Methods for treating giant cell arteritis using interleukin-17 (IL-17) antagonists

Abstract

The present disclosure relates to methods of treating giant cell arteritis (GCA) using IL-17 antagonists, such as secukinumab. Also disclosed herein are the use of IL-17 antagonists, such as IL-17 antibodies including secukinumab, for treating patients with GCA, and medicaments, dosing regimens, pharmaceutical formulations, dosage forms, and kits for use in the uses and methods of the present disclosure.

Description

Technical Field

[0001] The present disclosure relates to a method of treating giant cell arteritis (GCA) using an IL-17 antagonist, such as an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab or ixekizumab, or an IL-17 receptor antibody or an antigen-binding fragment thereof, such as brodalumab.

Background Art

[0002] Giant cell arteritis (GCA) is a form of primary systemic vasculitis most commonly seen in people over 50 years of age (Koster et al 2016). GCA is an inflammatory chronic disease with a prevalence of 24-278 per 100,000 in the European Union (EU) and the United States of America (USA). Typical clinical symptoms of primary GCA associated with inflammation of the aorta and medium-sized arteries are headache, jaw claudication, scalp tenderness, and new onset of visual impairment. Characteristic systemic symptoms include fever, malaise, weight loss, and polymyalgia (Ness et al 2013). Anterior ischemic optic neuropathy, which results in irreversible vision loss, is a common and feared symptom of GCA. Therefore, rapid and effective immunosuppressive treatment is extremely important in GCA (Hoffmann et al 2002, Jover et al 2001).

[0003] High-dose glucocorticoids are the mainstay of GCA treatment and effectively suppress vascular inflammation (Salvarani et al 2004, Petri et al 2014). While glucocorticoids continue to be the mainstay of treatment, relapses are common and treatment-related morbidity occurs frequently (Koster et al 2016). High cumulative doses of glucocorticoids are associated with a high rate of adverse events (AE), with a major drawback being that over 80% of patients develop serious adverse events (SAE). High total doses of glucocorticoids are a major concern because they lead to a substantial increase in infections, osteoporosis, and severe metabolic side effects. Furthermore, treatment failure occurs in over 50% of patients (Salvarani et al 2004, Petri et al 2014). Immunosuppressive therapies that can induce long-term remission while avoiding the harmful effects of glucocorticoids are an unmet need (Koster et al 2016).

[0004] Studies on anti - tumor necrosis factor α (TNFα) therapy and azathioprine have not been able to clarify important effects, while the research results regarding methotrexate as a glucocorticoid - sparing agent have been conflicting (Petri et al 2014, De Silvia et al 1986, Hayat 2008). In the GIACTA trial (Stone et al 2017), regarding the maintenance of remission without the use of glucocorticoids in GCA patients, the combination of tocilizumab, an interleukin - 6 receptor antagonist (administered weekly or every other week), and prednisone taper over 26 weeks was shown to be superior to either prednisone taper over 26 weeks or 52 weeks + placebo over 52 weeks. However, there were some drawbacks to consider regarding tocilizumab therapy in GCA patients. The achievement rates of the primary endpoint (remission maintenance at week 52) were 56% in the tocilizumab once - weekly group and 53% in the tocilizumab every - other - week group. Thus, almost half of the patients did not achieve remission. Furthermore, high - sensitivity CRP, which was selected as part of the definition of remission in the GIACTA trial, is not reliable as an inflammatory marker (for indicating disease relapse or infectious complications) in GCA patients treated with tocilizumab because CRP is suppressed under tocilizumab therapy. Additionally, in the follow - up magnetic resonance imaging (MRI) of the phase II trial by Reichenbach et al (2018) regarding the use of tocilizumab in GCA, persistent contrast enhancement of large blood vessels was shown, indicating that the inflammation of large blood vessels continued. Therefore, in GCA, additional treatment options other than glucocorticoids and tocilizumab are needed.

[0005] The cause of GCA has not yet been clearly identified, but it is thought to be caused by an unknown environmental factor that, based on a genetic background, can activate and mature dendritic cells located in the adventitia of normal arteries. The activated dendritic cells then cause the activation, proliferation, and polarization of Th1 and Th17 cells, each of which produces interferon-γ and interleukin 17 (IL-17) (Samson et al 2017). Interleukin 17A (IL-17A) appears to be involved in the pathogenesis of GCA, and increased IL-17A expression in temporal artery lesions is a predictor of sustained response to glucocorticoid treatment in GCA patients (Espigol-Frigole et al 2013, Samson et al 2012). Recent findings suggest that GCA has histological lesion heterogeneity and is correlated with Th9, particularly Th17 (Ciccia et al 2017). Marquez et al found a new association between polymorphisms within the IL-17A locus and GCA, supporting the related role of Th17 cells in the pathophysiology of this vasculitis (Marquez et al 2014). Another study showed the overproliferation of regulatory T cells that overexpress the FoxP3Δ2 domain lacking Δ2. Dysfunction of the FoxP3Δ2 domain is known to contribute to enhanced Th17 differentiation and, consequently, overproduction of IL-17A. Consistent with this finding, IL-17A is upregulated in patients with active GCA in that study. Tocilizumab, an IL-6 receptor antagonist, can reconstruct a functional FoxP3 domain in regulatory T cells, reduce the production of IL-17A, and effectively control GCA. This finding suggests that IL-17A is an important cytokine in active GCA and that its direct inhibition could be a new therapeutic target for patients suffering from active disease. (Miyabe et al 2017).

[0006] Two case reports (Rotar et al 2018, Sammut et al 2018) have reported treating patients with secukinumab to maintain remission in giant cell arteritis (GCA). However, in the case of Rotar et al, it was clear that the patient was already in remission before secukinumab treatment was initiated. In Sammut, the patient's GCA seemed to be well controlled by high-dose oral prednisone prior to secukinumab treatment. Therefore, for example, effective treatment with an IL-17 antagonist for patients with active GCA has not been proven. Furthermore, the persistence of the treatment response has not been shown.

Summary of the Invention

[0007] Secukinumab is a selective and high-affinity fully human monoclonal antibody that neutralizes IL17A and is approved for the treatment of plaque psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS). It has been found that systemic use of an IL-17 antagonist, such as an IL-17 antibody, such as secukinumab, can treat giant cell arteritis (GCA).

[0008] A method, use, pharmaceutical composition, and kit for inducing vascular tissue regeneration, promoting vascular repair, or reducing vascular inflammation in a patient having GCA, comprising subcutaneously administering to a patient in need of inducing vascular tissue regeneration, promoting vascular repair, or reducing vascular inflammation an IL-17 antibody or an antigen-binding fragment thereof at a dose of about 150 mg to about 300 mg (for example, a fixed dose of about 150 mg, a fixed dose of about 300 mg), wherein the IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of a human IL-17 homodimer having two mature human IL-17 protein chains, The epitope contains Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, The IL-17 antibody or its antigen-binding fragment has a K D of about 100-200 pM for human IL-17, The IL-17 antibody or its antigen-binding fragment has a half-life in vivo of about 4 weeks, Methods, uses, pharmaceutical compositions, and kits are disclosed herein.

[0009] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient is administered an IL-17 antibody or its antigen-binding fragment once a week.

[0010] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient is administered an IL-17 antibody or its antigen-binding fragment during weeks 0, 1, 2, 3, and 4.

[0011] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient is administered an IL-17 antibody or its antigen-binding fragment every 2 weeks or every 4 weeks, preferably every 4 weeks.

[0012] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient is administered an IL-17 antibody or its antigen-binding fragment for a total treatment period of at least 2 months, at least 26 weeks, at least 28 weeks, at least 52 weeks, or at least 2 years.

[0013] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient is administered, for example, 150 or 300 mg of an IL-17 antibody or its antigen-binding fragment once a week during weeks 0, 1, 2, 3, and 4, and then every 4 weeks thereafter.

[0014] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, a patient is administered an IL-17 antibody or an antigen-binding fragment thereof during weeks 0, 1, 2, 3, 4, 8, and 12.

[0015] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, a patient is administered an IL-17 antibody or an antigen-binding fragment thereof once a week during weeks 0, 1, 2, 3, and 4, and then every 4 weeks for a total treatment period of at least 26 weeks.

[0016] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, prior to treatment with an IL-17 antibody or an antigen-binding fragment thereof, a patient has not responded, has responded inadequately, or has been intolerant to prior GCA treatment selected from the group consisting of corticosteroids such as prednisone, prednisolone, or methylprednisolone, treatment with a TNF-α inhibitor, treatment with an IL-6 inhibitor, treatment with methotrexate, and combinations thereof.

[0017] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, a patient has active GCA.

[0018] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, treatment with an IL-17 antibody or an antigen-binding fragment thereof reduces the burden of corticosteroid therapy, decreases the cumulative corticosteroid dose, induces or maintains GCA remission, or results in a combination thereof.

[0019] In some embodiments of the uses, methods, and kits of the present disclosure, the IL-17 antagonist is an IL-17 antibody or an antigen-binding fragment thereof. In some embodiments of the uses, methods, and kits of the present disclosure, the IL-17 antibody or an antigen-binding fragment thereof is selected from the group consisting of: a) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129; b) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80; c) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, wherein the epitope comprises Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 in one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 in the other chain, an IL-17 antibody or an antigen-binding fragment thereof; d) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, wherein the epitope comprises Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 in one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 in the other chain, and the IL-17 antibody or an antigen-binding fragment thereof has a K D of about 100 to 200 pM (e.g., about 200 pM) and the IL-17 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 23 to about 35 days (e.g., about 27 days), an IL-17 antibody or an antigen-binding fragment thereof; and e) an IL-17 antibody or an antigen-binding fragment thereof comprising: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth as SEQ ID NO: 8; ii) an immunoglobulin light chain variable domain (VL ); iii) Immunoglobulin V comprising the amino acid sequence set forth as SEQ ID NO:8 H domain, and the amino acid sequence set forth as SEQ ID NO: 10. L domain; iv) immunoglobulin V comprising the hypervariable regions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 H domain; v) immunoglobulin V comprising the hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6 L domain; vi) immunoglobulin V comprising the hypervariable regions set forth as SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13; H vii) immunoglobulin V domains including the hypervariable regions set forth as SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3 H Immunoglobulin V comprising the domains and hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6. L domain; viii) immunoglobulin V comprising the hypervariable regions set forth as SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13; H Immunoglobulin V comprising the domains and hypervariable regions set forth as SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6. L domain; ix) an immunoglobulin light chain comprising the amino acid sequence set forth as SEQ ID NO: 14; x) an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 15; or xi) an immunoglobulin light chain comprising the amino acid sequence set forth as SEQ ID NO: 14, and an immunoglobulin heavy chain comprising the amino acid sequence set forth as SEQ ID NO: 15.

[0020] In some embodiments of the uses, methods, and kits of the present disclosure, the IL-17 antibody or antigen-binding fragment thereof is secukinumab (AIN457), a high-affinity recombinant fully human anti-human interleukin-17A monoclonal antibody of the IgG1 / κ class.

[0021] Also disclosed herein are methods, uses, pharmaceutical compositions, and kits for treating patients having active GCA, comprising administering to a patient about 300 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4, and then every 4 weeks for a total treatment period of at least 26 weeks. Also disclosed herein are methods, uses, pharmaceutical compositions, and kits for treating patients having active GCA, comprising administering to a patient about 150 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4, and then every 4 weeks for a total treatment period of at least 26 weeks.

[0022] In some embodiments of the method, use, pharmaceutical composition, and kit, the patient has not experienced biological therapy prior to receiving the treatment described herein, for example, has not experienced treatment with a biological TNF-α inhibitor, a biological IL-17 antagonist, a biological IL-6 inhibitor, or a combination thereof. In some embodiments of the method, use, pharmaceutical composition, and kit, the patient has, within 6 or 8 weeks of the first treatment with IL-17 therapy, symptoms and / or signs of GCA activity, and an inflammatory marker CRP of 10 mg / L or more or an ESR of 30 mm / hour or more elevated due to GCA. When inflammatory markers indicating active disease are not available (especially when the patient has been treated with corticosteroids), the activity of the disease can be confirmed by temporal artery biopsy (TAB) or imaging diagnosis (e.g., MRA, ultrasound). In some embodiments of the method, use, pharmaceutical composition, and kit, the patient has primary GCA or relapsing GCA. In some embodiments, primary GCA is defined as GCA that has been recently diagnosed, for example, diagnosed within 6 weeks. In some embodiments, relapsing GCA includes patients who were diagnosed with GCA more than 6 weeks prior to the start of the treatment described herein, and this patient has experienced a recurrence of active disease, for example, after the start of appropriate treatment other than anti-IL-17. For example, relapse may occur after the start of corticosteroid treatment. In some embodiments of the method, use, pharmaceutical composition, and kit, the patient is treated with vitamin D (1000 IU / day) and / or a calcium supplement. In some embodiments, the patient has one or more head symptoms of GCA (initial localized headache, scalp or temporal artery tenderness, vision loss associated with ischemia, or pain in the mouth or jaw during chewing that is not explained by other causes). In some embodiments, treatment with anti-IL-17 reduces, alleviates, or eliminates one or more head symptoms of GCA (e.g., by at least 20% or more compared to a standard corticosteroid course).

Brief Description of the Drawings

[0023]

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Mode for Carrying Out the Invention

[0024] As used herein, the expression "did not respond" is used to mean that in response to a particular GCA treatment, the patient's symptoms were not resolved, not treated, not reduced, etc. In some embodiments, the GCA patient did not respond to previous GCA treatment, such as treatment with corticosteroids such as prednisone, prednisolone, or methylprednisolone, an IL-6 inhibitor, a TNF-α inhibitor, or a combination thereof.

[0025] As used herein, the expression "responded poorly" is used to mean that in response to a particular GCA treatment, the patient's symptoms were not fully resolved, not treated, not reduced, etc. In some embodiments, the GCA patient responded poorly to previous GCA treatment, such as treatment with corticosteroids such as prednisone, prednisolone, or methylprednisolone, an IL-6 inhibitor, a TNF-α inhibitor, or a combination thereof.

[0026] As used herein, the expression "intolerant" is used to mean that the patient experienced an adverse reaction to a particular GCA treatment. In some embodiments, the GCA patient was intolerant to previous GCA treatment, such as treatment with corticosteroids such as prednisone, prednisolone, or methylprednisolone, an IL-6 inhibitor, a TNF-α inhibitor, or a combination thereof.

[0027] As used herein, "fixed dose" refers to a flat dose, i.e., a dose that is not adjusted based on patient characteristics. That is, a fixed dose is different from, for example, a dose based on body surface area or a dose based on body weight (typically given as mg / kg). In a preferred embodiment, the doses used in the methods, uses, indicators, kits, etc. of the present disclosure are fixed doses. In a most preferred embodiment, a patient is administered a fixed dose of an IL-17 antibody, such as a fixed dose of secukinumab, such as a fixed dose of about 75 mg, about 150 mg, or about 300 mg of secukinumab.

[0028] As used herein, IL-17 refers to interleukin-17A (IL-17A).

[0029] As used herein, IL-17AF refers to a heterodimer consisting of monomers of IL-17A and IL-17F.

[0030] The term "comprising" encompasses "including" and "consisting of". For example, a composition "comprising" X may consist only of X or may include something additional (e.g., X + Y).

[0031] As used herein, the expression "TNF-α antagonist" refers to small molecules and biomolecules capable of inhibiting, reducing, and / or blocking the signal, transmission, and / or activity of TNF-α. Examples of TNF-α antagonists include Enbrel® (etanercept), Humira® (adalimumab), Remicade® (infliximab), and Simponi® (golimumab).

[0032] As used herein, unless otherwise specified or clear from the context, the term "about" in relation to a numerical value is understood to be within the normal tolerances in the relevant technical field, for example, within two standard deviations of the average value. Thus, "about" can be within ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.1%, ±0.05%, or ±0.01% of the recited value, preferably within ±10%. When used before a numerical range or an enumeration of numerical values, the term "about" applies to each numerical value in the series. For example, the expression "about 1 to 5" should be interpreted as "about 1 to about 5", or, for example, the expression "about 1, 2, 3, 4" should be interpreted as "about 1, about 2, about 3, about 4, etc.".

[0033] The term "substantially" does not exclude "completely". For example, a composition that is "substantially free of" Y may not completely contain Y. If necessary, the term "substantially" may be excluded from the definitions of the present disclosure.

[0034] As used herein, the term "antibody" includes naturally occurring antibodies and whole antibodies. A naturally occurring "antibody" is a glycoprotein that includes at least two heavy (H) chains and two light (L) chains linked to each other by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated as V H in this specification) and a heavy chain constant region. This heavy chain constant region is composed of three domains called CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated as V L in this specification) and a light chain constant region. This light chain constant region is composed of one domain called CL. These V H and V L regions can be further subdivided into regions of hypervariability called hypervariable regions or complementarity determining regions (CDRs) and more conserved regions called framework regions (FRs) that are interspersed between them. V H and V LEach consists of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Each variable region of the heavy and light chains contains a binding domain that interacts with the antigen. The constant region of the antibody may mediate binding to host tissues of immunoglobulins, or may mediate binding to host factors including various immune system cells (e.g., effector cells) and the first component of the classical complement system (C1q). Exemplary antibodies include secukinumab (Table 1) and ixekizumab (U.S. Patent No. 7,838,638).

[0035] As used herein, the term "antigen-binding fragment" of an antibody refers to a fragment of an antibody that retains the ability to specifically bind to an antigen (e.g., 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 included within the term "antigen-binding portion" of an antibody include L the V H domain, the V H domain, the CL domain, and the Fab fragment, which is a monovalent fragment consisting of the CH1 domain; the F(ab)2 fragment, which is a divalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; the Fd fragment consisting of the V L domain and the CH1 domain; the Fv fragment consisting of the V H domain and the V H domain of a single arm of the antibody; the dAb fragment consisting of the V L domain (Ward et al., 1989 Nature 341:544-546); and isolated CDRs. Exemplary antigen-binding sites include the CDRs of secukinumab as set forth in SEQ ID NOs: 1-6 and 11-13 (Table 1), preferably the heavy chain CDR3. Further, the two domains of the Fv fragment (V H ) are encoded by separate genes, but using recombinant methods, the V L region and the V HSingle protein chains in which domains pair to form monovalent molecules (known as single-chain Fv (scFv); see, for example, Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Natl. Acad. Sci. 85:5879-5883) can be linked by synthetic linkers that enable such production. Such single-chain antibodies are also intended to be encompassed by the term "antibody". Single-chain antibodies and antigen-binding sites can be obtained using techniques known to those of ordinary skill in the art.

[0036] As used herein, "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds to IL-17 is substantially free of antibodies that specifically bind to antigens other than IL-17). The terms "monoclonal antibody" or "monoclonal antibody composition" as used herein refer to a preparation of antibody molecules of a single molecular composition. The term "human antibody" as used herein is intended to encompass antibodies having variable regions in which both the framework regions and the CDR regions are derived from sequences of human origin. A "human antibody" need not be produced by a human, human tissue, or human cell. The human antibodies of the present disclosure may contain amino acid residues not encoded by human sequences (e.g., mutations induced by random mutagenesis or site-directed mutagenesis in vitro, N-nucleotide addition at junctions in vivo during recombination of antibody genes, or somatic mutations in vivo). In some embodiments of the processes and compositions of the present disclosure, the IL-17 antibody is a human antibody, an isolated antibody, and / or a monoclonal antibody.

[0037] The term "IL-17" refers to IL-17A (formerly CTLA8) and encompasses wild-type IL-17A from various species (e.g., human, mouse, and monkey), polymorphic variants of IL-17A, and functional equivalents of IL-17A. The functional equivalents of IL-17A according to the present disclosure preferably have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% overall sequence identity with wild-type IL-17A (e.g., human IL-17A) and substantially retain the ability to induce IL-6 production by human skin fibroblasts.

[0038] The term "K D " is intended to refer to the dissociation rate of a particular antibody-antigen interaction. The term "K D ", as used herein, refers to the dissociation constant obtained from the ratio of K d to K a (i.e., K d / K a ) and expressed as molar concentration (M). The K D value of an antibody can be determined using methods established in the art. Methods for determining the K D of an antibody include methods by using surface plasmon resonance or methods by using a biosensor system such as a Biacore® system. In some embodiments, an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab, binds to human IL-17 with a K D of about 1 to 250 pM, preferably about 100 to 200 pM (e.g., about 200 pM).

[0039] The term "affinity" refers to the strength of the interaction between an antibody and an antigen at a single antigenic site. Within each antigenic site, the variable regions of the antibody "arms" interact with the antigen at multiple sites via non-covalent weak forces; the more interactions there are, the stronger the affinity. Standard assays for evaluating the binding affinity of antibodies to various species of IL-17 are known in the art and include, for example, ELISA, Western blot, and RIA. The binding kinetics of an antibody (e.g., binding affinity) can also be evaluated by assays known in the art, such as by Biacore® analysis.

[0040] An antibody that "inhibits" one or more of these IL-17 functional properties (e.g., biochemical activity, immunochemical activity, cellular activity, physiological activity, or other biological activity, etc.) as determined according to the methodologies described herein and known in the art is understood to be associated with a statistically significant decrease in a particular activity when compared to the activity confirmed in the absence of the antibody (or in the presence of a control antibody having an irrelevant specificity). An antibody that inhibits IL-17 activity shows a statistically significant decrease in the measured parameter, e.g., a decrease of at least about 10%, at least 50%, at least 80%, or at least 90%, and in certain embodiments of the methods and compositions of the present disclosure, the IL-17 antibodies used can inhibit more than 95%, more than 98%, or more than 99% of the IL-17 functional activity.

[0041] As used herein, "inhibiting IL-6" refers to the ability of an IL-17 antibody or an antigen-binding fragment thereof (e.g., secukinumab) to reduce IL-6 production from primary human dermal fibroblasts. Production of IL-6 in primary human (dermal) fibroblasts is IL-17-dependent (Hwang et al., (2004) Arthritis Res Ther;6:R120-128). Briefly, human dermal fibroblasts are stimulated with recombinant IL-17 in the presence of various concentrations of an IL-17-binding molecule having an Fc portion or human IL-17 receptor. It may be convenient to use Simulect® (basiliximab), a chimeric anti-CD25 antibody, as a negative control. The supernatant is collected 16 hours after stimulation and IL-6 is quantified by ELISA. An IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab, typically has an IC 50 (in the presence of 1 nM of human IL-17) of about 50 nM or less (e.g., about 0.01 to about 50 nM) when tested as described above, i.e., when the inhibitory activity is measured against IL-6 production induced by human IL-17 in human dermal fibroblasts. In some embodiments of the methods and compositions of the present disclosure, an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab, and functional derivatives thereof, have an IC of IL-6 production inhibition as defined above 50 of 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.

[0042] Unless otherwise specified, the term "derivative" is used to define an amino acid sequence variant of an IL-17 antibody or an antigen-binding fragment thereof according to the present disclosure, such as secukinumab, for example, of a specific sequence (such as a variable domain), and covalent modifications (such as pegylation, deamidation, hydroxylation, phosphorylation, methylation, etc.). "Functional derivatives" include molecules having a qualitative biological activity common to the IL-17 antibodies of the present disclosure. Functional derivatives include fragments and peptide analogs of IL-17 antibodies as disclosed herein. The fragment includes a region within the sequence of the polypeptide according to the present disclosure, for example, a region of a specific sequence. The functional derivatives of the IL-17 antibodies disclosed herein (for example, the functional derivatives of secukinumab) preferably have the V H sequence and / or V L sequence and have an overall sequence identity of at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% with the V H domain and / or V L domain and substantially retain the ability to bind to human IL-17 or, for example, the ability to inhibit IL-6 production in human skin fibroblasts after IL-17 induction.

[0043] The expression "substantially identical" means that the relevant amino acid sequence or nucleotide sequence (for example, the V H domain or V L domain) is identical to a specific reference sequence or is substantially no different (for example, via conservative amino acid substitutions) in comparison to a specific reference sequence. Being substantially no different means that a specific region (for example, the V H domain or V LMinor amino acid changes are included, such as one or two substitutions in the 5 - amino acid sequence of the (domain). In the case of an antibody, the second antibody has the same specificity and has at least 50% of the affinity of the same antibody. Sequences that are substantially identical to the sequences disclosed herein (e.g., at least about 85% sequence identity) are also part of this application. In some embodiments, the sequence identity of an induced IL - 17 antibody (e.g., a derivative of secukinumab, e.g., a biosimilar antibody of secukinumab) can be about 90% or more, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, relative to the sequences of this disclosure.

[0044] As used herein, "identity" with respect to a native polypeptide and functional derivatives thereof refers to the percentage of amino acid residues in a candidate sequence that are identical to the residues of the corresponding native polypeptide after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent identity, with any conservative substitutions not being considered part of the sequence identity. Whether at the N-terminus or C-terminus, extensions or insertions should be construed as decreasing identity. Methods and computer programs for alignment are known. Percent identity can be determined by standard alignment algorithms such as those described by Altshul et al. ((1990) J. Mol. Biol., 215:403-410); the algorithm of Needleman et al. ((1970) J. Mol. Biol., 48:444-453); the Basic Local Alignment Search Tool (BLAST); or the algorithm of Meyers et al. ((1988) Comput. Appl. Biosci., 4:11-17). A set of parameters can be a Blosum62 scoring matrix, a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5. Percent identity between two amino acid sequences or two nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4:11-17), which is incorporated into the ALIGN program (version 2.0) and uses a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

[0045] "Amino acid" refers to all naturally occurring L-α-amino acids, for example, and includes D-amino acids. The expression "amino acid sequence variant" refers to a molecule that has some differences in the amino acid sequence when compared to the sequences according to the present disclosure. An amino acid sequence variant of an antibody according to the present disclosure, for example, of a specific sequence, still has the ability to bind to human IL-17 or, for example, the ability to inhibit IL-6 production in human skin fibroblasts after IL-17 induction. Amino acid sequence variants include variants by substitution (where at least one amino acid residue is removed and a different amino acid is inserted in place at the same position within the polypeptide according to the present disclosure), variants by insertion (where one or more amino acids are inserted immediately adjacent to an amino acid at a specific position within the polypeptide according to the present disclosure), and variants by deletion (where one or more amino acids within the polypeptide according to the present disclosure are removed).

[0046] The term "pharmaceutically acceptable" means a non-toxic substance that does not interfere with the effectiveness of the biological activity of the active ingredient.

[0047] The term "administering" with respect to a compound, for example, an IL-17 binding molecule or another agent, is used to refer to the delivery of the compound to a patient by any route.

[0048] As used herein, "therapeutically effective amount" refers to an amount of an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), that is effective upon single or multiple administrations to a patient (such as a human) to treat, prevent, prevent the onset of, cure, delay, reduce the severity of, improve at least one symptom of, or extend the survival of a disorder or a recurrent disorder, beyond what would be expected in the absence of such treatment. When applied to an individual active ingredient administered alone (e.g., an IL-17 antagonist, such as secukinumab), the term refers to that ingredient alone. When applied to a combination, the term refers to the total amount of the active ingredients that produce a therapeutic effect, whether administered continuously in combination or simultaneously.

[0049] The terms "treatment" or "treating" are defined herein as the application or administration to a subject, or to tissue or cell lines removed from a subject, of an IL-17 antibody according to the present disclosure, such as secukinumab or ixekizumab, or a pharmaceutical composition comprising said anti-IL-17 antibody, wherein the subject has a particular disease (e.g., GCA), a symptom associated with the disease (e.g., GCA), or a predisposing factor for the disease (if applicable), and the purpose is to cure the disease (if applicable), delay its onset, reduce its severity, alleviate it, improve one or more of its symptoms, improve the disease, reduce or improve any accompanying symptom of the disease or a predisposing factor for the disease. The terms "treatment" or "treating" include treating a patient suspected of having a disease, and a patient diagnosed as being ill or suffering from a disease or medical condition, and include suppressing clinical recurrence or maintaining remission.

[0050] As used herein, with respect to a patient, "selecting" and "selected" are used to mean that a particular patient is specially selected from a larger group of patients based on (and because of) having a predetermined criterion. Similarly, "selectively treating" refers to providing treatment to a patient having a particular disease, where the patient is specially selected from a larger group of patients based on the particular patient having a predetermined criterion. Similarly, "selectively administering" refers to administering a drug to a patient who is specially selected from a larger group of patients based on (and because of) the particular patient having a predetermined criterion. Selecting, selectively treating, and selectively administering mean that the patient does not receive a standard treatment regimen based solely on membership in a larger group of patients, but rather receives an individualized treatment based on the patient's personal history (e.g., prior treatment interventions, e.g., treatment with a prior biologic), biology (e.g., certain gene markers), and / or manifestation of symptoms (e.g., not meeting certain diagnostic criteria, etc.). Selecting, as used herein with respect to a method of treatment, does not refer to performing an accidental treatment on a patient having a particular criterion, but rather refers to an intentional selection to treat a patient based on the patient having a particular criterion. Thus, selective treatment / administration is different from standard treatment / administration that delivers a particular drug to all patients having a particular disease without regard to the patients' personal history, manifestation of the disease, and / or biological characteristics.

[0051] IL-17 antagonist The various processes, kits, uses, and methods of the present disclosure utilize IL-17 antagonists. IL-17 antagonists are capable of blocking, reducing, and / or inhibiting the signal, activity, and / or transmission of IL-17. Examples of IL-17 antagonists include, for example, IL-17 binding molecules (e.g., soluble IL-17 receptors, IL-17 antibodies or antigen-binding fragments thereof, such as secukinumab and ixekizumab), and IL-17 receptor binding molecules (e.g., IL-17 receptor antibodies or antigen-binding fragments thereof, such as brodalumab). In some embodiments, the IL-17 antagonist is an IL-17 binding molecule, preferably an IL-17 antibody or an antigen-binding fragment thereof. IL-17 antibodies and antigen-binding fragments thereof, as used herein, can be fully human, CDR-grafted, or chimeric. The constant region domain of the antibody or antigen-binding fragment thereof for use in the methods, uses, kits, etc. of the present disclosure preferably includes a stable human constant region domain, such as described in, for example, "Sequences of Proteins of Immunological Interest", Kabat E.A. et al (Department of Health and Human Services, Public Health Service, National Institutes of Health, United States of America).

[0052] Particularly preferred IL-17 antibodies or antigen-binding fragments thereof used in the methods of the present disclosure are human antibodies, particularly secukinumab, as described in Examples 1 and 2 of International Publication No. WO 2006 / 013107, which is hereby incorporated by reference in its entirety. Secukinumab is a recombinant, high-affinity, fully human anti-human interleukin-17A (IL-17A, IL-17) monoclonal antibody of the IgG 1 / κ isotype. Secukinumab has a high affinity for IL-17, i.e., a K D of about 100 - 200 pM (e.g., about 200 pM), shows an IC 50 of about 0.4 nM for in vitro neutralization of the biological activity of human IL-17A of about 0.67 nM, and has a half-life of about 4 weeks.

[0053] For ease of reference, the amino acid sequences of the hypervariable regions of the monoclonal antibody secukinumab, based on the Kabat definition, determined using the approach of Chothia et al. by X-ray analysis, are shown in Table 1 below.

[0054] [Table 1] Table 1: Amino acid sequences of the hypervariable regions of secukinumab. The DNA encoding the V L of secukinumab is set forth in SEQ ID NO: 9. The DNA encoding the V H of secukinumab is set forth in SEQ ID NO: 7.

[0055] In one embodiment, the IL-17 antibody or an antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V H ) that is a hypervariable region, CDR1, CDR2, and CDR3, wherein said CDR1 has the amino acid sequence of SEQ ID NO: 1, said CDR2 has the amino acid sequence of SEQ ID NO: 2, and said CDR3 has the amino acid sequence of SEQ ID NO: 3. In one embodiment, the IL-17 antibody or an antigen-binding fragment thereof comprises at least one immunoglobulin light chain variable domain (V L’ ) that is a hypervariable region, CDR1', CDR2', and CDR3', wherein said CDR1' has the amino acid sequence of SEQ ID NO: 4, said CDR2' has the amino acid sequence of SEQ ID NO: 5, and said CDR3' has the amino acid sequence of SEQ ID NO: 6. In one embodiment, the IL-17 antibody or an antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V H ) that is a hypervariable region, CDR1-x, CDR2-x, and CDR3-x, wherein said CDR1-x has the amino acid sequence of SEQ ID NO: 11, said CDR2-x has the amino acid sequence of SEQ ID NO: 12, and said CDR3-x has the amino acid sequence of SEQ ID NO: 13.

[0056] In one embodiment, the IL-17 antibody or an antigen-binding fragment thereof comprises at least one immunoglobulin VH Domain and at least one immunoglobulin V L domain, wherein a) the immunoglobulin V H domain comprises (e.g., in order): i) CDR1, CDR2, and CDR3 which are hypervariable regions, wherein said CDR1 has the amino acid sequence of SEQ ID NO: 1, said CDR2 has the amino acid sequence of SEQ ID NO: 2, and said CDR3 has the amino acid sequence of SEQ ID NO: 3; or, ii) CDR1-x, CDR2-x, and CDR3-x which are hypervariable regions, wherein said CDR1-x has the amino acid sequence of SEQ ID NO: 11, said CDR2-x has the amino acid sequence of SEQ ID NO: 12, and said CDR3-x has the amino acid sequence of SEQ ID NO: 13; and, b) the immunoglobulin V L domain comprises (e.g., in order), CDR1', CDR2', and CDR3' which are hypervariable regions, wherein said CDR1' has the amino acid sequence of SEQ ID NO: 4, said CDR2' has the amino acid sequence of SEQ ID NO: 5, and said CDR3' has the amino acid sequence of SEQ ID NO: 6.

[0057] In one embodiment, the IL-17 antibody or its antigen-binding fragment comprises: a) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth as SEQ ID NO: 8; b) an immunoglobulin light chain variable domain (V L ) comprising the amino acid sequence set forth as SEQ ID NO: 10; c) an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 8, and an immunoglobulin V L domain comprising the amino acid sequence set forth as SEQ ID NO: 10; d) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3; e) an immunoglobulin V L domain comprising the hypervariable regions set forth as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6; f) an immunoglobulin V H domain comprising the hypervariable regions set forth as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13; g) an immunoglobulin VH domain, and an immunoglobulin V domain containing the hypervariable regions described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L domain; or (h) an immunoglobulin V domain containing the hypervariable regions described as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 H domain, and an immunoglobulin V domain containing the hypervariable regions described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L domain.

[0058] In some embodiments, the IL-17 antibody or an antigen-binding fragment thereof (e.g., secukinumab) comprises the three CDRs of SEQ ID NO: 10. In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 8. In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 10 and the three CDRs of SEQ ID NO: 8. Each CDR of SEQ ID NO: 8 and SEQ ID NO: 10 can be found in Table 1. The free cysteine (CysL97) of the light chain can be found in SEQ ID NO: 6.

[0059] In some embodiments, the IL-17 antibody or an antigen-binding fragment thereof comprises the light chain of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof comprises the heavy chain of SEQ ID NO: 15 (with or without the C-terminal lysine). In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof comprises the light chain of SEQ ID NO: 14 and the heavy domain of SEQ ID NO: 15. In some embodiments, the IL-17 antibody or an antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or an antigen-binding fragment thereof comprises the three CDRs of SEQ ID NO: 14 and the three CDRs of SEQ ID NO: 15. Each CDR of SEQ ID NO: 14 and SEQ ID NO: 15 can be found in Table 1.

[0060] The hypervariable region may be linked to any type of framework region, but a human-derived framework region is preferred. Suitable framework regions are described in Kabat E.A. et al (ibid). Preferred heavy chain frameworks are human heavy chain frameworks, such as the human heavy chain framework of the secukinumab antibody. Preferred heavy chain frameworks consist, in order, of, for example, an FR1 region (amino acids 1-30 of SEQ ID NO: 8), an FR2 region (amino acids 36-49 of SEQ ID NO: 8), an FR3 region (amino acids 67-98 of SEQ ID NO: 8), and an FR4 region (amino acids 117-127 of SEQ ID NO: 8). Considering the hypervariable regions of secukinumab determined by X-ray diffraction, another preferred heavy chain framework consists, in order, of an FR1-x region (amino acids 1-25 of SEQ ID NO: 8), an FR2-x region (amino acids 36-49 of SEQ ID NO: 8), an FR3-x region (amino acids 61-95 of SEQ ID NO: 8), and an FR4 region (amino acids 119-127 of SEQ ID NO: 8). Similarly, the light chain framework consists, in order, of an FR1' region (amino acids 1-23 of SEQ ID NO: 10), an FR2' region (amino acids 36-50 of SEQ ID NO: 10), an FR3' region (amino acids 58-89 of SEQ ID NO: 10), and an FR4' region (amino acids 99-109 of SEQ ID NO: 10).

[0061] In one embodiment, the IL-17 antibody or an antigen-binding fragment thereof (e.g., secukinumab) is selected from human IL-17 antibodies comprising at least: a) an immunoglobulin heavy chain or a fragment thereof comprising a variable domain comprising, in order, CDR1, CDR2, and CDR3, which are the hypervariable regions of the human heavy chain, and a constant region or a fragment thereof, wherein CDR1 has the amino acid sequence of SEQ ID NO: 1, CDR2 has the amino acid sequence of SEQ ID NO: 2, and CDR3 has the amino acid sequence of SEQ ID NO: 3; and b) an immunoglobulin light chain or a fragment thereof comprising a variable domain comprising, in order, CDR1′, CDR2′, and CDR3′, which are the hypervariable regions of the human light chain, and a constant region or a fragment thereof, wherein CDR1′ has the amino acid sequence of SEQ ID NO: 4, CDR2′ has the amino acid sequence of SEQ ID NO: 5, and CDR3′ has the amino acid sequence of SEQ ID NO: 6.

[0062] In one embodiment, the IL-17 antibody or an antigen-binding fragment thereof is selected from single-chain antibodies or antigen-binding fragments thereof comprising an antigen-binding site comprising: a) a first domain comprising, in order, CDR1, CDR2, and CDR3, which are hypervariable regions, wherein CDR1 has the amino acid sequence of SEQ ID NO: 1, CDR2 has the amino acid sequence of SEQ ID NO: 2, and CDR3 has the amino acid sequence of SEQ ID NO: 3; b) a second domain comprising, in order, CDR1′, CDR2′, and CDR3′, which are hypervariable regions, wherein CDR1′ has the amino acid sequence of SEQ ID NO: 4, CDR2′ has the amino acid sequence of SEQ ID NO: 5, and CDR3′ has the amino acid sequence of SEQ ID NO: 6; and c) a peptide linker that binds to the N-terminus of the first domain and the C-terminus of the second domain or to the C-terminus of the first domain and the N-terminus of the second domain.

[0063] Alternatively, an IL-17 antibody or an antigen-binding fragment thereof as used in the methods of the present disclosure may include derivatives based on the sequences of the IL-17 antibodies described herein (e.g., a PEGylated form of secukinumab). Alternatively, the V H domain or V L domain of the IL-17 antibody or an antigen-binding fragment thereof used in the methods of the present disclosure may have a V H domain or V L domain that is substantially identical to the V H domain or V L domain. The human IL-17 antibodies disclosed herein may include a heavy chain that is substantially identical to that set forth in SEQ ID NO: 15 and / or a light chain that is substantially identical to that set forth in SEQ ID NO: 14. The human IL-17 antibodies disclosed herein may include a heavy chain comprising SEQ ID NO: 15 and a light chain comprising SEQ ID NO: 14. The human IL-17 antibodies disclosed herein include: a) one heavy chain comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 8 and a constant region of a human heavy chain; and b) one light chain comprising a variable domain having an amino acid sequence substantially identical to that shown in SEQ ID NO: 10 and a constant region of a human light chain.

[0064] Alternatively, the IL-17 antibody or an antigen-binding fragment thereof used in the methods of the present disclosure may be an amino acid sequence variant of the reference IL-17 antibody described herein, as long as it includes CysL97. The present disclosure includes the V H domain or V LOne or more, typically a very small number (e.g., 1 to 10) of the amino acid residues of the domain (but not CysL97) are changed, for example by mutation, for example by site-directed mutagenesis of the corresponding DNA sequence, and IL-17 antibodies or antigen-binding fragments thereof (e.g., secukinumab) are also included. In the case of all such derivatives and variants, the IL-17 antibody or antigen-binding fragment thereof is capable of inhibiting the activity of about 1 nM (= 30 ng / ml) of human IL-17 at a concentration of about 50 nM or less, about 20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nM or less, or more preferably about 1 nM or less of said molecule by 50%, and said inhibitory activity is measured against IL-6 production induced by human IL-17 in human skin fibroblasts as described in Example 1 of International Publication No. 2006 / 013107.

[0065] In some embodiments, the IL-17 antibody or antigen-binding fragment thereof, e.g., secukinumab, binds to an epitope of mature human IL-17 comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129. In some embodiments, the IL-17 antibody, e.g., secukinumab, binds to an epitope of mature human IL-17 comprising Tyr43, Tyr44, Arg46, Ala79, Asp80. In some embodiments, the IL-17 antibody, e.g., secukinumab, binds to an epitope of an IL-17 homodimer having two mature human IL-17 chains, said epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 in one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 in the other chain. The residue numbering system used herein to define the IL-17 epitope is based on the first residue of the mature protein (i.e., IL-17A starts with glycine without a 23-amino acid N-terminal signal peptide). The sequence of immature IL-17A is described in Swiss-Prot entry Q16552.

[0066] In some embodiments, the IL-17 antibody has a K of about 100-200 pM. D In some embodiments, the IL-17 antibody has an IC of about 0.4 nM in the in vitro neutralization of the biological activity of about 0.67 nM of human IL-17A. 50 In some embodiments, the absolute bioavailability of the subcutaneously (SC) administered IL-17 antibody has a range of about 60 - about 80%, for example, about 73%, about 76%, etc. In some embodiments, an IL-17 antibody such as secukinumab has an elimination half-life of about 4 weeks (e.g., about 23 - about 35 days, about 23 - about 30 days, e.g., about 30 days). In some embodiments, the IL-17 antibody (such as secukinumab) has a T of about 7 - 8 days. max has.

[0067] Other preferred IL-17 antagonists for use in the methods, kits, and regimens of the present disclosure include KHK4872 (Kyowa Hakko Kirin Co., Ltd.), ABT-122 (AbbVie Inc.), BCD-085 (JCS Biopharm Co., Ltd.), vidofludimus (4SC-101), NI-1401 (RG7624; MCAF5352A - Novimmune SA), ANB004 (AnaptysBio, Inc.), E-036041 (Ensemble Therapeutics, Inc.), Qβ-IL-17 (virus-like particle-based vaccine), PRS-190 (Pieris AG), bimekizumab (UCB4940 - UCB), ALX-0761, CNTO6785 (Janssen Pharmaceutica N.V.), LY3074828 (Eli Lilly and Company), LY3114062 (Eli Lilly and Company), SCH-900117, MSB0010841 (ALX-0761 - Merck & Co., Inc.), ABT-122, COVA322 (Covagen AG), ixekizumab and brodalumab, and those described in U.S. Patent Nos. 9,193,788; 8,057,794; 7,767,206; 8,003,099; 8,110,191; and 7,838,638, and U.S. Patent Application Publication Nos. 20120034656 and 20110027290, which are incorporated herein by reference with respect to the disclosure of the sequences and / or structures of the IL-17 antagonists.

[0068] In some embodiments of the uses, methods, and kits of the present disclosure, the IL-17 antibody or an antigen-binding fragment thereof is selected from the group consisting of: a) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of IL-17 between the Arg55 residue and the Trp67 residue; b) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of IL-17 containing Arg55, Glu57, and Trp67; c) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of IL-17 containing Arg55, Glu57, Trp67, Tyr62, and Arg101; d) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of IL-17 containing Arg55, Glu57, Trp67, Tyr62, Arg101, Pro59, Ser64, and Val65; e) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of IL-17 containing Arg55, Glu57, Trp67, Tyr62, Arg101, Pro59, Ser64, Val65, Val22*, Leu26, Asp58, Glu60, Pro63, Pro107, Phe110, and Lys114*, wherein ( * ) the amino acids marked with () indicate the residues provided by the second IL-17 subunit of the IL-17A homodimer, and the IL-17 antibody or an antigen-binding fragment thereof has a K D for human IL-17 of about 1 to 10 pM (e.g., about 6 pM), and the IL-17 antibody or an antigen-binding fragment thereof has a half-life in vivo of about 14 to 23 days, e.g., about 20 days; and f) an IL-17 antibody or an antigen-binding fragment thereof comprising: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence set forth as SEQ ID NO: 30; ii) an immunoglobulin light chain variable domain (V L ) comprising the amino acid sequence set forth as SEQ ID NO: 22; iii) an immunoglobulin V H domain comprising the amino acid sequence set forth as SEQ ID NO: 30, and an immunoglobulin V LDomain; iv) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 24, SEQ ID NO: 26, and SEQ ID NO: 28 H Domain; v) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20 L Domain; vi) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 25, SEQ ID NO: 27, and SEQ ID NO: 29 H Domain; vii) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 17, SEQ ID NO: 19, and SEQ ID NO: 21 L Domain; viii) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 24, SEQ ID NO: 26, and SEQ ID NO: 28 H Domain, and an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 16, SEQ ID NO: 18, and SEQ ID NO: 20 L Domain; ix) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 25, SEQ ID NO: 27, and SEQ ID NO: 29 H Domain, and an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 17, SEQ ID NO: 19, and SEQ ID NO: 21 L Domain; x) a light chain comprising SEQ ID NO: 23; xi) a heavy chain comprising SEQ ID NO: 31; or, xii) a light chain comprising SEQ ID NO: 23 and a heavy chain comprising SEQ ID NO: 31.

[0069] In some embodiments of the uses, methods, and kits of the present disclosure, the IL-17 antibody or an antigen-binding fragment thereof is an IgG 1 / κ class high-affinity recombinant fully human anti-human IL-17 monoclonal antibody, CJM112. CJM112 also binds to IL-17AF and antagonizes this cytokine (see, e.g., U.S. Patent No. 9,193,788, which is hereby incorporated by reference in its entirety).

[0070] IL-17AF antagonists may also be useful in treating GCA, for example, by inducing a reduction of blood vessel (e.g., large blood vessel or aorta) inflammation (vasculitis) in patients having GCA. Such antagonists include antibodies that cross-react with IL-17A and IL-17F, as well as bispecific anti-IL-17A / F antibodies, FynomAbs (e.g., COVA322), nanobodies (e.g., ALX-0761), etc., which can be found in U.S. Patent Application Publication Nos. 20140314763, 2013 / 0195872, 20160326241, U.S. Patent Nos. 8496936, 8945553, and International Publication No. 2016 / 070062.

[0071] Methods of treating GCA and use of IL-17 antagonists The IL-17 antagonists of the present disclosure, for example, IL-17 binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof, such as secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 receptor antibodies or antigen-binding fragments thereof), may be used in vitro, ex vivo, or incorporated into a pharmaceutical composition for treating GCA (e.g., a human patient having GCA such as active GCA) and administered in vivo.

[0072] In some embodiments, the patient has one or more or all of the selection criteria described in Example 1. In some embodiments, the patient has one or more or all of the selection criteria described in Example 2. In some embodiments, the patient does not have one or more or all of the exclusion criteria described in Example 1. In some embodiments, the patient does not have one or more or all of the exclusion criteria described in Example 2.

[0073] In some embodiments, the patient is a bi-naïve. In some embodiments, the patient has been previously treated with a biological for GCA. In some embodiments, the patient has been previously treated with biologics for different diseases but has not been treated with a different biological for GCA. In some embodiments, the patient had an insufficient response or no response to previous biological treatment for GCA.

[0074] The response of the patient to the treatment disclosed herein may be evaluated using patient-reported outcomes (PROs), clinician-reported outcomes, laboratory parameters, image processing techniques, etc. Clinician-reported outcomes include, for example, a physician's global assessment of disease activity (PhGA) (e.g., using a VAS score). Image processing techniques include, for example, MRI (such as that described in the follow-up of the Phase II tocilizumab study by Reichenbach et al (2018)); and ultrasound. PROs include, for example, a patient's global assessment of disease activity (PGA) (e.g., using a VAS score), FACIT-Fatigue score, SF36 score, and EQ-5D-5L score. Laboratory parameters include C-reactive protein (CRP) levels and / or erythrocyte sedimentation rate (ESR).

[0075] EuroQuol 5D (EQ-5D-5L) (euroqol.org / eq-5d-instruments / eq-5d-5l-about / ) is a widely used self-administered questionnaire designed to assess health status in adults (Xu et al 2011, Mc Clure et al 2017). The aim of EQ-5D-5L in this trial was to assess the overall health status of patients. FACIT-Fatigue (copyright) is a 13-item questionnaire that assesses self-reported fatigue and its impact on daily activities and function (Cella 1993 and Yellen 1997). The SF-36 is a widely used and well-researched instrument for measuring health-related quality of life among healthy subjects as well as patients with acute and chronic conditions. The SF-36 consists of eight subscales that can be scored individually: physical function, role physical, bodily pain, general health, vitality, social function, role emotional, and mental health (Ware 1993). Two overall summary scores can also be calculated: the Physical Component Summary (PCS) score for the physical aspects of QOL and the Mental Component Summary (MCS) score for the mental aspects of QOL (Ware 1994).

[0076] The Visual Analog Scale (VAS) is a means for measuring a characteristic or attitude that is considered to span a range of continuous values. For example, the amount of pain a patient feels spans a continuous range from none to extreme. From the patient's perspective, this spectrum seems continuous and their pain does not involve discrete jumps as suggested by the classifications of no pain, mild, moderate, and severe. The VAS pain scale is commonly used in clinical research as an outcome measure to characterize pain intensity. The VAS pain scale is typically presented as a 100-mm horizontal line, and the intensity of the patient's pain is represented by a point between the two extremes of "no pain at all" and "the worst pain imaginable" (or something similar). Respondents are asked to draw a line perpendicular to the VAS line at the point that best represents their current pain. This tool is scored in millimeters (although scores are often recorded in tenths of a centimeter on a 10-point scale). Usually, in chronic pain management, a score of less than 40 millimeters (or 4 points in the case of centimeters) is desirable.

[0077] In some embodiments, the patient experiences at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% reduction in pain, reduction in inflammation, improvement in one or more PROs or physician-reported outcomes, or laboratory parameters or imaging parameters, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, or twelve months (preferably one month, two months, or three months, more preferably six months, twelve months, or twenty-four months or more after the period) after the method according to the claimed method. In a preferred embodiment, the patient experiences at least 20% reduction in pain, reduction in inflammation, after the method according to the claimed method.

[0078] In some embodiments, the patient experiences an improvement in the VAS score, PGA score, FACIT-Fatique, SF-36, and / or EQ-5D-5L score of at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, or twelve months (preferably one month, two months, or three months) after the method according to the claimed method. In a preferred embodiment, the patient experiences a reduction in pain of at least 20% as determined by the VAS score after the method according to the claimed method. In a preferred embodiment, the patient experiences an overall improvement of at least 20% as determined by the PGA score after the method according to the claimed method.

[0079] IL-17 antagonists, such as IL-17 binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof, such as secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof), can be used as pharmaceutical compositions when combined with a pharmaceutically acceptable carrier. Such compositions can contain, in addition to the IL-17 antagonist, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizing agents, and other substances. The characteristics of the carrier depend on the route of administration. The pharmaceutical compositions for use in the methods of the present disclosure can also contain additional therapeutic agents for treating a specific target disorder. For example, the pharmaceutical composition can also contain an anti-inflammatory agent. Such additional elements and / or agents can be included in the pharmaceutical composition to produce a synergistic effect with the IL-17 binding molecule or to minimize side effects caused by an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or antigen-binding fragment thereof).

[0080] The pharmaceutical compositions for use in the methods of the present disclosure can be manufactured by known methods. In one embodiment, the pharmaceutical composition is provided in lyophilized form. For immediate administration, this lyophilized pharmaceutical composition is dissolved in a suitable aqueous carrier, such as sterile distilled water for injection or sterile buffered saline. If it is considered desirable to make a large-volume solution for infusion rather than bolus administration, it can be advantageous to mix human serum albumin or the patient's own heparinized blood with saline during formulation. The presence of such physiologically inert proteins in excess prevents loss of the antibody due to adsorption to the walls of the containers and tubing used with the infusion. When albumin is used, a suitable concentration is 0.5 to 4.5 wt% of the saline. Other formulations include liquid formulations or lyophilized formulations.

[0081] Antibodies, such as antibodies against IL-17, are typically formulated in an aqueous solution form that is ready for parenteral administration or as a lyophilized product for reconstitution with a suitable diluent prior to administration. In some embodiments of the methods and uses of the present disclosure, an IL-17 antagonist, such as an IL-17 antibody, such as secukinumab, is formulated as a ready-to-use liquid pharmaceutical composition. Suitable lyophilized formulations can be reconstituted in a small liquid volume (e.g., 2 ml or less) for subcutaneous administration and provide an aqueous solution with low levels of antibody aggregation. The use of antibodies as active ingredients in pharmaceuticals has now become widespread, and products such as Herceptin (trademark) (trastuzumab), Rituxan (trademark) (rituximab), SYNAGIS (trademark) (palivizumab) can be mentioned. Techniques for purifying antibodies to pharmaceutical grade are known. When a therapeutically effective amount of an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or its antigen-binding fragment, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or its antigen-binding fragment) is administered by intravenous, cutaneous, or subcutaneous injection, the IL-17 antagonist will be in the form of a pyrogen-free parenterally acceptable solution. Pharmaceutical compositions for intravenous, cutaneous, or subcutaneous injection may contain, in addition to the IL-17 antagonist, an isotonic solvent such as sodium chloride, Ringer's solution, glucose, glucose and sodium chloride, lactated Ringer's solution, or other solvents known in the art.

[0082] In preferred embodiments of the methods, uses, kits, etc. of the present disclosure, the IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof) or the IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof) is secukinumab, and secukinumab is provided as a stable liquid pharmaceutical formulation containing from about 25 mg / mL to about 150 mg / mL of secukinumab, from about 10 mM to about 30 mM of histidine (pH 5.8), from about 200 mM to about 225 mM of trehalose, about 0.02% of polysorbate 80, and from about 2.5 mM to about 20 mM of methionine, and this liquid formulation is not reconstituted from a lyophilized product. One preferred pharmaceutical for use in the methods, uses, kits, etc. of the present disclosure comprises a stable liquid formulation containing 150 mg / ml of secukinumab in 20 mM histidine buffer (pH 5.8), 200 mM of trehalose, 0.02% of polysorbate 80, and 5 mM of L-methionine, and is provided as a prefilled syringe or an autoinjector (i.e., containing 1 mL or 2 mL of the formulation).

[0083] Appropriate dosages vary, for example, depending on the particular IL-17 antagonist used, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), the host, the mode of administration, and the nature and severity of the condition being treated, as well as the nature of any previous treatments the patient has received. Ultimately, the attending healthcare provider determines the amount of the IL-17 antagonist for treating an individual patient. In some embodiments, the attending healthcare provider may administer a low dose of the IL-17 antagonist and observe the patient's response. In other embodiments, the initial dose of the IL-17 antagonist administered to the patient is increased and then gradually decreased until signs of relapse occur. The IL-17 antagonist may be administered at an increased dose until an optimal therapeutic effect is obtained for the patient, but usually the dose does not increase further thereafter.

[0084] In practicing some of the methods of treatment or use of the present disclosure, a therapeutically effective amount of an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof), is administered to a patient, such as a mammal (e.g., a human). The methods of the present disclosure are understood to enable the treatment of GCA patients with an IL-17 antagonist (e.g., secukinumab), but this does not preclude the possibility that such IL-17 antagonist therapy will necessarily be monotherapy if the patient is ultimately treated with an IL-17 antagonist. Indeed, if a patient is selected for treatment with an IL-17 antagonist, the IL-17 antagonist (e.g., secukinumab) can be administered alone or in combination with other agents and therapies (e.g., other standard therapies for GCA, such as corticosteroids, IL-6 inhibitors, anti-TNFα, methotrexate, etc.) in accordance with the methods of the present disclosure.

[0085] When co-administered with one or more additional GCA agents, the IL-17 antagonist may be administered simultaneously with, or sequentially to, the other agents. When administered sequentially, the attending physician determines the appropriate order for administering the IL-17 antagonist in combination with the other agents and the appropriate dosages for simultaneous delivery. The IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof), is preferably administered parenterally, such as intravenously (e.g., into the antecubital vein or other peripheral vein), intramuscularly, or subcutaneously.

[0086] The duration of treatment using the pharmaceutical composition of the present disclosure varies depending on the severity of the disease being treated, as well as the condition of the individual patient and the response of each person. A healthcare provider determines the appropriate duration of treatment and the timing of administration of the treatment using the pharmaceutical composition of the present disclosure. As used herein, the expression "total treatment period" refers to the total time a patient is treated with an IL-17 antagonist, including, where applicable, an induction period (e.g., initial weekly administration). That is, for example, if a patient is administered an IL-17 antagonist once a week for weeks 0, 1, 2, 3, and 4, and then every 4 weeks for a total treatment period of 2 months, the patient is administered during weeks 0, 1, 2, 3, 4, and 8. Similarly, for example, if a patient is administered an IL-17 antagonist once a week for weeks 0, 1, 2, 3, and 4, and then every 4 weeks for a total treatment period of 3 months, the patient is administered during weeks 0, 1, 2, 3, 4, 8, and 12.

[0087] Preferred total treatment periods are 1 to 3 months, 3 to 6 months, 6 to 9 months, or 9 to 12 months. In some embodiments, a patient is treated for 3 months or less, e.g., 1 month, 2 months, or 3 months. In other embodiments, a patient is treated for up to 12 months, e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months. The most preferred total treatment periods are 1 month, 2 months, or 3 months.

[0088] Preferred SC treatment regimens (including both induction and maintenance regimens) using secukinumab that can be employed in the treatment of GCA patients are provided in International Applications PCT / US2011 / 064307 and PCT / IB2014 / 063902, which are hereby incorporated by reference in their entirety where applicable.

[0089] In some embodiments, a patient may be administered an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab), or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof), at a dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) in a single subcutaneous administration.

[0090] In some embodiments, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof), may be administered subcutaneously to a patient once a week at a dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) between week 0, week 1, week 2, week 3, and week 4.

[0091] In a preferred embodiment, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof), is administered subcutaneously to a patient once a week at a fixed dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) between week 0, week 1, week 2, week 3, and week 4, and thereafter may be administered subcutaneously to the patient once every 4 weeks (once a month) at a dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg). Thus, a patient may be administered an IL-17 antagonist (e.g., secukinumab) at a dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) between week 0, week 1, week 2, week 3, week 4, week 8, etc.

[0092] In other embodiments, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof), may be administered to a patient without a loading regimen. For example, the antagonist may be subcutaneously administered to the patient once every 4 weeks (once a month) as a fixed dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg). Thus, a patient may be subcutaneously administered an IL-17 antagonist (e.g., secukinumab) of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) between week 0, week 4, week 8, week 12, etc. Ideally, a patient, such as a patient having GCA, is administered an IL-17 antagonist (e.g., secukinumab) once a month (every 4 weeks) for a total of 4 times (at week 0, week 4, week 8, and week 12).

[0093] In other preferred embodiments, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof), may be administered to a patient twice a month (bimonthly) (every 2 weeks, every other week), once a month, 4 times a year (every 3 months), twice a year (biyearly) (every 6 months), or once a year.

[0094] Preferred subcutaneous dosages (e.g., fixed dosages) are from about 150 mg to about 300 mg, preferably about 150 mg or about 300 mg. However, it should be understood that in certain patients, e.g., patients who show only an inadequate response to treatment with an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof), an increase in dosage may be required (e.g., during the induction and / or maintenance phases). That is, the subcutaneous dosage of an IL-17 antagonist, e.g., secukinumab, may be greater than from about 150 mg to about 300 mg and can be, for example, about 175 mg, about 200 mg, about 250 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, etc. It should be understood that in certain patients, e.g., patients who exhibit an adverse event or adverse reaction to treatment with an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab), a decrease in dosage may be required (e.g., during the induction and / or maintenance phases). That is, the dosage of an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) may be less than from about 150 mg to about 300 mg (SC) and can be, for example, about 75 mg, about 100 mg, about 125 mg, about 175 mg, about 200 mg, about 250 mg, about 275 mg, etc. In some embodiments, an IL-17 antagonist, e.g., an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof), may be administered to a patient as a single or multiple loading doses of 150 mg delivered SC, after which the dosage may be increased, at the discretion of the physician, up to about 300 mg if necessary.In some embodiments, an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof), may be administered to a patient by SC delivery at 300 mg as a single or multiple initial doses, and thereafter the dose may be titrated up to about 450 mg if necessary, at the discretion of the physician.

[0095] The administration timing is typically counted from the first drug administration date (also known as the "baseline"). However, healthcare providers often use different naming conventions to specify the dosing schedule, as shown in Table 2.

[0096] [Table 2] Table 2: Common naming conventions for dosing regimens. The bolded items are the naming conventions used in this specification.

[0097] In particular, the 0th week may be referred to as the 1st week by some medical providers, and the 0th day may be referred to as the 1st day by some medical providers. Thus, different physicians may specify administration, for example, at the 3rd week / 21st day, 3rd week / 22nd day, 4th week / 21st day, 4th week / 22nd day while referring to the same dosing schedule. For the sake of consistency, herein, the first week of administration will be referred to as the 0th week, and the first day of administration will be referred to as the 1st day. However, this naming convention is used solely for consistency and should not be construed restrictively, that is, it will be understood by those skilled in the art that regardless of whether a physician refers to a particular week as the "1st week" or the "2nd week", once-weekly administration is the once-weekly provision of the IL-17 antibody. In one dosing regimen, the antibody is administered monthly, such as at the 0th week, 4th week, 8th week, 12th week, etc. In one dosing regimen, the antibody is administered at the 0th week, 1st week, 2nd week, 3rd week, 4th week, 8th week, 12th week, etc. While one provider may make this regimen once-weekly for 5 weeks and then monthly (or every 4 weeks) starting from the 8th week, another provider may make this regimen once-weekly for 4 weeks and then monthly (or every 4 weeks) starting from the 4th week. It will be understood by those skilled in the art that administering an injection to a patient at the 0th week, 1st week, 2nd week, 3rd week and then monthly (every 4 weeks) starting from the 4th week is the same as: 1) administering an injection to a patient at the 0th week, 1st week, 2nd week, 3rd week, and 4th week and then monthly starting from the 8th week; 2) administering an injection to a patient at the 0th week, 1st week, 2nd week, 3rd week, and 4th week and then every 4 weeks; and, 3) administering an injection to a patient at the 0th week, 1st week, 2nd week, 3rd week, and 4th week and then monthly.

[0098] A method of treating a patient having GCA, comprising administering a therapeutically effective amount of an IL-17 antibody or an antigen-binding fragment thereof to a patient in need of treatment for GCA, wherein the IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, said epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 in one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 in the other chain, and the IL-17 antibody or an antigen-binding fragment thereof has a K D for human IL-17 of about 100 - 200 pM and the IL-17 antibody or an antigen-binding fragment thereof has a half-life in vivo of about 4 weeks is disclosed herein.

[0099] Furthermore, an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, said epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 in one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 in the other chain, and the IL-17 antibody or an antigen-binding fragment thereof has a K D for human IL-17 of about 100 - 200 pM and the IL-17 antibody or an antigen-binding fragment thereof has a half-life in vivo of about 4 weeks, and a therapeutically effective amount of an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) for use in the treatment of a patient having GCA is disclosed herein.

[0100] Furthermore, an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, said epitope containing Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 in one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 in the other chain, and the IL-17 antibody or an antigen-binding fragment thereof has a K D for human IL-17 of about 100-200 pM and the IL-17 antibody or an antigen-binding fragment thereof has an in vivo half-life of about 4 weeks, an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) for use in the manufacture of a medicament for treating a patient having GCA is disclosed herein.

[0101] Furthermore, an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) for use in the manufacture of a medicament for treating a patient having GCA, wherein the medicament is formulated to contain a container, and each container contains an amount of the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) sufficient to enable subcutaneous delivery of at least about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) of the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) per unit dose, and further, the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, said epitope containing Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 in one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 in the other chain, and the IL-17 antibody or an antigen-binding fragment thereof has a K DAn IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab), wherein the dissociation constant is about 100 to 200 pM and the in vivo half-life of the IL-17 antibody or its antigen-binding fragment is about 4 weeks, is disclosed herein.

[0102] As used herein, the expression "a container containing an amount of IL-17 antagonist sufficient to enable delivery of [the specified dose]" is used to mean that a given container (e.g., a vial, pen, syringe) has disposed therein an amount of IL-17 antagonist (e.g., as part of a pharmaceutical composition) that can be used to provide the desired dose. By way of example, if the desired dose is 300 mg, a clinician might use 2 ml from a container containing an IL-17 antibody formulation having a concentration of 150 mg / ml, or 1 ml from a container containing an IL-17 antibody formulation having a concentration of 300 mg / ml, or 0.5 ml from a container containing an IL-17 antibody formulation having a concentration of 600 mg / ml, etc. In each such case, these containers contain an amount of IL-17 antagonist sufficient to enable delivery of the desired 300 mg dose. In one embodiment, the container has disposed therein 1 ml of a formulation containing 150 mg / ml of secukinumab. In another embodiment, the container has disposed therein 2 ml of a formulation containing 150 mg / ml of secukinumab. Preferred formulations are liquid pharmaceutical compositions containing about 25 mg / mL to about 150 mg / mL of secukinumab, about 10 mM to about 30 mM of histidine, pH 5.8, about 200 mM to about 225 mM of trehalose, about 0.02% of polysorbate 80, and about 2.5 mM to about 20 mM of methionine.

[0103] Furthermore, an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) for use in the manufacture of a medicament for treating patients with GCA, wherein the medicament is formulated in a dosage to enable subcutaneous delivery of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) of the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) to a patient, and further, the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) binds to an epitope of an IL-17 homodimer having two mature IL-17 protein chains, the epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 in one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 in the other chain, and the IL-17 antibody or its antigen-binding fragment has a K D of about 100 to 200 pM for human IL-17 and the IL-17 antibody or its antigen-binding fragment has a half-life in vivo of about 4 weeks, an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) is disclosed herein.

[0104] As used herein, the expression "formulated in a dosage to enable [specified dosage] of [route of administration] delivery" means that a given pharmaceutical composition can be used to provide a desired dosage of an IL-17 antagonist, e.g., an IL-17 antibody, e.g., secukinumab, via a specified route of administration (e.g., SC or IV). By way of example, if the desired subcutaneous dosage is 300 mg, a clinician may use 2 ml of an IL-17 antibody formulation having a concentration of 150 mg / ml, or 1 ml of an IL-17 antibody formulation having a concentration of 300 mg / ml, or 0.5 ml of an IL-17 antibody formulation having a concentration of 600 mg / ml, etc. In each of such cases, these IL-17 antibody formulations are at a high enough concentration to enable subcutaneous delivery of the IL-17 antibody. Subcutaneous delivery typically requires delivery of a volume of 2 ml or less. In one embodiment, a patient is administered a single 2 ml subcutaneous injection of a formulation containing 150 mg / ml of secukinumab. In another embodiment, a patient is administered two 1 ml subcutaneous injections of a formulation containing 150 mg / ml of secukinumab.

[0105] A method, use, pharmaceutical composition, and kit for treating giant cell arteritis (GCA) in a patient having GCA, comprising subcutaneously administering to a patient in need of treatment for GCA from about 150 mg to about 300 mg of an IL-17 antibody or an antigen-binding fragment thereof, wherein the IL-17 antibody or an antigen-binding fragment thereof binds to an epitope of a human IL-17 homodimer having two mature human IL-17 protein chains, the epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 in one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 in the other chain, and the IL-17 antibody or an antigen-binding fragment thereof has a K D for human IL-17 of about 100 to 200 pM and the IL-17 antibody or an antigen-binding fragment thereof has a half-life in vivo of about 4 weeks, are disclosed herein.

[0106] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof only once.

[0107] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof once a week.

[0108] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof between week 0, week 1, week 2, week 3, and week 4.

[0109] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof every four weeks.

[0110] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof for a total treatment period of at least two months.

[0111] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof for a total treatment period of at least four months.

[0112] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof once a week between week 0, week 1, week 2, week 3, and week 4, and then every four weeks thereafter.

[0113] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient is administered the IL-17 antibody or an antigen-binding fragment thereof between week 0, week 1, week 2, week 3, week 4, week 8, and week 12.

[0114] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, a patient is administered an IL-17 antibody or an antigen-binding fragment thereof once a week for 5 weeks during weeks 0, 1, 2, 3, and 4, and then every 4 weeks for a total treatment period of at least 3 months.

[0115] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, prior to treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient has been non-responsive, poorly responsive, or intolerant to a previous GCA treatment selected from the group consisting of corticosteroids, anti-IL-6, anti-TNF-α, methotrexate, and combinations thereof.

[0116] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, the patient has active GCA.

[0117] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, after treatment with an IL-17 antibody or an antigen-binding fragment thereof, the patient experiences at least a 20% improvement in one or more clinical-reported outcomes, laboratory-reported outcomes, or patient-reported outcomes, or physician evaluation, resulting from GCA.

[0118] In some embodiments of the uses, methods, pharmaceutical compositions, and kits of the present disclosure, the IL-17 antibody or an antigen-binding fragment thereof comprises: i) an immunoglobulin heavy chain variable domain (V H H) comprising the amino acid sequence set forth as SEQ ID NO: 8; ii) an immunoglobulin light chain variable domain (V L L) comprising the amino acid sequence set forth as SEQ ID NO: 10; iii) an immunoglobulin V H H domain comprising the amino acid sequence set forth as SEQ ID NO: 8 and an immunoglobulin V LDomain; iv) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H Domain; v) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L Domain; vi) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 H Domain; vii) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H Domain, and an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L Domain; viii) an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 H Domain, and an immunoglobulin V domain comprising the hypervariable regions described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 L Domain; ix) an immunoglobulin light chain comprising the amino acid sequence described as SEQ ID NO: 14; x) an immunoglobulin heavy chain comprising the amino acid sequence described as SEQ ID NO: 15; or, xi) an immunoglobulin light chain comprising the amino acid sequence described as SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence described as SEQ ID NO: 15. In some embodiments of the uses, methods, and kits of the present disclosure, the IL-17 antibody or antigen-binding fragment thereof is secukinumab.

[0119] Also disclosed herein are methods, uses, pharmaceutical compositions, and kits for treating patients having active GCA, comprising administering to the patient about 300 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4, and then every 4 weeks for a total treatment period of at least 3 months.

[0120] Also disclosed herein are methods, uses, pharmaceutical compositions, and kits for treating patients having overuse giant cell arteritis (GCA), comprising administering to the patient about 150 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4, and then every 4 weeks for a total treatment period of at least 3 months.

[0121] In some embodiments of the methods, uses, pharmaceutical compositions, and kits of the present disclosure, prior to treatment with secukinumab, the patient was refractory to prior GCA treatment selected from the group consisting of corticosteroids, anti-TNF-α, anti-IL-6, methotrexate, and combinations thereof.

[0122] Kit The present disclosure also encompasses kits for treating GCA patients. Such kits include a therapeutically effective amount of an IL-17 antagonist, such as an IL-17 binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 antibody or an antigen-binding fragment thereof) (e.g., in liquid form or lyophilized form), or a pharmaceutical composition comprising a therapeutically effective amount of an IL-17 antagonist (as described above). Further, such kits may include means for administering the IL-17 antagonist (e.g., an autoinjector, syringe and vial, prefilled syringe, prefilled pen), and may include instructions for use. These kits may, for example, include additional therapeutic agents (as described above) for treating GCA for delivery in combination with an IL-17 antagonist of the present disclosure, such as an IL-17 binding molecule, such as an IL-17 antibody, such as secukinumab. Such kits may also include instructions for administration of an IL-17 antagonist (e.g., an IL-17 antibody, such as secukinumab) for treating GCA patients. Such instructions may provide dosage (e.g., about 150 mg to about 300 mg, e.g., about 150 mg, about 300 mg), route of administration (e.g., IV, SC, IM), dosing schedule (e.g., once weekly between weeks 0, 1, 2, 3, and 4; once weekly between weeks 0, 1, 2, 3, and 4, then every 4 weeks), and total treatment duration (e.g., 1 month, 2 months, 3 months, 4 months, 6 months, 8 months, 12 months, etc. [preferably 3 to 12 months, e.g., 3 to 6 months, e.g., 3 months]) for use in combination with an IL-17 antagonist of the present disclosure, such as an IL-17 binding molecule, such as an IL-17 antibody, such as secukinumab.

[0123] The expression "means for administration" is used to denote any available means for systemic administration of a medicament to a patient, including but not limited to prefilled syringes, vials and syringes, injection pens, autoinjectors, IV drip and bag, pumps, etc. Such means may be used for self-administration of the medicament by the patient (i.e., administration of the medicament without the assistance of a physician), or for administration of the medicament by a physician. In some embodiments, a total dose of 300 mg will be delivered in a total volume of 2 ml contained in a single PFS or autoinjector containing 150 mg / ml of an IL-17 antibody, such as secukinumab. In some embodiments, a total dose of 300 mg will be delivered in a total volume of 2 ml contained in two PFSs or autoinjectors, each containing a volume of 1 ml of 150 mg / ml of an IL-17 antibody, such as secukinumab.

[0124] A kit for use in the treatment of patients with GCA, comprising an IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab), is disclosed herein. In some embodiments, the kit further comprises means for administering the IL-17 antagonist to a patient. In some embodiments, the kit further comprises instructions for administration of the IL-17 antagonist, and the instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) should be administered subcutaneously (SC) to the patient at a dosage of about 150 mg to about 300 mg (e.g., about 150 mg, or about 300 mg). In some embodiments, the instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) should be administered to the patient once a week during weeks 0, 1, 2, 3, and 4. In some embodiments, the instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) should be administered to the patient once every 4 weeks (monthly) during a total treatment period of at least 2 months, e.g., 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months (preferably 2 months or 3 months). In some embodiments, the instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody or an antigen-binding fragment thereof, e.g., secukinumab) should be administered to the patient once a week during weeks 0, 1, 2, 3, and 4, and then once every 4 weeks (monthly) during a total treatment period of at least 3 months, i.e., 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 12 months (preferably 2 months or 3 months).In some embodiments, the instructions enable a titration (e.g., from a dose of about 150 mg to a higher dose of about 300 mg, or from a dose of about 300 mg to a dose of about 450 mg) as may be determined by a physician, as needed.

[0125] General In preferred embodiments of the methods, treatments, medicaments, regimens, uses, and kits of the present disclosure, the IL-17 antagonist is an IL-17 binding molecule. In preferred embodiments, the IL-17 binding molecule is an IL-17 antibody or an antigen-binding fragment thereof. In preferred embodiments of the methods, treatments, regimens, uses, and kits of the present disclosure, the IL-17 antibody or an antigen-binding fragment thereof is a human antibody of the IgG 1 isotype having a κ light chain. In a preferred embodiment of the methods of the present disclosure, the antibody or an antigen-binding fragment thereof is secukinumab.

[0126] Details of one or more embodiments of the present disclosure are set forth in the accompanying description above. Any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, but the preferred methods and materials are described below. Other features, objects, and advantages of the present disclosure will become apparent from the description and claims. In this specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference, where applicable, unless otherwise indicated. The following examples are provided to more fully illustrate preferred embodiments of the present disclosure. These examples should in no way be construed as limiting the disclosed subject matter, which is defined by the appended claims.

Examples

[0127] Example 1: A placebo - controlled, double - blind, parallel - group, multi - center, phase III trial to examine the efficacy and safety of 300 mg subcutaneous secukinumab in combination with glucocorticoid tapering regimen in patients with giant cell arteritis (GCA)

[0128]

Table 3 - 1

[0129]

Table 3 - 2

[0130]

Table 3 - 3

[0131]

Table 3 - 4

[0132]

Table 3 - 5

[0133]

Table 3 - 6

[0134]

Table 3 - 7

[0135]

Table 3 - 8

[0136]

Table 3 - 9

[0137] Purpose and related endpoints

[0138] [Table 4-1]

[0139] [Table 4-2]

[0140] Trial plan Study design This randomized, parallel-group, double-blind, placebo-controlled, multi-center Phase II trial was designed to evaluate the efficacy of secukinumab in combination with a 26-week prednisone taper regimen compared to placebo from the perspective of remission maintenance in patients with newly diagnosed or relapsing GCA who have not experienced biologic therapy.

[0141] The trial consists of a 6-week (maximum) screening period, a 52-week treatment period, and an 8-week safety follow-up period (Error! Reference source not found.). Patients who do not achieve remission by week 12, experience relapse after remission, or are unable to comply with the prednisone taper regimen (described below) enter "withdrawal". Upon entering "withdrawal", patients are administered prednisone at a dose determined by the physician's clinical judgment and continue to receive blinded secukinumab or placebo. Patients included in "withdrawal" must continue to participate in all scheduled clinic evaluations thereafter.

[0142] Patients who have received additional corticosteroids as described in a tapered regimen are not considered to be following the prednisone taper regimen specified in the protocol. Patients not following the prednisone taper are classified as non-responders in the primary analysis, regardless of their state of sustained remission. Patients whose prednisone dose is less than the full amount required for tapering (due to loss of tablets) are not classified as non-responders unless they meet other non-response criteria.

[0143] Screening period: During the screening period, at the discretion of the treating investigator, patients may receive glucocorticoid treatment for GCA. By the end of the screening period, patients must be switched to prednisone provided by the sponsor of the trial in order to follow the prednisone taper regimen specified in the protocol.

[0144] Randomization: Patients are randomized 1:1 to one of the following two groups: · Group 1: Secukinumab 300 mg subcutaneous + 26-week prednisone taper regimen · Group 2: Placebo subcutaneous + 26-week prednisone taper regimen

[0145] Patients receive secukinumab / placebo at the trial center at baseline, week 1, week 2, week 3, week 4, and then every 4 weeks until week 48 (last dose). Assessments are performed according to the trial schedule. Patients in both groups follow the prednisone taper regimen specified in the protocol.

[0146] At each visit, the disease activity and status of each patient are evaluated (open-label manner) to determine whether the patient can comply with the specified prednisone taper regimen. If a patient is unable to comply with the taper regimen or has experienced a relapse (as defined above), the patient enters the "withdrawal" group and must receive prednisone at a dose determined by the physician based on clinical necessity, and subcutaneous administration of secukinumab 300 mg or placebo is continued (even in this case, blinding is maintained).

[0147] Include safety evaluations in all hospital visits, including two safety follow-up hospital visits conducted 8 weeks and 12 weeks after the final administration of the investigational drug in Week 48 (which would be Week 56 and Week 60 if the patient completed the trial according to the protocol).

[0148] For the primary analysis, a treatment period of 24 weeks was selected for this trial. This is shorter than the 52-week treatment period in the GiACTA trial (Stone et al 2017); however, in the GiACTA trial, most relapses occurred within the first 6 months. Therefore, the primary analysis time point is set at Week 28 so that the effect of secukinumab in patients receiving investigational drug or placebo for 24 weeks can be evaluated. The evaluation for the primary analysis is conducted at Week 28, which is 2 weeks after the last prednisolone administration in Week 26.

[0149] The secondary evaluation items are targeted at both evaluations at Week 28 after 24 weeks of treatment, including 26 weeks of prednisolone tapering, and also at the evaluation at Week 52 after a total of 48 weeks of treatment without concomitant prednisolone after Week 27.

[0150] From Week 27 to Week 52, evaluate whether secukinumab is effective in maintaining remission, reducing vascular lesions (evaluated by imaging diagnosis), and improving quality of life without concomitant prednisolone. Patients receive double-blind treatment consisting of two injections at each time point until Week 48, and the final efficacy evaluation is conducted at Week 52.

[0151] By conducting regular evaluations, patients who may experience relapse in any treatment group will be transferred to the withdrawal group to receive prednisolone administration based on the clinical judgment of the trial physician in charge.

[0152] The 8-week follow-up period after the investigational drug ends is provided to generate follow-up data on the likelihood of relapse and to obtain treatment safety follow-up data in GCA indications. The 26-week prednisone taper regimen was selected because this regimen has been demonstrated to be effective enough to achieve corticosteroid-free remission in GCA patients when used in combination with tocilizumab in the GIACTA trial (Stone et al 2017). In pivotal Phase III trials of secukinumab in other chronic inflammatory diseases (e.g., psoriasis, PsA), peak efficacy (i.e., disease remission) was shown at Week 12 and persisted through Week 24. In this Phase II trial, patients who have not achieved remission by Week 12 will enter an "off-treatment" arm in which they continue to receive secukinumab or placebo in a blinded manner, although prednisone treatment may be adjusted by the investigator based on clinical need.

[0153] The study population consists of 50 patients diagnosed with GCA (in accordance with Inclusion Criterion 4) who meet all other inclusion criteria. Both patients with newly diagnosed GCA (diagnosed within 6 weeks of baseline) and patients with relapsing disease (previous diagnosis more than 6 weeks from baseline) are included. Inclusion of relapsing GCA patients is preferentially limited to 50%, but may increase depending on the ratio of incident to relapsing patients.

[0154] Investigational drug Test article and comparator The overview of the investigational drug is shown in a table. Patients will receive all secukinumab and placebo injections in the facility by the facility staff. The PFS is packaged in a double-blind fashion and is ready-to-use. The investigational drug will be labeled as follows: · The double-blind secukinumab PFS and placebo PFS will be labeled AIN457 150mg / 1ml / placebo and used for dosing through Week 48.

[0155] Patients are also administered prednisone tablets for tapered dosing from baseline to week 26. Patients are administered prednisone tablets by local facility staff at the time of the study facility visit, and sufficient tablets for home administration are dispensed between study visits.

[0156]

Table 5

[0157] Additional Treatments As described herein, in this study, prednisone is administered together with the investigational drug (secukinumab) and placebo. No further additional treatments are included in this study.

[0158] Treatment Groups Patients are assigned to one of the following two treatment groups at a 1:1 ratio, with approximately 25 patients per group. · Group 1: Secukinumab 300 mg subcutaneously (2 × 150 mg) + 26-week prednisone taper regimen · Group 2: Placebo subcutaneously (2 injections) + 26-week prednisone taper regimen

[0159] Patients receive secukinumab or placebo at the study center at week 0 (baseline), week 1, week 2, week 3, week 4, and then every 4 weeks until week 48 (final dose).

[0160] Patients are administered a daily dose of prednisone, which is decreased (i.e., tapered) from baseline to week 26.

[0161] Patients who do not achieve remission by week 12, patients who experience relapse after remission, or patients who cannot comply with the prednisone taper regimen enter "withdrawal." Upon entering "withdrawal," patients are administered prednisone at a dose determined by the clinician's clinical judgment and continue to receive subcutaneous secukinumab 300 mg in a double-blind manner. Patients included in "withdrawal" must continue to participate in all scheduled follow-up assessments.

[0162] Patients who are administered additional corticosteroids as described in the taper regimen are not considered to be complying with the prednisone taper regimen specified in the protocol. Patients who do not comply with prednisone tapering are classified as non-responders in the primary analysis, regardless of the state of sustained remission. Patients whose prednisone dose is less than the full dose required for tapering (due to loss of tablets) are not classified as non-responders.

[0163]

Table 6

[0164] Depending on the patient's prednisone value at the baseline, two different prednisone taper regimens (Table 0-1 for patients receiving 40 - 60 mg / day of prednisone at baseline; Table for patients receiving 25 - 40 mg / day of prednisone at baseline) are used in both treatment groups. From week 8, all patients are administered the same level of prednisone (15 mg / day) and the taper continues.

[0165] Prednisone is supplied by the sponsor in an open-label manner. Reporting of prednisone administration for weeks not included in the assessment schedule is required (date, home administration form).

[0166]

Table 7

[0167]

Table 8

[0168] Prednisolone before baseline Patients need to have a prednisolone dose of 25 - 60 mg / day at baseline for inclusion in the study.

[0169] Prednisolone after baseline Patients are administered a daily dose of prednisolone, which is decreased (i.e., tapered) from baseline until week 26 as described.

[0170] Methotrexate Patients taking MTX at 25 mg / week or less (≤25 mg / week) are permitted to continue drug treatment only if they have been taking MTX for at least 3 months, at a stable dose for at least 4 weeks before randomization, and throughout the study.

[0171] Patients taking MTX need to take folic acid supplements before randomization and during the trial to minimize the potential for MTX - related toxicity.

[0172] Cholestyramine - mediated wash - out of leflunomide In the case of leflunomide treatment, a 8-week drug washout is necessary; alternative washout methods may be considered. To wash out leflunomide, cholestyramine can be administered orally at a dose of 8 g three times a day. Cholestyramine has been shown to reduce the plasma levels of the active leflunomide metabolite by approximately 40% in 24 hours and 49% - 65% in 48 hours in three healthy individuals. Administration of cholestyramine is recommended in patients who require a drug elimination procedure. If a patient receives 8 g three times a day for 11 days, the patient can be safely randomized 4 weeks after the start of the 11-day cholestyramine treatment period.

[0173] Vitamin D During the trial, vitamin D (1000 I.E. / day) is strongly recommended.

[0174] Efficacy Primary efficacy evaluation The primary efficacy objective is to evaluate the efficacy of secukinumab, in combination with a 26-week prednisone taper regimen, compared to placebo, based on the proportion of GCA patients with sustained remission.

[0175] The primary efficacy endpoint is the proportion of GCA patients with sustained remission (defined below) at week 28.

[0176] Definition of remission : Absence of relapse (see below). Definition of sustained remission : The patient has no relapse (see below) until week 28 and is compliant with the prednisone taper regimen implementation plan.

[0177] Definition of relapse : As determined by the investigator and defined as follows. Recurrence after remission of signs or symptoms of GCA and / or, due to GCA, an ESR of 30 mm / h or more and / or a CRP of 10 mg / L or more.

[0178] Signs and symptoms of GCA disease The evaluation of clinical signs and symptoms by the efficacy assessor for each visit to the clinical trial in accordance with the evaluation schedule includes the following: · Fever (above 38°C). · Symptoms of polymyalgia rheumatica (PMR) (morning stiffness and / or pain in the shoulders and / or pelvic girdle). · Local headache, temporal artery, or scalp tenderness. · Signs or symptoms in vision such as arteritic anterior ischemic optic neuropathy (A-AION), acute or subacute vision loss due to transient blurring (usually monocular, or at least one eye affected initially but both eyes may be affected). · Pain in the jaw or mouth. · Onset or worsening of lower limb claudication. · Other features judged by the clinician - principal investigator of the clinical trial to be consistent with relapse of GCA or PMR.

[0179] Secondary efficacy evaluation Evaluate the following secondary efficacy evaluation items as described in this specification or as described in the section of each implementation plan: · Remission rate at the 12 - week time point · Time to first relapse of GCA after clinical remission (up to week 52) · Total cumulative prednisolone dosage up to week 28 and week 52 · Proportion of GCA patients maintaining remission at week 52 ○ Definition of remission: No relapse. ○ Definition of sustained remission: The patient has no relapse up to week 52, complies with the implementation plan of the prednisolone taper regimen, and has not used prednisolone since week 27. ○ Definition of relapse: Determined by the researcher and defined as follows. Recurrence of signs or symptoms of GCA after remission, and / or due to GCA, an erythrocyte sedimentation rate (ESR) of 30 mm / h or more, and / or a C - reactive protein (CRP) of 10 mg / L or more. · Proportion of patients with a prednisolone dosage of less than 5 mg / day at week 19 / week 28 / week 52 ·Change from baseline in measures of disease activity and quality of life at week 4, 8, 12, 16, 20, 24, 28, 36, 44, and 52 in each of the following cases: ·PhGA, VAS ·PRO: ·PGA, VAS ·FACIT-Fatigue ·SF-36 ·EQ-5D ·Change from baseline in CRP and ESR at week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52

[0180] All efficacy assessments should be performed before administration of the investigational drug.

[0181] The primary efficacy assessment of this trial is consistent with the primary efficacy assessment in the GIACTA trial (Stone et al 2017), which showed the efficacy of the combination of glucocorticoid tapering (i.e., prednisone) similar to that of another humanized monoclonal antibody (i.e., tocilizumab) for the treatment of GCA patients. Other efficacy assessments, including patient-reported outcome (PRO) assessments including PhGA and PGA, are also very well consistent with those included in other Phase II and Phase III clinical trials in the clinical development program for secukinumab for other chronic inflammatory diseases.

[0182] Before the clinical assessment is performed on the patient, it is necessary to hand over the PRO scale to be filled in at the scheduled hospital visit. Sufficient space and time should be given to the patient to fill in the PRO scale.

[0183] Facility staff (referring to those who can be responsible for administration and checking the filling in of the PRO scale) should check the filling in of the PRO scale and ask the patient to fill it in if there are any omissions in the answers. Consider the answers electronically stored on the database as the original materials.

[0184] For the post - entry scales and the spontaneous comments written by the patient, the principal investigator of the clinical trial must review and evaluate before the clinical trial tests whether there are any responses that may indicate the possibility of an AE or SAE. This evaluation should be appended to the original records of the trial. If an AE or SAE is confirmed, the principal investigator of the clinical trial must not advise the patient to change the responses reported in the post - entry questionnaire. The principal investigator of the clinical trial must follow the reporting instructions outlined in the clinical trial protocol.

[0185] Overall assessment of disease activity by the patient The overall assessment of disease activity by the patient is performed using a 100 - mm VAS ranging from "no impact at all" to "the worst imaginable impact" after the following question: "On a scale of 0 to 100, how would you rate the overall impact that giant cell arteritis is having on you at the present time?"

[0186] The overall assessment of disease activity by the patient is filled in by the patient at all scheduled visits before the administration of the investigational drug.

[0187] FACIT - Fatigue (copyright) is a 13 - item questionnaire (Cella 1993 and Yellen 1997) that assesses self - reported fatigue and its impact on daily activities and function.

[0188] In the eCRF, the purpose of collecting available FACIT - Fatigue (copyright) data in accordance with the treating physician's clinical routine is to evaluate the impact of fatigue on GCA patients. The questionnaire is used at all scheduled visits before the administration of the investigational drug.

[0189] The SF-36 is a widely used and well-researched instrument for measuring health-related quality of life among healthy subjects as well as patients with acute and chronic conditions. The SF-36 consists of eight subscales that can be scored individually: physical function, role physical, bodily pain, general health perceptions, vitality, social functioning, role emotional, and mental health (Ware 1993). Two overall summary scores can also be calculated: the Physical Component Summary (PCS) score for the physical aspects of QOL and the Mental Component Summary (MCS) score for the mental aspects of QOL (Ware 1994). The SF-36 has proven useful for monitoring general and specific populations, comparing the relative burden of various diseases, differentiating health benefits resulting from treatment differences, and screening individual patients.

[0190] The purpose of the SF-36 in this trial is to evaluate the health-related quality of life of the patients. The standard version with a 4-week recall period is used at all visits designated before the administration of the investigational drug.

[0191] The EQ-5D-5L is a widely used self-administered questionnaire designed to assess health status in adults (Xu et al 2011, Mc Clure et al 2017). The purpose of the EQ-5D-5L in this trial was to evaluate the overall health status of the patients. This scale is divided into two distinct sections. The first section contains one item corresponding to each of five dimensions (mobility, self-care, usual activities, pain / discomfort, and anxiety / depression). Patients rate each of these items as "no problem", "mild problem", "moderate problem", "severe problem", or "extreme problem / cannot do". A composite health index is then defined by combining the levels of each dimension. In the second section of the questionnaire, self-rated (overall) health status is measured using a vertical VAS where 100 represents "the best health state possible" and 0 represents "the worst health state possible". Respondents are asked to mark their current health state along this continuum. The recall period is "today" and it takes about 5 - 10 minutes to complete the questionnaire.

[0192] The EQ-5D-5L includes six items designed to assess health status from the perspective of a single index value or health utility value. One of the strengths of the EQ-5D-5L approach is the ability to "weight" a particular health state by the patient and generate a patient utility value. Using published weights, a composite score can be created that results in a single health utility value ranging from 0 to 1, where a lower score represents a higher level of disability. The EQ-5D-5L is completed by the patient at the time of clinic visit as specified prior to administration of the investigational drug.

[0193] Results The results are illustrated and described in Figures 2 to 7. Among 52 randomized patients (secukinumab (SEC), n = 27; placebo, n = 25), 71.2% (n = 37) completed the investigational drug (SEC, 81.5%; placebo, 60.0%). Overall, at baseline, 42 patients (80.8%) had newly diagnosed GCA and 10 patients (19.2%) had relapsing GCA. The proportion of GCA patients who maintained remission until week 28 (post hoc median with 95% confidence interval) was higher with SEC at 70.1% (51.6% - 84.9%) than with placebo at 20.3% (12.4% - 30.0%); the odds ratio (post hoc median with 95% confidence interval) was 9.31 (3.54 - 26.29). By week 52, the proportion of GCA patients who maintained remission (95% confidence interval) was 59.3% (38.8% - 77.6%) in the SEC group and 8.0% (1.0% - 26.0%) in the placebo group. The median time (95% confidence interval) to the first GCA relapse after baseline was not reached in GCA patients treated with SEC and was 197.0 (101.0 - 280.0) days in the placebo group.

[0194] Randomized parallel-group double-blind placebo-controlled multi-center Phase 2 trial (TitAIN) to examine the safety and efficacy of secukinumab (AIN457) in patients with giant cell arteritis

[0195]

Table 9-1

[0196]

Table 9-2

[0197]

Table 9-3

[0198]

Table 9-4

[0199]

Table 9-5

[0200]

Table 9-6

[0201]

Table 9-7

[0202]

Table 9-8

[0203] 1.2 Objectives The objective of this study is to demonstrate the efficacy and safety of the combination of 52 weeks of subcutaneous (s.c.) secukinumab 300 mg and 26 weeks of prednisone taper in adult subjects with newly diagnosed or relapsing giant cell arteritis (GCA).

[0204] 2 Objectives and Endpoints Table 0-2 Objectives and Related Endpoints

[0205]

Table 10-1

[0206]

Table 10-2

[0207]

Table 10-3

[0208] Primary Estimand The main scientific question of interest is what is the relative effect on the proportion of subjects achieving sustained remission at Week 52, without discontinuation of the investigational drug, and without withdrawal or rescue dosing, of the combination of secukinumab 300 mg subcutaneous and a 26-week prednisone taper regimen compared to the combination of placebo and a 52-week prednisone taper regimen in subjects with GCA?

[0209] The primary estimand is characterized by the following attributes: Target population: Defined through appropriate inclusion and exclusion criteria to reflect the targeted GCA patient population. Treatments of interest: Comparison of secukinumab 300 mg subcutaneous + 26-week prednisone taper regimen vs placebo + 52-week prednisone taper regimen

[0210] Primary variable: Sustained remission at Week 52 is defined as remission achieved at Week 12, maintained from Week 12 to Week 52, without discontinuation of the investigational drug, and without withdrawal or rescue dosing for GCA.

[0211] Handling of remaining intercurrent events: · Discontinuation of investigational drug (for any reason): Non-responder (composite strategy) · Use of prohibited drugs: Drugs not permitted in the protocol that may have a confounding effect on the efficacy of secukinumab. Subjects who use a prohibited drug and discontinue the investigational drug are considered non-responders (as defined in the above-mentioned intercurrent event (investigational drug discontinuation)) (composite strategy). If the subject does not discontinue the investigational drug after using a prohibited drug, the potential confounding effect due to prohibited drug intake can be ignored (treatment policy strategy). ·Withdrawal treatment for GCA: Receiving withdrawal treatment including GC at a dose determined by the investigator in charge of the trial according to the standard treatment is incorporated as a component of the primary variable. Subjects who receive withdrawal treatment are considered non-responders (composite strategy). ·Rescue treatment for GCA: Receiving rescue treatment is incorporated as a component of the primary variable. In addition, subjects who receive rescue treatment will also have the investigational drug discontinued. These subjects are considered non-responders (composite strategy).

[0212] Summary measure: The difference in the remission duration rate between the secukinumab group and the placebo group.

[0213] Secondary estimand For all secondary evaluation items, relevant supplementary estimands may be specified in the statistical analysis plan.

[0214] Time to clinical failure Scientific question of interest: What is the relative effect of the combination of secukinumab 300 mg subcutaneous and a 26-week prednisone taper regimen compared with the combination of placebo and a 52-week prednisone taper regimen in extending the time to clinical failure (considering withdrawal / rescue treatment for GCA, discontinuation of the investigational drug, and trial discontinuation as clinical failures) in GCA patients?

[0215] Estimands are characterized by the following attributes: Target population: Defined through appropriate inclusion and exclusion criteria to reflect the targeted GCA patient population. Treatments of interest: Comparison of secukinumab 300 mg subcutaneous + 26-week prednisone taper regimen with placebo + 52-week prednisone taper regimen. Primary variable: The time to clinical failure as described herein, considering discontinuation of the investigational drug and withdrawal / rescue treatment for GCA as clinical failures.

[0216] Handling of remaining intermediate events: · Discontinuation of investigational drug before week 52 for any reason: Composite strategy (reflected in the above variables). · Withdrawal therapy for GCA: Composite strategy (reflected in the above variables). · Rescue therapy for GCA: Composite strategy (reflected in the above variables). · Discontinuation of the trial before week 52 for any reason: Composite strategy (reflected in the above variables).

[0217] Aggregate measure: Hazard ratio of time to clinical failure between the secukinumab group and the placebo group.

[0218] Cumulative GC dose up to week 52 Scientific question of interest: What is the relative effect of the combination of secukinumab 300 mg subcutaneously and a 26-week prednisone taper regimen compared to the combination of placebo and a 52-week prednisone taper regimen in GCA patients on the cumulative GC dose up to week 52, when patients continued investigational drug dosing without receiving rescue therapy for GCA?

[0219] The estimand is characterized by the following attributes: Target population: Defined through appropriate inclusion and exclusion criteria to reflect the targeted GCA patient population. Treatments of interest: Comparison of secukinumab 300 mg subcutaneously + 26-week prednisone taper regimen with placebo + 52-week prednisone taper regimen. Variable: Cumulative GC dose up to week 52.

[0220] Handling of remaining intermediate events: Use of prohibited drugs before week 52 for any reason is handled with a hypothetical strategy (if the prohibited drug was not available to the subject).

[0221] Aggregate measure: Difference in mean (median) cumulative GC dose between the secukinumab group and the placebo group.

[0222] PRO (SF-36 PCS, EQ-5D, FACIT-Fatigue score) and GTI total score Scientific question of interest: What is the relative effect of the combination of secukinumab 300 mg subcutaneous and a 26-week prednisone taper regimen compared to the combination of placebo and a 52-week prednisone taper regimen in GCA patients on the change in PRO scores and GTI scores from baseline to week 52 in GCA patients who continued investigational drug dosing without receiving rescue treatment for GCA?

[0223] Target population: Defined through appropriate inclusion and exclusion criteria to reflect the targeted GCA patient population.

[0224] Treatments of interest: Comparison of secukinumab 300 mg subcutaneous + 26-week prednisone taper regimen with placebo + 52-week prednisone taper regimen.

[0225] Variables (SF-36 PCS, EQ-5D, FACIT-Fatigue score, GTI total score): Change in variables of interest from baseline to week 52

[0226] Handling of remaining intermediate events: · Discontinuation of investigational drug before week 52 for any reason: If the subject did not discontinue (hypothetical) · Rescue treatment for GCA: If rescue treatment was not available to the subject (hypothetical). · Discontinuation of the trial before week 52 for any reason: If the subject did not discontinue (hypothetical).

[0227] Aggregate measure: Difference in mean values between the secukinumab group and the placebo group.

[0228] Study design This randomized, parallel-group, double-blind, placebo-controlled, multi-center, phase III trial is designed to evaluate the efficacy of combining secukinumab with a 26-week prednisone taper regimen compared to combining placebo with a 52-week prednisone taper regimen, based on the persistence of remission at week 52 in subjects with newly diagnosed or relapsing GCA. Approximately 240 subjects will be enrolled in this trial.

[0229] The trial consists of a 6-week screening period, a 56-week treatment period (treatment period 1), a 52-week second treatment period (treatment period 2), and an 8-week safety follow-up period (Figure 8).

[0230] Screening period: During the screening period, subjects are expected to receive GCA treatment with GC at the discretion of the investigator. By the end of the screening period, subjects must be switched to prednisone provided by the sponsor at baseline in order to follow the prednisone taper regimen specified in the protocol. The starting dose of prednisone at baseline shall be at the discretion of the investigator and shall be 20 mg / day, 25 mg / day, 30 mg / day, 35 mg / day, 40 mg / day, 50 mg / day, or 60 mg / day.

[0231] If a major medical breakdown (e.g., pandemic or epidemic) occurs and on-site visits to the trial sites are restricted or impeded, the screening period may be extended up to 8 weeks prior to baseline.

[0232] First treatment period (from baseline (BSL) to pre-dose at week 56): At baseline, subjects shall be randomly assigned in a 2:1 ratio to one of the following two groups: · Group 1: Secukinumab 300 mg (2 mL PFS) is administered subcutaneously at BSL, week 1, week 2, week 3, and every 4 weeks thereafter. Secukinumab is administered in combination with the designated 26-week prednisone taper regimen. · Group 2: Placebo against secukinumab 300 mg (2 mL PFS) was subcutaneously administered at BSL, week 1, week 2, and week 3, and subcutaneously every 4 weeks after week 4. The placebo was administered in combination with the designated 52-week prednisone taper regimen.

[0233] To achieve a well-balanced distribution of baseline prednisone dosage and GCA status in each treatment group, randomization in these two groups was stratified by the subject's GCA status (new-onset GCA or relapsing GCA) and baseline prednisone dosage (prednisone of 30 mg / day or less or prednisone of more than 30 mg / day).

[0234] Subjects who have not achieved clinical remission by week 12 or who have experienced a clinical relapse after clinical remission may have their GC dosage changed by the investigator in charge of the trial according to the standard treatment, but the blinding of the investigational drug (secukinumab or placebo) is maintained. These subjects are said to be receiving rescue treatment. For subjects receiving rescue treatment, GC is administered unblinded, and the dosage is determined by the investigator in charge of the trial according to the standard treatment.

[0235] Clinical remission at week 12 is defined as the subject meeting all of the following at week 12 and not having the following relapses if remission was achieved before week 12: · No signs or symptoms attributable to GCA that require an increase in prednisone dosage compared to the pre-specified taper (or rescue treatment) · No increase in ESR to 30 mm / h attributable to GCA that requires an increase in prednisone dosage compared to the pre-specified taper (or rescue treatment) · No non-compliance with the pre-specified prednisone taper due to an increase in GC dosage

[0236] Since the CRP test value is blinded, the CRP value is not included in the definition of clinical remission.

[0237] For subjects undergoing withdrawal treatment, prednisone is administered in an open-label manner. Subjects undergoing withdrawal treatment must remain in the study and continue to participate in all scheduled study visits.

[0238] If a subject receives rescue treatment (another treatment for GCA other than prednisone alone), the investigational drug is discontinued before the rescue treatment is initiated. Such subjects may remain in the study and participate in all scheduled study evaluations (first treatment period and follow-up study visits).

[0239] Second treatment period (from week 56 dosing to week 108): At week 56, subjects will be classified into and receive further treatment as follows: Subjects with persistent clinical remission at week 56: Subjects with persistent clinical remission (as defined above) at week 56 will first be randomly assigned to secukinumab and then randomly re-assigned 1:1 to either 300 mg of blinded secukinumab or placebo subcutaneously and follow a randomized treatment discontinuation design until week 108. Subjects initially randomly assigned to placebo will undergo dummy re-randomization and continue placebo administration in a blinded manner. Re-randomization is stratified by the subject's baseline GCA status (new-onset GCA or relapsing GCA). Since prednisone has already been discontinued by week 26 (initial secukinumab group) or week 52 (initial placebo group), these subjects will not receive concomitant prednisone treatment.

[0240] If a subject experiences a clinical relapse during the second treatment period, the investigational drug will be discontinued and the subject will be provided with open-label (OL) 300 mg of secukinumab subcutaneously. The start of OL secukinumab treatment is similar to that of the initial secukinumab treatment, with weekly (qw) dosing for the first 4 weeks and then every 4 weeks (q4w) starting 4 weeks after the start of OL secukinumab. GC will also be administered, and the dose will be determined by the study physician in charge according to standard treatment.

[0241] Subjects who have not achieved clinical remission by 12 weeks after the start of olokizumab or who have had a clinical relapse during olokizumab in the second treatment period discontinue olokizumab and receive further GCA treatment at the discretion of the principal investigator of the clinical trial. Subjects participate in the visits at the end of the administration of the investigational drug (EOT) and at the end of the trial (EOS).

[0242] Subjects who do not maintain clinical remission at week 56: Subjects who do not maintain clinical remission at week 56, including those who are receiving withdrawal treatment, are provided with olokizumab 300 mg subcutaneously q4w treatment, including GC combination administration, as determined by the principal investigator of the clinical trial according to the standard treatment. The start of olokizumab treatment is similar to that of the initial secukinumab treatment, with administration once a week (qw) for the first 4 weeks and then once every 4 weeks (q4w) starting 4 weeks after the start of olokizumab. Subjects who have received olokizumab but have not achieved clinical remission by 12 weeks after the start of olokizumab or who have had a clinical relapse after achieving clinical remission discontinue the investigational drug and participate in the EOT visit and the EOS visit. Further GCA treatment is determined by the principal investigator of the clinical trial.

[0243] Follow-up period: Following the EOT visit at week 108, there is an EOS visit for safety evaluation at week 116.

[0244] Subjects administered the blinded investigational drug (secukinumab or placebo) at week 108: Subjects who were administered the blinded investigational drug at week 108 and who maintain clinical remission (i.e., only the investigational drug is administered and GC is not combined) complete the treatment (the last administration at week 104), complete the EOT visit at week 108, and complete the EOS visit at week 116. For subjects who are considered by the principal investigator of the clinical trial according to the standard practice to obtain clinical benefits from secukinumab administration after the trial, every effort will be made to provide olokizumab in accordance with local regulations. For subjects who start olokizumab after the completion of the investigational drug, the EOS visit at week 116 is waived.

[0245] Subjects Administered OL Secukinumab in Week 108: Subjects administered OL secukinumab in Week 108 completed the treatment (last dose in Week 104), completed the EOT visit in Week 108, and completed the EOS visit in Week 116. For subjects who are still deriving clinical benefits from OL secukinumab as per the opinion of the principal investigator of the clinical trial, every effort will be made to continue the provision of OL secukinumab in accordance with local regulations. If post-trial access to OL secukinumab is provided, the EOS visit in Week 116 will be waived. For subjects who have not yet received OL secukinumab for 12 weeks, the principal investigator of the clinical trial will evaluate whether the subject is deriving clinical benefits from OL secukinumab and whether treatment needs to be continued with post-trial access.

[0246] Imaging Diagnosis Sub-study MRA is a non-invasive radiological technique without X-ray exposure. However, MRA scanning devices may cause claustrophobia in highly sensitive individuals, and the presence of metal in the body may also pose safety problems or affect the quality of MRA images. Therefore, subjects can consider this type of imaging diagnosis only if they have no contraindications to MRA. For further information, please refer to the exclusion criteria.

[0247] MRA measurements require the injection of a gadolinium-based contrast agent (GBCA) during each MRA session. There is the latest finding that gadolinium deposits in brain tissue after the use of GBCA. Although no symptoms or diseases related to gadolinium accumulation in the brain have been confirmed, insurance authorities are taking a cautious approach as the data on long-term effects in the brain are limited (e.g., GBCA EMA restrictions regarding brain accumulation). For this reason, the use of some linear GBCAs has been discontinued, and the use of another class of GBCAs called macrocyclic agents is recommended because they are considered to be more stable and have a lower gadolinium release tendency than linear agents. This has been much debated, but the current view is that such agents, particularly the linear gadolinium agents, may also increase the risk of a rare but serious disease called nephrogenic systemic fibrosis (NSF). As evidence of this, in a recent review of 639 patients with biopsy-confirmed NFS, the NFS case rate per million exposures was shown to be 1.52 for group I (i.e., linear) GPCAs but only 0.008 for group II (i.e., macrocyclic) agents (Attari et al 2019). To further reduce this risk, and in accordance with guidance from health authorities (e.g., GBCA UK health authority guidance on NSF, GBCA FDA guidance on NSF, etc.), people with severe renal insufficiency, subjects who have previously had a severe allergic / anaphylactic-like reaction to gadolinium-based contrast agents, and subjects with severe renal disease [estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m2] or acute worsening of renal function are excluded from participation in the imaging diagnostic substudy, as defined in the exclusion criteria.

[0248] Selection Criteria Patients eligible for inclusion in this trial must meet all of the following criteria: 1. An informed consent form signed prior to participation in the trial must be obtained. 2. The patient must be able to understand the investigator's words, communicate information, and comply with the requirements of the trial. 3. Male patients or female patients who are not pregnant or lactating, at least 50 years of age. 4. Diagnosis of GCA based on meeting all of the following criteria: · Age of onset of the disease is 50 years or older. · Clear head symptoms of GCA (initial localized headache, scalp or jaw pain during chewing), and / or symptoms of polymyalgia rheumatica (PMR) (defined as zonal pain in the shoulders and / or hips with inflammatory morning stiffness), and / or symptoms of ischemic limbs (claudication). ·TAB showing the characteristics of GCA, and / or cross-sectional imaging diagnosis such as ultrasound (e.g., head or axilla) where vasculitis is observed, MRA, CTA, or PET-CT. 5. Active disease defined by meeting both of the following within 6 weeks of baseline: · Presence of signs or symptoms of GCA · ESR increased by 30 mm / h or more or CRP 10 mg / L or more due to active GCA, or temporal artery biopsy (TAB) or imaging diagnosis of active GCA. 6. The patient must meet the definition of either primary GCA or relapsing GCA: · Definition of primary GCA: Diagnosis of GCA within 6 weeks of baseline visit. · Definition of relapsing GCA: Diagnosis of GCA more than 6 weeks prior to baseline visit and the patient has experienced recurrence of active disease after the start of treatment. 7. The patient must be eligible to receive once-daily prednisone (or equivalent) at a dose of 20 mg to 60 mg at baseline. 8. Patients taking MTX (25 mg / week or less) are permitted to continue drug treatment only if they have been taking MTX for at least 3 months, at a stable dose starting at least 4 weeks before randomization, and have received stable folic acid treatment before randomization.

[0249] Exclusion Criteria Patients meeting any of the following criteria are ineligible for inclusion in this trial: The principal investigator of the clinical trial shall not apply any further exclusion criteria so that the study population represents all eligible patients.

[0250] 1. Women who are pregnant or breastfeeding (pregnancy is defined as the state of a woman from conception until the end of pregnancy confirmed by a positive clinical test for human chorionic gonadotropin (hCG)). 2. Women of childbearing potential (defined as all women who are physiologically capable of becoming pregnant), except when using an effective method of contraception during the administration of the investigational drug and for at least 20 weeks after the last dose of secukinumab. Examples of basic contraceptive methods: · Complete abstinence (if consistent with the usual lifestyle preferred by the patient). Periodic abstinence (e.g., calendar method, ovulation method, symptothermal method, post-ovulation method) and withdrawal are not recognized as contraceptive methods. · Female sterilization (with or without hysterectomy, having had surgical bilateral oophorectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking the investigational drug. In the case of oophorectomy only, it is limited to the case where the reproductive status is confirmed by follow-up evaluation of hormonal values. · Male sterilization (at least 6 months before screening). In the case of female patients participating in this trial, the male partner who has had vasectomy must be the only partner of the patient. · Barrier contraceptive methods: condom or closure cap (pessary or cervical / vault cap). · Use of hormonal contraceptive methods by oral (estrogen and progesterone), injection, implantation, or other hormonal contraceptive methods with equivalent effectiveness. When using oral contraception, the woman must have been stable on the same pill for at least 3 months before taking the investigational drug. · The woman has had natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., appropriate age, history of vasomotor symptoms) for at least 12 months or more, or is considered to be postmenopausal and not likely to give birth if she has had surgical bilateral oophorectomy (regardless of hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before. In the case of oophorectomy only, the woman is considered not likely to give birth only if the reproductive status is confirmed by follow-up evaluation of hormonal values. If local regulations differ from the above contraceptive methods for preventing pregnancy, local regulations apply and are described in the Informed Consent Document (ICF). 3. Having been previously exposed to secukinumab or other biological agents that directly target IL-17 or the IL-17 receptor. 4. Patients treated with any cell depletion therapy. 5. Having previously participated in a clinical trial targeting GCA. 6. Patients who were treated within 4 weeks before baseline or within 5 half-lives of the drug (whichever is longer) with an inhibitor that directly targets IL-1, or the IL-1 receptor, IL-12, and IL-23, or abatacept. 7. When treated within 12 weeks before baseline or within 5 half-lives of the drug (whichever is longer) with tocilizumab, other IL-6 / IL6-R inhibitors or JAK inhibitors, or if the patient did not respond to treatment or experienced a relapse during treatment prior to baseline. 8. If there was treatment administered for GCA other than GC, and the patient did not respond to treatment or experienced a relapse during treatment prior to baseline. 9. Patients who were treated with intravenous immunoglobulin or plasmapheresis within 8 weeks before baseline. 10. Patients who were treated with cyclophosphamide, tacrolimus, everolimus, hydroxychloroquine, cyclosporine A, azathioprine, sulfasalazine, mycophenolate mofetil within 6 months before baseline. 11. Patients who were treated with leflunomide within 8 weeks before baseline. However, if a washout with cholestyramine was performed, the patient must have been treated within 4 weeks of baseline. 12. Patients who were treated with an alkylating agent within 5 years before baseline, except as specified by other exclusion criteria. 13. Patients who require long-term systemic glucocorticoid therapy for any reason other than GCA. 14. If they had received more than 100 mg of once-daily methylprednisolone pulse intravenous therapy within 6 weeks before baseline. 15. Patients who require chronic (i.e., not on an occasional "as needed (prn)") strong opioid analgesics for pain management. 16. Patients who were treated with any investigational drug within 4 weeks before baseline or within 5 half-lives of the drug (whichever is longer). 17. Contraindication or hypersensitivity to secukinumab. 18. Ongoing active inflammatory diseases other than GCA that may confound the assessment of the benefit of secukinumab therapy, including inflammatory bowel disease or uveitis. 19. Serious ischemic events (e.g., myocardial infarction, stroke, etc.) or transient ischemic attacks (TIAs) (excluding vision loss related to ischemia), regardless of whether they are related to GCA, within 12 weeks of screening. 20. Definite diagnosis of primary systemic vasculitis other than GCA. 21. Treated with other biological agents within 4 weeks before baseline or within 5 half-lives of the agent (whichever is longer). 22. Ongoing active diseases that, in the opinion of the principal investigator of the clinical trial, render the patient immunocompromised and / or expose the patient to unacceptable risks of being treated with immunomodulatory therapy. 23. Serious medical problems and diseases including, but not limited to: poorly controlled hypertension (160 / 95 mmHg or higher), congestive heart failure (New York Heart Association (NYHA) class III or IV), and poorly controlled diabetes. 24. History of clinically significant liver disease or liver injury indicated by abnormal liver function tests (LFTs) such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), or serum bilirubin. The principal investigator of the clinical trial should use the following criteria as a guide: · SGOT (AST) and SGPT (ALT) should not exceed 3 times the upper limit of normal (ULN). Parameters elevated above 3×ULN should be retested as soon as possible, in any case, at least before randomization, to rule out laboratory error. · Alkaline phosphatase should not exceed 2 times the ULN. If elevated above 2×ULN, it should be retested as soon as possible, in any case, at least before randomization, to rule out laboratory error. · Total bilirubin should not exceed 2 times the ULN. When the total bilirubin concentration is elevated above 2×ULN, the total bilirubin should be differentiated into direct-reacting bilirubin and indirect-reacting bilirubin. 25. Patients with severe renal function decline [estimated glomerular filtration rate (eGFR) by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) less than 30 mL / min / 1.73m 2 ²]. 26. Total WBC count less than 3000 cells / μL, or platelet count less than 100,000 cells / μL, or neutrophil count less than 1500 cells / μL, or Hgb less than 8.3 g / dL (83 g / L) at screening. 27. Active systemic infection (except for cold) in the past 2 weeks before randomization. 28. History of ongoing, chronic or recurrent infectious disease defined by a positive QuantiFERON TB Gold Plus test, or evidence of tuberculosis infection. Even for patients with a positive test, they may participate in the trial if it is conclusively proven that there is no evidence of active tuberculosis by further detailed examination (in accordance with local practice / guidelines). If the presence of latent tuberculosis is proven, treatment must be initiated according to the local country's guidelines before randomization. 29. Known to be infected with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C at screening or randomization. 30. History of lymphoproliferative disease or any known malignancy within the past 5 years, or history of malignancy in any organ system (except for basal cell carcinoma or actinic keratosis treated within the past 3 months without evidence of recurrence, excised cervical intraepithelial neoplasia or non-invasive malignant colorectal polyps). 31. Live vaccine administration within 6 weeks before baseline, or scheduled vaccine administration during the trial until 12 weeks after the last administration of the investigational drug. 32. There is currently a severe progressive disease or an uncontrollable disease that, in the judgment of the principal investigator of the trial, makes the patient inappropriate for the trial. 33. Any medical or psychiatric condition that, in the opinion of the principal investigator of the trial, would prevent the patient from complying with the protocol or completing the trial according to the protocol. 34. Blood donation or loss of 400 mL or more of blood within 8 weeks before randomization. 35. History or evidence of continuous alcohol or drug abuse within the past 6 months before randomization. 36. Specific to the MRA imaging sub-study: Absolute contraindications to MRA (e.g., metal implants, metallic foreign bodies, pacemakers, defibrillators), and absolute contraindications to the use of gadolinium-based agents (e.g., patients with severe renal insufficiency, patients who have previously shown severe allergy / anaphylaxis-like reactions to gadolinium-based contrast agents); patients with severe renal disease [eGFR by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) < 30 mL / min / 1.73m 2 2, or rapidly deteriorating renal function that would put the patient at risk of nephrogenic systemic fibrosis.

[0251] Treatment Investigational Medicinal Product Investigational Medicinal Product and Control Medicinal Product Each study site will be supplied with the Investigational Medicinal Product in identical-appearing packaging by Novartis. The packaging of the Investigational Medicinal Product will have a two-part label. Each part of the label will be printed with a unique randomization number that corresponds to either placebo or active drug.

[0252] An overview of the Investigational Medicinal Product administration is shown in Figure 8. Subjects will receive all secukinumab injections and placebo injections in the facility by the facility staff during the first treatment period (from baseline until just prior to dosing at Week 56). The Week 56 dose will also be administered in the facility.

[0253] For dosing during the second treatment period (from dosing at Week 56 until Week 108), starting from Week 60, subjects will be given the option of home dosing after receiving sufficient training on the procedure. However, if the subject wishes to come to the facility for Investigational Medicinal Product administration, the subject may do so. At Week 56, the facility staff will administer the Investigational Medicinal Product in the facility and dispense the Investigational Medicinal Product for home dosing for the next two months. All subjects will make facility visits every 2 - 3 months from Week 56 until the end of the study. PFS is packaged in a double-blind manner and requires no preparation. The investigational drug is labeled as follows: · Double-blind secukinumab and placebo prefilled syringes (PFS) labeled "AIN457 300 mg / 2 mL / placebo".

[0254] Subjects will also receive prednisone, unblinded at 20 mg / day or more from baseline to week 52 in a tapering regimen and blinded at less than 20 mg / day. Patients will have prednisone administered in the facility by the facility staff at the time of study facility visits and will be supplied with sufficient prednisone for home administration between study visits.

[0255]

Table 11

[0256] Additional investigational drug Prednisone after baseline After baseline, prednisone is given to subjects as part of the GC tapering regimen. Prednisone tablets and placebo tablets of various strengths (1 mg, 2.5 mg, 5 mg, 20 mg) that have undergone over-encapsulation processing are combined and packed into blisters (4 blisters per day) to meet the daily dosing requirements according to the tapering specified for the treatment group (secukinumab group or placebo group) to which the subject has been randomly assigned. The over-encapsulation process enables blinding of the daily dose of prednisone and is required to start when prednisone less than 20 mg / day is administered. Over-encapsulated tablets are also packed into blisters in combination when the total daily dose is 20 mg / day or more, but the dose will be known to the study responsible physician and the subject.

[0257] Treatment group (arm) / group Approximately 240 subjects will be randomly assigned in a 2:1 (secukinumab: placebo) ratio to one of the following two treatment groups. · Group 1: Secukinumab 300 mg subcutaneously (2 mL) + prednisone taper regimen for 26 weeks · Group 2: Placebo subcutaneously (2 mL) + prednisone taper regimen for 52 weeks

[0258] Stratification: To achieve a well-balanced distribution of baseline prednisone doses in each treatment group, randomization is stratified at baseline by the subject's GCA status (new-onset GCA or relapsing GCA) and baseline prednisone dose (prednisone > 30 mg / day and prednisone ≤ 30 mg / day).

[0259] First treatment period (from baseline to pre-dose at week 56): Subjects receive secukinumab or placebo at the study site at baseline, week 1, week 2, and week 3, and then every 4 weeks from week 4 until week 52.

[0260] In accordance with a pre-specified prednisone taper (26 weeks for the secukinumab group; 52 weeks for the placebo group), subjects receive a combination of prednisone and secukinumab, or prednisone and placebo, from baseline until week 52.

[0261] Subjects who do not achieve clinical remission by week 12 or who experience a clinical relapse of GCA after achieving clinical remission enter the withdrawal treatment. Subjects in the withdrawal treatment receive GC (prednisone or prednisone equivalent) at a dose determined by the study physician in accordance with standard treatment and continue to receive the original randomized double-blind study drug. Alternatively, at the discretion of the study physician, subjects may discontinue the study drug to receive rescue treatment (alternative treatment for GCA). Subjects in the withdrawal treatment or rescue treatment continue to participate in all scheduled visits and evaluations thereafter.

[0262] Second treatment period (from the administration in the 56th week to the 108th week): Starting from the 56th week, during the second treatment period, the subject will receive further treatment based on the subject's clinical remission status as follows: · Subjects who maintain clinical remission at the 56th week (defined as subjects who achieved clinical remission at the 52nd week and had no relapse until the 56th week) will continue to receive the investigational drug administration as follows until the end of the 108th week throughout the second treatment period.

[0263] · Subjects who were initially randomly assigned to secukinumab will be re-randomized in a double-blind manner to secukinumab 300 mg subcutaneously q4w or placebo at a 1:1 ratio.

[0264] · Subjects who were initially randomly assigned to placebo will continue to receive placebo administration in a blinded manner.

[0265] · If a subject experiences a clinical relapse during the second treatment period, the subject will receive OL secukinumab 300 mg subcutaneously. The start of OL secukinumab treatment is similar to that of secukinumab treatment in the first treatment period, with weekly (qw) administration for the first 4 weeks and then every 4 weeks (q4w) starting 4 weeks after the first administration. GC is administered according to the standard treatment, and the dosage is determined by the responsible investigator of the trial.

[0266] · Subjects who do not achieve clinical remission within 12 weeks after the start of OL secukinumab or who experience a clinical relapse during the administration of OL secukinumab during the second treatment period will discontinue OL secukinumab and participate in the EOT visit and EOS visit. Further treatment according to the standard treatment is determined by the responsible investigator of the trial.

[0267] · Subjects who do not maintain clinical remission at the 56th week (including subjects who are in the withdrawal treatment) will receive OL secukinumab 300 mg subcutaneous treatment starting from the 56th week: ·The initiation of ol-secukinumab treatment is similar to that for the secukinumab treatment group, administered weekly (qw) for the first 4 weeks, and then every 4 weeks (q4w) starting 4 weeks after the first dose. Subjects will also receive GC treatment, and the dosage will be determined by the principal investigator in charge of the trial according to the standard treatment.

[0268] ·Subjects who have not achieved clinical remission by 12 weeks after the start of ol-secukinumab, or who have experienced clinical recurrence during the administration of ol-secukinumab in the second treatment period, will discontinue ol-secukinumab and participate in the EOT visit and EOS visit. Further treatment determined by the principal investigator in charge of the trial.

[0269] Treatment period The maximum planned period of investigational drug administration in this trial is 108 weeks, and the final dose in the trial is at week 104. Subjects may discontinue the investigational drug early for reasons such as unacceptable toxicity, disease exacerbation, and / or at the discretion of the principal investigator in charge of the trial or the subject, as mentioned above.

[0270] Post-trial access Subjects who received the blinded investigational drug (secukinumab or placebo) at week 108: Subjects who received the blinded investigational drug at week 108 and maintained clinical remission (i.e., only receiving the investigational drug and not receiving GC in combination) will complete the treatment (last dose at week 104), complete the EOT visit at week 108, and complete the EOS visit at week 116. For subjects who, in the opinion of the principal investigator in charge of the trial following the standard practice, can obtain clinical benefits from secukinumab administration after the trial, every effort will be made to provide ol-secukinumab in accordance with local regulations. For subjects who started ol-secukinumab after the completion of the investigational drug, the EOS visit at week 116 will be waived.

[0271] Subjects Administered with OL Secukinumab in Week 108: Subjects administered with OL secukinumab in Week 108 completed the treatment (last dose in Week 104), completed the EOT visit in Week 108, and completed the EOS visit in Week 116. For subjects who are still obtaining clinical benefits from OL secukinumab according to the opinion of the principal investigator of the clinical trial, all efforts will be made to continue the provision of OL secukinumab in accordance with local regulations. If post-trial access to OL secukinumab is provided, the EOS visit in Week 116 will be waived. For subjects who have not received OL secukinumab for 12 weeks, the principal investigator of the clinical trial will evaluate whether the subject is obtaining clinical benefits from OL secukinumab and determine whether treatment needs to be continued with post-trial access.

[0272] Other Treatments Combined Therapies All medications, treatments, and important non-pharmacological therapies (including physical therapy and transfusions) administered after the subject is enrolled in the trial must be recorded in the appropriate case report form (CRF).

[0273] Each concomitant medication must be individually evaluated against all exclusion criteria / prohibited medications. If in doubt, the principal investigator of the clinical trial should contact the Novartis medical monitor before randomizing the subject or before permitting the initiation of a new medication. If the subject has already been enrolled, contact Novartis to determine whether the subject should continue to participate in the trial.

[0274] Permitted Concomitant Treatments Requiring Attention and / or Measures Methotrexate (MTX) Subjects taking MTX at a dose of 25 mg / week or less (25 mg / week or less) are permitted to continue drug treatment only if they have been taking MTX for at least 3 months, at a stable dose for at least 4 weeks before randomization, and throughout the trial.

[0275] Subjects taking MTX need to take folic acid supplements before randomization and during the trial to minimize the potential for MTX-related toxicity.

[0276] Vitamin D Since corticosteroids are used in all treatment groups, vitamin D (at a dose of 1000 IU / day) and calcium supplements are strongly recommended during the trial for the prevention of osteoporosis. References Cella DF, Tulsky DS, Gray G, et al (1993) The Functional Assessment of Cancer Therapy (FACT) scale: Development and validation of the general measure. Journal of Clinical Oncology; 11(3):570-579. Ciccia F, Rizzo A, Ferrante A, et al (2017) New insights into the pathogenesis of giant cell arteritis. Autoimmunity Reviews;16(7):675-683. De Silvia M and Hazleman B (1986) Azathioprine in giant cell arteritis polymyalgia rheumatica: a double-blind study. Ann Rheum Dis;45(2):136-138. Espigol-Frigole G, Corbera-Bellalta M, Planas-Rigol E, et al (2013) Increased IL17A expression in temporal artery lesions is a predictor of sustained response to glucocorticoid treatment in patients with giant-cell arteritis. Ann Rheum Dis;72(9):1481-1487. Hayat S (2008) Infliximab for Maintenance of Glucocorticosteroid-Induced Remission of Giant Cell Arteritis: A Randomized Trial. Yearbook of Medicine:38-39. Hoffmann G, Cid M, Hellmann D, et al (2002) A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum;46(5):1309-1318. ICH E2D (2004) Post Approval Safety Data Management: Note for guidance on definitions and standards for expedited reporting. Available from: http: / / www.ema.europa.eu / docs / en_GB / document_library / Scientific_guideline / 2009 / 09 / WC500002807.pdf (Accessed on 29-May-2018) Jover J, Hernandez-Garcia C, Morado I, et al (2001) Combined treatment of giant-cell arteritis with methotrexate and prednisone. A randomized double-blind, placebo-controlled trial. Ann Intern Med;134(2):106-114. Koster M, Warrington J, Kermani T, et al (2016) Update on Epidemiology and Treatment of Giant Cell Arteritis. 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Dtsch Arztebl Int;110(21):376-385. Petri H, Nevitt A, Sarsour K, et al (2014) Incidence of giant cell arteritis and characteristics of patients: data-driven analysis of cormorbidities. Arthritis Gare Res (Hoboken);67(3):390-395. Proven A, Gabriel SE, Orces C, et al (2003) Glucocorticoid therapy in giant cell arteritis: Duration and adverse outcomes. Arthritis & Rheumatism 2003;49(5):703-708. Reichenbach S, Adler S, Bonel H, et al (2018) Magnetic resonance angiography in giant cell arteritis: results of a randomized controlled trial of tocilizumab in giant cell arteresis. Rheumatology;1:57(6):982-986. Rotar Z, Tomsic M, Hocevar A, et al (2018) Secukinumab for the maintenance of glucocorticoid-free remission in a patient with giant cell arteritis and psoriatic arthritis. Rheumatology;57(5):934-936. Salvarani C, Cantini F, Boiardi L, et al (2004) Polymyalgia rheumatica. Best Pract Res Clin Rheumaol;18(5):705-722. 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Tfelt-Hansen P, Pascual J, Ramadan N, et al [International Headache Society Clinical Trials Subcommittee members] (2012) Guidelines for controlled trials of drugs in migraine: Third edition. A guide for investigators. Cephalalgia;32(1):6-38. Ware J, Kosinki M, Gandeck B (1993) SF-36 Health Survey manual and interpretation guide. Boston: The Health Institute, New England Medical Center. Ware J, Kosinki M, Gandeck B (1994) SF-36 Health Survey manual and interpretation guide. Update. Boston: The Health Institute, New England Medical Center. Xu R, Insinga R, Golden W, et al (2011) EuroQol (EQ-5D) health utility scores for patients with migraine. Qual Life Res;20(4):601-8. Yellen SB, Cella DF, Webster K, et al (1997) Measuring Fatigue and Other Anemia-Related Symptoms with the Functional Assessment of Cancer Therapy (FACT) Measurement System. Journal of Pain and Symptom Management;13:63-74. Sequence Listing <110> Novartis AG The University Court of the University of Glasgow McInnes, Iain Millar, Neal Kolbinger, Frank Carter, Shea Weber, Eckhard Mindeholm, Linda Schieker, Matthias Bruin, Gerard <120> METHODS OF TREATING GCA USING INTERLEUKIN-17 (IL-17) ANTAGONISTS <130> PAT057898 FF <140> Herewith <141> Herewith <150> 62 / 580,715 <151> 2017-11-02 <160> 31 <170> PatentIn version 3.5 <210> 1 <211> 5 <212> PRT <213> artificial <220> <223> CDR1 = hypervariable region 1 of heavy chain of AIN457 <400> 1 Asn Tyr Trp Met Asn 1 5 <210> 2 <211> 17 <212> PRT <213> ARTIFICIAL <220> <223> CDR2 = hypervariable region 2 of heavy chain of AIN457 <400> 2 Ala Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val Gly Ser Val Lys 1 5 10 15 Gly <210> 3 <211> 18 <212> PRT <213> ARTIFICIAL <220> <223> CDR3 = hypervariable region 3 of heavy chain of AIN457 <400> 3 Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr Trp Tyr Phe 1 5 10 15 Asp Leu <210> 4 <211> 12 <212> PRT <213> ARTIFICIAL <220> <223> CDR1' = hypervariable region 1 of light chain of AIN457 <400> 4 Arg Ala Ser Gln Ser Val Ser Ser Ser Tyr Leu Ala 1 5 10 <210> 5 <211> 7 <212> PRT <213> ARTIFICIAL <220> <223> CDR2' = hypervariable region 2 of light chain AIN457 <400> 5 Gly Ala Ser Ser Arg Ala Thr 1 5 <210> 6 <211> 9 <212> PRT <213> ARTIFICIAL <220> <223> CDR3' = hypervariable region 3 of light chain AIN457 <400> 6 Gln Gln Tyr Gly Ser Ser Pro Cys Thr 1 5 <210> 7 <211> 381 <212> DNA <213> HOMO SAPIENS <220> <221> CDS <222> (1)..(381) <400> 7 gag gtg cag ttg gtg gag tct ggg gga ggc ttg gtc cag cct ggg ggg 48 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 tcc ctg aga ctc tcc tgt gca gcc tct gga ttc acc ttt agt aac tat 96 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 tgg atg aac tgg gtc cgc cag gct cca ggg aaa ggg ctg gag tgg gtg 144 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 gcc gcc ata aac caa gat gga agt gag aaa tac tat gtg ggc tct gtg 192 Ala Ala Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val Gly Ser Val 50 55 60 aag ggc cga ttc acc atc tcc aga gac aac gcc aag aac tca ctg tat 240 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 ctg caa atg aac agc ctg aga gtc gag gac acg gct gtg tat tac tgt 288 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 gtg agg gac tat tac gat att ttg acc gat tat tac atc cac tat tgg 336 Val Arg Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr Trp 100 105 110 tac ttc gat ctc tgg ggc cgt ggc acc ctg gtc act gtc tcc tca 381 Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 8 <211> 127 <212> PRT <213> HOMO SAPIENS <400> 8 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ala Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val Gly Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr Trp 100 105 110 Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 9 <211> 327 <212> DNA <213> HOMO SAPIENS <220> <221> CDS <222> (1)..(327) <400> 9 gaa att gtg ttg acg cag tct cca ggc acc ctg tct ttg tct cca ggg 48 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt agc agc agc 96 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 tac tta gcc tgg tac cag cag aaa cct ggc cag gct ccc agg ctc ctc 144 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 atc tat ggt gca tcc agc agg gcc act ggc atc cca gac agg ttc agt 192 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 ggc agt ggg tct ggg aca gac ttc act ctc acc atc agc aga ctg gag 240 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 cct gaa gat ttt gca gtg tat tac tgt cag cag tat ggt agc tca ccg 288 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 tgc acc ttc ggc caa ggg aca cga ctg gag att aaa cga 327 Cys Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105 <210> 10 <211> 109 <212> PRT <213> HOMO SAPIENS <400> 10 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Cys Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg 100 105 <210> 11 <211> 10 <212> PRT <213> artificial <220> <223> CDR1-x = hypervariable domain x of heavy chain of AIN457 <400> 11 Gly Phe Thr Phe Ser Asn Tyr Trp Met Asn 1 5 10 <210> 12 <211> 11 <212> PRT <213> artificial <220> <223> CDR2-x = hypervariable domain of heavy chain x of AIN457 <400> 12 Ala Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr 1 5 10 <210> 13 <211> 23 <212> PRT <213> ARTIFICIAL <220> <223> CDR3-x = hypervariable domain x of heavy chain AIN457 <400> 13 Cys Val Arg Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr 1 5 10 15 Trp Tyr Phe Asp Leu Trp Gly 20 <210> 14 <211> 215 <212> PRT <213> homo sapiens <400> 14 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85 90 95 Cys Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys Arg Thr Val Ala 100 105 110 Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser 115 120 125 Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu 130 135 140 Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser 145 150 155 160 Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu 165 170 175 Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val 180 185 190 Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys 195 200 205 Ser Phe Asn Arg Gly Glu Cys 210 215 <210> 15 <211> 457 <212> PRT <213> homo sapiens <400> 15 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ala Ile Asn Gln Asp Gly Ser Glu Lys Tyr Tyr Val Gly Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Asp Tyr Tyr Asp Ile Leu Thr Asp Tyr Tyr Ile His Tyr Trp 100 105 110 Tyr Phe Asp Leu Trp Gly Arg Gly Thr Leu Val Thr Val Ser Ser Ala 115 120 125 Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys Ser 130 135 140 Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe 145 150 155 160 Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly 165 170 175 Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu 180 185 190 Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr 195 200 205 Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Arg 210 215 220 Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro 225 230 235 240 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 245 250 255 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 260 265 270 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 275 280 285 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 290 295 300 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 305 310 315 320 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 325 330 335 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 340 345 350 Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met 355 360 365 Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro 370 375 380 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 385 390 395 400 Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu 405 410 415 Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 420 425 430 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 435 440 445 Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 <210> 16 <211> 11 <212> PRT <213> homo sapiens <400> 16 Arg Pro Ser Gln Gly Ile Asn Trp Glu Leu Ala 1 5 10 <210> 17 <211> 7 <212> PRT <213> homo sapiens <400> 17 Ser Gln Gly Ile Asn Trp Glu 1 5 <210> 18 <211> 7 <212> PRT <213> homo sapien <400> 18 Asp Ala Ser Ser Leu Glu Gln 1 5 <210> 19 <211> 3 <212> PRT <213> homo sapien <400> 19 Asp Ala Ser 1 <210> 20 <211> 9 <212> PRT <213> homo sapien <400> 20 Gln Gln Phe Asn Ser Tyr Pro Leu Thr 1 5 <210> 21 <211> 6 <212> PRT <213> homo sapien <400> 21 Phe Asn Ser Tyr Pro Leu 1 5 <210> 22 <211> 107 <212> PRT <213> homo sapien <400> 22 Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Pro Ser Gln Gly Ile Asn Trp Glu 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Glu Gln Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 100 105 <210> 23 <211> 214 <212> PRT <213> homo sapien <400> 23 Ala Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Pro Ser Gln Gly Ile Asn Trp Glu 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Ser Leu Glu Gln Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Phe Asn Ser Tyr Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 24 <211> 5 <212> PRT <213> homo sapien <400> 24 Ser Tyr Trp Met Ser 1 5 <210> 25 <211> 7 <212> PRT <213> homo sapien <400> 25 Gly Phe Thr Phe Ser Ser Tyr 1 5 <210> 26 <211> 17 <212> PRT <213> homo sapien <400> 26 Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val Lys 1 5 10 15 Gly <210> 27 <211> 6 <212> PRT <213> homo sapien <400> 27 Lys Gln Asp Gly Ser Glu 1 5 <210> 28 <211> 7 <212> PRT <213> homo sapien <400> 28 Asp Arg Gly Ser Leu Tyr Tyr 1 5 <210> 29 <211> 7 <212> PRT <213> homo sapien <400> 29 Asp Arg Gly Ser Leu Tyr Tyr 1 5 <210> 30 <211> 116 <212> PRT <213> homo sapien <400> 30 Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Gly Ser Leu Tyr Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 31 <211> 446 <212> PRT <213> homo sapien <400> 31 Glu Val Gln Leu Val Glu Ser Gly Gly Asp Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Gly Ser Leu Tyr Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445

Claims

1. A therapeutic agent for giant cell arteritis comprising an IL-17 antibody or its antigen-binding fragment as an active ingredient, The IL-17 antibody or its antigen-binding fragment binds to an epitope of a human IL-17 homodimer having two mature human IL-17 protein chains. The epitope contains Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 in one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 in the other chain. The IL-17 antibody or its antigen-binding fragment is a K for human IL-17. Ｄ The concentration is approximately 100-200 pM. The IL-17 antibody or its antigen-binding fragment has an in vivo half-life of approximately four weeks. In patients requiring treatment for giant cell arteritis (GCA), approximately 150 mg to approximately 300 mg of the IL-17 antibody or its antigen-binding fragment is administered subcutaneously. Adrenocortical steroids (e.g., prednisone or prednisolone) are administered during the first 26 weeks of treatment. The dose of corticosteroids is gradually reduced during the first 26 weeks. A therapeutic agent.

2. The therapeutic agent according to claim 1, wherein the IL-17 antibody or its antigen-binding fragment comprises the following: i) Immunoglobulin heavy chain variable domain (V) containing the amino acid sequence described as Sequence ID No. 8 Ｈ ); ii) Immunoglobulin light chain variable domain (V) containing the amino acid sequence described as Sequence ID No. 10 Ｌ ); iii) Immunoglobulin V containing the amino acid sequence described as Sequence ID No. 8 Ｈ Immunoglobulin V containing the domain and the amino acid sequence described as SEQ ID NO: 10 Ｌ domain; iv) Immunoglobulin V containing the hypervariable region described as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 Ｈ domain; v) Immunoglobulin V containing the hypervariable region described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6 Ｌ domain; vi) Immunoglobulin V containing the hypervariable region described as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 Ｈ domain; vii) Immunoglobulin V domains containing the hypervariable regions described as SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, and immunoglobulin V domains containing the hypervariable regions described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6; Ｈ and; Ｌ immunoglobulin V domains containing the hypervariable regions described as SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6; viiii) Immunoglobulin V containing the hypervariable region described as SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13 Ｈ Immunoglobulin V including the domain and the hypervariable regions described as SEQ ID NOs: 4, 5, and 6. Ｌ domain; ix) Immunoglobulin light chain containing the amino acid sequence described as Sequence ID No. 14; x) An immunoglobulin heavy chain containing the amino acid sequence described as Sequence ID No. 15; or, xi) An immunoglobulin light chain containing the amino acid sequence described as SEQ ID NO: 14, and an immunoglobulin heavy chain containing the amino acid sequence described as SEQ ID NO:

15.

3. The therapeutic agent according to claim 2, wherein the IL-17 antibody is secukinumab.

4. The therapeutic agent according to any one of claims 1 to 3, wherein the patient is administered the IL-17 antibody or its antigen-binding fragment as a loading dose, particularly once a week.

5. The therapeutic agent according to any one of claims 1 to 3, wherein the patient is administered the IL-17 antibody or its antigen-binding fragment every two weeks or every four weeks, in particular for a total treatment period of at least 26 weeks, or at least 52 weeks, or at least 2 years.

6. The therapeutic agent according to any one of claims 1 to 3, wherein the patient is administered the IL-17 antibody or its antigen-binding fragment as a loading dose once a week during weeks 0, 1, 2, 3, and 4, and thereafter administered every two weeks, or thereafter administered every four weeks.

7. The therapeutic agent according to any one of claims 1 to 3, wherein, prior to treatment with the IL-17 antibody or its antigen-binding fragment, the patient had not responded, responded poorly, or was intolerant to previous GCA treatments selected from the group consisting of treatment with corticosteroids such as prednisone, prednisolone, or methylprednisolone, treatment with TNF-α inhibitors, treatment with IL-6 inhibitors, treatment with methotrexate, and combinations thereof.

8. The therapeutic agent according to any one of claims 1 to 3, wherein treatment with the IL-17 antibody or its antigen-binding fragment reduces the dose of corticosteroids sufficient to induce or maintain effective GCA treatment or GCA remission.

9. The therapeutic agent according to any one of claims 1 to 3, wherein the patient has active GCA, newly diagnosed GCA, or relapsing GCA.

10. The therapeutic agent according to any one of claims 1 to 3, wherein the patient is at least 50 years old.

11. For example, the therapeutic agent according to any one of claims 1 to 3, wherein, prior to treatment, the patient has active GCA as indicated by clear head symptoms of GCA; temporal artery biopsy (TAB) showing characteristics of GCA, and / or vasculitis as indicated by ultrasound (e.g., cranial or axillary), MRA, CTA, or PET-CT.

12. For example, the therapeutic agent according to any one of claims 1 to 3, wherein, prior to treatment, the patient has an elevated erythrocyte sedimentation rate (ESR) of 30 mm / hour or more, or a C-reactive protein (CRP) of 10 mg / L or more, or active GCA as measured by TAB or imaging test, due to active GCA.

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