment" of an antibody, as used herein, refers to an antibody that binds to an antigen (e.g., This refers to antibody fragments (including single chains) that retain the ability to specifically bind to IL-17. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments that fall within the term "original binding fragments" include V L , V H, CL and CH1 Fab fragments are monovalent fragments consisting of a single domain, bound by disulfide bridges in the hinge region. F(ab)2 fragment, a bivalent fragment containing two Fab fragments linked together; V H and C The Fd fragment consists of the H1 domain, and the V L and V H Fv fragment consisting of domains piece, V H domain-based dAb fragments (Ward et al., 1989 Nature 341, 544-546) and Exemplary antigen-binding sites include those shown in SEQ ID NOs: 1-6 and 11-13. The CDRs of secukinumab shown in Table 1, preferably the heavy chain CDR3, are also shown. In addition, the two domains V of the Fv fragment L and V H are encoded by separate genes, They are V L and V H A single protein chain in which the domains pair together to form a monovalent molecule ( Also known as single chain Fv (scFv), see, e.g., Bird et al., 1988 Science 242:423-42 6, and Huston et al., 1988 Proc. Natl. Acad. Sci. 85, 5879-5883). The nucleic acid can be linked by a synthetic linker that allows the nucleic acid to be linked by recombinant methods. Such single chain antibodies are also intended to be included within the scope of the phrase "antigen-binding fragment." and other antigen-binding fragments can be obtained using conventional techniques known to those skilled in the art.

[0026] An "isolated antibody," as used herein, is an antibody that is isolated from other antibodies having different antigen specificities. An isolated antibody that specifically binds IL-17 is substantially free of IL-17. (Substantially free of antibodies that specifically bind to antigens other than 17). " or "monoclonal antibody composition," as used herein, refers to a single The term "human antibody" as used herein refers to a preparation of antibody molecules of a given molecular composition. Thus, both the framework and CDR regions have variable regions derived from human sequences. A "human antibody" includes 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, antibody genes can be generated by random or site-specific mutagenesis in vitro. by the addition of an N-nucleotide at the binding site upon in vivo recombination of The disclosed techniques may include mutations introduced by in vivo somatic mutations. In some embodiments of the methods and compositions, the IL-17 antibody is a human antibody, an isolated antibody, or and / or monoclonal antibodies.

[0027] The term "IL-17" refers to IL-17A, formerly known as CTLA8. In addition, wild-type IL-17A, IL-17A subunits, and IL-17A subunits from various species (e.g., human, mouse, and monkey) were The functional equivalents of IL-17A according to the present disclosure include polymorphic variants and functional equivalents of IL-17A. Equivalents preferably have at least a partial homology to wild-type IL-17A (e.g., human IL-17A). Approximately 65%, 75%, 85%, 95%, 96%, 97%, 98% or even 99% of the total The antibody has sequence identity with the IL-6 antibody and substantially retains the ability to induce IL-6 production by human dermal fibroblasts. I have it.

[0028] "K D The term "K" refers to the off-rate of a particular antibody-antigen interaction. D " as used herein means K d and K. a (i.e., K d / K a ) and expressed as a molar concentration (M). K D The values ​​can be determined, for example, by surface plasmon resonance or a biosensor system (e.g., Biac In some embodiments, the I The L-17 antibody or antigen-binding fragment thereof, for example, secukinumab, has a molecular weight of about 100 to 250 pM. K of M D It binds to human IL-17 at

[0029] The term "affinity" refers to the strength of the interaction between an antibody and an antigen at a single antigenic site. Within each antigen site, the variable regions of the antibody "arms" are weakly non-covalently linked to the antigen at multiple sites. They interact through avidity. The greater the interaction, the stronger the affinity. For example, ELIS A, Binding affinity of antibodies to IL-17 in various species, including Western blot and RIA. Standard assays for assessing potency are known in the art. For example, binding affinity) can also be determined using methods published in the art, such as Biacore® analysis. The activity can be assessed by known standard assays.

[0030] These IL-17 functions are measured by methods known in the art and described herein. Properties (e.g., biochemical, immunochemical, cellular, physiological or other biological activity or the like) An antibody that "inhibits" one or more of the following (or more) Statistically significant increase in specific activity compared to that observed in the presence of a control antibody of specificity It is understood that an antibody that inhibits IL-17 activity is associated with a significant decrease in the measured parameters. Statistically significant for at least about 10%, at least 50%, 80%, or 90% of the parameters In certain embodiments of the disclosed methods and compositions, the IL-1 7 antibodies may inhibit greater than 95%, 98% or 99% of IL-17 functional activity.

[0031] "Inhibiting IL-6," as used herein, refers to the inhibition of IL-6 production from primary human dermal fibroblasts. IL-17 antibodies or antigen-binding fragments thereof (e.g., sec- numab) ability to stimulate IL-6 production in primary human (skin) fibroblasts. 17 (Hwang et al., (2004) Arthritis Res Ther, vol. 6, pp. R120-128). Human dermal fibroblasts were incubated with various concentrations of IL-17 binding molecules or human IL-17 bearing the Fc region. Stimulated by recombinant IL-17 in the presence of the IL-17 receptor. Chimeric anti-CD25 antibody S Imulect® (basiliximab) is conveniently used as a negative control. After 16 hours of stimulation, the supernatants were collected and assayed for IL-6 by ELISA. The IL-17 antibody or antigen-binding fragment thereof, for example, secukinumab, is i.e., induced by hu-IL-17 in human dermal fibroblasts. When the inhibitory activity against the production of IL-6 was measured, it was about 50 nM or less (for example, Inhibition of IL-6 production (in the presence of 1 nM human IL-17) from about 0.01 to about 50 nM IC on Harm 50 Some implementations of the disclosed methods, uses and kits include In one embodiment, the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab and A functional derivative of is about 20 nM or less, more preferably about 10 nM or less, more preferably about 5 nM or less, more preferably about 2 nM or less, more preferably about 1 nM or less, as defined above. IC for inhibition of IL-6 production 50 has.

[0032] The term "derivative" refers, unless otherwise indicated, to amino acid sequence variants as well as to the and the like. Covalent modifications of sequences (e.g., variable domains) (e.g., pegylation, deamidation, hydrolysis, etc.) "Functional derivatives" are used to define the functional groups of the disclosed Functional derivatives include molecules that have the same qualitative biological activity as the IL-17 antibody. Fragments and peptide analogs of the IL-17 antibodies disclosed herein are included. The present invention relates to a polypeptide comprising a polypeptide sequence, for example, a region within a sequence of a specified sequence. A functional derivative of the L-17 antibody (e.g., a functional derivative of secukinumab) is preferably The V of the IL-17 antibody and antigen-binding fragment 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 having 96%, 97%, 98% or even 99% overall sequence identity H and / or V L domain, which binds to human IL-17 or inhibits, for example, IL-17-induced human skin inflammatory cytokines. It substantially retains the ability to inhibit IL-6 production by fibroblast cells.

[0033] The phrase "substantially the same" refers to related amino acid or nucleotide sequences (e.g., H Or V L domains) are the same or have minor differences compared to a particular reference sequence ( For example, by conservative amino acid substitutions). , V H Or V L A few amino acids such as one or two substitutions in the five amino acid sequence of the domain In the case of antibodies, the second antibody has the same specificity and a lower affinity for the same. At least 50% of the sequence is substantially the same as the sequences disclosed herein (e.g., at least Approximately 85% sequence identity) sequences are also part of this application. IL-17 antibodies (e.g., derivatives of secukinumab, e.g., secukinumab biosimilars) The sequence identity of the antibody to the disclosed sequence is about 90% or more, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher It could be.

[0034] "Identity" in relation to naturally occurring polypeptides and their functional derivatives is defined herein as follows: Align sequences and introduce gaps, if necessary, to achieve the maximum percent identity. After insertion, the corresponding native polypeptide is determined without considering conservative substitutions as part of the sequence identity. It is defined as the percentage of amino acid residues in a candidate sequence that are identical to the residues in the N- or C-terminal extension. Neither lengthening nor insertions shall be construed as reducing identity. Percent identity can be determined using standard alignment algorithms, such as Alignment Algorithms. Basic Lo described by Tshul et al. ((1990) J. Mol. Biol., vol. 215, pp. 403-410) cal Alignment Search Tool (BLAST), Needleman et al. algorithm ((1970) J. Mol. Biol., vol. 48, pp. 444-453) or the algorithm of Meyers et al. ((1988) Comput. Appl. Biosci., vol. 4, pp. 11-17). The parameters are gap penalty 12, gap extension penalty 4, frameshift penalty Blosum 62 scoring matrix with gap penalty of 5 The percent identity between two amino acid or nucleotide sequences is AL using a weighted residue table, a gap length penalty of 12 and a gap penalty of 4 The IGN program (version 2.0) includes the work of E. Meyers and W. Miller. It can also be calculated using the algorithm ((1989) CABIOS, Vol. 4, pp. 11-17).

[0035] "Amino acid(s)" refers to all naturally occurring L-α-amino acids; Also included, for example, are D-amino acids. The phrase "amino acid sequence variants" is used herein to refer to refers to molecules that have slight differences in their amino acid sequence compared to a specified sequence. The amino acid sequence variants of the antibodies according to the present disclosure bind to human IL-17, or For example, we still have not demonstrated the ability to inhibit IL-17-induced human dermal fibroblast IL-6 production. Amino acid sequence variants include substitution variants (in which at least one amino acid residue is removed). A different amino acid sequence may be inserted at the same position in a polypeptide according to the present disclosure. insertion mutants (those having a 3'-amino acid at a particular position in a polypeptide according to the disclosure); (having one or more amino acids inserted immediately adjacent to the amino acid in question), deletion mutations and the like, including those in which one or more amino acids in a polypeptide according to the present disclosure have been removed. nothing.

[0036] As used herein, "once a month" means 30 days or more, as the context may dictate. Used to mean four weeks.

[0037] As used herein, the phrase "biologic naive" means: No prior treatment with biologic agents, e.g., ustekinumab, TNF-alpha inhibitors, etc. As used herein, the term "biologic-experienced" refers to a PsA patient who has undergone The term refers to treatment with biologic agents for PsA, e.g., ustekinumab, TNF-alpha inhibitors, etc. As used herein, "TNF antagonist" refers to a PsA patient who has previously received "No prior treatment with rituximab" and "No prior TNF medication" The term refers to patients with PsA who have not previously been treated with a TNF-alpha inhibitor for PsA. As used herein, "previously treated with a TNF antagonist" means The terms "experienced" and "TNF-experienced" refer to TNF alpha inhibitors (e.g., infliximab). Treatment with cimetidine, etanercept, adalimumab, certolizumab, and golimumab This means that the PsA patients who had previously received TNF-alpha inhibitor treatment were refractory to the treatment. or inadequate response, and those who are considering treatment with a TNF-alpha inhibitor for safety or tolerability reasons. This includes patients who discontinued treatment with a toxic drug. The terms "TNF-IR" and "TNF-IN" refer to TNF-alpha inhibitors for PsA (e.g., infliximab, etanercept, adriamycin, Previous treatment with rituximab, certolizumab, or golimumab) for symptoms (e.g. , skin and / or joint symptoms) were not adequately controlled by TNF alpha inhibitors. Patients who have been treated with anti-TNF drugs for at least 4 weeks at approved doses for at least 8 weeks despite at least 14 weeks, at least 3 months, or at least 4 months of treatment The disclosed method, kit, and IL-17 antagonist are In some embodiments of the invention and method of use, the patient has never been medicated with a biologic. naive, biologic-experienced, TNF-naive, TNF-experienced or TNF -IR.

[0038] As used herein, "select" and "selected" with respect to a patient are used interchangeably. Based on the fact that a patient has a predefined criterion, It is used to mean specifically selected from a larger group of patients. "Selective treatment" refers to the treatment of patients with specific diseases according to predefined criteria. Providing treatment to patients who are specifically selected from a larger group of patients on the basis that they Similarly, "selective administration" means that an individual patient is administered administering a drug to a patient specifically selected from a larger group of patients on the basis of having Selecting, selectively treating, and selectively administering refer to administering to a patient Because the provider provides a standard treatment regimen based solely on the fact that the patient has a particular disease, and the patient's personal history (e.g., prior therapeutic interventions, e.g., prior treatment with biologics). , e.g., prior treatment with a TNF alpha antagonist) and / or biologically based Select means to provide individualized treatment to a patient. Select is used herein in connection with a method of treatment. As used herein, it does not refer to the incidental treatment of patients with certain criteria, but rather to patients It means a deliberate choice to administer treatment to a patient on the basis that the patient has a particular criterion. Therefore, selective treatment / administration is considered to be a given treatment regardless of the patient's medical history and / or biology. This differs from standard treatment / administration, which provides a specific drug to all patients with a disease.

[0039] As used herein, "a patient has not previously been treated with a TNF antagonist." "Selecting patients for treatment based on their TNF antagonist status" Selecting specific PsA patients from a larger group of PsA patients based on their prior exposure to The disclosed methods, kits, IL-17 antagonists and uses In some embodiments, the patient has previously received a TNF alpha antagonist. Based on these results, patients with PsA should be treated with IL-17 antagonists (e.g., secukinumab). Treatment with

[0040] As used herein, "DMARD" refers to disease-modifying antirheumatic drugs, e.g., methadone, ketamine, ketamine-1, ketamine-2, It means thotrexate.

[0041] As used herein, "active PsA" is defined as >3 swollen and >3 tender joints. In some embodiments, the patient to be treated is has active PsA.

[0042] As used herein, a patient with "concomitant psoriasis" also has plaque psoriasis. The present invention relates to a PsA patient having a PsA syndrome. In some embodiments, the patient has associated psoriasis, e.g., associated moderate to severe psoriasis. Clinicians usually define moderate to severe psoriasis as >10 skin lesions. In addition to having a DLQI (Diagnosis and Life Quality Index), patients were required to have a body surface area of ​​psoriasis >10 cm (BS A) and a PASI severity index of >10 (e.g., Mrowietz et al. et al. (2011) Arch. Dermatol. Res. 303:1-10).

[0043] IL-17 antagonists Various disclosed methods, kits, and methods include administering to a subject an IL-17 antagonist, e.g., an IL -17 binding molecules (e.g., soluble IL-17 receptors, IL-17 antibodies or antigen-binding fragments, e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 receptor In some embodiments, an IL-17 receptor antibody or antigen-binding fragment thereof is used. The antagonist is an IL-17 binding molecule, preferably an IL-7 antibody or an antigen binding It is a fragment.

[0044] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises the hypervariable region CDRs 1. At least one immunoglobulin heavy chain variable domain (V) comprising CDR2 and CDR3 H ), wherein CDR1 has the amino acid sequence SEQ ID NO: 1, and CDR2 has the amino acid sequence SEQ ID NO: The CDR1 has the amino acid sequence SEQ ID NO:2, and the CDR2 has the amino acid sequence SEQ ID NO:3. In some embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises a hypervariable region CDR1′, a CD4 domain, a CD5 domain, a CD6 domain, a CD7 domain, a CD8 domain, a CD9 domain, a CD10 domain, a CD11 domain, a CD12 domain, a CD13 domain, a CD14 domain, a CD15 domain, a CD16 domain, a CD17 domain, a CD18 domain, a CD19 domain, a CD20 domain, a CD2 At least one immunoglobulin light chain variable domain (V L’ ), wherein the CDR1' has the amino acid sequence SEQ ID NO:4, and the CDR2' has the amino acid sequence The CDR3' has the amino acid sequence SEQ ID NO: 5, and the CDR3' has the amino acid sequence SEQ ID NO: 6. In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises the hypervariable region CDR1-x At least one immunoglobulin heavy chain variable domain comprising CDR2-x and CDR3-x N(V H ), wherein the CDR1-x has the amino acid sequence SEQ ID NO: 11, 2-x has the amino acid sequence SEQ ID NO: 12, and said CDR3-x has the amino acid sequence SEQ ID NO: It has number 13.

[0045] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one Immunoglobulin (Ig) V H domain and at least one immunoglobulin V L domain a) Ig V H The domains may be (e.g., in order of) i) hypervariable region CDR1, CDR CDR1 has the amino acid sequence SEQ ID NO: 1 and CDR2 has the amino acid sequence SEQ ID NO: the CDR3 has the amino acid sequence SEQ ID NO:3; or ii) hypervariable regions CDR1-x, CDR2-x and CDR3-x, wherein CDR1-x is The CDR2-x has the amino acid sequence SEQ ID NO:12. and b) an Ig V CDR3-x having the amino acid sequence SEQ ID NO: 13; L A domain may be made up of (for example, in order) hypervariable regions CDR1', CDR2' and CDR3' (see above). CDR1' has the amino acid sequence SEQ ID NO: 4 and said CDR2' has the amino acid sequence SEQ ID NO: SEQ ID NO:5, and said CDR3' has the amino acid sequence SEQ ID NO:6).

[0046] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises: a) An immunoglobulin heavy chain variable domain (V) comprising the amino acid sequence set forth as SEQ ID NO:8. H ) b) an Ig light chain variable domain (V L ), c) an IgV comprising the amino acid sequence shown as SEQ ID NO:8; H Domain and SEQ ID NO:10 Ig V containing the amino acid sequence shown as L domain, d) SEQ ID NO: 1, SEQ ID NO: 2, and and an IgV comprising the hypervariable region shown as SEQ ID NO:3. H domain, e) SEQ ID NO: 4, Ig V comprising the hypervariable region shown as sequence number 5 and SEQ ID NO:6 L Domain, f) Sequence Ig V comprising the hypervariable regions shown as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 H D g) I comprising the hypervariable regions shown as SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 g V H The domains and hypervariable regions shown as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 Ig V, including the L domain, or h) SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13; Ig V containing hypervariable regions designated as H Domain and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: Ig V containing the hypervariable region shown as column number 6 L domain.

[0047] For ease of reference, the following are used: Ultrastructural characterization of secukinumab monoclonal antibody using the approach of hothia and coworkers The amino acid sequences of the variable regions are shown in Table 1 below.

[0048] [Table 1]

[0049] In a preferred embodiment, the constant region domain is also preferably, e.g., Proteins of Immunological Interest”, Kabat EA et al., US Department of Health and As documented in the National Institute of Health, the Public Health Service, and the Human Services, The DNA encoding the VL of secukinumab is sequenced. Number 9 shows the V of secukinumab. H The DNA encoding this is shown in SEQ ID NO:7.

[0050] In some embodiments, an IL-17 antibody or antigen-binding fragment thereof (e.g., sec- numab) comprises the three CDRs of SEQ ID NO: 10. In another embodiment, the antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:8. The IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:10 and the CDR of SEQ ID NO:8. The CDRs of SEQ ID NO:8 and SEQ ID NO:10 can be found in Table 1. Cut.

[0051] In some embodiments, the IL-17 antibody or antigen-binding fragment thereof is SEQ ID NO: 14. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises a light chain of SEQ ID NO: In another embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises a heavy chain of In some embodiments, the I The L-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 14. In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO:15. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises the amino acid sequence of SEQ ID NO: 3. The CDRs of SEQ ID NO: 14 and SEQ ID NO: 15 are included. The DRs can be found in Table 1.

[0052] The hypervariable regions are preferably of human origin, but any type of framework region may be used. Suitable framework regions can be associated with the ribozyme-binding domain. A preferred heavy chain framework is a human heavy chain framework, e.g., The heavy chain framework of the Numab antibody is, in order, for example, FR1 (SEQ ID NO: 8) FR2 (amino acids 36 to 49 of SEQ ID NO: 8), FR3 (amino acids 1 to 30 of SEQ ID NO: 8), 8) and FR4 (amino acids 117-127 of SEQ ID NO: 8) Taking into account the defined hypervariable regions of secukinumab by X-ray analysis, other preferred heavy chain The framework is, in order, FR1-x (amino acids 1 to 25 of SEQ ID NO: 8), FR2-x ( FR3-x (amino acids 36 to 49 of SEQ ID NO: 8), FR3-x (amino acids 61 to 95 of SEQ ID NO: 8), and and FR4 (amino acids 119 to 127 of SEQ ID NO: 8). The workpiece is, in order, FR1' (amino acids 1 to 23 of SEQ ID NO: 10), FR2' (amino acids 1 to 23 of SEQ ID NO: 1 0), FR3' (amino acids 58 to 89 of SEQ ID NO: 10), and FR4' ' (amino acids 99 to 109 of sequence number 10) region.

[0053] In one embodiment, an IL-17 antibody or antigen-binding fragment thereof, e.g., Seckinumab The antibody comprises at least a) a variable domain comprising hypervariable regions CDR1, CDR2 and CDR3 in that order; and an immunoglobulin heavy chain or a fragment thereof containing a constant region of a human heavy chain or a fragment thereof (see above). DR1 has the amino acid sequence SEQ ID NO:1, and said CDR2 has the amino acid sequence SEQ ID NO:2. and b) a hypervariable region CDR3 having the amino acid sequence SEQ ID NO:3, A variable domain including DR1', CDR2' and CDR3' and a constant region of a human light chain or or a fragment thereof, comprising the amino acid sequence SEQ ID NO: and said CDR2' has the amino acid sequence SEQ ID NO:5, and said CDR3' has the amino acid sequence SEQ ID NO:6. It is a human IL-17 antibody having the amino acid sequence SEQ ID NO:6.

[0054] 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 domains, said CDR1 being The CDR2 has the amino acid sequence SEQ ID NO:2, and the CDR3 has the amino acid sequence SEQ ID NO:3. , having the amino acid sequence SEQ ID NO: 3), and b) the 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 or a peptide linker linked to the C-terminus of the first domain and the N-terminus of the second domain. The antibody is selected from a single chain antibody or an antigen-binding fragment thereof that comprises an antigen-binding site that includes an anchor.

[0055] Alternatively, the IL-17 antibody or antigen-binding fragment thereof for use in the disclosed method may be identified by its sequence as These may include derivatives of the IL-17 antibodies described herein (e.g., pegylated versions of secukinumab). Alternatively, the V of the IL-17 antibody or antigen-binding fragment thereof used in the disclosed method H Or V L The domains are shown in the V H Or V L Domains (e.g., those shown in SEQ ID NOs: 8 and 10) V H Or V L The human IgG1 gene may have a domain. The human IL-17 antibody has a heavy chain and a nucleic acid sequence substantially identical to those set forth as SEQ ID NO:15. and / or a light chain substantially the same as that shown as SEQ ID NO: 14. The human IL-17 antibody disclosed herein comprises a heavy chain comprising SEQ ID NO:15 and a heavy chain comprising SEQ ID NO:14. The human IL-17 antibodies disclosed herein may comprise a light chain comprising a) the amino acid sequence shown in SEQ ID NO:8 The invention relates to a method for producing a human heavy chain comprising administering to a mammalian animal or animal the ... and b) a heavy chain having substantially the same amino acid sequence as set forth in SEQ ID NO:10. The antibody may comprise one light chain comprising a variable domain having a constant region of a human light chain and a variable domain having a constant region of a human light chain.

[0056] Alternatively, the IL-17 antibody or antigen-binding fragment thereof for use in the disclosed methods may be any of the antibodies described herein. The present disclosure also relates to secukinumab. V H Or V L one or more amino acid residues in a domain (e.g., Cys97 in the light chain); Typically only a small number (e.g., 1-10) of mutations in the corresponding DNA sequence, e.g. IL-17 antibodies or their antigen binding altered, e.g., by site-directed mutagenesis In all such cases, derivatives and variants are included. In the present invention, the IL-17 antibody or antigen-binding fragment thereof has a concentration of about 50 nM or less, about 20 nM or less, about 1 of said molecule at 0 nM or less, about 5 nM or less, about 2 nM or less, or more preferably about 1 nM or less At a concentration of about 1 nM (= 30 ng / ml), the activity of human IL-17 was inhibited by 50%, and the inhibitory activity was The properties are as described in Example 1 of WO 2006 / 013107. Based on the IL-6 production induced by hu-IL-17 in human skin fibroblasts, It is measured by

[0057] In some embodiments, an IL-17 antibody or antigen-binding fragment thereof, e.g., sec- Numab is a marker for Leu74, Tyr85, His86, Met87, Asn88, and Val12. 4. Constituents containing Thr125, Pro126, Ile127, Val128, and His129 In some embodiments, the IL-17 antibody binds to an epitope on mature human IL-17. For example, secukinumab has Tyr43, Tyr44, Arg46, Ala79, and As In some embodiments, the p80 epitope of mature human IL-17 is IL-17 antibodies, such as secukinumab, are IL-17 antibodies that have two mature human IL-17 chains. 17 homodimer epitope, which is comprised of Leu74 on one chain, T yr85, His86, Met87, Asn88, Val124, Thr125, Pro 126, Ile127, Val128, His129 and Tyr43, Tyr on the other chain These epitopes include 44, Arg46, Ala79, and Asp80. The residue numbering scheme used is one in which one is the residue that is the first amino acid in the mature protein ( That is, IL-17A lacks the 23 amino acid N-terminal signal peptide and begins with glycine. The sequence of immature IL-17A is based on Swiss-Prot entry Q16 In some embodiments, the IL-17 antibody is at about 100-2 K 00pM D In some embodiments, the IL-17 antibody has a IC of approximately 0.4 nM for in vitro neutralization of the biological activity of human IL-17A 50 Have In some embodiments, the absolute concentration of the subcutaneously (sc) administered IL-17 antibody is The overall bioavailability ranges from about 60% to about 80%, for example about 76%. In embodiments, an IL-17 antibody, such as, for example, secukinumab, is administered for about 4 weeks (e.g., about It has a half-life of about 23 to about 35 days, about 23 to about 30 days, for example, about 30 days. In some embodiments, the IL-17 antibody (e.g., secukinumab) exhibits a T of about 7 to 8 days. m ax has.

[0058] 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. Antibodies, in particular those described in Examples 1 and 2 of WO 2006 / 013107. Secukinumab is currently in clinical trials for the treatment of immune-mediated inflammatory conditions. Currently available recombinant high affinity fully human monoclonal anti-human IgG1 / kappa isotype Secukinumab (e.g., For example, see International Publication No. WO 2006 / 013107 and International Publication No. WO 2007 / 11 (see brochure no. 7749) has a very high affinity for IL-17, i.e., approximately K of 100-200 pM D and about 0.4 nM of about 0.67 nM of human IL-17A. IC of in vitro neutralization of antimicrobial activity 50 Therefore, secukinumab has a This high binding affinity makes secukinumab suitable for therapeutic applications. Moreover, secukinumab has been shown to be particularly useful in the treatment of chronic, lifelong diseases such as PsA. Allows for long periods between doses, a particularly attractive property when treating sexual disorders It has been confirmed that it has a very long half-life (about 4 weeks).

[0059] Other preferred IL-17 antagonists for use in the disclosed methods, kits and regimens include , U.S. Pat. No. 7,767,200, which are incorporated by reference herein in their entireties. Broerdal, which is described in Specification No. 6 (International Publication No. 08054603 Pamphlet) Mabs and other antagonists and U.S. Pat. No. 8,057,794, Specification Nos. 3,099, 8,110,191 and 7,838,638 and U.S. Patent Application Publication Nos. 20120034656 and 2011002729 The IL-17 antibody is described in the specification of No. 0.

[0060] Methods of Treatment and Use of IL-17 Antagonists The disclosed IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL- 17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor-binding fragment The antibody (e.g., an IL-17 antibody or antigen-binding fragment thereof) can be used in vitro or ex vivo. They can be used in vo or incorporated into pharmaceutical compositions and administered in vivo to individuals (e.g., human patients). In vivo administration to PsA patients, e.g., those who have not previously been treated with TNF inhibitors Patients with PsA who had not received TNF medication (TNF-naive patients) and those who had not received TNF inhibitor treatment Previously treated PsA patients, e.g., those who had been treated with TNF inhibitors but had a poor response to them Patients who had an adequate response (e.g., failure or less than desirable response) (TNF-I It can inhibit the progression of structural damage in patients with RA.

[0061] IL-17 antagonists, e.g., 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 ( For example, the IL-17 receptor antibody or antigen-binding fragment thereof may be administered in a pharma- ceutically acceptable carrier. When mixed with IL-1, it can be used as a pharmaceutical composition. In addition to the 7 antagonists, carriers, various diluents, bulking agents, salts, buffers, stabilizers, solubilizers, The characteristics of the carrier may depend on the route of administration. The pharmaceutical compositions used in the disclosed methods may be used as additional therapeutic agents for the treatment of specific target disorders. For example, the pharmaceutical composition may also include an anti-inflammatory drug. Additional factors / agents may be used to synergize with the IL-17 binding molecule or to inhibit IL- 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., Minimize side effects caused by IL-17 receptor antibody or its antigen-binding fragment The compound can be included in a pharmaceutical composition to provide a

[0062] The pharmaceutical compositions used in the disclosed methods can be prepared in a conventional manner. In the present embodiment, the pharmaceutical composition is provided as a lyophilized form. Dissolve in a suitable aqueous carrier, such as sterile water for injection or sterile buffered saline. It may be desirable to prepare a larger volume of solution for administration by injection rather than If necessary, human serum albumin or the patient's own heparinized blood should be mixed with saline at the time of preparation. It may be advantageous to have contamination with such physiologically inactive proteins in excess. This reduces the loss of antibodies due to adsorption onto the walls of containers and tubing used with the infusion solution. When albumin is used, the appropriate concentration is 0.5 to 4.5 ml of saline solution. 5% by weight. Other formulations include liquid or lyophilized formulations.

[0063] Antibodies, e.g., antibodies against IL-17, are generally available in aqueous formulations ready for parenteral administration. The pharmaceutical composition may be formulated in a liquid form or as a lyophilizate for reconstitution with an appropriate diluent prior to administration. In some embodiments of the disclosed methods and uses, an IL-17 antagonist, e.g. For example, the IL-17 antibody, e.g., secukinumab, is formulated as a lyophilizate. The dry formulation can be reconstituted with a small amount of liquid (e.g., 1 ml) to allow for subcutaneous administration. This allows for a solution with low levels of antibody aggregation. ) (trastuzumab), RITUXAN(TM) (rituximab), SYNAGIS(TM) The use of antibodies as active ingredients in pharmaceuticals, including palivizumab, is now widely known. Techniques for purifying antibodies for pharmaceutical use are well known in the art. IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies or or an 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 injected intravenously, cutaneously, or subcutaneously. In this case, the IL-17 antagonist is administered in the form of a pyrogen-free, parenterally acceptable solution. The pharmaceutical composition for intravenous, cutaneous or subcutaneous injection contains, in addition to the IL-17 antagonist, , sodium chloride, Ringer's solution, dextrose, dextrose and sodium chloride, Isotonic excipients such as lactated Ringer's solution, or other excipients known in the art, may be included.

[0064] The appropriate dose will depend, for example, on the particular IL-17 antagonist used, e.g., IL- IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab mab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or its The specific therapeutic agent (i.e., the agonist binding fragment), the host, the method of administration, and the nature and severity of the condition being treated and the patient's ability to tolerate the treatment. Ultimately, the cost of treatment varies depending on the nature of the prior treatment received. In some embodiments, the amount of IL-17 antagonist is determined for use in providing medical care. The researchers could administer low doses of an IL-17 antagonist and observe the patient's response. In another embodiment, the initial dose (s) of IL-17 antagonist administered to the patient The dose is then adjusted downward until signs of relapse occur. Administer higher doses of IL-17 antagonist until optimal therapeutic effect is achieved. and generally does not require further increase in dose.

[0065] In carrying out some of the methods of treatment or uses of the present disclosure, a therapeutically effective amount of IL-17 antigen is administered. antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies or their antagonists) IL-17 receptor binding fragments (e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL- 17 receptor antibody or antigen-binding fragment thereof) to a patient, e.g., a mammal (e.g., a human). The disclosed methods use an IL-17 antagonist (e.g., secukinumab). The present invention provides a method for treating PsA patients by administering IL-17 antagonists to the patients. If patients should ultimately be treated with IL-17 antagonist therapy, such IL-17 antagonist therapy may be necessary. This does not necessarily exclude monotherapy. Indeed, if patients are receiving IL-17 antagonists, If selected for treatment, an IL-17 antagonist (e.g., secukinumab) may be used in accordance with the present disclosure. alone or in combination with other drugs and therapies for treating patients with PsA, according to the methods of , for example, immunosuppressants, disease-modifying antirheumatic drugs (DMARDs) (e.g., MTX), pain Control medications (e.g. tramadol or paracetamol), steroids (e.g. prednisolone ), nonsteroidal anti-inflammatory drugs (NSAIDs), cytokine antagonists, bone anabolic at least one of the following: It can be administered in combination with one or more additional PsA medications. When administering the IL-17 antagonist, it is possible to administer the IL-17 antagonist simultaneously or sequentially with other agents. If administered sequentially, your physician may recommend administering the IL-17 antagonist in combination with other agents. Determine the appropriate order in which to administer the agents, as well as appropriate doses for co-delivery.

[0066] Nonsteroidal anti-inflammatory and anti-inflammatory drugs useful in combination with secukinumab for the treatment of patients with PsA Pain management drugs include propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, Cox inhibitors, such as lumiracoxib, ibuprofen, fenoprofen, ketoprofen Fen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodora ketorolac, nabumetone, aspirin, naproxen, valdecoxib, etorix sib, MK0966; rofecoxib, acetominophen, celecoxib Sib, diclofenac, tramadol, piroxicam, meloxicam, tenoxicam, doxorubicin, Roxicam, lornoxicam, isoxicam, mefanamemic acid, meclofenamic acid, flufenamic acid Enamic acid, tolfenamic, valedecoxib, parecoxib, etodolac, These include indomethacin, aspirin, ibuprofen, and firocoxib. DMA useful in combination with IL-17 antagonists, e.g., secukinumab, for the treatment of RDs are prescribed methotrexate (MTX), antimalarials (e.g., hydroxychloroquine, and chloroquine), sulfasalazine, leflunomide, azathioprine, cyclosporine, Gold salts, minocycline, cyclophosphamide, D-penicillamine, minocycline, These include lanofin, tacrolimus, myocrisin, and chlorambucil. Steroids useful in combination with IL-17 antagonists, e.g., secukinumab, for (e.g., glucocorticoids) include prednisolone, prednisone, dexamethasone, Cortisol, cortisone, hydrocortisone, methylprednisolone, betamethasone, Triamcinolone, beclometasome, fludrocortisone, deoxycortisone Contains corticosterone and aldosterone.

[0067] In combination with IL-17 antagonists, e.g., secukinumab, for the treatment of patients with PsA. Biologic agents useful for this purpose include adalimumab (Humira®), etanercept (Enbrel®), infliximab (Remicade®); TA-650), certolizumab pegol (Cimzia®; CDP870), Golimumab (Simponi®; CNTO148), Anakinas (Kiner et®), rituximab (Rituxan®); MabThera Registered Trademark), abatacept (Orencia®), tocilizumab (RoAc temAS / Actemra®), integrin antagonist (TYSAB RI® (natalizumab)), IL-1 antagonist (ACZ885 (Ilarizumab)), AnakinAS (Kineret®), CD4 antagonist, Other IL-17 antagonists (LY2439821, RG4934, AMG827, SCH900117, R05310074, MEDI-571, CAT-2200), I L-23 antagonist, IL-20 antagonist, IL-6 antagonist, TNF Alpha antagonists (e.g., TNF alpha antagonists or TNF alpha receptors) receptor antagonists (e.g., pegsnercept, etc.), BLyS antagonists (e.g., , Atacicept, Benlysta® / LymphoStat-B® ) (belimumab)), P38 inhibitors, CD20 antagonists (ocrelizumab, ophar Tumor tumour (Arzerra®), interferon gamma antagonist ( Hontolizumab).

[0068] IL-17 antagonists, such as secukinumab, can be administered parenterally, e.g., into the antecubital or iliac artery. The pharmaceutical compositions of the present disclosure are conveniently administered intravenously into a peripheral vein, intramuscularly, or subcutaneously. The duration of intravenous (iv) therapy with the composition will depend on the severity of the disease being treated and on the individual The administration of the pharmaceutical composition of the present disclosure subcutaneously (sc .) therapy is also contemplated. Healthcare providers may administer IV or s.v. therapy using the pharmaceutical compositions of the present disclosure. c. Determine the appropriate duration and timing of therapy to treat patients with PsA. The preferred administration and treatment regimens (including both induction and maintenance regimens) of PCT Application No. PCT / U.S. Pat. No. 6,313,636, which is incorporated herein by reference as it relates to the present invention. This is presented in application publication no. 2011 / 064307.

[0069] In one embodiment, the IL-17 antagonist (e.g., secukinumab) is administered at 0, 2 and 3 times a day. Patients were administered approximately 10 mg / kg intravenously (iv) every other week for weeks 1 and 4, then 8 and Start at 75 mg to 300 mg once a month (for example, 75 mg, 150 mg, 3 Patients were administered subcutaneous (sc) doses of 0.000 mg each at 0, 2 and 4 weeks. Approximately 10 mg / kg is administered iv, and then the patient is administered approximately 75 mg / kg at weeks 8, 12, 16, 20, etc. mg to about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) of IL-17 The antagonist (eg, secukinumab) is administered sc.

[0070] In another embodiment, the IL-17 antagonist (e.g., secukinumab) is administered at 0, 1 and about 75 mg to about 300 mg (e.g., about 75 mg, about 150 mg, about 3 00 mg) sc to patients, then approximately once a month (every 4 weeks) starting in the 4th week. 75 mg to about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) for patients In this way, patients were administered the drug sc at weeks 0, 1, 2, 3, 4, 8, 12, 16, and 20. etc., about 75 mg to about 300 mg (for example, about 75 mg, about 150 mg, about 300 mg) An IL-17 antagonist (eg, secukinumab) is administered sc.

[0071] Alternatively, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., IL- 17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor-binding fragment The compound (e.g., an IL-17 antibody or antigen-binding fragment thereof) can be administered to a patient without a loading dose regimen. For example, secukinumab can be administered at about 75 mg to about 30 mg every 4 weeks (once a month). 0 mg (e.g., about 75 mg, about 150 mg, about 300 mg) and administer sc to the patient. In this way, patients can be given approximately 75 mg to 20 mg of the drug at weeks 0, 4, 8, 12, 16, 20, etc. About 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) of IL-17 antagonist A gonist (e.g., secukinumab) is administered sc.

[0072] Certain patients, for example, may be treated with IL-17 antagonists, e.g., IL-17 binding molecules (e.g., For example, an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab, or an IL-1 7 receptor-binding molecules (e.g., IL-17 receptor antibodies or antigen-binding fragments thereof) Dose escalation may be necessary for patients who respond inadequately to treatment (e.g., induction therapy). It will be understood that the use of secukinumab sc is The amount is from about 75 mg to about 300 mg (sc), e.g., about 80 mg, about 10 0mg, about 125mg, about 175mg, about 200mg, about 250mg, about 350mg, about Similarly, an iv dose may be greater than about 10 mg / kg, e.g. For example, about 11 mg / kg, 12 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg kg, 30 mg / kg, 35 mg / kg, etc. Depending on the particular patient, e.g., adverse events or showed adverse reactions to treatment with IL-17 antagonists (e.g., secukinumab). Dose reduction may be necessary for patients with , as will be understood. Therefore, the dose of secukinumab is about 75 mg to about 300 mg (s. c.) less than about 25 mg, about 50 mg, about 80 mg, about 100 mg, about 125 mg g, about 175 mg, about 200 mg, 250 mg, etc. Similarly, the iv dose can be Less than about 10 mg / kg, for example, about 9 mg / kg, 8 mg / kg, 5 mg / kg, 4 mg / kg, 3 mg / kg, 2 mg / kg, 1 mg / kg, etc. In the present invention, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., IL- 17 antibody or antigen-binding fragment thereof, e.g., secukinumab) or IL-17 receptor-binding fragment The antibody (e.g., an IL-17 receptor antibody or antigen-binding fragment thereof) can be delivered, for example, sc. Patients can be administered an initial dose of 75 mg or 150 mg, which can then be administered by a physician. Increase the dose to 150 mg or 300 mg if necessary, as determined by the patient's doctor.

[0073] In some embodiments, the dosage used is indicated for each individual patient. For example, in some embodiments, a biologic (e.g., a TNF alpha antagonist) Previously failed treatment with or biologics (e.g., TNF-alpha antagonists) In patients with concomitant moderate to severe plaque psoriasis who have previously responded inadequately to Preferably, a dose of 300 mg of IL-17 antibody (secukinumab) is administered.

[0074] The timing of administration is generally on the day of the first dose of secukinumab (also known as the "baseline"). However, healthcare providers should clarify the dosing schedule, as shown in Table 2. They often use different naming conventions to facilitate consistency.

[0075] [Table 2]

[0076] In particular, week 0 is sometimes referred to as week 1 by some healthcare providers, while day 0 is sometimes referred to as Day 1 by some healthcare providers. Therefore, While mentioning this, different doctors may, for example, give the following treatment at week 3 / day 21, week 3 / day 22, and week 4: For consistency, the study may specify dosing on week 12 / day 21 or week 4 / day 22. For purposes of this discussion, the first week of administration is referred to herein as week 0, while the first day of administration is referred to herein as week 1. shall be called Day 1. However, this naming convention is used solely for consistency. and should not be construed as limiting, i.e., a physician may refer to a particular week as "week 1" or "week Regardless of whether it is referred to as "week 2," the once-weekly dosing is in keeping with the once-weekly dosing rules for IL-17 antibodies. Further, in a preferred dosing regimen, the antibody is administered at 0, 1, 2, 3, 4, 8, It is administered at weeks 12, 16, 20, etc. One provider uses this regimen weekly for 5 weeks. This can be referred to as administration of antibody once a month (or every 4 weeks) starting at week 8 and then once a month thereafter. while other providers may administer this regimen once a week for 4 weeks and then once a week for the 4th week. This could be called a monthly (or every 4 weeks) dose of the antibody, starting at 10:00 a.m. Nonetheless, it will be appreciated by those of skill in the art that the different naming conventions identify the same regimen. Well understood. Weekly doses at weeks 0, 1, 2, 3, and 4, then every 4 weeks. is administered once a week during weeks 0, 1, 2, and 3, followed by administration every 4 weeks starting in week 4. It will be appreciated by those skilled in the art that this is the same regimen.

[0077] Thus, disclosed herein is an IL-17 antagonist for use in treating patients in need thereof. The present invention relates to a method for inhibiting the progression of structural damage in a patient with PsA, the method comprising administering to a patient having Also disclosed herein are methods for administering IL-17 antagonists to patients in need thereof. and reducing the signs and symptoms of active PsA in PsA patients, including administering inhibits the progression of structural (e.g., bone and / or joint) damage in PsA patients and In some embodiments of the above method, the patient is , and biologic-naïve. In some embodiments, the patient is biologic-experienced. In some embodiments, the patient has previously been treated with a TNF alpha antagonist. In some embodiments of the disclosed uses, methods and kits, the patient is Previously treated with an NF alpha antagonist. Disclosed uses, methods and kits In some embodiments, the patient has had prior treatment with a TNF alpha antagonist. had an inadequate response to treatment (TNF-inadequate responders (TNF-IR)). In some embodiments of the methods and kits, the inhibition of progression of structural damage is der Heijde psoriatic arthritis measured by modified total Sharpe score (mTSS) In some embodiments of the disclosed uses, methods and kits, inhibition of progression of structural damage. Harm is measured by erosion and joint space narrowing (JSN) scores. and in some embodiments of the kit, the method comprises administering to the subject a therapeutically effective amount of ... The progression of joint enlargement, joint narrowing, subluxation, bone proliferation, osteolysis and / or ankylosis is inhibited. In some embodiments, the disclosed methods involve administering a DMARD, e.g., MTX. and administering to a patient. In this study, IL-17 antagonist was administered at approximately 10 mg / kg every other week at weeks 0, 2, and 4. The drug is administered intravenously (iv) to patients, and then approximately 75 mg and approximately 150 mg once a month starting in the 8th week. The disclosed uses, methods and kits are administered subcutaneously (sc) to patients at a dose of about 300 mg or about 300 mg. In some embodiments, the IL-17 antagonist is administered at weeks 0, 1, 2 and 3. Patients are given sc doses of about 75 mg, about 150 mg, or about 300 mg once weekly, followed by 4 Patients will receive sc doses of approximately 75 mg, 150 mg, or 300 mg once a month starting on week 14. In some embodiments of the disclosed uses, methods and kits, the patient is diagnosed with concomitant dry eye. In some embodiments of the disclosed uses, methods and kits, structural damage Inhibition of progression is defined as a change from baseline in mTSS of ≦0.5. In some embodiments of the uses, methods and kits, the inhibition of progression of structural damage is ≦0. The efficacy and safety of the disclosed uses, methods and methods are defined as a change from baseline in erosion score of 0.3. In some embodiments of the present invention, inhibition of progression of structural damage is achieved by a JSN score of ≦0.2. The change from baseline in the level of schizophrenia is defined as the change from baseline in the level of schizophrenia. In an embodiment, the patient is a patient who has previously received treatment with a TNF alpha antagonist. In some embodiments, TNF-alpha antibodies are selected for treatment based on the level of the antibody. Patients were treated with IL-17 antagonists based on prior treatment with an IL-17 antagonist. (Secukinumab) is administered selectively.

[0078] 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 comprises: a) Leu74 ,Tyr85,His86,Met87,Asn88,Val124,Thr125,P Epitopes of IL-17 including ro126, Ile127, Val128, and His129 b) an IL-17 antibody or an antigen-binding fragment thereof that binds to Tyr43, Tyr44, Arg; IL-17 antibody that binds to epitopes of IL-17 including 46, Ala79, and Asp80 or an antigen-binding fragment thereof, c) an IL-17 homozygote having two mature IL-17 protein chains. Binds to a dimeric epitope, which is located at Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, I Le127, Val128, His129 and Tyr43, Tyr44, Ar on the other chain IL-17 antibody or antigen-binding fragment thereof, comprising g46, Ala79, and Asp80; d) 2 Binds to an epitope on the IL-17 homodimer having two mature IL-17 protein chains, The epitope is located at Leu74, Tyr85, His86, Met87, As on one chain. n88, Val124, Thr125, Pro126, Ile127, Val128, H Tyr43, Tyr44, Arg46, Ala79, Asp8 on is129 and other strands K of approximately 100-200 pM, including 0 D It has an in vivo half-life of about 23 to about 35 days. and e) an IL-17 antibody or antigen-binding fragment thereof having the structure shown as SEQ ID NO: 8. The immunoglobulin heavy chain variable domain (V H ), ii) SEQ ID NO: 1 The immunoglobulin light chain variable domain (V L ), iii ) Immunoglobulin V comprising the amino acid sequence shown as SEQ ID NO:8 H Domain and sequence number Immunoglobulin V containing the amino acid sequence shown as No. 10 L domain, iv) sequence number 1, an immunoglobulin V comprising a hypervariable region shown as SEQ ID NO:2 and SEQ ID NO:3 H Domestic v) an immunological compound comprising the hypervariable regions shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; Globulin V L vi) domains shown as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 Immunoglobulin V containing the hypervariable region H domain, vii) SEQ ID NO:1, SEQ ID NO:2 and an immunoglobulin V comprising a hypervariable region as shown in SEQ ID NO:3 H Domains and sequences Immunoglobulin V comprising the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L domain, viii) the hyperpolymerization domains shown as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13; Immunoglobulin V containing variable regions H Domains and SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6 Immunoglobulin V containing a hypervariable region designated as L Domain, ix) SEQ ID NO: 14 x) an immunoglobulin light chain comprising the amino acid sequence shown as SEQ ID NO: 15; or xi) an immunoglobulin heavy chain comprising the amino acid sequence shown as SEQ ID NO: 14. and an immunoglobulin light chain comprising the amino acid sequence shown as SEQ ID NO: 15. The antibody is selected from the group consisting of an IL-17 antibody or an antigen-binding fragment thereof that comprises a globulin heavy chain. In some embodiments of the disclosed uses, methods and kits, an IL-17 antibody or its The antigen-binding fragment is secukinumab.

[0079] Further disclosed herein is a method for administering about 75 mg to about 300 mg of secukinumab once a month to a patient. and administering to a subject who has previously been treated with a TNF alpha antagonist, A method for inhibiting the progression of structural damage in sA patients.

[0080] Further disclosed herein is an initial administration at weeks 0, 1, 2 and 3 followed by 4 Patients will receive approximately 150 mg or 300 mg of secukinumab once a month starting on week 1 of each month. The present invention relates to a method for treating a patient with a TNF alpha antagonist, the method comprising administering the TNF alpha antagonist to a patient by subcutaneous injection. This is a method to inhibit the progression of structural damage in PsA patients who have previously received

[0081] Further disclosed herein is a method for administering about 10 mg / kg of cerebrospinal fluid by intravenous injection at weeks 0, 2 and 4. Patients were administered 15 kg of secukinumab followed by approximately 15 mg of secukinumab by subcutaneous injection starting at week 8. administering to a patient about 0 mg or about 300 mg of secukinumab. Inhibits progression of structural damage in PsA patients previously treated with antagonists This is how to do it.

[0082] Further disclosed herein is a method for treating rheumatoid arthritis in patients who have previously undergone treatment with a TNF alpha antagonist. and the use of IL-1 in the manufacture of a drug to inhibit the progression of structural damage in PsA patients. 17 antagonists (e.g., secukinumab).

[0083] Further disclosed herein is a method for administering about 75 mg to about 300 mg of secukinumab once a month to a patient. Previous treatment with a TNF-alpha antagonist, including administration to patients with This is a method to inhibit the progression of structural damage in PsA patients, who are then selected for treatment based on do.

[0084] Further disclosed herein is a method for administering about 75 mg to about 300 mg of secukinumab once a month to a patient. selective administration to subjects who have previously received treatment with a TNF alpha antagonist; Inhibits progression of structural damage in PsA patients who are selected for treatment based on This is the method.

[0085] Further disclosed herein is a method for preparing a pharmaceutical composition comprising the steps of: At least about 75 mg to about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) g) sufficient to allow delivery of an IL-17 antagonist (e.g., secukinumab) PsA patients with adequate amounts of IL-17 antagonists (e.g., TNF alpha antagonists) to inhibit the progression of structural damage in patients with PsA who had previously been treated with agonists and an IL-17 antagonist (e.g., secukinumab) for use in the manufacture of a medicament for treating IL-17 infection.

[0086] Further disclosed herein is a method for preparing a pharmaceutical composition comprising the steps of: At least about 75 mg to about 300 mg (e.g., about 75 mg, about 150 mg, about 300 mg) g) to enable subcutaneous delivery of an IL-17 antagonist (e.g., secukinumab); PsA patients with sufficient IL-17 antagonists (e.g., TNF-alpha antagonists) To inhibit the progression of structural damage in patients previously treated with anti-inflammatory drugs and an IL-17 antagonist (e.g., secukinumab) for use in the manufacture of a medicament for the treatment of cancer.

[0087] Further disclosed herein is a method for preparing a pharmaceutical composition comprising the steps of: A sufficient amount of IL-17 antagonist to allow delivery of at least about 10 mg / kg. PsA patients with a history of pulmonary stenosis (e.g., those previously treated with a TNF-alpha antagonist) The IL-17 antigen for use in the manufacture of a drug to inhibit the progression of structural damage in patients with antagonists (e.g., secukinumab).

[0088] Further disclosed herein is a method for the intravenous delivery of approximately 10 mg / kg per unit dose. In patients with PsA (e.g., those treated with TNF alpha antagonists) For use in the manufacture of a medicament for inhibiting the progression of structural damage in patients previously treated with and IL-17 antagonists (e.g., secukinumab).

[0089] As used herein, "a dosage that allows for the delivery of a [specified dose] by a [route of administration]" means a The phrase "prescribed in an amount" refers to the amount administered by a specified route of administration (e.g., sc or iv). and administering a desired dose of an IL-17 antagonist, e.g., an IL-17 antibody, e.g., secukinumab. It is used to indicate that certain pharmaceutical compositions can be used to deliver mabs. As an example, if the desired subcutaneous dose is 300 mg, the clinician may administer a 150 mg / ml 2 ml of IL-17 antibody formulation having a concentration of 300 mg / ml, 1 ml of I IL-17 antibody preparation, 0.5ml of IL-17 antibody preparation having a concentration of 600mg / ml, etc. In each such case, these IL-17 antibody preparations may be used. The concentration is high enough to allow subcutaneous delivery of the L-17 antibody. Subcutaneous delivery is generally Delivery of a volume of less than about 2 ml, preferably about 1 ml or less, is required.

[0090] As used herein, "an amount sufficient to permit delivery of [a specified dose]" means "an amount sufficient to permit delivery of [a specified dose]" The "container having the IL-17 antagonist" refers to a predetermined container (e.g., a vial, a pen, The volume of IL-17 antagonist that can be used to deliver the desired dose is determined by the syringe. It means that a drug substance (e.g., as part of a pharmaceutical composition) has been placed therein. Therefore, if the desired dose is 150 mg, the clinician should administer an IL-1000 with a concentration of 75 mg / ml. -2 ml from a container (e.g., a prefilled syringe or autoinjector) containing the antibody formulation , into a container (e.g., drug-filled) containing an IL-17 antibody formulation having a concentration of 150 mg / ml. IL-1 with a concentration of 300 mg / ml was administered using a used syringe or automatic injection device. 7. 0.5 ml from a container (e.g., a prefilled syringe or autoinjector) containing the antibody formulation. etc. In each such case, these containers (e.g., A prefilled syringe or autoinjector (prefilled syringe or autoinjector) is used to allow delivery of the desired 150 mg dose. Having a sufficient amount of IL-17 antagonist.

[0091] Disclosed herein is a formulation that contains containers, each container containing at least one unit dose. Approximately 150 mg to approximately 300 mg of an IL-17 antagonist (e.g., secukinumab) having an IL-17 antagonist in an amount sufficient to allow delivery of IL-17 antagonists (e.g., secukinumab) for the manufacture of a medicament for the treatment of sA. (B).

[0092] Disclosed herein is a formulation that contains containers, each container containing at least one unit dose. and a sufficient amount of IL-17 antagonist (e.g., For the manufacture of a medicament for the treatment of PsA in a patient having An IL-17 antagonist (e.g., secukinumab).

[0093] Disclosed herein is a compound that allows intravenous delivery of approximately 10 mg / kg per unit dose. IL-1 for the manufacture of a drug for the treatment of PsA in patients, prescribed in doses 7 antagonists (e.g., secukinumab).

[0094] Disclosed herein is an IL-17 antigen containing about 150 mg to about 300 mg per unit dose. Drugs for the treatment of PsA, formulated in doses that allow for subcutaneous delivery of the antagonist and an IL-17 antagonist (e.g., secukinumab) for the manufacture of a therapeutic agent for treating rheumatoid arthritis.

[0095] kit The present disclosure provides a method for preventing structural damage (e.g., bone and joint) in PsA patients. Such kits also include kits that contain an IL-17 antagonist, e.g., an IL-17 binding an antibody or an antigen-binding fragment thereof, such as an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab; The IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof) (e.g., in liquid or lyophilized form) or a medicament comprising an IL-17 antagonist Further, such kits include a composition (described above) for administering an IL-17 antagonist. means for administering the agent (e.g., autoinjector, syringe and vial, pre-filled syringe, pre-filled pen) and instructions for use. These kits may include an encapsulated IL-17 antagonist, For example, an IL-17 binding molecule, e.g., an IL-17 antibody, e.g., secukinumab, For example, an additional therapeutic agent (described above) for treating PsA for delivery in combination. Such kits may include a kit for administering to a PsA patient (e.g., a patient who is TNF-naive). and / or TNF-IR to inhibit the progression of structural damage in PsA patients -Regarding administration of an IL-17 antagonist (e.g., an IL-17 antibody, e.g., secukinumab) Such instructions may also include instructions for use in administering the encapsulated IL-17 antagonist. and an IL-17 binding molecule, e.g., an IL-17 antibody, e.g., secukinumab. Dosages for use together (e.g., 10 mg / kg, 75 mg, 150 mg, 300 mg ), route of administration (e.g., iv or sc) and dosing regimen (e.g., 0, 2 and Approximately 10 mg / kg iv every other week starting in the 4th week, then approximately once a month starting in the 8th week 75 mg, about 150 mg, or about 300 mg administered sc; or 0, 1, 2, and 75 mg, 150 mg, or 300 mg sc once weekly for the third week, then Patients were given sc at approximately 75 mg, 150 mg, or 300 mg once a month starting in the 4th week. .administered).

[0096] The phrase "means for administering" includes pre-filled syringes, vials and syringes, and pen-type syringes. , automatic injection devices (e.g., with a syringe in it), IV drips and bags, pumps, etc. Any available device or vessel for systemic administration of a drug to a patient, including, but not limited to, Such an object is used to describe a device by which a patient self-administers a drug (i.e. (i.e., administer the drug for themselves) or a physician may administer the drug .

[0097] Disclosed herein are IL-17 antagonists (e.g., IL-17 binding molecules). , e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab), A kit for use in inhibiting the progression of structural damage in a patient. In some embodiments, the kit further comprises a means for administering the IL-17 antagonist to a patient. In some embodiments, the kit includes an IL-17 antagonist (e.g., IL-1 7-binding molecule, e.g., an IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab) Patients (TNF-naive) were randomly assigned to receive approximately 10 mg / kg of TNF-α every other week at weeks 0, 2, and 4. and / or TNF-experienced) should be administered intravenously (iv) starting at week 8. and about 75 mg to about 300 mg (for example, about 75 mg, about 150 mg, or about 300 mg) once a month. The IL-17 antagonist should be administered subcutaneously (sc) to patients at 1 mg In some embodiments, the kit further comprises instructions for administration of the IL-17 antagonists (e.g., IL-17 binding molecules, e.g., IL-17 antibodies or or an antigen-binding fragment thereof, e.g., secukinumab) at about 75 mg once weekly at weeks 0, 1, 2, and 3 ~ about 300 mg (e.g., about 75 mg, about 150 mg, or about 300 mg) sc to the patient should be administered once a month starting in the fourth week at about 75 mg to about 300 mg (e.g. For example, about 75 mg, about 150 mg, or about 300 mg should be administered sc to patients. The invention further includes instructions for administration of the IL-17 antagonist, the instructions including:

[0098] general In a preferred embodiment of the disclosed methods, treatments, regimens, uses and kits, IL- In a preferred embodiment, 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 preferred embodiment of the methods, regimens, uses and kits, an IL-17 antibody or an antigen thereof is administered. The binding fragment of the IL-17 antibody or antigen-binding fragment thereof is is86, Met87, Asn88, Val124, Thr125, Pro126, Il IL-17 binds to epitopes containing e127, Val128, and His129. 17 antibody or antigen-binding fragment thereof, b) Tyr43, Tyr44, Arg46, Ala79 IL-17 antibody that binds to an epitope of IL-17 containing Asp80 or antigen binding thereof c) an epitope of the IL-17 homodimer having two mature IL-17 protein chains and the epitope is located at Leu74, Tyr85, His86, Me on one chain. t87, Asn88, Val124, Thr125, Pro126, Ile127, Va l128, His129 and Tyr43, Tyr44, Arg46, Ala7 on the other chain 9. An IL-17 antibody or an antigen-binding fragment thereof, comprising Asp80; d) two mature IL-1 Binds to an epitope of the IL-17 homodimer having 7 protein chains, said epitope being Leu74, Tyr85, His86, Met87, Asn88, Val1 on one strand 24, Thr125, Pro126, Ile127, Val128, His129 and others IL-1, including Tyr43, Tyr44, Arg46, Ala79, and Asp80 on the IL-1 chain 17 binding molecules have a K of approximately 100-200 pM D and about 23 to about 35 days in and e) an IL-17 antibody or antigen-binding fragment thereof having a half-life in vivo; The immunoglobulin (Ig) heavy chain variable domain (V) containing the amino acid sequence shown as No. 8 H ii) an Ig light chain variable domain (V L iii) Ig V comprising the amino acid sequence shown as SEQ ID NO:8 H Domains and Sequences Ig V containing the amino acid sequence shown as number 10 L domain, iv) SEQ ID NO: 1, Ig V comprising the hypervariable region shown as sequence number 2 and SEQ ID NO:3 H domain, v) sequence Ig V comprising the hypervariable regions shown as SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L domain and vi) comprising the hypervariable regions set forth as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13. IgV H vii) the superfamily shown as SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3; Ig V containing the variable region H Domain and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 Ig V containing the indicated hypervariable regions L domain, viii) SEQ ID NO:11, SEQ ID NO:12 and an Ig V comprising the hypervariable region shown as SEQ ID NO:13. H Domain and SEQ ID NO:4 , an Ig V comprising the hypervariable regions shown as SEQ ID NO:5 and SEQ ID NO:6 L Domain, ix a) an Ig light chain comprising the amino acid sequence shown as SEQ ID NO: 14; and b) an Ig light chain comprising the amino acid sequence shown as SEQ ID NO: 15. or xi) an Ig heavy chain comprising the amino acid sequence shown as SEQ ID NO: 14. and an Ig heavy chain comprising the amino acid sequence shown as SEQ ID NO: 15. L-17 antibody or an antigen-binding fragment thereof.

[0099] In a preferred embodiment of the disclosed uses, methods and kits, an IL-17 antibody or its The antigen-binding fragment is IgG 1 In a preferred embodiment, the antibody or In a preferred embodiment, the antigen-binding fragment is secukinumab. The formulation, e.g., secukinumab, may be administered in a liquid pharmaceutical composition (e.g., reconstituted from a lyophilized formulation or in a liquid pharmaceutical composition). was not reconstituted from a lyophilizate).

[0100] The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Methods and materials similar to those described in or equivalent to those described in the above may be used in the practice or testing of the present disclosure. However, preferred methods and materials are now described. The following aspects of the present invention are apparent from the description and claims. In this context, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Unless otherwise noted, all technical and scientific terms used herein are of the art to which this disclosure belongs. All terms referred to in this specification have the same meaning as commonly understood by those skilled in the art. The patents and publications are incorporated by reference. The following examples are illustrative of preferred embodiments of the present disclosure. These examples are presented in order to more fully illustrate the embodiments defined by the appended claims. should not be construed to limit the scope of disclosed patient matter as defined in do not have. Working Example EXAMPLES

[0101] Proof-of-concept PsA study CAIN4572206 Example 1.1 - Study Design CAIN4572206 This is an activity based on the Current Proposed Classification Criteria for Clinical Trials (CASPAR). Repeated doses of AIN457 at 10 mg / kg for the treatment of patients with a diagnosis of progressive PsA ( This is a randomized, double-blind, placebo-controlled, multicenter, proof-of-concept study of Patients with moderate to severe PsA who met the following criteria were enrolled: (i) psoriasis; CASPAR criteria for the diagnosis of chronic arthritis (Taylor Wet et al. (2006) Arthritis Rheum, 54, 26 pp. 65-73); with correction for swelling and tenderness of at least three peripheral joints; (ii) P (iii) inflammatory pain ≥ 40; (iv) the disease persists for at least 3 months at the maximum tolerated dose. inadequately controlled with at least one DMARD administered monthly; (v) RF ≤ 100I U and negative CCP ELISA test. Efficacy was evaluated according to the OMERACT8 consensus. The eligibility assessment domains were based on the following: 1. Peripheral joint disorder (68 / 68 joint count) The ACR response criteria used, the PsARC with the DIP joint included in the joint count (Clegg et al. (1999) 96) Arthritis Rheum, Vol. 39, 2013-20) (i.e. 78 / 76 joint count); DAS2 8;2. Skin assessment (PASI score) (Feldman and Krueger (2005) Ann. Rheum. Dis. , vol. 64, pp. ii65-ii68); 3. Pain (VAS); 4. Function: SF36 physical aspect; 5. V Patient Global Assessment (PGA) by AS; and 6.HAQ.

[0102] Tender 78 joints and swollen 76 joints The distal interphalangeal joints of the foot and the carpometacarpal bones of the hand were examined using the usual ACR function of 68 tender and 66 swollen joints. In addition to the segment count, 78 and 76 joints were counted, respectively. Therefore, tenderness was evaluated. The joints are the distal interphalangeal, proximal interphalangeal and metacarpophalangeal joints of the hand, and the metatarsophalangeal joints of the foot, the carpal joints, and the medial interphalangeal joints of the hand and the metatarsophalangeal joints of the foot. The bones of the hand and wrist (counted separately), elbow, shoulder, acromion, clavicle, sternoclavicular, hip, knee, talocrural-tibial, and All of these except the hip joints are evaluated for swelling. Tenderness and swelling should be scored as present (1) or absent (0). ACR Scoring System Other individual components of the program, patient pain VAS score, patient global assessment, physician global assessment, health Health Assessment Questionnaire (HAQ) and acute phase reactants, C-reactive protein (CRP) or red blood cell counts. The erythrocyte sedimentation rate (ESR) was modified from that used in the standard test for rheumatoid arthritis. Tender and swollen joint counts and individual The components of the study (patient pain VAS score, physician and patient global assessment, disability scale (HAQ) and acute At least 20% of three of the five scores for endogenous reaction substances (ESR or CRP) , 50% or 70% improvement.

[0103] Based on the ACR and PsARC, as well as the evaluation of 28 joints for tenderness and swelling, Calculate DAS28 using: metacarpophalanges I-V (10), interphalangeal spaces of the thumb (2), proximal digits of the hand (10), Intersegments II-V (8), carpus (2), elbow (2), shoulder (2) and knee (2).

[0104] Definition of ACR20, ACR50, and ACR70 responders A subject is considered an ACR20 responder if and only if the following three conditions are met: Defined as: 1. Subject has ≥ 20% improvement in tender joint count (based on 68 joints) 2. Subjects have a ≥ 20% improvement in the number of swollen joints (based on 66 joints); have a ≥ 20% improvement in three of the following five domains: Patient Global Assessment (measured on the VAS scale (0-100)) Physician Global Assessment (measured on a VAS scale (0-100)) Pain (measured on a VAS scale (0-100)) Disability (measured by health assessment questionnaire) Acute phase reactants (measured by CRP)

[0105] ACR50 and ACR70 responders were similar with improvements of ≥50% and ≥70%, respectively. Define it in such a way.

[0106] Definition of PsARC Responders Subjects improved in two of the following four factors (at least one factor was joint count): ) and there is no deterioration of the remaining factors, a subject is considered a PsARC responder if and only if is defined as: Patient Global Assessment (0–100 VAS scale, defined as a decrease of at least 20 units) improvement), Physician Global Assessment (0–100 VAS scale, defined as a decrease of at least 20 units) improvement), Tender 78 joint count (improvement defined as at least a 30% reduction), · Swelling 76 joint count (improvement defined as at least a 30% reduction). The proportion of subjects meeting each of the four responder definitions will be summarized by treatment group and time point. Plots of these percentages versus time are shown.

[0107] DAS28 score The DAS28 score is calculated using the following formula: DAS28 = 0.56 * √(tenderness 28 )+0.28√(swelling 28)+0.36*loge(CRP+1)+0.014*GH+ 0.96, where tenderness 28 = number of tender joints (based on 28 joints), swelling 28 = number of swollen joints ( based on 28 joints), CRP = C-reactive protein (measured in mg / L) and GH = total patient General assessment (measured on the VAS scale (0-100)).

[0108] Patient's assessment of pain intensity Patients' assessment of pain was performed using a 100 mm VAS ranging from no pain to unbearable pain. The distance in mm from the left end of the scale was measured at the investigator's facility and the value was The eCRF was completed.

[0109] Patient Global Assessment of Disease Activity Patient global assessment of disease activity was assessed by asking, “How severely has your overall health been affected in the past week?” were asked, "Have you been affected by this?" followed by a 100mm scale ranging from not serious to very serious. The VAS was used. The score was measured at the investigator's facility in mm from the left end of the scale. Distances were measured and values ​​entered into the eCRF.

[0110] Physician's Global Assessment of Disease Activity The physician's global assessment of disease activity is "all the ways in which the disease is affecting your patient." Considering this, draw a line on the scale for how good his or her situation is today. After the question, "Please tell me how much you care about your health," participants were asked to choose a scale ranging from no disease activity to maximum disease activity over a 100-m scale. To improve objectivity, the physicians were asked to provide their own assessment of the patient. When performing a personal assessment, patients should be unaware of a particular patient's global assessment of disease activity. The investigator then measures the distance in mm from the left end of the scale and records the value as the eCR. Entered in F.

[0111] C-reactive protein (CRP) To determine the presence of inflammation, determine its severity, and monitor response to treatment Blood was obtained for this evaluation at 12:00 p.m. on the 1st day of the study. The results of this study were provided by unblinded investigators. Therefore, results from the central site will be provided for screening and baseline purposes only. CRP results from samples collected during the treatment period will be revealed only after database lock. It was made clear.

[0112] Erythrocyte Sedimentation Rate (ESR) It is useful in diagnosing inflammatory diseases and in monitoring disease activity and response to treatment. Blood was obtained to measure the ESR, which was provided by a central facility. Measurements were performed on-site using standard kits.

[0113] Patients with Disease Activity Score 28 (DAS28) and in remission The DAS28 will be performed according to the planned assessments as described (Aletaha D, Smole n J (2005) Clin. Exp. Rheumatol, vol. 23(5 Suppl 39), pp. S100-S108, Aletaha et al. (2005 (Arthritis Rheum., Vol. 52 (No. 9), pp. 2625-36). The proportion of patients was determined at weeks 6 and 24 / end of study.

[0114] Mastricht Ankylosing Spondylitis Enthesitis Score (MASES) Mastricht Ankylosing Spondylitis Enthesitis Score (MASES) (Heuft-Dorenbosch L et al. (2003) Ann Rheum Dis, 62, pp. 127-32, Gladman DD (2007) Curr Rheumatol Rep, 9, pp. 455-60) is constructed from the Mander index and includes the evaluation of 13 sites. The sites of enthesitis included in the S index are the first costal cartilage, the seventh costal cartilage, the posterior superior iliac spine, the anterior superior iliac spine, iliac crest (all of the above evaluated bilaterally), 5th lumbar spinous process, and proximal Achilles (bilaterally).

[0115] SPARCC (SpA Canadian Research Consortium) SPARCC (SpA Canadian Research Consortium) (Maksymowych et al. (2003) J. Rheum (J. Atology, Vol. 30, pp. 1356-63) describes the medial and lateral epicondyles of the humerus, the supraspinous fossa attachment, and the proximal aki The kneecap, the greater trochanter, the medial and lateral condyles of the femur, the attachment of the plantar fascia, the attachment of the quadriceps muscle of the patella, The inferior pole of the patella and 18 attachment sites of the tibial tubercle are evaluated.

[0116] Leeds Dactylitis Scale (LDI) Leeds Dactylitis Scale (LDI) (Helliwell et al. (2005) J Rheumatol, 32, 1745 (p. 50) uses a minimum difference of 10% to define dactylitis, measuring the circumference of the affected finger and the circumference of the contralateral hand. This is a basic measure of the ratio of the circumference of the toes to the circumference of the foot. The tenderness score is multiplied by the modified LDI, which is 1 for tenderness and 0 for non-tenderness. If you suspect that you have a disease, compare the numbers with the data shown in the table. This correction is This is called DI Basic and is applied to this test. LDI requires a device to measure finger circumference. (Available from www.rehaboutlet.com, Miami, FL, USA Noh).

[0117] Psoriasis Area and Severity Index (PASI) PASI (Feldman and Krueger (2005) Ann. Rheum. Dis., vol. 64, pp. ii65-ii68) , extent and plaques of psoriasis on four body surface sites (head, trunk, and upper and lower extremities) The PASI score evaluates the degree of erythema, desquamation, and thickness. The score is based on the extent of affected body surface area and the severity of these measures. The range of scores is , ranging from 0 (no disease) to 72 (maximal disease).

[0118] Example 1.2 - Secukinumab improves signs and symptoms of PsA CAIN4572206 inhibits interleukin-17, a novel target for the treatment of PsA We evaluated the safety and preliminary efficacy of secukinumab, an inhibitor of cerebrospinal fluid A. Forty-two patients with active PsA were randomized to receive secukinumab (1 mg / kg every 3 weeks). Patients were randomized 2:1 to receive two injections of placebo or 0 mg / kg. Efficacy endpoints were proportion of ACR20 responders at week 6 for active vs placebo. Thirty-five patients (83.3%) (25% secukinumab-treated) Five patients (four secukinumab and ten placebo recipients) completed the study. One patient was excluded from the efficacy analysis due to a protocol violation, and seven patients (three secukinumab patients, one prophylaxis patient) were excluded from the efficacy analysis due to a protocol violation. Four placebo patients were discontinued early due to lack of efficacy or withdrawal of consent. Demographic and baseline characteristics, including meter, were balanced between groups: mean ± SD SD SJC (secukinumab vs placebo): 8.3±5.6 vs 9.5±5.4; TJC2 3.5±19.4 vs. 22.6±11.0; DAS28 4.8±1.2 vs. 4.8±1.2 MASES 3.0±4.1 vs. 3.4±2.3. Coexisting psoriasis, prior TNFi exposure and Concomitant medications with DMARDS were secukinumab in 23, 11, and 21 patients, respectively. were present in 11, 5, and 10 patients receiving placebo, respectively. The ACR20 responders for placebo were 39% vs. 23% at 6 weeks (P=0.27) and 12 weeks (P=0.01). The rates were 39% vs. 15% at week 1 and 43% vs. 18% at week 28. ACR50 and ACR70 responders in the study were 17% vs. 8% and 9% vs. 0%, respectively, at week 6. The reduction in CRP at week 6 was greater with secukinumab treatment (baseline vs. week 6) median [range]: 4.9 [0.3, 43.0] vs. 3.0 [0.2, 15.2] was greater than placebo (6.2 [1.3, 39.7] vs 5.0 [0.8, 29.6]) I did.

[0119] The overall incidence of adverse events (AEs) was 26 (93%) with secukinumab vs. 11 (7 9%). 7 Serious AEs occurred in 4 secukinumab patients and in Infections were reported in 16 (57%) secukinumab-treated patients and 1 (11%) placebo-treated patients. In conclusion, patients had no clinical or clinically significant improvement in their outcome up to 28 weeks. Demonstrated rapid and sustained improvement in CRP levels, but primary endpoint not met The safety profile of secukinumab was favorable. EXAMPLES

[0120] Secukinumab results from the AIN457F2306 (FUTURE1) trial in PsA Example 2.1: Overview of FUTURE1 In this double-blind, phase 3 study, 606 subjects received iv secukinumab 10 mg / kg (weeks 0, 2, and 4) followed by sc secukinumab 150 mg (sec) every 4 weeks Kukinumab 10mg / kg iv → 150mg sc) or 75mg (sc) Kinumab 10 mg / kg iv → 75 mg sc) or a combination of the same dosing schedule The primary endpoint was the outcome at 24 weeks in the US Ribosomal There was a 20% improvement in the ACR20 (ACR20) criteria.

[0121] The ACR20 response rate at week 24 was 15% with secukinumab 10 mg / kg iv. 0 mg sc (50.0%) and secukinumab 10 mg / kg iv → 75 mg The rate was significantly higher in the sc group (50.5%) than in the placebo group (17.3%; P < 0.001). ACR50 and ACR70 response rates were also significantly improved in the first week. Improvements were greater in biologic-naïve and biologic-treated subjects. Both were observed in subjects with a previous inadequate response to secukinumab. , significantly inhibited radiographic disease progression at 24 weeks compared with placebo (P < 0.05). At 24 weeks, significant improvements with secukinumab were observed in skin psoriasis, enthesitis, and Improvements in dactylitis, disease activity scores, physical function and quality of life were also observed. Secukinumab was generally well tolerated, with no unexpected safety findings. was not accepted.

[0122] Secukinumab demonstrated rapid progression of key clinical domains of psoriatic arthritis, including radiographic progression , resulting in significant and sustained improvement, demonstrating the role of interleukin-17A in this disease setting. It was confirmed that it is a valid therapeutic target.

[0123] Example 2.2: Detailed Consideration of FUTURE1 Subjects were aged 18 years or older and met the criteria for classification of psoriatic arthritis [CASPAR] (Taylor et al. The diagnosis of psoriatic arthritis and non-psoriatic arthritis according to the guidelines of the American Academy of Pediatrics (AHA) and the American College of Pediatrics (AHA) Treatment with steroid anti-inflammatory drugs, disease-modifying antirheumatic drugs and / or TNF inhibitors Active disease was defined as ≥3 tender joints and ≥3 swollen joints without any pain or swelling. If the dose was stable, concomitant oral corticosteroids (≤10 mg / day) were mg prednisone or equivalent) and methotrexate (≤25 mg per week) are tolerated. Subjects who had previously received TNF inhibitors (biologic-experienced) had an inadequate response. Treatment must have been discontinued for experience or reasons related to safety or tolerability.

[0124] Key exclusion criteria were prior therapy with biologic immunomodulators other than TNF inhibitors; Treatment with different TNF inhibitors; Active inflammatory disease other than psoriatic arthritis; Prior to randomization History of active infection or persistent, chronic or recurrent infection during the past 2 weeks was included.

[0125] After a 4-week screening period, subjects were assigned to one of two secukinumab treatment arms or placebo. Patients were randomized in a 1:1:1 ratio to either 1 or 2 of the 2 groups. The study design is shown in Figure 1. Subjects received 10 mg / kg intravenously at baseline (week 0) and at weeks 2 and 4. Then, secukinumab 150mg (secukinumab 10mg / kg iv → 150mg g sc) or 75 mg (secukinumab 10 mg / kg iv → 75 mg s. c.) every 4 weeks thereafter. Subjects in the placebo group received the same i.v. At week 16, all subjects were followed up for evaluation of tenderness and swelling. Responders or non-responders, defined as at least a 20% improvement from baseline in node counts Subjects who received placebo were classified as non-responders at week 16 (non-responders) or 24 (non-responders). Secukinumab 150mg or 75mg administered subcutaneously every 4 weeks starting from week 1 (responders) Subjects were stratified according to prior exposure to TNF inhibitors. Approximately 70% of subjects were required to be biologic naive.

[0126] Efficacy and safety assessments were performed at each study visit through week 52. Primary efficacy endpoints The endpoint was a 20% improvement in the American College of Rheumatology response criteria (ACR20; 24 Secondary efficacy outcomes at week 10 included ACR50 response; Area and severity of psoriasis in the subgroup of subjects with at least 3% of the body surface area affected Psoriasis Area-and-Severity Index 75% and 90% improvement in core (PASI 75 and PASI 90; Weisman et al. J Dermatolog Treat. 2003;14:158-65); subjects with these characteristics at baseline Dactylitis (assessed by the number of dactylitis joints) and enthesitis (assessed by a 4-point enthesitis index) were assessed in the subjects. The presence of C-reactive protein-based 28-joint disease activity score (DAS28- Change from baseline in CRP (Wells et al. Ann Rehum Dis 2009;68:954-60); 3 6-item simplified health questionnaire (Medical Outcomes Study 36-It) em Short-Form Health Survey)(SF-36)versi Quality of life assessed using the Health Assessment Scale (HAS) 2 [Ware et al. Med Care 1992;30:473-83]; health assessment Health Assessment Questionnaire Disability Index Disability Index)(HAQ-DI;Fries et al. Arthritis Rheum Radiographic progression was assessed using the van der Waals method. der Heijde psoriatic arthritis modified total Sharp score (mTSS, vdH-mTSS ;van der Heijde et al. Arthritis Rheum 2005;52:49-60). Radiographic assessment of the neck and feet was performed at baseline, 16 or 24 weeks (depending on response) and The study was performed at weeks 1 and 52. Images were centrally reviewed by two independent reviewers. The efficacy and safety of the treatment was assessed by ACR70 response rate at 24 weeks and radiographic evaluation of erosion and joint space narrowing. Includes evaluations of each efficacy endpoint over time and beyond 24 weeks. Prespecified subgroup analyses based on prior biologic therapy demonstrated important efficacy endpoints. Several other exploratory evaluations were performed, including pharmacokinetic measurements. were performed but are not described here.

[0127] Safety will be assessed by adverse events, serious adverse events, and routine hematological and clinical laboratory values. The National Cancer Institute's Common Terminology Criteria for Adverse Events (CTEAC) Criteria for Adverse Events), version 4. The severity of adverse events was graded using a 0 to 1 scale. Potential major adverse cardiac events were graded by an independent expert. judged by the House Committee.

[0128] A sample size of 600 subjects was used to predict the ACR20 outcome with a two-sided type I error alpha of 0.05. The study was estimated to have 99% power to detect a 27% improvement in response rate at 24 weeks. For efficacy assessment, statistical analysis included imputation of non-responder data for dichotomous variables and continuous We used a mixed-effects repeated measures model for the variables and linear extrapolation for the radiographic data. We followed a predefined hierarchical hypothesis testing strategy to adjust for multiplicity. Safety analyses will be reported after Week 24 unless otherwise specified. All subjects who underwent and were randomized into the study were included.

[0129] A total of 817 subjects were screened, of which 606 were randomized (trial (n=202 per study arm), 553 subjects (91.3%) completed the 24-week evaluation period. Results: 515 patients (85.0%) completed the 52-week study period.

[0130] Baseline demographics, disease characteristics, and prior or concomitant medication use were similar across study arms. Approximately half (53.6%) of randomized subjects had at least 3% of their body surface area covered with had psoriasis affecting the pediatric population, 53.4% ​​had dactylitis, and 61.4% had enthesitis. Approximately two-thirds (70.5%) of the participants were biologic-naïve, and 59.4% received concomitant methotrexate.

[0131] At week 24, secukinumab 10 mg / kg iv → 150 mg compared with placebo Received secukinumab 10 mg / kg iv → 75 mg sc A significantly higher percentage of subjects achieved an ACR20 response (50.0% and 50.5% vs. 17. ACR 0.3%; P < 0.001; Table 4), with significant improvement observed as early as the first week. The ACR50 and ACR70 responses were also significantly higher with secukinumab compared with placebo at week 24 ( Table 4; Figure 2). Significant improvements with both doses of secukinumab compared with placebo were observed in PASI7 5 and PASI90 response, DAS28-CRP, SF-36 physical aspect score and HAQ - Change from baseline in DI score and proportion of subjects with dactylitis and enthesitis All other prespecified secondary endpoints, including No significant differences in clinical response were observed between secukinumab doses through week 24 (Table 4). There wasn't.

[0132] [Table 3]

[0133] [Table 4-1]

[0134] [Table 4-2]

[0135] Subjects in both secukinumab-treated groups had m Significantly less radiographic progression as measured by change from baseline in TSS Improvement was maintained through week 52 (Figure 3).

[0136] Improvement at week 24 with secukinumab compared with placebo was The magnitude of the response was greater in biologic-naïve subjects. Although ACR response rates were higher in biologic-naïve and biologic-treated patients, was higher with both doses of secukinumab compared with placebo in both experienced subjects ( Figure 4). Significant improvement in ACR response with secukinumab compared with placebo was observed in patients receiving concomitant methotrexate. Similar responses were observed in both populations, both with and without the use of axate (Figure 5).

[0137] The clinical benefit from secukinumab treatment was maintained through week 52 of treatment (Table 5). At week 52, ACR20, ACR50, and ACR70 response rates using observational analysis were Secukinumab 10 mg / kg iv → 150 mg sc was 69.5% and 50.0% and 28.2%, respectively, and secukinumab 10 mg / kg iv → 75 mg The rates were 66.9%, 38.4% and 25.6% for sc (Fig. 5).

[0138] [Table 5] EXAMPLES

[0139] Radiographic results 24 and 52 of PsA trial AIN457F2306 (FUTURE1) Week Summary 606 adults with moderate to severe PsA were randomized to receive either placebo (PBO) or one of two treatment arms. Kinumab treatment arm: Secukinumab 10 mg / kg iv followed by 75 mg s .c.(10IV→75SC) or 150mg sc(10IV→150SC) All patients were evaluated for joint response at 16 weeks (pressure Based on ≥20% improvement in painful and swollen joint counts). PBO-treated patients were randomized to receive ≥100 mg / kg / day at Week 16 (non-responders). They were randomized to receive secukinumab 75 or 150 mg sc at week 24 (responders) or 25 (nonresponders). van der Heijde total modified Sharp score (vdH-mTSS, mTSS ) and erosion and joint space narrowing (JSN) scores at baseline, 16 / 24 weeks (repeated Radiographs from baseline to week 24 were evaluated at week 52 and at baseline (depending on response). The effect of secukinumab on progression was evaluated using a nonparametric ANCOVA model. For patients who underwent radiographic evaluation at week 16, the results were evaluated by linear extrapolation. Patients with no structural progression (defined as a change from baseline in mTSS of ≤0.5) The proportion of patients with eosinophilic stenosis who had eosinophilic stenosis and maintenance of this effect over time were assessed. Changes from baseline were based on whether patients had prior TNF inhibitor treatment or whether secukinumab was Patients were asked whether they received monotherapy or concomitant methotrexate (MTX, Table 6). Secukinumab-treated patients showed a greater improvement from baseline to week 24 compared with PBO-treated patients. The results demonstrated that patients with OA had statistically significantly less progression of joint structural damage. Inhibition of scarring was sustained with secukinumab through week 52. PB switched to secukinumab Analysis of patients who switched to secukinumab provides additional support for efficacy Compared to baseline from week 24 to week 52 (mean decline of -0.03) From baseline to week 24 (mean increase of 0.48) mTSS in the POB group The mean changes were greater than those seen in the 16 / 24 and 52 week groups. Analysis of patients who completed the X-ray showed that the randomized control group was significantly lower than the control group from week 24 to week 52. Patients experienced no progression (using a threshold of ≤0.5 in radiological completers) from initiation through 24 weeks The proportion of patients was consistently higher in the secukinumab group, 92.3 vs 75 SC in 10 IV, respectively. % vs. 85.8%, and 10IV→150SC was 82.3% vs. 85.7%. Among patients initially randomized to O, 75.7% were progression-free through 24 weeks from randomization This was achieved in 8 patients between weeks 24 and 52 after active treatment with secukinumab. The difference in the mean mean mean was 6.8% (P<0.05). The threshold of ≦0.5 is within the margin of error of the measurements. , which may be clinically meaningful for PsA and quantify inhibition of radiographic progression It has been used by other trials of biologics in PsA to ).

[0140] [Table 6]

[0141] These results suggest that the radiographic benefit of secukinumab was independent of prior anti-TNF exposure. From week 24 to week 52, the X Sustained inhibition of radiographic progression was achieved with secukinumab, an NTF alpha inhibitor. Inadequate responders to NTF alpha inhibitors in the drug-naive subgroup This was observed to a greater extent in patients who were EXAMPLES

[0142] Further analysis of inhibition of structural damage by secukinumab in patients with PsA (FUTURE1) To assess the effect of secukinumab on structural joint damage at 24 and 52 weeks As shown in Figure 6, in the full analysis set (FAS), The erosion score, joint space narrowing score (75 mg) and van der Heijde-modified total Sharpe score (mTSS, vdH-mTSS) compared with placebo There was significant improvement with both secukinumab 75 mg and 150 mg.

[0143] The cumulative distribution plot of total vdH-mTSS scores, also called the “S-curve” (Figure 7 ), Individual patient data is shown to indicate whether there are outliers that drive the mean. The grey circles indicate , which represents placebo patients, more of these patients than those in the 10 mg / kg-150 or -75 groups It was found that the subjects had a large change from baseline, suggesting progression of structural damage. Two major outliers (one placebo, one secukinumab) did not alter the overall results. The results are not driven by a small number of placebo patients having large progressions during this time. This suggests that

[0144] As shown in Figure 8, the 10 mg / kg → 150 mg and 75 mg groups showed significantly improved efficacy compared to placebo. By week 24, all placebo Note that patients were switched to secukinumab at 75 or 150 mg sc. The change from baseline in these placebo-switched patients was 0.01 at week 24. This is also shown in Table 7. Therefore, the sc treatment of secukinumab (with or without a loading dose) appears to inhibit the progression of structural damage associated with PsA .

[0145] Figure 9 shows the results for TNF-IR (Figure 9A) and TNF-naïve (Figure 9B) patients at week 24. B) Analysis of inhibition of structural damage measured by vdH-mTSS in patients. mg / kg → Both the 150 mg and 75 mg groups (separately or pooled) were compared with placebo In particular, secukinumab demonstrated a reduction in the mean change from baseline in TN F in both drug-naive and TNF-IR PsA patients (boxed) This shows a significant inhibition of the structural damage of the cells, as shown in Table 8. Kukinumab is used in patients with PsA who have previously been treated with a TNF-alpha antagonist (e.g. It is the first biologic to show inhibition of progression of structural damage in patients with TNF-IR. Secukinumab significantly inhibited structural damage in patients with MTX despite concomitant treatment. are also shown (Table 9).

[0146] X-ray completers were patients who had an X-ray assessment at baseline, 16 or 24, and 52 weeks. The number of patients who completed X-ray was 175 (86.6%) in the 10IV→150SC group, 169 cases (83.7%) in the 10IV→75SC group and 152 cases (75.3%) in the placebo group The number of patients who underwent linear extrapolation to the 24-week endpoint was 10IV There were 55 cases in the 150SC group, 40 cases in the 10IV→75SC group, and 109 cases in the placebo group. Data from patients who completed radiology demonstrated durable treatment benefit with secukinumab out to 1 year. The results were consistent with those of placebo patients who were switched to secukinumab at week 24 (non- (including linear extrapolation for responders) and the mean change in mTSS during week 52 (Figure 10B) , -0.03, whereas the placebo period (from baseline to week 24 [Figure 1 0A]) was 0.48, suggesting that secukinumab may be associated with radiographic disease progression. Inhibition is shown (Figure 10).

[0147] Data from those who completed radiographs showed a high proportion of secukinumab patients were and experienced no progression from week 24 to week 52. In the study, 82.3% of patients were progression-free from randomization to 24 weeks, and 85.7% of patients were progression-free from 2 weeks No progression was observed from week 4 to week 52. The proportion of patients who progressed was 92.3% and 85.8%, respectively. The proportion of placebo-treated patients with schizophrenia ranged from 75.7% (from randomization to week 24) to The rate significantly increased to 86.8% (from week 24 to week 52) after numb therapy (P<0.0 5).

[0148] The 1-year results from the FUTURE1 trial reported here demonstrate that secukinumab inhibits IL-17A Therapy inhibits radiographic disease progression in patients with PsA The radiographic benefits of treatment observed at 24 weeks persisted for up to one year and were consistent with prior anticancer therapy. Improvement was observed regardless of TNF treatment. as well as in methotrexate-naive patients. The progression of structural damage in cebo-treated patients was reduced by switching to secukinumab treatment. Delayed treatment remains beneficial, as secukinumab loading regimens were inhibited by It turns out that a single member is not necessary to achieve this result. Analysis showed that a high proportion of secukinumab-treated patients experienced structureless progression.

[0149] A recent systematic review has demonstrated the inhibitory effect of TNF blockade on structural damage in PsA. The emphasis was on the use of rheumatoid arthritis (Goulabchand et al (2014) Ann Rheum Dis 73:414-9). Failure, lack of efficacy and intolerance of anti-TNF treatment in patients may be due to the need for alternative therapies with alternative mechanisms of action. There is an urgent unmet need for t al (2009) Arthritis Res Ther 11:R52; Fagerli et al (2013) Ann Rheum Dis 72:184 To this end, the results of this study demonstrate that selective inhibition of IL-17A enhances Ps These results suggest that gliomas with ...cerebrospinal fluid (CSF) may benefit patients with gliomas with cerebrospinal fluid (CSF) and may provide additional therapeutic opportunities.

[0150] [Table 7]

[0151] [Table 8]

[0152] [Table 9] EXAMPLES

[0153] Clinical trial CAIN457F2312 (FUTURE2): Secukinumab administered subcutaneously Improved active PsA in a Phase 3 randomized, multicenter, double-blind, placebo-controlled study of To: 24 week results The objective was to evaluate the efficacy and safety of FUTURE2 (NCT01752634) in patients with active PsA. ) Secukinumab in a randomized, double-blind, placebo-controlled, phase 3 study The objective of this study was to evaluate the efficacy and safety of loading and maintenance dosing.

[0154] 397 adults with active PsA were randomly assigned to receive a randomized controlled trial at baseline (week 0), weeks 1, 2, 3, and 4. and then every 4 weeks sc secukinumab (300, 150 or 75 mg Patients were randomized to receive either chemotherapy or PBO. Randomization was subject to prior exposure to anti-TNF therapy. The primary endpoint was ACR20 response at 24 weeks. PASI 75 / 90, Disease Activity Score 28 using C-reactive protein (DAS) 28-CRP), Short-Form 36-Item Physical Profile Summary (SF-36PCS), Health Assessment Quality The primary and secondary outcomes included the Hazard Questionnaire-Disability Index (HAQ-DI), ACR50, dactylitis, and enthesitis. Objective endpoints were included in a hierarchical study analysis to adjust for multiplicity.

[0155] At week 24, ACR20 responses were greater with secukinumab 300, 150, and 75 mg than with PBO. The proportion of patients with pulmonary circulation disorders was significantly higher than that of those with pulmonary circulation disorders, at 54.0%, 51.0%, and 29.3% vs. 15.3%, respectively. (P < 0.0001 for secukinumab 300 and 150 mg; P < 0.0001 for secukinumab 75 mg) Secukinumab 300 and 150 mg also significantly improved PA compared with PBO. Secondary endpoints included significant improvements in SI75 / 90 score and DAS28-CRP. The exposure-adjusted rates of treatment-emergent AEs (maximum exposure to secukinumab) were Exposure: 372 days) was 1 in secukinumab (pooled) and placebo-treated subjects, respectively. The respective rates of serious AEs were 222.2 and 309.3 per 00 patient-years. , 7.8 and 8.8.

[0156] Secukinumab 300 and 150 mg sc demonstrated clinically significant reductions in the signs and symptoms of PsA. The safety profile of secukinumab was consistent with that previously reported. I was doing it.

[0157] [Table 10]

Claims

1. A method for treating PsA, comprising administering an IL-17 antagonist to a patient in need thereof. A method for inhibiting the progression of structural damage in a subject.

2. 13. The method of claim 1, wherein the patient is biologic naive.

3. 10. The method of claim 1, wherein the patient is biologic-experienced.

4. 12. The method of claim 1, wherein the patient has not previously been treated with a TNF alpha antagonist. The method according to

5. 10. The method of claim 1, wherein the patient has previously been treated with a TNF alpha antagonist. How to.

6. said patient having an inadequate response to prior treatment with said TNF alpha antagonist The method of claim 5, wherein the patient has a TNF-IR.

7. Inhibition of the progression of said structural damage is consistent with the van der Heijde Psoriatic Arthritis Modified Total Sha 2. The method according to claim 1, wherein the mTSS score is measured by the mTSS metric.

8. Inhibition of the progression of the structural damage was measured by erosion and joint space narrowing (JSN) scores.

20. The method according to claim 19,

9. Erosion, narrowing of joint space, pencil-in-cup phenomenon, joint enlargement, joint narrowing, subluxation, bone The method according to any of the preceding claims, in which the progression of proliferation, osteolysis and / or joint ankylosis is inhibited. Law.

10. further comprising administering to the patient a DMARD, e.g., methotrexate.

2. A method according to any of the preceding claims.

11. 20. The method of any of the above claims, wherein the patient has concomitant psoriasis.

12. Inhibiting the progression of said structural damage is a change from baseline in mTSS of ≦0.5 4. The method according to any of the preceding claims, wherein:

13. Inhibiting the progression of said structural damage is an improvement from baseline in erosion score of ≦0.

3.

4. The method according to any of the preceding claims, wherein the change is defined as

14. Inhibiting the progression of said structural damage is a reduction from baseline in JSN score of ≦0.

2.

4. The method according to any of the preceding claims, wherein the change is defined as

15. The above-mentioned claim, wherein the IL-17 antagonist is an IL-17 antibody or an antigen-binding fragment thereof. The method according to any one of claims 1 to 5.

16. the IL-17 antibody or antigen-binding fragment thereof, a) Leu74, Tyr85, His86, Met87, Asn88, Val124, IL- containing Thr125, Pro126, Ile127, Val128, and His129 IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17; b) IL-1 containing Tyr43, Tyr44, Arg46, Ala79, Asp80 IL-17 antibody or antigen-binding fragment thereof that binds to the epitope of c) an epitope of the IL-17 homodimer having two mature IL-17 protein chains; An IL-17 antibody or antigen-binding fragment thereof that binds to an IL-17 epitope (the epitope is a Leu on one chain) 74, Tyr85, His86, Met87, Asn88, Val124, Thr125 , Pro126, Ile127, Val128, His129 and Tyr43 on the other strand , Tyr44, Arg46, Ala79, Asp80), d) an epitope of the IL-17 homodimer having two mature IL-17 protein chains; An IL-17 antibody or antigen-binding fragment thereof that binds to an IL-17 epitope (the epitope is a Leu on one chain) 74, Tyr85, His86, Met87, Asn88, Val124, Thr125 , Pro126, Ile127, Val128, His129 and Tyr43 on the other strand , Tyr44, Arg46, Ala79, Asp80), K of 0 pM Ｄ and having an in vivo half-life of about 23 to about 35 days. or an antigen-binding fragment thereof, e) i) an immunoglobulin heavy chain variable domain comprising the amino acid sequence shown as SEQ ID NO:8 (V) Ｈ ) ii) an immunoglobulin light chain variable domain comprising the amino acid sequence shown as SEQ ID NO: 10; In (V Ｌ ), iii) Immunoglobulin V comprising the amino acid sequence shown as SEQ ID NO:8 Ｈ domain and an immunoglobulin V comprising the amino acid sequence shown as SEQ ID NO:

10. Ｌ domain, iv) an immunoglobulin comprising the hypervariable regions shown as SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3; Globulin V Ｈ domain, v) an immunoglobulin comprising the hypervariable regions shown as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6; Roblin V Ｌ domain, vi) comprising the hypervariable regions shown as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13; Immunoglobulin V Ｈ domain, vii) an immunogen comprising the hypervariable regions shown as SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3; Epidemic globulin V Ｈ The domains are shown as SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:

6. Immunoglobulin V containing hypervariable regions Ｌ domain, viii) hypervariable regions shown as SEQ ID NO:11, SEQ ID NO:12 and SEQ ID NO:13 Immunoglobulin V containing Ｈ Domain and SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 Immunoglobulin V containing the hypervariable region shown 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 shown as SEQ ID NO: 15; or xi) an immunoglobulin light chain comprising the amino acid sequence shown as SEQ ID NO: 14; and An immunoglobulin heavy chain comprising the amino acid sequence shown as number 15. or an antigen-binding fragment thereof, 16. The method of claim 15, selected from the group consisting of:

17. The method of claim 16, wherein the IL-17 antibody or antigen-binding fragment thereof is secukinumab. method.

18. Secukinumab was administered intravenously (i.v.) to patients at approximately 10 mg / kg every other week at weeks 0, 2, and 4. ) and then administering about 150 mg or about 300 mg once a month starting at week 8 to said patient.

18. The method of claim 17, wherein the administration is subcutaneous (s.c.).

19. Secukinumab at about 150 mg or about 300 mg once weekly at weeks 0, 1, 2, 3, and 4; Thereafter, the patient is administered s.c. at about 150 mg or about 300 mg every four weeks.

7. The method according to claim 7.

20. Secukinumab is administered sc to the patient at about 150 mg or about 300 mg once a month. Item 18. The method according to item 17.

21. The patient has not previously been treated with TNF alpha antagonist alpha. and selectively administering an IL-17 antagonist to the patient based on the above.

21. The method according to claim 2, 4 or 7 to 20.

22. Based on the patient's prior treatment with a TNF alpha antagonist, IL-17 antagonist is selectively administered to the patient.

2. The method according to claim 1 .

23. Secukinumab is administered subcutaneously to a patient at a dose of about 150 mg to about 300 mg every four weeks. and (b) administering to a patient suffering from PsA a therapeutically effective amount of at least one active ingredient selected from the group consisting of phenylephrine, bromine, nitric oxide, nicotinamide, nitric oxide, benzoyl peroxide, and nitric oxide.

24. Initial dosing at weeks 0, 1, 2, and 3 followed by monthly dosing starting at week 4 and administering secukinumab at a dose of about 150 mg to about 300 mg to the patient via subcutaneous injection.

23. A method for inhibiting the progression of structural damage in a PsA patient, comprising:

25. said dose is about 300 mg, and said patient has concomitant moderate to severe plaque psoriasis. or had an inadequate response to prior treatment with a TNF alpha antagonist.

25. The method according to claim 23 or 24.

26. said dose is about 150 mg, and said patient has concomitant moderate to severe plaque psoriasis. and the patient has not previously been treated with a TNF alpha antagonist.

25. The method according to claim 23 or 24.

27. further comprising administering to the patient a DMARD, e.g., methotrexate.

27. The method according to any one of claims 23 to 26.

28. 28. The method according to any one of claims 17 to 27, wherein secukinumab is administered as a liquid pharmaceutical composition. How to.

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