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

Abstract

The present disclosure relates to methods of treating giant cell arteritis (GCA) using an IL-17 antagonist (e.g., Jukoulikumab). Also disclosed herein are uses of IL-17 antagonists (e.g., IL-17 antibodies, such as Jiukumab) for the treatment of GCA patients, as well as medicaments, dosing regimens, pharmaceutical formulations, dosage forms, and kits for use in the disclosed uses and methods.

Description

Technical Field

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

[0003] Giant cell arteritis (GCA) is the most common form of primary systemic vasculitis in people over 50 years of age (Koster et al. 2016). GCA is an inflammatory chronic disease with a prevalence of 24 to 278 per 100,000 people in the European Union (EU) and the United States of America (USA). The typical clinical manifestations of new-onset GCA associated with inflammation of large and medium-sized arteries are new-onset headache, jaw claudication, scalp tenderness, and visual disturbances. Characteristic systemic manifestations include fever, malaise, weight loss, and polymyalgia (Ness et al. 2013). Ischemic anterior optic neuropathy leading to irreversible visual loss is a common and dreaded symptom of GCA. Therefore, timely and effective immunosuppressive treatment is crucial for GCA (Hoffmann et al. 2002, Jover et al. 2001).

[0004] High-dose glucocorticoids are the mainstay of GCA treatment and are effective in reducing vascular inflammation (Salvarani et al. 2004, Petri et al. 2014). Although glucocorticoids remain the mainstay of treatment, relapses are common and treatment-related morbidity often occurs (Koster et al. 2016). The main disadvantage of high cumulative glucocorticoid doses is the high incidence of adverse events (AEs), with more than 80% of patients experiencing serious adverse events (SAEs). High total glucocorticoid doses are a major concern as they lead to a substantial increase in infections, osteoporosis, and serious metabolic side effects. In addition, treatment failure occurs in more than 50% of patients (Salvarani et al. 2004, Petri et al. 2014). There is an unmet need for immunosuppressive therapies that can induce long-term remission while avoiding the adverse effects of glucocorticoids (Koster et al. 2016).

[0005] Studies of anti-tumor necrosis factor alpha (TNFα) therapy and azathioprine have failed to demonstrate a comparable effect, and studies of methotrexate as a glucocorticoid-sparing agent have had conflicting results (Petri et al. 2014, De Silvia et al. 1986, Hayat 2008). The GIACTA trial (Stone et al. 2017) showed that tocilizumab (an interleukin-6 receptor antagonist) combined with 26 weeks of prednisolone taper therapy (administered weekly or every other week) was superior to 26 or 52 weeks of prednisolone taper therapy plus placebo in terms of sustained glucocorticoid-free remission in patients with GCA. Nevertheless, there are some disadvantages to tocilizumab therapy in patients with GCA that should be considered. The primary endpoint (sustained remission at week 52) was achieved by 56% of patients in the group receiving tocilizumab weekly and 53% of patients in the group receiving tocilizumab every other week; 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 a reliable marker of inflammation (indicating disease flare or infectious complications) in GCA patients treated with tocilizumab because CRP is suppressed under tocilizumab treatment. Furthermore, follow-up magnetic resonance imaging (MRI) in the phase II study of tocilizumab in GCA by Reichenbach et al. (2018) showed persistent macrovascular contrast enhancement, suggesting persistent macrovascular inflammation. Therefore, other treatment alternatives are needed for GCA in addition to glucocorticoids and tocilizumab.

[0006] The etiology of GCA has not been definitively identified, but it is believed that GCA occurs based on genetic background and is triggered by unknown environmental factors that activate dendritic cells located in the adventitia of normal arteries and lead to their maturation. Activated dendritic cells subsequently lead to the activation, proliferation, and polarization of Th1 and Th17 cells, which produce interferon-γ and interleukin 17 (IL-17), respectively (Samson et al. 2017). Interleukin 17A (IL-17A) appears to be involved in the pathogenesis of GCA; 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 evidence suggests that there is a heterogeneity in the histological lesions in GCA, which is associated with Th9 and especially Th17 (Ciccia et al. 2017). Marquez et al. found a novel association between polymorphisms within the IL17A locus and GCA, supporting a relevant role for Th17 cells in the pathophysiology of this vasculitis (Marquez et al. 2014). Another study showed that regulatory T cells that overexpress the FoxP3Δ2 domain and lack Δ2 overproliferate. Dysfunctional FoxP3Δ2 domains are known to lead to enhanced Th17 differentiation, resulting in excessive IL-17A production. Consistent with this observation, IL-17A was upregulated in patients with active GCA in this study. The IL-6 receptor antagonist tocilizumab was able to reconstitute functional FoxP3 domains in regulatory T cells, resulting in reduced IL-17A production and effective control of GCA. This observation suggests that IL-17A is an important cytokine in active GCA and its direct inhibition is a new therapeutic target for patients with active disease (Miyabe et al. 2017).

[0007] Two case reports have been reported regarding GCA using secukinumab to treat patients to maintain remission of GCA (Rotar et al. 2018, Sammut et al. 2018). However, in the case of Rotar et al., it was apparent that the patient was already in remission prior to starting secukinumab treatment. In Sammut, the patient's GCA appeared to be well controlled with high-dose oral prednisolone prior to secukinumab treatment. Thus, therapeutically effective treatment of patients with, for example, active GCA using IL-17 antagonists has not been demonstrated. Furthermore, the durability of the treatment response has not been demonstrated. SUMMARY OF THE INVENTION

[0009] Secukinumab is a selective, 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). We have now established that IL-17 antagonists (e.g., IL-17 antibodies, such as secukinumab) can be used systemically to treat giant cell arteritis (GCA).

[0010] Disclosed herein are methods, uses, pharmaceutical compositions and kits for inducing vascular tissue regeneration or promoting vascular repair or reducing vascular inflammation in patients with GCA, comprising subcutaneously administering to a patient in need thereof about 150 mg to about 300 mg (e.g., a fixed dose of about 150 mg, a fixed dose of about 300 mg) of an IL-17 antibody or an antigen-binding fragment thereof, wherein the IL-17 antibody or the antigen-binding fragment thereof binds to a human IL-17 having two mature human IL-17 protein chains. The present invention relates to an antibody that binds to an epitope of a homodimer of IL-7, wherein the epitope comprises Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 antibody or antigen-binding fragment thereof has a K of about 100-200 pM for human IL-17. D , and wherein the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

[0011] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient weekly.

[0012] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient during weeks 0, 1, 2, 3 and 4.

[0013] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient every two weeks or every 4 weeks, preferably every 4 weeks.

[0014] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient for a total treatment duration of at least two months, at least 26 weeks, at least 28 weeks, at least 52 weeks, or at least 2 years.

[0015] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the patient is administered, for example, 150 or 300 mg of an IL-17 antibody or antigen-binding fragment thereof, weekly during weeks 0, 1, 2, 3 and 4 and every 4 weeks thereafter.

[0016] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient during weeks 0, 1, 2, 3, 4, 8 and 12.

[0017] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the patient is administered an IL-17 antibody or antigen-binding fragment thereof weekly during weeks 0, 1, 2, 3 and 4 and every 4 weeks thereafter, for a total treatment duration of at least 26 weeks.

[0018] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient had no response, insufficient response or intolerance to a previous GCA treatment selected from a corticosteroid (e.g., prednisone, prednisolone or methylprednisolone), treatment with a TNF-α inhibitor, treatment with an IL-6 inhibitor, treatment with methotrexate and a combination thereof.

[0019] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has active GCA.

[0020] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, treatment with an IL-17 antibody or antigen-binding fragment thereof reduces the burden of corticosteroid therapy, reduces the cumulative dose of corticosteroids, induces or maintains remission of GCA, or a combination thereof.

[0021] In some embodiments of the disclosed uses, methods, and kits, the IL-17 antagonist is an IL-17 antibody or an antigen-binding fragment thereof. In some embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is selected from: a) an IL-17 antibody or antigen-binding fragment thereof that binds to an IL-17 epitope comprising Leu74, Tyr85, His86, Met87, Asn88, Val124, Thr125, Pro126, Ile127, Val128, His129; b) an IL-17 antibody or antigen-binding fragment thereof that binds to an IL-17 epitope comprising Tyr43, Tyr44, Arg46, Ala79, Asp80; c) an IL-17 antibody or 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, Va124, Thr125, Pro126, Ile127, Val128, His129 on one chain; l124, Thr125, Pro126, Ile127, Val128, His129, and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain; 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 on one chain, and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 antibody or antigen-binding fragment thereof has a K of about 100-200 pM (e.g., about 200 pM) for human IL-17 D , and wherein the IL-17 antibody or its antigen-binding fragment has an in vivo half-life of about 23 to about 35 days (e.g., about 27 days); and e) an IL-17 antibody or its antigen-binding fragment, comprising: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence shown in SEQ ID NO: 8 H );ii) an immunoglobulin light chain variable domain (V L );iii) an immunoglobulin V comprising the amino acid sequence shown in SEQ ID NO: 8 H Domain and an immunoglobulin V comprising the amino acid sequence shown in SEQ ID NO: 10 L domain; iv) an immunoglobulin V comprising a hypervariable region as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 Hdomain; v) an immunoglobulin V comprising a hypervariable region as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L domain; vi) an immunoglobulin V comprising a hypervariable region as shown in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H vii) an immunoglobulin V domain comprising a hypervariable region as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 H Domain and immunoglobulin V comprising the hypervariable region shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L viii) an immunoglobulin V domain comprising a hypervariable region as shown in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H Domains and immunoglobulin V comprising the hypervariable regions shown in 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 as shown in SEQ ID NO: 14; x) an immunoglobulin heavy chain comprising the amino acid sequence as shown in SEQ ID NO: 15; or xi) an immunoglobulin light chain comprising the amino acid sequence as shown in SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence as shown in SEQ ID NO: 15.

[0022] In some embodiments of the disclosed uses, methods, and kits, the IL-17 antibody or antigen-binding fragment thereof is secukinumab (AIN457), which is a high-affinity, recombinant fully human monoclonal anti-human interleukin-17A antibody of the IgG1 / κ class.

[0023] Also disclosed herein are methods, uses, pharmaceutical compositions, and kits for treating patients with active GCA, comprising administering to the patient about 300 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4 and every four weeks thereafter, for a total treatment duration of at least 26 weeks. Also disclosed herein are methods, uses, pharmaceutical compositions, and kits for treating patients with active GCA, comprising administering to the patient about 150 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4 and every four weeks thereafter, for a total treatment duration of at least 26 weeks.

[0024] In some embodiments of the methods, uses, pharmaceutical compositions and kits, the patient has not received biological therapy before receiving treatment described herein, for example, has not received treatment with a biological inhibitor of TNF-α, a biological IL-17 antagonist, a biological IL-6 inhibitor or a combination thereof. In some embodiments of the methods, uses, pharmaceutical compositions and kits, the patient develops active symptoms and / or signs of GCA within 6 or 8 weeks after the first treatment with IL-17 therapy and an elevated inflammatory marker CRP of ≥10 mg / L or an ESR of ≥30 mm / hr due to GCA. If there are no inflammatory markers available showing active disease (especially considering that the patient will receive corticosteroid treatment), disease activity can be confirmed by temporal artery biopsy (TAB) or diagnostic imaging (e.g., MRA, ultrasound). In some embodiments of the methods, uses, pharmaceutical compositions and kits, the patient suffers from new or recurrent GCA. In some embodiments, new GCA is defined as recently diagnosed GCA, for example within 6 weeks. In some embodiments, recurrent GCA includes patients who were diagnosed with GCA > 6 weeks before starting treatment as described herein, and the patient experienced a recurrence of active disease, for example, after starting appropriate non-anti-IL-17 treatment. For example, relapse may occur after starting corticosteroid treatment. In some embodiments of the methods, uses, pharmaceutical compositions, and kits, the patient is treated with vitamin D (1000 I.U. per day) and / or calcium supplements. In some embodiments, the patient has one or more cranial symptoms of GCA (new localized headache, scalp or temporal artery tenderness, ischemia-related vision loss, or other unexplained oral or mandibular pain when chewing). In some embodiments, treatment with anti-IL-17 reduces, alleviates, or eliminates one or more cranial symptoms of GCA (e.g., reducing, alleviating, or eliminating at least 20% or at least 20% more than a standard course of corticosteroids).

[0025] BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The giant cell arteritis clinical study design of Example 1 is provided. The study consists of a 6-week (maximum duration) screening period, a 52-week treatment period, and an 8-week safety follow-up period. Patients who do not achieve remission, have an attack after remission, or are unable to comply with the prednisolone reduction regimen (as described below) until week 12 will enter the "way out" state. After entering the "way out" state, patients will receive a dose of prednisolone determined by the clinical judgment of the physician and continue to receive secukinumab or placebo in a blinded manner. Patients in the "way out" state should continue to participate in all subsequent scheduled visit assessments.

[0027] Figure 2 The disposition of patients after completion of the study described in Example 1 is shown.

[0028] Figure 3 Baseline demographics and disease characteristics for the study described in Example 1 are shown.

[0029] Figure 4 The proportion of patients who achieved the primary endpoint in Example 1 is shown.

[0030] Figure 5 The proportion of patients achieving the secondary endpoints in Example 1 is shown.

[0031] Figure 6 The time to onset after baseline until week 52 in Example 1 is shown.

[0032] Figure 7 The total cumulative dose of the corticosteroid prednisolone administered to patients treated in Example 1 is shown.

[0033] Figure 8 The giant cell arteritis clinical study design is provided in Example 2. The study will consist 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. DETAILED DESCRIPTION OF THE INVENTION

[0035] As used herein, the phrase "is unresponsive to" is used to indicate that a patient's symptoms are not eliminated, treated, alleviated, etc. in response to a particular GCA treatment. In some embodiments, the GCA patient has not responded to a previous GCA treatment (e.g., treatment with a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone), an IL-6 inhibitor, a TNF-α inhibitor, or a combination thereof).

[0036] As used herein, the phrase "inadequately responsive to" is used to indicate that a patient's symptoms are not adequately resolved, treated, alleviated, etc. in response to a particular GCA treatment. In some embodiments, the GCA patient has had an inadequate response to a previous GCA treatment (e.g., treatment with a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone), an IL-6 inhibitor, a TNF-α inhibitor, or a combination thereof).

[0037] As used herein, the phrase "intolerance" is used to indicate that a patient has an adverse reaction to a particular GCA treatment. In some embodiments, the GCA patient is intolerant to a previous GCA treatment (e.g., treatment with a corticosteroid (e.g., prednisone, prednisolone, or methylprednisolone), an IL-6 inhibitor, a TNF-α inhibitor, or a combination thereof).

[0038] As used herein, "fixed dose" refers to a stable dose, i.e., a dose that is not modified based on the patient's characteristics. Thus, a fixed dose is different from, for example, a dose based on body surface area or a dose based on body weight (usually given in mg / kg). In a preferred embodiment, the dose used for the disclosed methods, uses, indications, kits, etc. is a fixed dose. In a most preferred embodiment, a fixed dose of IL-17 antibody, such as a fixed dose of secukinumab, is administered to the patient, such as a fixed dose of about 75 mg, about 150 mg, or about 300 mg of secukinumab.

[0039] As used herein, IL-17 refers to interleukin-17A (IL-17A).

[0040] As used herein, IL-17AF refers to a heterodimer composed of monomers of IL-17A and IL-17F.

[0041] The term "comprising" encompasses "including" as well as "consisting of," for example, a composition "comprising" X may consist of X alone or may include other substances, such as X+Y.

[0042] As used herein, the phrase "TNF-α antagonist" refers to small molecules and biomolecules that are capable of inhibiting, reducing and / or blocking TNF-α signaling, transduction, and / or activity. Examples of TNF-α antagonists include (etanercept), (adalimumab), (infliximab) and (golimumab).

[0043] Unless otherwise specifically stated or apparent from the context, as used herein, the term "about" with respect to a numerical value should be understood to be within the normal tolerance of the art, e.g., within two standard deviations of the mean. Thus, "about" can be within + / -10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.1%, 0.05%, or 0.01% of the value, preferably within + / -10% of the value. When used before a numerical range or a list of numbers, the term "about" applies to each number in the series, e.g., the phrase "about 1-5" should be understood to be "about 1-about 5", or, for example, the phrase "about 1, 2, 3, 4" should be understood to be "about 1, about 2, about 3, about 4, etc."

[0044] The word "substantially" does not exclude "completely", for example, a composition "substantially free of" Y may be completely free of Y. If necessary, the word "substantially" may be omitted from the definitions of the present disclosure.

[0045] The term "antibody" as used herein includes naturally occurring and intact antibodies. A naturally occurring "antibody" is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated herein as V H ) and a heavy chain constant region. The heavy chain constant region comprises three domains, namely CH1, CH2 and CH3. Each light chain comprises a light chain variable region (abbreviated herein as V L ) and a light chain constant region. The light chain constant region comprises a domain, namely CL. V H and V L The V region can be further subdivided into hypervariable regions, termed hypervariable regions or complementarity determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). H and V L It is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of an antibody can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. Exemplary antibodies include secukinumab (Table 1) and ixekizumab (U.S. Patent No. 7,838,638).

[0046] 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 fragments of a full-length antibody can perform the antigen-binding function of an antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include a Fab fragment, a V-binding fragment, and a Fab fragment. L 、V H A monovalent fragment consisting of the V, CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment comprising two Fab fragments connected by a disulfide bridge at the hinge region; an Fd fragment, which consists of the V H and CH1 domains; Fv fragment, which consists of the V L and V H Domain composition; composed of V H dAb fragments composed of domains (Ward et al., 1989 Nature 341: 544-546); and isolated CDRs. Exemplary antigen binding sites include the CDRs of secukinumab listed in SEQ ID NOs: 1-6 and 11-13 (Table 1), preferably the heavy chain CDR3. In addition, although the two domains V L and V Hare encoded by separate genes, but the two domains can be joined using recombinant methods via a synthetic linker that enables them to be made in which V L and V H The single chain Fv (scFv) is a single protein chain that is paired with the antibody domains to form a monovalent molecule (referred to as a single chain Fv (scFv); see, e.g., Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Natl. Acad. Sci. 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the scope of the term "antibody". Single chain antibodies and antigen binding portions are obtained using techniques known to those skilled in the art.

[0047] As used herein, an "isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigenic 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). As used herein, the term "monoclonal antibody" or "monoclonal antibody composition" refers to a preparation of antibody molecules having a single molecular composition. As used herein, the term "human antibody" is intended to include antibodies having variable regions in which both the framework region and the CDR region are derived from sequences of human origin. "Human antibodies" do not need to be produced by humans, human tissues, or human cells. The human antibodies of the present disclosure may include amino acid residues that are not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro, by N-nucleotide additions at junctions in vivo during antibody gene recombination, or by somatic mutations in vivo). In some embodiments of the disclosed procedures and compositions, the IL-17 antibody is a human antibody, an isolated antibody, and / or a monoclonal antibody.

[0048] The term "IL-17" refers to IL-17A, previously known as CTLA8, and includes wild-type IL-17A, polymorphic variants of IL-17A, and functional equivalents of IL-17A from different species (e.g., humans, mice, and monkeys). 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 human dermal fibroblasts to produce IL-6.

[0049] The term "K D " is intended to refer to the dissociation rate of a particular antibody-antigen interaction. As used herein, the term "K D " is intended to refer to d With K a The ratio (i.e. K d / K a) and expressed as a dissociation constant of molar concentration (M). The K of an antibody can be determined using methods well established in the art. D Used to determine the K value of an antibody D The method is through the use of surface plasmon resonance, or using biosensor systems, such as In some embodiments, the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) has a K of about 1-250 pM, preferably about 100-200 pM (e.g., about 200 pM). D Binds human IL-17.

[0050] The term "affinity" refers to the strength of 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 many sites through weak non-covalent forces; the more interactions, the stronger the affinity. Standard assays for assessing the binding affinity of antibodies to IL-17 of various species are known in the art and include, for example, ELISA, Western blot, and RIA. The binding kinetics (e.g., binding affinity) of an antibody can also be assessed by assays known in the art, such as by analyze.

[0051] An antibody that "inhibits" one or more of these IL-17 functional properties (e.g., biochemical, immunochemical, cellular, physiological or other biological activity, etc.) as determined by methods known in the art and described herein will be understood to involve a statistically significant reduction in a particular activity relative to that observed in the absence of the antibody (or when a control antibody of irrelevant specificity is present). An antibody that inhibits IL-17 activity affects a statistically significant reduction, e.g., a reduction of at least about 10% of a measured parameter, a reduction of at least 50%, 80% or 90%, and in certain embodiments of the disclosed methods and compositions, the IL-17 antibodies used may inhibit greater than 95%, 98% or 99% of IL-17 functional activity.

[0052] As used herein, "inhibition of IL-6" refers to the ability of an IL-17 antibody or an antigen-binding fragment thereof (e.g., secukinumab) to reduce the production of IL-6 by primary human dermal fibroblasts. The production of IL-6 in primary human (dermal) fibroblasts is dependent on IL-17 (Hwang et al., (2004) Arthritis Res Ther; 6: R120-128). Briefly, human dermal fibroblasts were stimulated with recombinant IL-17 in the presence of varying concentrations of an IL-17 binding molecule or a human IL-17 receptor with an Fc portion. A chimeric anti-CD25 antibody may be used. (basiliximab) is conveniently used as a negative control. After 16 h stimulation, the supernatant was taken and IL-6 was measured by ELISA. When tested as above, IL-17 antibodies or antigen-binding fragments thereof (e.g., secukinumab) typically have an IC of 2.0 for inhibition of IL-6 production (in the presence of 1 nM human IL-17). 50 The inhibitory activity is about 50 nM or less (e.g., from about 0.01 nM to about 50 nM), i.e., the inhibitory activity is measured against IL-6 production induced by hu-IL-17 in human dermal fibroblasts. In some embodiments of the disclosed methods and compositions, as defined above, the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) and its functional derivatives have an IC of inhibiting IL-6 production. 50 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.

[0053] Unless otherwise indicated, according to the present disclosure, the term "derivative" is used to define amino acid sequence variants and covalent modifications (e.g., pegylation, deamidation, hydroxylation, phosphorylation, methylation, etc.) of, for example, a specific sequence (e.g., variable domain) of an IL-17 antibody or its antigen-binding fragment (e.g., secukinumab). "Functional derivatives" include molecules that have the same qualitative biological activity as the disclosed IL-17 antibodies. Functional derivatives include fragments and peptide analogs of IL-17 antibodies as disclosed herein. Fragments contain regions within a polypeptide sequence according to the present disclosure (e.g., a specified sequence). The functional derivatives of the IL-17 antibodies disclosed herein (e.g., functional derivatives of secukinumab) preferably include the following V H and / or V L Domain: The domain is related to the V domain of the IL-17 antibody and antigen-binding fragment thereof disclosed herein. H and / or V L The sequences have at least about 65%, 75%, 85%, 95%, 96%, 97%, 98%, or even 99% overall sequence identity and substantially retain the ability to bind to human IL-17, or, for example, inhibit IL-17-induced IL-6 production by human dermal fibroblasts.

[0054] The phrase "substantially identical" means that the amino acid or nucleotide sequence (e.g., V H or V L domain) or have insubstantial differences therefrom (e.g., by conservative amino acid substitutions). Insubstantial differences include minor amino acid changes, such as in a particular region (e.g., V H or V Ldomain). In the case of an antibody, the second antibody has the same specificity and has at least 50% of its affinity. Sequences substantially identical to the sequences disclosed herein (e.g., having at least about 85% sequence identity) are also part of this application. In some embodiments, the sequence identity of a derivative IL-17 antibody (e.g., a derivative of secukinumab, such as a secukinumab biosimilar antibody) relative to the disclosed sequence can be about 90% or higher, such as 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher.

[0055] "Identity" with respect to a natural polypeptide and its functional derivative is defined herein as the percentage of amino acid residues in a candidate sequence that are identical to the residues of a corresponding natural polypeptide, after aligning the sequences and introducing spaces, if necessary, to achieve maximum percent identity, and without considering any conservative substitutions as part of the sequence identity. Neither N-terminal nor C-terminal extensions nor insertions should be interpreted as reducing identity. Methods and computer programs for alignment are known. Percent identity can be determined by standard alignment algorithms, such as the basic local alignment search tool (BLAST) described by Altshul et al. ((1990) J. Mol. Biol., 215: 403 410); Needleman et al.'s algorithm ((1970) J. Mol. Biol., 48: 444 453); or Meyers et al.'s algorithm ((1988) Comput. Appl. Biosci., 4: 11 17). One set of parameters can be a Blosum 62 scoring matrix with a gap penalty of 12, a gap extension penalty of 4, and a frameshift gap penalty of 5. The percent identity between two amino acid or nucleotide sequences can also be determined using the algorithm of E. Meyers and W. Miller ((1989) CABIOS, 4: 11-17), which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

[0056] "One or more amino acids" refers to, for example, all naturally occurring L-α-amino acids and includes D-amino acids. The phrase "amino acid sequence variant" refers to a molecule whose amino acid sequence has some differences when compared to a sequence according to the present disclosure. Amino acid sequence variants of antibodies according to the present disclosure, such as variants of a specific sequence, still have the ability to bind to human IL-17 or, for example, the ability to inhibit IL-6 production by human dermal fibroblasts induced by IL-17. Amino acid sequence variants include substitution variants (those variants in which at least one amino acid residue is removed and a different amino acid is inserted at the same position in a polypeptide according to the present disclosure), insertion variants (those variants in which one or more amino acids are inserted adjacent to an amino acid at a specific position in a polypeptide according to the present disclosure) and deletion variants (those variants in which one or more amino acids are removed in a polypeptide according to the present disclosure).

[0057] The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of one or more active ingredients.

[0058] The term "administering" with respect to a compound (eg, an IL-17 binding molecule or another agent) is used to refer to delivery of the compound to a patient by any route.

[0059] As used herein, "therapeutically effective amount" refers to an amount of an IL-17 antagonist (e.g., 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)) that, when administered to a patient (e.g., a human) in a single dose or multiple doses, is effective to treat, prevent, prevent the onset of a disorder or a recurring disorder, cure, delay, reduce the severity of a disorder or a recurring disorder, alleviate at least one symptom of a disorder or a recurring disorder, or prolong the patient's survival beyond what would be expected in the absence of such treatment. When applied to an individual active ingredient (e.g., an IL-17 antagonist, such as secukinumab) administered alone, the term refers only to that ingredient. When applied to a combination, the term refers to the combined amounts of the active ingredients (whether administered in combination, either serially or simultaneously) that produce a therapeutic effect.

[0060] The term "treatment" or "treat" is defined herein as the application or administration of an IL-17 antibody (e.g., secukinumab or ixekizumab) or a pharmaceutical composition containing the anti-IL-17 antibody according to the present disclosure to a subject or to an isolated tissue or cell line from a subject, wherein the subject suffers from a particular disease (e.g., GCA), has symptoms associated with a disease (e.g., GCA), or has a predisposition to develop a disease (e.g., GCA), if applicable, wherein the purpose is to cure (if applicable) the disease, delay the onset of the disease, reduce the severity of the disease, slow, ameliorate one or more symptoms of the disease, ameliorate the disease, reduce or ameliorate any symptom associated with the disease or a predisposition to develop the disease. The term "treatment" includes treatment of patients suspected of having a disease as well as patients who are ill or have been diagnosed with a disease or medical condition, and includes inhibiting clinical relapse and maintaining remission.

[0061] As used herein, "selection (selecting)" and "selected (selected)" about patients are used to mean that specific patients are specially selected from a larger group of patients based on (due to) having predetermined criteria. Similarly, "selective treatment" refers to providing treatment to patients with specific diseases, wherein the patient is specially selected from a larger group of patients based on specific patients with predetermined criteria. Similarly, "selective administration" refers to administering drugs to patients, and the patient is specially selected from a larger group of patients based on (due to) having predetermined criteria. By selection, selective treatment and selective administration, it is meant that personalized treatment is delivered to patients based on the patient's personal medical history (e.g., previous therapeutic interventions, such as previous treatment with biological agents), biological characteristics (e.g., specific genetic markers), and / or performance (e.g., not meeting specific diagnostic criteria), rather than delivering standard treatment regimens based solely on the patient's membership in a larger group. With reference to the treatment method used herein, selection does not refer to the accidental treatment of patients with specific criteria, but refers to the intentional selection of patients treated based on patients with specific criteria. Thus, selective treatment / administration is distinguished from standard treatment / administration, which delivers a particular drug to all patients with a particular disease, regardless of those patients' individual medical history, disease presentation, and / or biological characteristics.

[0062] IL-17 antagonists

[0063] Various disclosed processes, kits, uses and methods utilize IL-17 antagonists. IL-17 antagonists can block, reduce and / or inhibit IL-17 signals, activity and / or transduction. 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 broadalumab). In some embodiments, the IL-17 antagonist is an IL-17 binding molecule, preferably an IL-17 antibody or an antigen binding fragment thereof. As used herein, the IL-17 antibody and its antigen binding fragment can be fully human, CDR-grafted or chimeric. The constant region domains of the antibodies or antigen-binding fragments thereof preferably for use in the disclosed methods, uses, kits, etc. preferably comprise suitable human constant region domains, for example, as described in "Sequences of Proteins of Immunological Interest" (Kabat EA et al., US Department of Health and Human Services, Public Health Service, National Institute of Health).

[0064] Particularly preferred IL-17 antibodies or antigen-binding fragments thereof for use in the disclosed methods are human antibodies, in particular secukinumab as described in Examples 1 and 2 of WO 2006 / 013107 (which is incorporated herein by reference in its entirety). Secukinumab is a recombinant high affinity fully human monoclonal anti-human interleukin-17A (IL-17A, IL-17) antibody of the IgG1 / κ isotype. Secukinumab has a high affinity for IL-17, i.e., a K of about 100-200 pM (e.g., about 200 pM). D , neutralizing the biological activity of human IL-17A with an IC of approximately 0.67 nM in vitro 50 is about 0.4 nM, and has a half-life of about 4 weeks.

[0065] For ease of reference, the amino acid sequences of the hypervariable regions of the secukinumab monoclonal antibody are provided in Table 1 below, based on the Kabat definition and as determined by X-ray analysis and using the method of Chothia and colleagues.

[0066] Table 1: Amino acid sequence of the hypervariable region of secukinumab. L The DNA is shown in SEQ ID NO: 9. V encoding secukinumab HThe DNA is shown in SEQ ID NO:7.

[0067]

[0068] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V H ), the CDR1 has the amino acid sequence of SEQ ID NO: 1, the CDR2 has the amino acid sequence of SEQ ID NO: 2, and the CDR3 has the amino acid sequence of SEQ ID NO: 3. In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin light chain variable domain (V L '), the CDR1' has the amino acid sequence of SEQ ID NO: 4, the CDR2' has the amino acid sequence of SEQ ID NO: 5 and the CDR3' has the amino acid sequence of SEQ ID NO: 6. In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin heavy chain variable domain (V H ) comprising hypervariable regions CDR1-x, CDR2-x and CDR3-x. H ), the CDR1-x has the amino acid sequence of SEQ ID NO:11, the CDR2-x has the amino acid sequence of SEQ ID NO:12, and the CDR3-x has the amino acid sequence of SEQ ID NO:13.

[0069] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises at least one immunoglobulin V H domain and at least one immunoglobulin V L domain, wherein: a) the immunoglobulin V H The structural domain comprises (for example, in order): i) hypervariable regions CDR1, CDR2 and CDR3, wherein CDR1 has an amino acid sequence of SEQ ID NO: 1, CDR2 has an amino acid sequence of SEQ ID NO: 2, and CDR3 has an amino acid sequence of SEQ ID NO: 3; or ii) hypervariable regions CDR1-x, CDR2-x and CDR3-x, wherein CDR1-x has an amino acid sequence of SEQ ID NO: 11, CDR2-x has an amino acid sequence of SEQ ID NO: 12, and CDR3-x has an amino acid sequence of SEQ ID NO: 13; and b) immunoglobulin V LThe domain comprises (eg in order) hypervariable regions CDR1', CDR2' and CDR3', 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.

[0070] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof comprises: a) an immunoglobulin heavy chain variable domain (V) comprising the amino acid sequence shown in SEQ ID NO: 8; H ); b) an immunoglobulin light chain variable domain (V L ); c) an immunoglobulin V comprising the amino acid sequence shown in SEQ ID NO: 8 H domain and an immunoglobulin V comprising the amino acid sequence shown in SEQ ID NO: 10 L domain; d) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 H e) an immunoglobulin V comprising the hypervariable region shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L f) an immunoglobulin V comprising the hypervariable region shown in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H g) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H domain and an immunoglobulin V comprising the hypervariable region shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L domain; or h) an immunoglobulin V comprising the hypervariable region shown in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H domain and an immunoglobulin V comprising the hypervariable region shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L Structural domain.

[0071] In some embodiments, the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) comprises three CDRs of SEQ ID NO: 10. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 8. In other embodiments, the IL-17 antibody or antigen-binding fragment thereof comprises three CDRs of SEQ ID NO: 10 and three CDRs of SEQ ID NO: 8. The CDRs of SEQ ID NO: 8 and SEQ ID NO: 10 can be found in Table 1. The free cysteine ​​(CysL97) in the light chain can be seen in SEQ ID NO: 6.

[0072] In some embodiments, the IL-17 antibody or its antigen-binding fragment comprises a light chain of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or its antigen-binding fragment comprises a heavy chain of SEQ ID NO: 15 (with or without a C-terminal lysine). In other embodiments, the IL-17 antibody or its antigen-binding fragment comprises a light chain of SEQ ID NO: 14 and a heavy chain domain of SEQ ID NO: 15. In some embodiments, the IL-17 antibody or its antigen-binding fragment comprises three CDRs of SEQ ID NO: 14. In other embodiments, the IL-17 antibody or its antigen-binding fragment comprises three CDRs of SEQ ID NO: 15. In other embodiments, the IL-17 antibody or its antigen-binding fragment comprises three CDRs of SEQ ID NO: 14 and three CDRs of SEQ ID NO: 15. Multiple CDRs of SEQ ID NO: 14 and SEQ ID NO: 15 can be found in Table 1.

[0073] Hypervariable regions can be associated with any type of framework region, but are preferably human. Suitable framework regions are described in Kabat EA et al. (supra). Preferred heavy chain frameworks are human heavy chain frameworks, such as the framework of the secukinumab antibody. The framework is composed of, for example, FR1 (SEQ ID NO: 8 amino acids 1 to 30), FR2 (SEQ ID NO: 8 amino acids 36 to 49), FR3 (SEQ ID NO: 8 amino acids 67 to 98) and FR4 (SEQ ID NO: 8 amino acids 117 to 127) regions in sequence. Considering the hypervariable regions of secukinumab determined by X-ray analysis, another preferred heavy chain framework is composed of FR1-x (SEQ ID NO: 8 amino acids 1 to 25), FR2-x (SEQ ID NO: 8 amino acids 36 to 49), FR3-x (SEQ ID NO: 8 amino acids 61 to 95) and FR4 (SEQ ID NO: 8 amino acids 119 to 127) regions in sequence. In a similar manner, the light chain framework is composed of the FR1' (amino acids 1 to 23 of SEQ ID NO: 10), FR2' (amino acids 36 to 50 of SEQ ID NO: 10), FR3' (amino acids 58 to 89 of SEQ ID NO: 10), and FR4' (amino acids 99 to 109 of SEQ ID NO: 10) regions in sequence.

[0074] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof (e.g., secukinumab) is selected from a human IL-17 antibody, which antibody comprises at least: a) an immunoglobulin heavy chain or a fragment thereof, comprising a variable domain and a constant part of a human heavy chain or a fragment thereof, wherein the variable domain comprises, in sequence, hypervariable regions CDR1, CDR2, and CDR3; the CDR1 has the amino acid sequence of SEQ ID NO: 1, the CDR2 has the amino acid sequence of SEQ ID NO: 2, and the 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 and a constant part of a human light chain or a fragment thereof, wherein the variable domain comprises, in sequence, hypervariable regions CDR1', CDR2', and CDR3', wherein the CDR1' has the amino acid sequence of SEQ ID NO: 4, the CDR2' has the amino acid sequence of SEQ ID NO: 5, and the CDR3' has the amino acid sequence of SEQ ID NO: 6.

[0075] In one embodiment, the IL-17 antibody or antigen-binding fragment thereof is selected from a single-chain antibody or antigen-binding fragment thereof comprising an antigen-binding site comprising: a) a first domain comprising hypervariable regions CDR1, CDR2 and CDR3 in sequence, wherein CDR1 has an amino acid sequence of SEQ ID NO: 1, CDR2 has an amino acid sequence of SEQ ID NO: 2, and CDR3 has an amino acid sequence of SEQ ID NO: 3; and b) a second domain comprising hypervariable regions CDR1', CDR2' and CDR3' in sequence, wherein CDR1' has an amino acid sequence of SEQ ID NO: 4, CDR2' has an amino acid sequence of SEQ ID NO: 5, and CDR3' has an amino acid sequence of SEQ ID NO: 6; and c) a peptide linker that is bound 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.

[0076] Alternatively, the IL-17 antibody or antigen-binding fragment thereof as used in the disclosed methods may comprise a derivative of the IL-17 antibody listed herein by sequence (e.g., a PEGylated variant of secukinumab). Alternatively, the V of the IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may be H or V L The domain may have the same V as listed in SEQ ID NO: 8 and 10. H or V L The domains are essentially the same as V H or V L Domain. The human IL-17 antibody disclosed herein may comprise a heavy chain substantially identical to the heavy chain listed in SEQ ID NO: 15 and / or a light chain substantially identical to the light chain listed in SEQ ID NO: 14. The human IL-17 antibody disclosed herein may comprise: a heavy chain comprising SEQ ID NO: 15 and a light chain comprising SEQ ID NO: 14. The human IL-17 antibody disclosed herein may comprise: a) a heavy chain comprising a variable domain having an amino acid sequence substantially identical to the amino acid sequence shown in SEQ ID NO: 8 and a constant portion of a human heavy chain; and b) a light chain comprising a variable domain having an amino acid sequence substantially identical to the amino acid sequence shown in SEQ ID NO: 10 and a constant portion of a human light chain.

[0077] Alternatively, the IL-17 antibody or antigen-binding fragment thereof used in the disclosed methods may be an amino acid sequence variant of the reference IL-17 antibody listed herein (as long as it contains CysL97). The present disclosure also includes IL-17 antibodies or antigen-binding fragments thereof (e.g., secukinumab), wherein the V H or V L Typically only a few (e.g., 1-10) of one or more amino acid residues of the domain (but not CysL97) are changed; for example, by mutation, such as site-directed mutagenesis of the corresponding DNA sequence. 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) human IL-17 by 50% 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 the molecule, as described in Example 1 of WO2006 / 013107 for IL-6 production induced by hu-IL-17 in human dermal fibroblasts.

[0078] 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, comprising 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 residue numbering scheme used to define the IL-17 epitope herein is based on the residue of the first amino acid of the mature protein (i.e., IL-17A lacking the 23 amino acid N-terminal signal peptide and starting with glycine). The sequence of immature IL-17A is listed in Swiss-Prot entry Q16552.

[0079] In some embodiments, the IL-17 antibody has a K of about 100-200 pM. DIn some embodiments, the IL-17 antibody has an IC of about 0.4 nM for in vitro neutralization of the biological activity of about 0.67 nM human IL-17A. 50 In some embodiments, the absolute bioavailability of the IL-17 antibody administered by subcutaneous injection (SC) has a range of about 60% to about 80%, for example, about 73%, about 76%. In some embodiments, the IL-17 antibody (e.g., secukinumab) has an elimination half-life of about 4 weeks (e.g., about 23 to about 35 days, about 23 to about 30 days, for example, about 30 days). In some embodiments, the IL-17 antibody (e.g., secukinumab) has a T max For about 7-8 days.

[0080] Other preferred IL-17 antagonists for use in the disclosed methods, kits and regimens include KHK4872 (KyowaHakko Kirin), ABT-122 (Abbvie), BCD-085 (JCS Biopharm), vedomis (4SC-101), NI-1401 (RG7624; MCAF5352A-NovImmune), ANB004 (AnaptysBio Inc.), E-036041 (Ensemble Therapeutics Corp.), Qβ-IL-17 (virus-like particle-based vaccine), PRS-190 (Pieris AG) bimekizumab (UCB 4940-UCB), ALX-0761, CNTO 6785 (Janssen Pharmaceuticals), LY3074828 (Eli Lilly), LY3114062 (Eli Lilly), SCH-900117, MSB0010841 (ALX-0761 - Merck), ABT-122, COVA322 (Covagen), ixekizumab and brolimumab, as well as 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. Published Patent Application Nos. 20120034656 and 20110027290, which are incorporated herein by reference for their disclosures regarding the sequence and / or structure of IL-17 antagonists.

[0081] In some embodiments of the disclosed uses, methods and kits, the IL-17 antibody or antigen-binding fragment thereof is selected from the group consisting of: a) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope between residues Arg 55 and Trp 67 of IL-17; b) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Arg 55, Glu 57, and Trp 67; c) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising: Arg 55, Glu 57, Trp 67, Tyr 62, and Arg 101; d) an IL-17 antibody or antigen-binding fragment thereof that binds to an epitope of IL-17 comprising Arg 55, Glu 57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser e) an IL-17 antibody or an antigen-binding fragment thereof that binds to an epitope of IL-17, the epitope comprising Arg 55, Glu57, Trp 67, Tyr 62, Arg 101, Pro 59, Ser 64, Val 65, Val 22*, Leu 26, Asp 58, Glu 60, Pro 63, Pro 107, Phe 110, and Lys 114*, wherein the amino acids marked with (*) represent residues contributed by the second IL-17 subunit of the IL-17A homodimer, wherein the IL-17 antibody or the antigen-binding fragment thereof has a K of 0.05 for human IL-17. D The invention relates to an IL-17 antibody or an antigen-binding fragment thereof, wherein the IL-17 antibody or the antigen-binding fragment thereof has an in vivo half-life of about 14-23 days, for example, about 20 days; and f) an IL-17 antibody or the antigen-binding fragment thereof, the antibody or the antigen-binding fragment thereof comprising: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence shown in SEQ ID NO: 30; H );ii) an immunoglobulin light chain variable domain (V L );iii) an immunoglobulin V comprising the amino acid sequence shown in SEQ ID NO: 30 H domain and an immunoglobulin V comprising the amino acid sequence shown in SEQ ID NO: 22 L domain; iv) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 24, SEQ ID NO: 26 and SEQ ID NO: 28 H domain; v) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 16, SEQ ID NO: 18 and SEQ ID NO: 20L domain; vi) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 25, SEQ ID NO: 27 and SEQ ID NO: 29 H vii) an immunoglobulin V domain comprising the hypervariable regions shown in SEQ ID NO: 17, SEQ ID NO: 19 and SEQ ID NO: 21 L h) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 24, SEQ ID NO: 26 and SEQ ID NO: 28 H domain and an immunoglobulin V comprising the hypervariable region shown in SEQ ID NO: 16, SEQ ID NO: 18 and SEQ ID NO: 20 L Domain; ix) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 25, SEQ ID NO: 27 and SEQ ID NO: 29 H Domains and immunoglobulin V comprising the hypervariable regions shown in 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.

[0082] In some embodiments of the disclosed uses, methods, and kits, the IL-17 antibody or antigen-binding fragment thereof is CJM112, a high-affinity recombinant fully human monoclonal anti-human IL-17 antibody of the IgG1 / κ class. CJM112 also binds to IL-17AF and antagonizes this cytokine (see, e.g., U.S. Pat. No. 9,193,788, which is incorporated herein by reference in its entirety).

[0083] IL-17AF antagonists can also be used to treat GCA by, for example, inducing a reduction in vascular (e.g., large vessel or artery) inflammation (vasculitis) in GCA patients. These antagonists (including antibodies that cross-react with IL-17A and IL-17F, as well as bispecific anti-IL-17A / F antibodies FynomAb (e.g., COVA322), nanobodies (e.g., ALX-0761), etc.) can be found in U.S. Published Patent Applications Nos. 20140314763, 2013 / 0195872, 20160326241, U.S. Patent Nos. 8496936, 8945553, and Published PCT Application No. WO / 2016 / 070062.

[0084] Methods and uses of IL-17 antagonists for treating GCA

[0085] The disclosed IL-17 antagonists, e.g., IL-17 binding molecules (e.g., IL-17 antibodies or antigen-binding fragments thereof, e.g., secukinumab) or IL-17 receptor binding molecules (e.g., IL-17 receptor antibodies or antigen-binding fragments thereof) can be used in vitro, ex vivo, or incorporated into pharmaceutical compositions and administered in vivo to treat GCA (e.g., human patients suffering from GCA, e.g., active GCA).

[0086] In some embodiments, the patient has one or more or all of the inclusion criteria listed in Example 1. In some embodiments, the patient has one or more or all of the inclusion criteria listed in Example 2. In some embodiments, the patient does not have one or more or all of the exclusion criteria listed in Example 1. In some embodiments, the patient does not have one or more or all of the exclusion criteria listed in Example 2.

[0087] In some embodiments, the patient has not received prior biologic therapy. In some embodiments, the patient has previously received a biologic therapy for GCA. In some embodiments, the patient has previously received a biologic therapy for a different disease but has not received an alternative biologic therapy for GCA. In some embodiments, the patient has had an inadequate or no response to a prior biologic therapy for GCA.

[0088] Patient response to the treatment disclosed herein can be measured using patient-reported outcomes (PROs), clinician-reported outcomes, laboratory parameters, imaging techniques, and the like. Clinician-reported outcomes include, for example, a physician's global assessment (PhGA) of disease activity (e.g., using a VAS score). Imaging techniques include, for example, MRI (as described by Reichenbach et al. (2018) in a follow-up study of a Phase II tocilizumab study); and ultrasound. PROs include, for example, a patient's global assessment (PGA) of disease activity (e.g., using a VAS score), a FACIT-Fatigue score, a SF36 score, and an EQ-5D-5L score. Laboratory parameters include C-reactive protein (CRP) levels and / or erythrocyte sedimentation rate (ESR).

[0089] EuroQuol 5D (EQ-5D-5L) (euroqol.org / eq-5d-instruments / eq-5d-5l-about / ) is a widely used self-administered questionnaire designed to assess the health status of adults (Xu et al. 2011, McClure et al. 2017). The purpose of EQ-5D-5L in this study was to assess the overall health status of patients. The SF-36 is a 13-item questionnaire (Cella 1993 and Yellen 1997) that assesses self-reported fatigue and its impact on daily activities and functioning. The SF-36 is a widely used and well-studied instrument that measures health-related quality of life in healthy subjects and patients with acute and chronic conditions. It consists of eight individually scoreable subscales: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health (Ware 1993). Two overall summary scores can also be calculated, the physical component summary (PCS) and the mental component summary (MCS) (Ware 1994).

[0090] The Visual Analog Scale (VAS) is a tool that measures a characteristic or condition whose values ​​are thought to range across a continuum. For example, the amount of pain a patient feels ranges from none across a continuum of extreme amounts of pain. From the patient's perspective, this range appears continuous ± their pain does not have discrete jumps, as the categories of none, mild, moderate, and severe would imply. The VAS pain scale is often used as an outcome measure to characterize pain intensity in clinical studies. It typically exists as a 100-mm horizontal line with points between the extremes of "no pain at all" and "worst pain imaginable" (etc.) where the patient's pain intensity lies. The respondent is asked to place a line perpendicular to the VAS line at the location that best represents their pain at the moment. This tool is scored in millimeters (although scores are often recorded in tenths of centimeters using a 10-point scale); scores below 40 millimeters (or 4 points if measured in centimeters) are generally considered desirable for chronic pain management.

[0091] In some embodiments, after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months (preferably 1, 2 or 3 months, more preferably 6, 12 or 24 months or longer) of treatment according to the claimed methods, 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% pain reduction, inflammation reduction, improvement in one or more PROs or physician-reported outcomes or laboratory or imaging parameters. In preferred embodiments, after treatment according to the claimed methods, the patient experiences at least 20% pain reduction, inflammation reduction.

[0092] In some embodiments, after 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months (preferably 1, 2 or 3 months) of treatment according to the claimed method, 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% improvement in VAS score, PGA score, FACIT-Fatique, SF-36 and / or EQ-5D-5L score. In a preferred embodiment, after treatment according to the claimed method, as determined by VAS score, the patient experiences at least 20% pain relief. In preferred embodiments, following treatment according to the claimed methods, the patient experiences at least a 20% overall improvement as determined by PGA score.

[0093] When used in combination with a pharmaceutically acceptable carrier, an IL-17 antagonist (e.g., 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)) can be used as a pharmaceutical composition. In addition to the IL-17 antagonist, such a composition may also contain a carrier, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials. The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition for use in the disclosed methods may also contain other therapeutic agents for treating a specific targeted disorder. For example, the pharmaceutical composition may also include an anti-inflammatory agent. Such additional factors and / or agents may be included in the pharmaceutical composition to produce a synergistic effect with the IL-17 binding molecule or to minimize side effects caused by the IL-17 antagonist (e.g., 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)).

[0094] The pharmaceutical composition for use in the disclosed method can be prepared in a known manner. In one embodiment, the pharmaceutical composition is provided in a lyophilized form. For immediate administration, it is dissolved in a suitable aqueous carrier, such as sterile water for injection or sterile buffered saline. If it is considered necessary to constitute a larger volume of solution for administration by infusion rather than a single rapid intravenous injection, it may be advantageous to incorporate human serum albumin or the patient's own heparinized blood into the saline during formulation. The presence of an excess of this physiologically inert protein prevents the loss of antibodies by adsorption to the walls of the container and the tubing used to infuse the solution. If albumin is used, a suitable concentration is from 0.5% to 4.5% by weight of the saline solution. Other formulations include liquid or lyophilized formulations.

[0095] Antibodies, such as antibodies to IL-17, are typically formulated in aqueous form for parenteral administration, or as lyophilisates for reconstitution with a suitable diluent prior to administration. In some embodiments of the disclosed methods and uses, the IL-17 antagonist (e.g., 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) to allow subcutaneous administration, and can provide a solution with low levels of antibody aggregation. Antibodies are now widely used as active ingredients in drugs, including the product HERCEPTIN TM (trastuzumab), RITUXAN TM (rituximab), SYNAGIS TM (palivizumab), etc. The technology for purifying antibodies into pharmaceutical grade antibodies is known. When a therapeutically effective amount of an IL-17 antagonist (e.g., 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 by intravenous, percutaneous or subcutaneous injection, the IL-17 antagonist will be in the form of a pyrogen-free, parenterally acceptable solution. In addition to the IL-17 antagonist, the pharmaceutical composition for intravenous, percutaneous or subcutaneous injection may contain an isotonic vehicle, such as sodium chloride, Ringer's solution, dextrose, dextrose and sodium chloride, lactated Ringer's solution, or other vehicles known in the art.

[0096] In preferred embodiments of the disclosed methods, uses, kits, etc., the IL-17 binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof) or the IL-17 receptor binding molecule (e.g., IL-17 antibody or antigen-binding fragment thereof) is secukinumab, which is provided in a stable liquid pharmaceutical formulation comprising about 25 mg / mL to about 150 mg / mL secukinumab, about 10 mM to about 30 mM histidine (pH 5.8), about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and about 2.5 mM to about 20 mM methionine, wherein the liquid formulation is not reconstituted from a lyophilisate. A preferred drug product for use in the disclosed methods, uses, kits, etc. comprises a stable liquid formulation having 150 mg / ml secukinumab, 200 mM trehalose, 0.02% polysorbate 80, and 5 mM L-methionine in 20 mM histidine buffer (pH 5.8), provided in a pre-filled syringe or autoinjector (i.e., having 1 mL or 2 mL of formulation).

[0097] The appropriate dosage will vary depending on, for example, the specific 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 and the nature of the treatment that the patient has previously undergone. Ultimately, the attending healthcare provider will determine the amount of IL-17 antagonist used to treat each individual patient. In some embodiments, the attending healthcare provider can 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 high, and then titrated down until signs of relapse appear. Larger doses of the IL-17 antagonist may be administered until the optimal therapeutic effect for the patient is obtained, and the dose is generally not further increased.

[0098] In practicing some of the treatment methods or uses 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 (e.g., a mammal (e.g., a human)). While it should be understood that the disclosed methods provide for the treatment of GCA patients with an IL-17 antagonist (e.g., secukinumab), this does not exclude that if the patient is to be ultimately treated with an IL-17 antagonist, such IL-17 antagonist therapy is necessarily a monotherapy. In fact, 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 of care therapies for GCA, e.g., corticosteroids, IL-6 inhibitors, anti-TNF-α, methotrexate, etc.) according to the methods of the present disclosure.

[0099] When co-administered with one or more additional GCA agents, the IL-17 antagonist can be administered simultaneously or sequentially with the other agents. If used sequentially, the attending physician will determine the appropriate order in which the IL-17 antagonist is administered in combination with the other agents and the appropriate dose for co-delivery. The 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 receptor antibody or antigen-binding fragment thereof) is conveniently administered parenterally, such as intravenously (e.g., in an antecubital or other peripheral vein), intramuscularly, or subcutaneously.

[0100] The duration of the therapy using the pharmaceutical composition of the present disclosure will vary according to the severity of the disease being treated and the condition and personal response of each individual patient. A healthcare provider will use the pharmaceutical composition of the present disclosure to determine the appropriate duration of therapy and the administration time of the therapy. As used herein, the phrase "total duration of treatment" refers to the total amount of time during the treatment of a patient with an IL-17 antagonist, including (if applicable) an induction phase (e.g., initial weekly administration). Therefore, for example, if an IL-17 antagonist is administered to a patient weekly during weeks 0, 1, 2, 3, and 4 and thereafter every 4 weeks, for a total duration of treatment of 2 months, then the patient is administered during weeks 0, 1, 2, 3, 4, and 8. Similarly, for example, if an IL-17 antagonist is administered to a patient weekly during weeks 0, 1, 2, 3, and 4 and thereafter every 4 weeks, for a total duration of treatment of 3 months, then the patient is administered during weeks 0, 1, 2, 3, 4, 8, and 12.

[0101] The preferred total duration of treatment is between 1-3 months, 3-6 months, 6-9 months or 9-12 months. In some embodiments, the patient is treated for 3 months or less, such as 1, 2 or 3 months. In other embodiments, the patient is treated for up to 12 months, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months. The most preferred total duration of treatment is 1, 2 or 3 months.

[0102] Preferred SC treatment regimens with secukinumab (including both induction and maintenance regimens) that can be used to treat GCA patients are provided in PCT Application Nos. PCT / US2011 / 064307 and PCT / IB2014 / 063902, which are incorporated herein by reference in their entirety, as appropriate.

[0103] In some embodiments, a single subcutaneous dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) 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 receptor antibody or an antigen-binding fragment thereof) can be administered to the patient.

[0104] 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) can be administered subcutaneously to the patient weekly during weeks 0, 1, 2, 3, and 4 at about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg).

[0105] In a preferred embodiment, an IL-17 antagonist (e.g., 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)) can be subcutaneously administered to a patient weekly at a fixed dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) during weeks 0, 1, 2, 3, and 4, and about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) of the antagonist is subcutaneously administered to the patient every 4 weeks (monthly) thereafter. In this manner, about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) of an IL-17 antagonist (e.g., secukinumab) is subcutaneously administered to a patient during weeks 0, 1, 2, 3, 4, 8, etc.

[0106] In other embodiments, an IL-17 antagonist (e.g., 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 receptor antibody or antigen-binding fragment thereof)) can be administered to a patient (without a loading regimen), for example, the antagonist can be administered subcutaneously to a patient at a fixed dose of about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) every 4 weeks (monthly). In this manner, about 150 mg to about 300 mg (e.g., about 150 mg, about 300 mg) of an IL-17 antagonist (e.g., secukinumab) is administered subcutaneously to a patient during weeks 0, 4, 8, 12, etc. Ideally, an IL-17 antagonist (e.g., secukinumab) is administered monthly (every 4 weeks) to a patient (e.g., a patient with GCA) for a total of four doses (weeks 0, 4, 8, and 12).

[0107] In other preferred embodiments, 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) can be administered to the patient twice a month (every 2 weeks, every other week), every other month, quarterly (every three months), twice a year (every 6 months), or annually.

[0108] A preferred subcutaneous dose (e.g., a fixed dose) is about 150 mg to about 300 mg, preferably about 150 mg or about 300 mg. However, it should be understood that for some patients, such as patients who show 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, such as secukinumab) or an IL-17 receptor binding molecule (e.g., an IL-17 receptor antibody or an antigen-binding fragment thereof)), a dose escalation may be required (e.g., during the induction and / or maintenance phase). Therefore, the subcutaneous dose of an IL-17 antagonist (e.g., secukinumab) may be greater than about 150 mg to about 300 mg, such as 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 also be understood that for certain patients, for example, patients who exhibit adverse events or adverse reactions to treatment with an IL-17 antagonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab), a dose reduction may also be required (e.g., during the induction and / or maintenance phase). Thus, the dose of an IL-17 antagonist (e.g., an IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) may be less than about 150 mg to about 300 mg SC, such as 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, the IL-17 antagonist (e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragment thereof, such as secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen binding fragment thereof)) can be administered to the patient at an initial dose (or multiple initial doses) of 150 mg delivered subcutaneously, and thereafter the dose is increased to about 300 mg if necessary, as determined by a physician. In some embodiments, the IL-17 antagonist (e.g., IL-17 binding molecule (e.g., IL-17 antibody or antigen binding fragment thereof, such as secukinumab) or IL-17 receptor binding molecule (e.g., IL-17 receptor antibody or antigen binding fragment thereof)) can be administered to the patient at an initial dose (or multiple initial doses) of 300 mg delivered subcutaneously, and thereafter the dose is increased to about 450 mg if necessary, as determined by a physician.

[0109] The timing of dosing is usually measured from the day of the first dose of medication (also called “baseline”). However, healthcare providers often use different nomenclature to determine dosing schedules, as shown in Table 2.

[0110] Table 2: General nomenclature for dosing regimens. Items in bold indicate the nomenclature used here.

[0111]

[0112] It is noteworthy that Week 0 may be referred to as Week 1 by some healthcare providers, while Day 0 may be referred to as Day 1 by some healthcare providers. Therefore, it is possible that different physicians will indicate that the dosage is given, for example, in Week 3 / during Day 21, in Week 3 / during Day 22, in Week 4 / during Day 21, in Week 4 / during Day 22, and refer to the same dosing schedule. For consistency, the first week of administration will be referred to as Week 0 herein, and the first day of administration will be referred to as Day 1. However, it will be understood by those skilled in the art that the naming convention is only used for consistency and should not be interpreted as limiting, i.e., weekly administration is to provide a weekly dose of IL-17 antibody, regardless of whether the physician refers to a specific week as "Week 1" or "Week 2". In one dosing regimen, antibodies are administered monthly during Weeks 0, 4, 8, 12, etc. In one dosing regimen, antibodies are administered during Weeks 0, 1, 2, 3, 4, 8, 12, etc. Some providers may refer to this regimen as weekly for five weeks and monthly (or every 4 weeks) thereafter beginning during week 8, while others may refer to this regimen as weekly for four weeks and monthly (or every 4 weeks) thereafter beginning during week 4. One skilled in the art will appreciate that administering injections to a patient at weeks 0, 1, 2, and 3, followed by monthly dosing (or every 4 weeks) beginning during week 4, is the same as: 1) administering injections to a patient at weeks 0, 1, 2, 3, and 4, followed by monthly dosing beginning at week 8; 2) administering injections to a patient at weeks 0, 1, 2, 3, and 4, followed by every 4 weeks; and 3) administering injections to a patient at weeks 0, 1, 2, 3, and 4, followed by monthly dosing.

[0113] Disclosed herein are methods for treating a patient suffering from GCA, comprising administering to a patient in need thereof a therapeutically effective amount of an IL-17 antibody or an antigen-binding fragment thereof, wherein the IL-17 antibody or antigen-binding fragment thereof 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 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 antibody or antigen-binding fragment thereof has a K of 1.044 for human IL-17. D The concentration of the IL-17 antibody or antigen-binding fragment thereof is about 100-200 pM, and the in vivo half-life of the IL-17 antibody or antigen-binding fragment thereof is about 4 weeks.

[0114] In addition, disclosed herein is a therapeutically effective amount of an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) for use in treating a patient with GCA, wherein the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as 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 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 antibody or antigen-binding fragment thereof has a K of 1.5 Å for human IL-17. D The concentration of the IL-17 antibody or antigen-binding fragment thereof is about 100-200 pM, wherein the in vivo half-life of the IL-17 antibody or antigen-binding fragment thereof is about 4 weeks.

[0115] In addition, disclosed herein is an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) for use in the manufacture of a medicament for treating a patient with GCA, wherein the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as 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 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 antibody or antigen-binding fragment thereof has a K of 1.147 for human IL-17. D The concentration of the IL-17 antibody or antigen-binding fragment thereof is about 100-200 pM, and the in vivo half-life of the IL-17 antibody or antigen-binding fragment thereof is about 4 weeks.

[0116] In addition, disclosed herein is an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) for use in the manufacture of a medicament for treating a patient with GCA, wherein the medicament is formulated to comprise containers, each container having a sufficient amount of an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) to allow 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, such as secukinumab) per unit dose, and further wherein the The IL-17 antagonist (e.g., IL-17 antibody or antigen-binding fragment thereof, such as 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 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 antibody or antigen-binding fragment thereof has a K of 1.14kDa for human IL-17. D The concentration of the IL-17 antibody or antigen-binding fragment thereof is about 100-200 pM, and the in vivo half-life of the IL-17 antibody or antigen-binding fragment thereof is about 4 weeks.

[0117] As used herein, the phrase "a container having a sufficient amount of IL-17 antagonist to allow delivery of [a specified dose]" is used to indicate that a given container (e.g., a vial, a pen, a syringe) has been configured therein a volume of IL-17 antagonist that can be used to provide the desired dose (e.g., as part of a pharmaceutical composition). As an example, if the desired dose is 300 mg, the clinician may use 2 ml from a container containing an IL-17 antibody formulation at a concentration of 150 mg / ml, 1 ml from a container containing an IL-17 antibody formulation at a concentration of 300 mg / ml, 0.5 ml from a container containing an IL-17 antibody formulation at a concentration of 600 mg / ml, etc. In each of these cases, these containers have a sufficient amount of IL-17 antagonist to allow delivery of the desired 300 mg dose. In one embodiment, 1 ml of a formulation containing 150 mg / ml of secukinumab has been configured in the container. In another embodiment, 2 ml of a formulation containing 150 mg / ml of secukinumab has been configured in the container. A preferred formulation is a liquid pharmaceutical composition comprising about 25 mg / mL to about 150 mg / mL of secukinumab, about 10 mM to about 30 mM histidine (pH 5.8), about 200 mM to about 225 mM trehalose, about 0.02% polysorbate 80, and about 2.5 mM to about 20 mM methionine.

[0118] In addition, disclosed herein is an IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) for use in the manufacture of a medicament for treating a patient with GCA, wherein the medicament is formulated as a dose that allows for 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, such as secukinumab) to the patient, and further wherein the IL-17 antagonist (e.g., an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) is administered to the patient. The present invention relates to an antibody or antigen-binding fragment thereof, such as secukinumab, which 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 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the K of the IL-17 antibody or its antigen-binding fragment to human IL-17 is D The concentration of the IL-17 antibody or antigen-binding fragment thereof is about 100-200 pM, and the in vivo half-life of the IL-17 antibody or antigen-binding fragment thereof is about 4 weeks.

[0119] As used herein, the phrase "formulated in a dosage that allows [route of administration] to deliver [specified dose]" is used to indicate that a given pharmaceutical composition can be used to provide a desired dose of an IL-17 antagonist, e.g., an IL-17 antibody, such as secukinumab, via a specified route of administration (e.g., SC or IV). As an example, if the desired subcutaneous dose is 300 mg, then the clinician may use 2 ml of an IL-17 antibody formulation having a concentration of 150 mg / ml, 1 ml of an IL-17 antibody formulation having a concentration of 300 mg / ml, 0.5 ml of an IL-17 antibody formulation having a concentration of 600 mg / ml, etc. In each of these cases, these IL-17 antibody formulations are at a sufficiently high concentration to allow subcutaneous delivery of the IL-17 antibody. Subcutaneous delivery generally requires delivery of < In one embodiment, the patient is administered one 2 ml SC injection of a formulation containing 150 mg / ml secukinumab. In another embodiment, the patient is administered two 1 ml SC injections of a formulation containing 150 mg / ml secukinumab.

[0120] Disclosed herein are methods, uses, pharmaceutical compositions and kits for treating GCA in a patient suffering from GCA, comprising subcutaneously administering to a patient in need thereof about 150 mg to about 300 mg of an IL-17 antibody or an antigen-binding fragment thereof, wherein the IL-17 antibody or 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 on one chain and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 antibody or antigen-binding fragment thereof has a K of 1.044, 1.034, 1.062, 1.096, 1.119, 1.208, 1.127, 1.219, 1.130, 1.141, 1.157, 1.166, 1.170, 1.180, 1.196, 1.219, 1.197, 1.223, 1.237, 1.243, 1.257, 1.267, 1.276, 1.283, 1.297, 1.309, 1.419, 1.509, 1.511, 1.52 D The concentration of the IL-17 antibody or antigen-binding fragment thereof is about 100-200 pM, and the in vivo half-life of the IL-17 antibody or antigen-binding fragment thereof is about 4 weeks.

[0121] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient only once.

[0122] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient weekly.

[0123] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, during weeks 0, 1, 2, 3 and 4, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient.

[0124] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient every 4 weeks.

[0125] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient for a total treatment duration of at least two months.

[0126] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient for a total treatment duration of at least four months.

[0127] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient weekly during weeks 0, 1, 2, 3 and 4 and every 4 weeks thereafter.

[0128] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the IL-17 antibody or antigen-binding fragment thereof is administered to the patient during weeks 0, 1, 2, 3, 4, 8 and 12.

[0129] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient is administered an IL-17 antibody or antigen-binding fragment thereof weekly during weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter for a total treatment duration of at least three months.

[0130] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient had no response, insufficient response or intolerance to a previous GCA treatment selected from the group consisting of corticosteroids, anti-IL-6, anti-TNF-α, methotrexate and combinations thereof.

[0131] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient has active GCA.

[0132] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, the patient experiences at least a 20% improvement in one or more clinical, laboratory, or patient-reported outcomes or physician assessments attributed to GCA following treatment with the IL-17 antibody or antigen-binding fragment thereof.

[0133] In some embodiments of the disclosed methods, uses, pharmaceutical compositions and kits, the IL-17 antibody or antigen-binding fragment thereof comprises: i) an immunoglobulin heavy chain variable domain (V H ) comprising the amino acid sequence shown in SEQ ID NO: 8; H );ii) an immunoglobulin light chain variable domain (V L );iii) an immunoglobulin V comprising the amino acid sequence shown in SEQ ID NO: 8 H domain and an immunoglobulin V comprising the amino acid sequence shown in SEQ ID NO: 10 L domain; iv) an immunoglobulin V comprising the hypervariable region shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 H domain; v) an immunoglobulin V comprising the hypervariable region shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L domain; vi) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H vii) an immunoglobulin V domain comprising the hypervariable regions shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3 H domain and an immunoglobulin V comprising the hypervariable region shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L viii) an immunoglobulin V domain comprising the hypervariable regions shown in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H Domains and immunoglobulin V comprising the hypervariable regions shown in 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 shown in SEQ ID NO: 14; x) an immunoglobulin heavy chain comprising the amino acid sequence shown in SEQ ID NO: 15; or xi) an immunoglobulin light chain comprising the amino acid sequence shown in SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence shown in SEQ ID NO: 15. In some embodiments of the disclosed uses, methods, and kits, the IL-17 antibody or antigen-binding fragment thereof is secukinumab.

[0134] Also disclosed herein are methods, uses, pharmaceutical compositions and kits for treating a patient with active GCA, comprising administering to the patient about 300 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3 and 4 and every four weeks thereafter for a total treatment duration of at least three months.

[0135] Also disclosed herein are methods, uses, pharmaceutical compositions, and kits for treating a patient with active overuse GCA, comprising administering to the patient about 150 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4 and every four weeks thereafter for a total treatment duration of at least three months.

[0136] In some embodiments of the disclosed methods, uses, pharmaceutical compositions, and kits, prior to treatment with secukinumab, the patient was resistant to a previous GCA treatment selected from the group consisting of corticosteroids, anti-TNF-α, anti-IL-6, methotrexate, and combinations thereof.

[0137] Reagent test kit

[0138] The present disclosure also encompasses kits for treating patients with GCA. 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 or lyophilized form) or a pharmaceutical composition comprising an IL-17 antagonist (as described above) in a therapeutically effective amount. In addition, such kits may include tools for administering IL-17 antagonists (e.g., automatic syringes, syringes and vials, pre-filled syringes, pre-filled pens) and instructions for use. These kits may contain additional therapeutic agents for treating GCA (as described above), such as for delivery in combination with the IL-17 antagonist (e.g., IL-17 binding molecule, such as an IL-17 antibody, such as secukinumab) included. Such kits may also include instructions for administering an IL-17 antagonist (e.g., an IL-17 antibody, such as secukinumab) to treat patients with GCA. Such instructions can provide a dose (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), regimen (e.g., weekly during weeks 0, 1, 2, 3, and 4; weekly during weeks 0, 1, 2, 3, and 4, and every 4 weeks thereafter), and total duration of treatment (e.g., 1, 2, 3, 4, 6, 8, 12 months, etc. [preferably 3-12 months, e.g., 3-6 months, such as 3 months]) for use with an included IL-17 antagonist (e.g., an IL-17 binding molecule, e.g., an IL-17 antibody, such as secukinumab).

[0139] The phrase "instrument for administration" is used to indicate any available means for systemically administering a drug to a patient, including but not limited to prefilled syringes, vials and syringes, injection pens, auto-injectors, IV drippers and infusion bags, pumps, etc. Using such items, a patient can self-administer the drug (i.e., administer the drug without the help of a physician) or a doctor can administer the drug. In some embodiments, a total dose of 300 mg is delivered in a total volume of 2 ml with 150 mg / ml of IL-17 antibody (e.g., secukinumab) configured in a single PFS or auto-injector. In some embodiments, a total dose of 300 mg is delivered in a total volume of 2 ml configured in two PFS or auto-injectors, each PFS or auto-injector containing: a volume of 1 ml with 150 mg / ml of IL-17 antibody (e.g., secukinumab).

[0140] Disclosed herein is a kit for use in the treatment of a patient with GCA, comprising an IL-17 antagonist (e.g., an IL-17 binding molecule, such as an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab). In some embodiments, the kit further comprises a tool for administering the IL-17 antagonist to the patient. In some embodiments, the kit further comprises instructions for administering the IL-17 antagonist, wherein the instructions indicate that the IL-17 antagonist (e.g., an IL-17 binding molecule, such as an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) is administered subcutaneously (SC) to the patient at a dose of about 150 mg to about 300 mg (e.g., about 150 mg or about 300 mg). In some embodiments, the instructions indicate that during weeks 0, 1, 2, 3, and 4, the IL-17 antagonist (e.g., an IL-17 binding molecule, such as an IL-17 antibody or an antigen-binding fragment thereof, such as secukinumab) is administered to the patient weekly. In some embodiments, the instructions indicate that the IL-17 antagonist (e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) is administered to the patient every 4 weeks (monthly) for a total treatment duration of at least 2 months (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months (preferably, 2 or 3 months)). In some embodiments, the instructions indicate that the IL-17 antagonist (e.g., IL-17 binding molecule, e.g., IL-17 antibody or antigen-binding fragment thereof, such as secukinumab) is administered to the patient every week during weeks 0, 1, 2, 3, and 4, and that the administration is performed every 4 weeks (monthly) thereafter for a total treatment duration of at least 3 months (i.e., 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 months (preferably, 2 or 3 months)). In some embodiments, the instructions will provide for dose escalation (eg, 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 needed as determined by a physician).

[0141] General Description

[0142] In preferred embodiments of the disclosed methods, treatments, medicaments, regimens, uses and kits, 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 disclosed methods, treatments, regimens, uses and kits, the IL-17 antibody or an antigen-binding fragment thereof is a human antibody of the IgG1 isotype with a kappa light chain. In preferred embodiments of the disclosed methods, the antibody or antigen-binding fragment thereof is secukinumab.

[0143] The details of one or more embodiments of the present disclosure are set forth in the specification attached above. Preferred methods and materials are now described, but any methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present disclosure. Other features, objects and advantages of the present disclosure will be clear according to the specification and according to the claims. In this specification and the appended claims, unless the context clearly indicates otherwise, the singular form includes plural references. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present disclosure belongs. Unless otherwise stated, all patents and publications cited in this specification are incorporated by reference when appropriate. The following examples are provided to more fully illustrate the preferred embodiments of the present disclosure. These examples should never be interpreted as limiting the scope of the disclosed subject matter defined by the appended claims. Example

[0144] Example 1 - A randomized, parallel-group, double-blind, placebo-controlled, multicenter phase III trial to investigate the efficacy and safety of 300 mg of subcutaneously administered secukinumab versus placebo in patients with giant cell arteritis (GCA) combined with a glucocorticoid-reducing regimen

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153] Objectives and relevant endpoints

[0154] Table 1 Objectives and relevant endpoints

[0155]

[0156]

[0157]

[0158] Investigation plan

[0159] Study Design

[0160] This randomized, parallel-group, double-blind, placebo-controlled, multicenter, phase II study was designed to evaluate the efficacy of secukinumab combined with a 26-week prednisolone taper regimen compared with placebo in maintaining remission in patients with newly diagnosed or relapsed GCA who had not received prior biologic therapy.

[0161] The study will include a 6-week (maximum duration) 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 at Week 12, experience a post-remission flare, or are unable to comply with the prednisolone taper regimen (as described below) will enter the "Out" state. Once in the "Out" state, patients will receive a dose of prednisolone determined by the physician's clinical judgment and continue to receive secukinumab or placebo in a blinded manner. Patients in the "Out" state should continue to attend all subsequent scheduled visit assessments.

[0162] Patients who have received additional corticosteroids as specified in the tapering regimen will be considered non-adherent to the protocol-defined prednisolone tapering regimen. Patients who do not adhere to the prednisolone tapering regimen will be classified as non-responders in the primary analysis, regardless of whether they are in sustained remission. Patients who receive less than the full amount of prednisolone required for the tapering (due to missing tablets) will not be classified as non-responders unless other non-response criteria are met.

[0163] Screening Period: During the Screening Period, patients may receive glucocorticoids for the treatment of GCA at the discretion of the Investigator. By the end of the Screening Period, patients should be able to switch to Sponsor-provided prednisolone to follow a plan-defined prednisolone taper schedule.

[0164] Randomization: Patients will be assigned in a 1:1 ratio to one of the following two arms:

[0165] Group 1: 300 mg of secukinumab subcutaneously plus 26 weeks of prednisolone taper

[0166] Group 2: Subcutaneous placebo + 26 weeks of prednisolone taper

[0167] Patients will receive secukinumab / placebo at baseline, Weeks 1, 2, 3, 4, and every 4 weeks thereafter until Week 48 (last dose) at the study center. Assessments will be performed as per the study plan. Patients in both groups will follow a planned prednisolone taper schedule.

[0168] At each visit, each patient's disease activity and status will be assessed to determine if the patient is able to adhere to the defined prednisolone taper (open-label). If they are unable to adhere to the taper or experience a flare (defined above), they must enter the "out" arm and receive a dose of prednisolone determined by the physician based on clinical need and will continue to receive 300 mg of secukinumab subcutaneously or placebo (still blinded).

[0169] All visits will include safety assessments, including two safety follow-up visits at 8 and 12 weeks after the last study drug administration at Week 48 (and at Weeks 56 and 60 for patients who complete the study per protocol).

[0170] For the primary analysis, a treatment duration of 24 weeks was selected for this study. This is shorter than the 52-week treatment duration in the GiACTA trial (Stone et al., 2017); however, most episodes occurred within the first 6 months of the GiACTA trial. Therefore, the time point for the primary analysis is Week 28 to assess the effect of secukinumab in patients who received study treatment or placebo for 24 weeks. The assessment for the primary analysis will be performed at Week 28 (i.e., 2 weeks after the last prednisolone dose at Week 26).

[0171] Secondary endpoints included assessments at week 28 (after 24 weeks of treatment, including a taper of prednisolone at week 26) and week 52 (after a total of 48 weeks of treatment, with no concomitant prednisolone starting at week 27).

[0172] Whether secukinumab is effective in providing sustained remission, reduced vascular involvement (assessed by imaging), and improved quality of life without the need for concomitant prednisolone will be evaluated from Week 27 to Week 52. Patients will receive double-blind treatment consisting of two injections at each time point until Week 48, with the final efficacy assessment to be performed at Week 52.

[0173] Regular assessments ensured that patients in any treatment group who were likely to experience an attack were placed in the exit arm to receive prednisolone at the investigator's clinical discretion.

[0174] An 8-week follow-up period after the end of study treatment was included to generate follow-up data for potential relapses and to obtain follow-up data on treatment safety in the GCA indication. The 26-week prednisolone taper was chosen because it was shown to be effective enough in combination with tocilizumab to achieve sustained glucocorticoid-free remission in patients with GCA in the GIACTA trial (Stone et al., 2017). In other chronic inflammatory diseases (e.g., psoriasis, PsA), pivotal Phase III trials of secukinumab have demonstrated peak efficacy (i.e., disease remission) at Week 12 that was sustained through Week 24. In this Phase II trial, those patients who did not achieve remission at Week 12 will enter the “out” treatment arm, where they will continue to receive secukinumab or placebo in a blinded manner, but investigators may adjust their prednisolone treatment based on their clinical needs.

[0175] The study population will include 50 patients diagnosed with GCA (meeting inclusion criterion number 4) and meeting all other inclusion criteria. Both patients with new-onset GCA (diagnosed within 6 weeks of baseline) and patients with recurrent disease (diagnosed >6 weeks before baseline) will be included. The enrollment rate for patients with recurrent GCA will be limited to 50% preferentially, but may be increased based on the enrollment rate of new-onset patients versus recurrent patients.

[0176] Study Treatment

[0177] Investigational and comparator drugs

[0178] Study treatments are summarized in the Table. Patients will be given all secukinumab and placebo injections by site staff. PFS is packaged in a double-blind fashion and requires no preparation. Study treatments will be labeled as follows:

[0179] Double-blind secukinumab and placebo PFS will be labeled AIN457 150 mg / 1 ml / placebo for dosing up to and including Week 48.

[0180] Patients will also receive open-label prednisolone tablets for gradual dose reduction from baseline to Week 26. Study site staff will provide prednisolone tablets to patients at the study site visit and provide patients with enough tablets to take at home during the study visit.

[0181] Table 2: Overview of study treatments

[0182]

[0183]

[0184] Additional treatment

[0185] In this trial, prednisolone will be administered with the study drug described herein (secukinumab) and placebo. No further add-on treatment will be included in this trial.

[0186] Treatment Arm

[0187] Patients will be assigned in a 1:1 ratio to one of the following two treatment arms, with approximately 25 patients in each arm.

[0188] Group 1: 300 mg of secukinumab subcutaneously (2 x 150 mg) + 26 weeks of prednisolone taper

[0189] Group 2: Subcutaneous placebo (2 injections) + 26 weeks of prednisolone reduction regimen

[0190] Patients will receive secukinumab or placebo at the study center at Week 0 (baseline), Weeks 1, 2, 3, 4, and then every 4 weeks until Week 48 (last dose).

[0191] Patients will receive a daily dose of prednisolone that will be reduced (i.e., tapered) from baseline to Week 26.

[0192] Patients who do not achieve remission, experience a post-remission flare, or are unable to comply with the prednisolone taper regimen by week 12 will be placed in the “out” state. Once in the “out” state, patients will receive a dose of prednisolone determined by the physician’s clinical judgment and continue to receive 300 mg of secukinumab subcutaneously in a double-blind fashion. Patients in the “out” state should continue to attend all subsequent scheduled visit assessments.

[0193] Patients who receive additional corticosteroids as per the tapering schedule will be considered not to have adhered to the planned defined prednisolone tapering schedule. Patients who do not adhere to the prednisolone tapering schedule will be classified as nonresponders in the primary analysis, regardless of their sustained remission status. Patients who receive less than the full amount of prednisolone required for the tapering (due to missing tablets) will not be classified as nonresponders.

[0194] Table 3 Study treatment plan

[0195]

[0196]

[0197] Two different prednisolone taper schedules (Table 0-1 for patients taking 40 to 60 mg / day prednisolone at baseline; Table 0-1 for patients taking 25 to 40 mg / day prednisolone at baseline) will be used in both treatment arms depending on the patient's prednisolone level at baseline. Starting at Week 8, all patients will receive the same level of prednisolone (15 mg / day) and will continue to taper gradually.

[0198] Prednisolone will be provided by the sponsor in an open-label fashion. Weekly prednisolone intake (not part of the assessment schedule) is required to be reported (date / home dosing form).

[0199] Table 0-1: 60-40 mg / day at baseline

[0200]

[0201]

[0202] Table 4: 40-25 mg / day at baseline

[0203]

[0204]

[0205]

[0206] Prednisolone before and up to baseline

[0207] Patients had to be taking a prednisolone dose of 25-60 mg / day at baseline to be included in the study.

[0208] Prednisolone from baseline

[0209] Patients will receive a daily dose of prednisolone that will be reduced (ie, tapered) from baseline to Week 26, as described.

[0210] Methotrexate

[0211] Patients taking MTX (≤25 mg / week) at study entry were allowed to continue taking the medication provided they had been taking it for at least 3 months and their dose was stable for at least 4 weeks before randomization and throughout the study.

[0212] Patients taking MTX were required to take folic acid supplements before randomization and during the trial to minimize the potential for MTX-related toxicity.

[0213] Elution of leflunomide with cholestyramine

[0214] If treatment with leflunomide is used, an 8-week drug washout is mandatory; however, an alternative washout procedure may be considered. Cholestyramine can be given orally at a dose of 8 grams three times daily to wash out leflunomide. In 3 healthy volunteers, cholestyramine has been shown to reduce plasma levels of the active leflunomide metabolite by approximately 40% within 24 hours and by 49% to 65% within 48 hours. Cholestyramine is recommended for patients who require a drug elimination procedure. If a patient takes 8 grams three times daily for 11 days, he / she can be safely randomized 4 weeks after the start of the 11-day cholestyramine treatment period.

[0215] Vitamin D

[0216] Vitamin D (1000 I.E. per day) was strongly recommended during the study period.

[0217] Efficacy

[0218] Main efficacy assessment

[0219] The primary efficacy objective was to evaluate the efficacy of secukinumab combined with a 26-week prednisolone taper compared with placebo, based on the proportion of patients with GCA who maintained remission.

[0220] The primary efficacy endpoint was the proportion of GCA patients who were in sustained remission (defined below) at Week 28.

[0221] Definition of remission: Freedom from an attack (see below). Definition of sustained remission: Patient is free from an attack by Week 28 (see below) and adheres to the prednisolone taper regimen.

[0222] Definition of an episode: Determined by the investigator and defined as a recurrence of signs or symptoms of GCA after resolution and / or an ESR ≥ 30 mm / hr and / or CRP ≥ 10 mg / L attributed to GCA.

[0223] Signs and symptoms of GCA disease

[0224] Assessment of clinical signs and symptoms by the efficacy assessors at each study visit according to the assessment schedule will include the following:

[0225] Fever (>38°C).

[0226] Symptoms of polymyalgia rheumatica (PMR) (morning stiffness and / or pain in the shoulder and / or pelvic girdle).

[0227] Localized headache, temporal artery or scalp tenderness.

[0228] Visual signs or symptoms such as acute or subacute loss of vision, transient blurred vision (usually unilateral or affecting at least one eye at a time, but may affect both eyes) due to arteritic anterior ischemic optic neuropathy (A-AION).

[0229] Jaw or mouth pain.

[0230] New or worsening limb lameness.

[0231] Other features judged by the clinician-investigator to be consistent with an episode of GCA or PMR.

[0232] Secondary Efficacy Assessments

[0233] The following secondary efficacy endpoints will be assessed as described herein or in the corresponding protocol sections:

[0234] Remission rate at week 12

[0235] Time to first GCA attack after clinical remission (up to week 52)

[0236] Total cumulative prednisolone dose up to Week 28 and Week 52

[0237] Proportion of GCA patients in sustained remission at week 52

[0238] oDefinition of remission: absence of an attack.

[0239] oSustained remission is defined as patients being flare-free by week 52 and adhering to the planned prednisolone taper plus a prednisolone-free phase from week 27.

[0240] o Definition of flare: Determined by the investigator and defined as the recurrence of signs or symptoms of GCA after resolution and / or erythrocyte sedimentation rate (ESR) ≥30 mm / hr and / or CRP ≥10 mg / L attributed to GCA.

[0241] Proportion of patients taking prednisolone < 5 mg / day at week 19 / week 28 / week 52

[0242] Change from baseline in disease activity and quality of life measures at Weeks 4, 8, 12, 16, 20, 24, 28, 36, 44, and 52 for each of the following:

[0243] ·

[0244] PhGA, VAS

[0245] ·

[0246] PRO:

[0247] PGA, VAS

[0248] ·FACIT-Fatigue

[0249] SF-36

[0250] EQ-5D

[0251] Changes from baseline in CRP and ESR at weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52

[0252] All efficacy assessments should be performed prior to administration of study treatment.

[0253] The primary efficacy assessment in this study was consistent with that in the GIACTA trial (Stone et al., 2017), which demonstrated the efficacy of another humanized monoclonal antibody (i.e., tocilizumab) in combination with similar corticosteroid reduction (i.e., prednisone) for the treatment of patients with GCA. Other efficacy assessments, including the PhGA and patient-reported outcome (PRO) assessments, including the PGA, correlated closely with those assessed in other Phase II and Phase III clinical trials in the clinical development program for secukinumab for other chronic inflammatory diseases.

[0254] Patients should be given PRO measurements to be completed at the scheduled visit prior to any clinical assessment. Patients should be given adequate space and time to complete PRO measurements.

[0255] Site personnel (the person responsible for administering and checking the completion of PRO measures) should review the PRO measures for completeness and ask patients to complete any missing responses. Responses stored electronically in the database will be considered source documents.

[0256] The investigator should review and evaluate completed measurements and any unsolicited comments written by the patient for responses that may indicate a potential AE or SAE prior to proceeding with any clinical study examinations. This evaluation should be documented in the study source record. If an AE or SAE is confirmed, the investigator should not encourage the patient to change the responses reported on the completed questionnaire. The investigator must follow the reporting instructions outlined in the study protocol.

[0257] The patient's global assessment of disease activity

[0258] After answering the question “On a scale of 0–100, how do you think your giant cell arteritis is affecting you overall right now?”, the patient’s global assessment of disease activity was performed using a 100-mm VAS ranging from “no effect at all” to “worst possible effect”.

[0259] The patient's Global Assessment of Disease Activity was completed by the patient at all visits designated prior to study drug administration.

[0260] The Fatigue Scale is a 13-item questionnaire that assesses self-reported fatigue and its impact on daily activities and functioning (Cella 1993 and Yellen 1997).

[0261] Collect available information in the eCRF according to the treating physician’s clinical routine. The purpose of the data is to evaluate the impact of fatigue in patients with GCA. This questionnaire will be used at all visits designated prior to study drug administration.

[0262] The SF-36 is a widely used and extensively studied instrument that measures health-related quality of life in healthy subjects and in patients with acute and chronic illnesses. It consists of eight subscales that can be scored individually: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health (Ware 1993). Two overall summary scores, the physical component summary (PCS) and the mental component summary (MCS), can also be calculated (Ware 1994). The SF-36 has been shown to be useful for monitoring general and specific populations, comparing the relative burden of different diseases, distinguishing the health benefits resulting from different treatments, and screening individual patients.

[0263] The purpose of the SF-36 in this study is to assess the patient's health-related quality of life. A standardized version with a 4-week recall period will be used at all visits designated prior to study drug administration.

[0264] The EQ-5D-5L is a widely used self-administered questionnaire designed to assess the health status of adults (Xu et al. 2011, McClure et al. 2017). The EQ-5D-5L in this study was designed to assess the patient's general health status. The measure is divided into two different parts. The first part includes 1 item covering each of the 5 dimensions (mobility, self-care, usual activities, pain / discomfort, and anxiety / depression). Patients rate these items from “no problem”, “slight problem”, “moderate problem”, “severe problem” to “extremely problematic / unsolvable”. A composite health index is then defined by combining the levels of each dimension. The second part of the questionnaire measures self-rated (overall) health status using a vertically oriented VAS, where 100 represents “best possible health status” and 0 represents “worst possible health status”. Respondents are asked to rate their current health status by marking on this continuum. The recall period is “today” and the questionnaire takes about 5 to 10 minutes to complete.

[0265] The EQ-5D-5L contains 6 items designed to assess health status based on a single indicator value or health utility score. One of the advantages of the EQ-5D-5L approach is that it allows patients to "weight" specific health states and generate a patient utility. The published weights allow for the creation of a single health utility score summary. The overall score ranges from 0 to 1, with lower scores indicating greater levels of functional impairment. The EQ-5D-5L is completed by patients at a designated visit prior to study drug administration.

[0266] result

[0267] The results are Figures 2 to 7 . Of the 52 randomized patients (SEC, n = 27; placebo, n = 25), 71.2% (n = 37) completed study treatment (SEC, 81.5%; placebo, 60.0%). Overall, 42 (80.8%) patients had new-onset GCA at baseline and 10 (19.2%) patients had recurrent GCA. The proportion of GCA patients who were in sustained remission before week 28 (posterior median with 95% confidence interval) was higher in the SEC group (70.1% (51.6%-84.9%)) than in the placebo group (20.3% (12.4%-30.0%)); the odds ratio (posterior median with 95% confidence interval) was 9.31 (3.54-26.29). The proportion of GCA patients in sustained 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 as of week 52. The median (95% confidence interval) time to first GCA attack after baseline was not reached for GCA patients treated with SEC and was 197.0 (101.0-280.0) days in the placebo group.

[0268] Example 2 - A randomized, parallel-group, double-blind, placebo-controlled, multicenter phase 2 trial to investigate the safety and efficacy of secukinumab (AIN457) in patients with giant cell arteritis (TitAIN)

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277] 1.2 Objective The objective of this study is to demonstrate the efficacy and safety of 300 mg of secukinumab administered subcutaneously (sc) for 52 weeks in combination with prednisone tapered over 26 weeks in adult participants with newly diagnosed or recurrent giant cell arteritis (GCA).

[0278] 2. Goals and End Points

[0279] Table 0-2 Objectives and related endpoints

[0280]

[0281]

[0282]

[0283] Main estimation objects

[0284] The primary scientific question of interest was: Among participants with GCA, what is the relative effect of subcutaneous secukinumab 300 mg combined with a 26-week prednisone taper compared with placebo combined with a 52-week prednisone taper on the proportion of participants who achieved sustained remission (without discontinuation of study treatment and without use of way-out or rescue medications) at week 52.

[0285] The main estimation objects are characterized by the following properties:

[0286] Population: Defined by appropriate inclusion / exclusion criteria to reflect the target GCA population.

[0287] Treatment of interest: 300 mg subcutaneous secukinumab plus prednisone for 26 weeks on a tapered schedule vs. placebo plus prednisone for 52 weeks on a tapered schedule

[0288] Main variables:

[0289] Sustained remission status at Week 52 was defined as achieving remission at Week 12 and maintaining remission from Week 12 to Week 52; no discontinuation of study treatment, and no use of escape or rescue medications for GCA.

[0290] Processing of other concurrent events:

[0291] Discontinuation of study treatment for any reason: nonresponder (comprehensive strategy)

[0292] Contraindicated medications: medications that are not permitted by the protocol and have a potential confounding effect on the efficacy of secukinumab. Participants who receive a contraindicated medication and discontinue study treatment will be considered non-responders (as defined in the previous intercurrent event - study treatment discontinuation) (Comprehensive Strategy). If a participant does not discontinue study treatment after taking a contraindicated medication, the potential confounding effect from taking the contraindicated medication is negligible (Treatment Policy Strategy).

[0293] · Outcome therapy for GCA: Receipt of outcome therapy including GC at a dose determined by the investigator according to standard of care was recorded as a component of the primary variable. Participants who received outcome therapy will be considered non-responders (combined strategy).

[0294] Rescue therapy for GCA: Receipt of rescue therapy was recorded as a component of the primary variable. In addition, participants who received rescue therapy were also discontinued from study treatment. These participants were considered nonresponders (combined strategy).

[0295] Summary measures:

[0296] Difference in sustained remission rate between the secukinumab group and the placebo group.

[0297] Secondary estimation objects

[0298] For all secondary endpoints, additional estimates of interest can be specified in the statistical analysis plan.

[0299] Time to clinical failure

[0300] Scientific question of interest: What is the relative effectiveness of subcutaneous secukinumab 300 mg combined with a 26-week prednisone taper compared with placebo combined with a 52-week prednisone taper in prolonging time to clinical failure (considering out / rescue therapy for GCA, study treatment discontinuation, and study discontinuation as clinical failure) in patients with GCA.

[0301] Estimation objects are characterized by the following properties:

[0302] Population: Defined by appropriate inclusion / exclusion criteria to reflect the target GCA population.

[0303] Treatment of interest: Secukinumab 300 mg subcutaneously plus prednisone for 26 weeks on a tapered regimen vs. placebo plus prednisone for 52 weeks on a tapered regimen.

[0304] Primary variables: Time to clinical failure as described herein, with discontinuation of study treatment and out-of-pocket / rescue therapy for GCA considered clinical failure.

[0305] Processing of other concurrent events:

[0306] • Discontinuation of study treatment before Week 52 for any reason: Comprehensive strategy (reflected in the variables above).

[0307] • Outcome treatment for GCA: comprehensive strategy (reflected in the variables above).

[0308] • Rescue therapy for GCA: comprehensive strategy (reflected in the variables above).

[0309] Discontinuation of study before Week 52 for any reason: Comprehensive strategy (reflected in variables above).

[0310] Summary measures: Hazard ratio for time to clinical failure between the secukinumab group and the placebo group.

[0311] Cumulative GC dose as of week 52

[0312] Scientific question of interest: In participants with GCA, what is the relative effect of subcutaneous secukinumab 300 mg combined with a 26-week prednisone taper compared with placebo combined with a 52-week prednisone taper on the cumulative GC dose through week 52, in which patients continued on study treatment without rescue therapy for GCA.

[0313] Estimation objects are characterized by the following properties:

[0314] Population: Defined by appropriate inclusion / exclusion criteria to reflect the target GCA population.

[0315] Treatment of interest: Secukinumab 300 mg subcutaneously plus prednisone for 26 weeks on a tapered regimen vs. placebo plus prednisone for 52 weeks on a tapered regimen.

[0316] Variables: Cumulative GC dose as of week 52.

[0317] Processing of other concurrent events:

[0318] Use of prohibited medications for any reason before week 52 will be handled using a what-if strategy (participants will not have access to prohibited medications).

[0319] Summary measure: Difference in mean (median) cumulative GC dose between the secukinumab and placebo groups.

[0320] PRO (SF-36PCS, EQ-5D, FACIT-Fatigue score) and GTI total score

[0321] Scientific question of interest: What is the relative effect of subcutaneous secukinumab 300 mg in combination with a 26-week prednisone taper compared with placebo in combination with a 52-week prednisone taper on the change from baseline to week 52 in participants with GCA, where patients continued on study treatment without rescue therapy for GCA.

[0322] Population: Defined by appropriate inclusion / exclusion criteria to reflect the target GCA population.

[0323] Treatment of interest: Secukinumab 300 mg subcutaneously plus prednisone for 26 weeks on a tapered regimen vs. placebo plus prednisone for 52 weeks on a tapered regimen.

[0324] Variables (SF-36 PCS, EQ-5D, FACIT-Fatigue score, GTI total score): Changes in variables of interest from baseline to week 52.

[0325] Processing of other concurrent events:

[0326] Discontinuation of study treatment before Week 52 for any reason: Participant is considered not to have discontinued (hypothetical)

[0327] Rescue treatment for GCA: Participants do not have access to rescue treatment (hypothetical).

[0328] • Discontinuation of study before Week 52 for any reason: Participant is considered not to have discontinued (hypothetical).

[0329] Summary measure: Difference in means between the secukinumab group and the placebo group.

[0330] Study Design

[0331] This randomized, parallel-group, double-blind, placebo-controlled, multicenter Phase III study is designed to evaluate the efficacy of secukinumab combined with a 26-week prednisone taper regimen compared with placebo combined with a 52-week prednisone taper regimen in patients with newly diagnosed or relapsed GCA based on sustained remission at Week 52. Approximately 240 participants will be enrolled in the study.

[0332] The study will include 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 ).

[0333] Screening Period: During the Screening Period, participants are expected to be treated with GC for GCA at the discretion of the Investigator. By the end of the Screening Period, participants should be able to switch to Sponsor-provided prednisone at baseline to follow a plan-defined prednisone taper. The starting dose of prednisone at baseline is 20, 25, 30, 35, 40, 50, or 60 mg / day, as determined by the Investigator.

[0334] In the event of a major medical disruption that limits or prevents on-site visits to the study site (e.g., a pandemic or epidemic), the Screening Period may be extended to a maximum of 8 weeks prior to baseline.

[0335] Treatment Period 1 (Baseline (BSL) to Initial Dose at Week 56): At baseline, participants will be randomized in a 2:1 ratio to one of the following two arms:

[0336] Arm 1: 300 mg of secukinumab (2 mL PFS) subcutaneously at BSL weeks 1, 2, and 3, then every four weeks starting at week 4. Secukinumab will be used in conjunction with the designated 26-week prednisone taper regimen.

[0337] - Group 2: Placebo (2 mL PFS) substituted for 300 mg of secukinumab subcutaneously at BSL weeks 1, 2, and 3, then every four weeks starting at week 4. Placebo will be administered in conjunction with the designated 52-week prednisone taper regimen.

[0338] To achieve a balanced distribution of baseline prednisone dose and GCA status in each treatment arm, randomization in both groups will be stratified according to the participant's GCA status (new-onset or recurrent GCA) and baseline prednisone dose (≤30 mg / day or >30 mg / day prednisone).

[0339] Participants who do not achieve clinical remission by Week 12 or who experience clinical relapse after clinical remission may have their GC dose adjusted as determined by the investigator based on standard of care but remain on blinded study treatment (secukinumab or placebo). These participants are referred to as receiving out-of-pocket treatment. For participants receiving out-of-pocket treatment, GC will be administered in an open-label fashion at a dose determined by the investigator based on standard of care.

[0340] Clinical remission at week 12 was defined as participants meeting all of the following criteria at week 12 and having no relapse of the following criteria if remission was achieved before week 12:

[0341] No signs or symptoms attributable to GCA that require an increase in prednisone dose compared to the prespecified reduction (or rescue therapy)

[0342] An ESR elevation of ≥30 mm / hr not attributed to GCA that requires an increase in prednisone dose compared to a prespecified reduction (or rescue therapy)

[0343] No failure to comply with prespecified prednisone reductions due to GC dose increases

[0344] Because CRP laboratory values ​​were measured blindly, CRP values ​​were not part of the definition of clinical remission.

[0345] For participants who receive exit therapy, prednisone will be administered in an open-label manner. Participants who receive exit therapy remain in the study and should continue to attend all subsequent scheduled visits.

[0346] If a participant is receiving rescue therapy (another treatment for GCA other than prednisone alone), study treatment will be stopped prior to initiation of rescue therapy. Such participants may continue to participate in the study and attend all subsequent scheduled visits for assessment (Treatment Period 1 and Follow-up).

[0347] Treatment Period 2 (dosing at Week 56 to Week 108): At Week 56, participants will be classified and receive further treatment as follows:

[0348] Participants with sustained clinical remission at Week 56: Participants initially randomized to secukinumab who are in sustained clinical remission (as defined above) at Week 56 will be re-randomized in a 1:1 ratio to receive double-blind subcutaneous secukinumab 300 mg or placebo, following a randomized withdrawal design through Week 108. Participants initially randomized to placebo will undergo a dummy re-randomization and continue to receive placebo in a blinded manner. Re-randomization will be stratified according to the participant's baseline GCA status (new-onset or recurrent GCA). These participants will not receive concomitant prednisone treatment as prednisone had been discontinued at Week 26 (initial secukinumab arm) or Week 52 (initial placebo arm).

[0349] If a participant experiences clinical relapse during Treatment Period 2, study treatment will be discontinued and the participant will be offered subcutaneous open-label (OL) secukinumab 300 mg. Treatment initiation with OL secukinumab will be similar to initial secukinumab treatment, administered weekly (qw) for the first 4 weeks and then every 4 weeks (q4w) starting 4 weeks after initiation of OL secukinumab. GC will also be administered at a dose determined by the investigator based on standard of care.

[0350] Participants who do not achieve clinical remission within 12 weeks after starting OL secukinumab or who experience clinical relapse while on OL secukinumab during Treatment Period 2 will discontinue OL secukinumab and receive further treatment for GCA at the discretion of the investigator. Participants will attend end-of-treatment (EOT) and end-of-study (EOS) visits.

[0351] Participants Not in Sustained Clinical Remission at Week 56: Participants who do not achieve sustained clinical remission at Week 56 (including those receiving exit therapy) will receive OL secukinumab 300 mg subcutaneously (sc q4w) every 4 weeks with concomitant administration of GC, as determined by the investigator based on standard of care. Treatment initiation with OL secukinumab is similar to initial secukinumab treatment and is administered weekly (qw) for the first 4 weeks and then every 4 weeks (q4w) starting 4 weeks after starting OL secukinumab. Participants who receive OL secukinumab and do not achieve clinical remission within 12 weeks of starting OL secukinumab or experience clinical relapse after achieving clinical remission will discontinue study treatment and attend EOT and EOS visits. Further treatment of GCA will be at the discretion of the investigator.

[0352] Follow-up Period: Following the EOT visit at Week 108, an EOS visit will be conducted at Week 116 for safety assessment.

[0353] Participants on blinded study treatment (secukinumab or placebo) at Week 108: Participants on blinded study treatment at Week 108 with ongoing clinical remission (i.e., receiving study treatment only, without concomitant GC) will complete treatment (last dose at Week 104), complete the EOT visit at Week 108, and complete the EOS visit at Week 116. For participants who are deemed by the investigator to derive clinical benefit from receiving secukinumab post-trial based on standard practice, every effort will be made to offer OL secukinumab in accordance with local laws and regulations. For participants who start receiving OL secukinumab after completing study treatment, the EOS visit at Week 116 will be waived.

[0354] Participants on OL Secukinumab at Week 108: Participants on OL Secukinumab at Week 108 will complete treatment (last dose at Week 104), complete the EOT visit at Week 108, and complete the EOS visit at Week 116. For participants who the investigator believes are still receiving clinical benefit from OL Secukinumab, every effort will be made to continue to offer OL Secukinumab in accordance with local laws and regulations. If post-trial access to OL Secukinumab is offered, the Week 116 EOS visit will be waived. For participants who have not received 12 weeks of OL Secukinumab, the investigator will assess whether the participant is receiving clinical benefit from OL Secukinumab and should continue treatment in the post-trial access.

[0355] Imaging sub-study

[0356] MRA is a noninvasive radiological technique with no X-ray exposure. However, the MRA scanning equipment may cause a feeling of claustrophobia in susceptible individuals, and the presence of metal in the body may also pose a safety hazard or affect the quality of MRA images. Therefore, participants should only be considered for such imaging if they do not have any contraindications to MRA. For more information, see Exclusion Criteria.

[0357] MRA measurements will require the injection of a gadolinium-containing contrast agent (GBCA) during each MRA. Recent evidence suggests that gadolinium deposition can occur in brain tissue following GBCA use. Although no symptoms or diseases have been identified that are associated with gadolinium accumulation in the brain, health authorities have taken preventive measures (e.g., GBCA EMA restriction re braindeposit), noting that data on long-term effects in the brain are limited. This has led to the suspension of use of several linear GBCAs and recommendations for use of another class of GBCAs, the macrocyclics, as they are considered more stable and have a lower tendency to release gadolinium than the linears. Although this view is highly controversial, current thinking is that this class of drugs, especially the linear gadolinium agents, may also increase the risk of a rare but serious disease called nephrogenic systemic fibrosis (NSF). In support of this, a recent review of 639 patients with biopsy-proven NFS showed an incidence of 1.52 cases of NFS per million exposures for group I (i.e., linear) GPCAs, whereas for group II (i.e., macrocyclics), the rate was only 0.008 (Attari et al., 2019). To further reduce this risk, and consistent with guidance from health authorities (e.g., GBCA UK Health Authority Guidance on NSF, GBCA FDA Guidance on NSF), persons with severe renal failure, participants with a previous severe allergic / anaphylactic reaction to gadolinium-based contrast agents, and those with severe renal disease [estimated glomerular filtration rate (eGFR) <30 mL / min / 1.73 m 2 ] or acute worsening of renal function will be excluded from the imaging substudy, as described in the exclusion criteria.

[0358] Inclusion criteria

[0359] Patients eligible for inclusion in this study must meet all of the following criteria:

[0360] 1. Signed informed consent must be obtained before participating in the study.

[0361] 2. The patient must be able to understand and communicate with the investigator and comply with the requirements of the study.

[0362] 3. Male patients or non-pregnant or non-lactating female patients who are at least 50 years old.

[0363] 4. GCA is diagnosed based on all of the following criteria:

[0364] Age of onset ≥50 years.

[0365] Clear-cut cerebral symptoms of GCA (new-onset localized headache, pain in the scalp or mouth or jaw when chewing) and / or symptoms of polymyalgia rheumatica (PMR) (defined as shoulder and / or pelvic girdle pain associated with inflammatory morning stiffness) and / or symptoms of limb ischaemia (claudication).

[0366] TAB shows features of GCA and / or evidence of vasculitis on cross-sectional imaging studies such as ultrasound (eg, cranial or axillary), MRA, CTA, or PET-CT.

[0367] 5. Active disease defined by both of the following criteria being met within 6 weeks of baseline:

[0368] Presence of signs or symptoms of GCA

[0369] Active GCA or elevated ESR (≥30 mm / hr) or CRP (≥10 mg / L) due to active GCA as shown by temporal artery biopsy (TAB) or imaging studies.

[0370] 6. Patients meet the definition of new-onset GCA or recurrent GCA:

[0371] New-onset GCA was defined as GCA diagnosed within 6 weeks of the baseline visit.

[0372] Recurrent GCA was defined as a GCA diagnosis >6 weeks before the baseline visit in which the patient experienced a recurrence of active disease after receiving treatment.

[0373] 7. Patients must be eligible to receive 20 mg-60 mg of prednisone (or equivalent) daily at baseline.

[0374] 8. Patients taking MTX (≤25 mg / week) may continue taking medication, provided they have been taking it for at least 3 months and have maintained a stable dose for at least 4 weeks before randomization, and are receiving stable folic acid therapy before randomization.

[0375] Exclusion criteria

[0376] Patients who meet any of the following criteria are not eligible for this study. Investigators should not make additional exclusions to ensure that the study population is representative of all eligible patients.

[0377] 1. Pregnant or lactating women, where pregnancy is defined as the state of a woman from conception to termination of pregnancy, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.

[0378] 2. Women of childbearing potential, defined as all women who are physiologically capable of becoming pregnant, unless they use effective contraception during study treatment and for at least 20 weeks after the last dose of secukinumab. Basic contraceptive methods include:

[0379] Complete abstinence (when this is consistent with the patient's preference and usual lifestyle). Periodic abstinence (e.g., calendar, ovulation, symptom temperature, post-ovulation method) and withdrawal are not acceptable methods of contraception.

[0380] Female sterilization (bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks prior to study drug administration. If only oophorectomy was performed, only if the female's reproductive status is confirmed by subsequent hormone level assessment.

[0381] Male sterilization (at least 6 months before screening). For female patients in the study, the vasectomized male partner should be the patient's only partner.

[0382] Barrier methods: condoms or occlusive caps (diaphragms or cervical / vault caps).

[0383] Use of oral (estrogen and progestin), injectable or implantable hormonal contraception or other forms of hormonal contraception with equivalent efficacy. If using oral contraceptives, women should be taking the same pill stably for at least 3 months before receiving study treatment.

[0384] Women were considered postmenopausal and infertile if they had at least 12 months of natural (spontaneous) amenorrhea and had appropriate clinical features (e.g., appropriate age, history of vasomotor symptoms), or had undergone bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks earlier. In the case of oophorectomy alone, a woman was considered infertile only if her reproductive status was confirmed by subsequent hormone level assessment.

[0385] If local regulations differ from the above contraceptive methods, local regulations apply and will be described in the Informed Consent Form (ICF).

[0386] 3. Previous exposure to secukinumab or other biological drugs directly targeting IL-17 or IL-17 receptor.

[0387] 4. Patients receiving any cell-depleting therapy.

[0388] 5. Have participated in GCA clinical trials before.

[0389] 6. Patients have received treatment with inhibitors directly targeting IL-1 or IL-1 receptor, IL-12 and IL-23 or abatacept within 4 weeks before baseline or within 5 half-lives of the drug (whichever is longer).

[0390] 7. Patients have received tocilizumab, other IL-6 / IL6-R inhibitors, or JAK inhibitors within 12 weeks before baseline or within 5 half-lives of the drug (whichever is longer), or patients have failed to respond to treatment at any time before baseline or relapsed during treatment.

[0391] 8. The patient has received any treatment for GCA other than GC, and the patient has not responded to treatment at any time before baseline or has relapsed during treatment.

[0392] 9. Patients received intravenous immunoglobulin or plasma exchange within 8 weeks before baseline.

[0393] 10. Patients have received cyclophosphamide, tacrolimus, everolimus, hydroxychloroquine, cyclosporine A, azathioprine, sulfasalazine, and mycophenolate mofetil within 6 months before baseline.

[0394] 11. Patients have received leflunomide within 8 weeks prior to baseline unless cholestyramine washout has been performed, in which case patients must be treated within 4 weeks of baseline.

[0395] 12. Patients have received alkylating agent treatment within 5 years before baseline, unless otherwise specified by other exclusion criteria.

[0396] 13. The patient requires chronic systemic glucocorticoid therapy for any reason other than GCA.

[0397] 14. Receiving daily intravenous methylprednisolone pulse therapy >100 mg within 6 weeks before baseline.

[0398] 15. The patient requires long-term (ie, not occasional "prn") high-potency opioid analgesics for pain management.

[0399] 16. Patients have received any study drug within 4 weeks before baseline or within 5 half-lives of the drug (whichever is longer).

[0400] 17. Contraindications or allergies to secukinumab.

[0401] 18. Active persistent inflammatory diseases other than GCA that may affect the assessment of the benefit of secukinumab treatment, including inflammatory bowel disease or uveitis.

[0402] 19. Major ischemic events (such as myocardial infarction, stroke, etc.) or transient ischemic attack (TIA) (excluding ischemia-related visual loss) related or unrelated to GCA within 12 weeks after screening.

[0403] 20. Diagnosed with any primary systemic vasculitis other than giant cell arteritis (GCA).

[0404] 21. Use of any other biologic within 4 weeks before baseline or within 5 half-lives of the drug (whichever is longer).

[0405] 22. In the opinion of the investigator, active, persistent disease would compromise the patient's immune function and / or place the patient at unacceptable risk for treatment with immunomodulatory therapy.

[0406] 23. Serious medical problems or illnesses, including but not limited to the following: uncontrolled hypertension (≥160 / 95 mmHg), congestive heart failure (New York Heart Association (NYHA) status class III or IV), and uncontrolled diabetes.

[0407] 24. History of clinically significant liver disease or liver damage, as indicated by abnormal liver function tests (LFTs) such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), or serum bilirubin. Investigators should follow the following criteria:

[0408] SGOT (AST) and SGPT (ALT) should not exceed 3× upper limit of normal (ULN). Individual parameters elevated up to and including 3× ULN should be rechecked as soon as possible and, in all cases, at least once before randomization to exclude laboratory error.

[0409] Alkaline phosphatase should not exceed 2×ULN. Elevations up to and including 2×ULN should be rechecked as soon as possible and, in all cases, at least once before randomization to exclude laboratory error.

[0410] Total bilirubin should not exceed 2×ULN. If the total bilirubin concentration rises above 2×ULN, the total bilirubin should be differentiated into direct and indirect reacting bilirubin.

[0411] 25. Patients with severely impaired renal function [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m 2 ].

[0412] 26. Screening total WBC count <3,000 / μL, or platelets <100,000 / μL, or neutrophils <1,500 / μL, or Hgb <8.3 g / dL (83 g / L).

[0413] 27. Active systemic infection during the last 2 weeks before randomization (exception: cold).

[0414] 28. History of persistent, chronic or recurrent infectious disease or evidence of tuberculosis infection, as defined by a positive QuantiFERON TB-Gold Plus test. Patients with a positive test may participate in the study if further investigation (according to local practice / guidelines) clearly determines that the patient has no evidence of active tuberculosis. If latent tuberculosis is identified, treatment must be started according to local national guidelines before randomization.

[0415] 29. Known infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C at screening or randomization.

[0416] 30. History of lymphoproliferative disease or any known malignancy or malignancy of any organ system within the past 5 years (except basal cell carcinoma or actinic keratosis treated within the past 3 months with no evidence of recurrence, excised cervical carcinoma in situ, or non-invasive malignant colon polyps).

[0417] 31. Received a live vaccine within 6 weeks prior to baseline or planned to receive a vaccine during study participation until 12 weeks after the last dose of study treatment.

[0418] 32. Currently suffering from a serious progressive or uncontrolled disease that the clinical investigator believes makes the patient unsuitable for participation in the trial.

[0419] 33. Any medical or psychiatric illness that, in the opinion of the investigator, would prevent the patient from complying with the protocol or completing the study as per the protocol.

[0420] 34. Donated blood or lost 400 mL or more of blood within 8 weeks before randomization.

[0421] 35. History or evidence of persistent alcohol or drug abuse within 6 months prior to randomization.

[0422] 36. MRA imaging sub-study specific: absolute contraindications to MRA (e.g., metal implants, metal foreign bodies, pacemakers, defibrillators) and use of gadolinium-based drugs (e.g., patients with severe renal failure, patients with previous severe allergic / anaphylactic reactions to gadolinium-based contrast media); patients with severe renal disease [Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR < 30 mL / min / 1.73 m 2 ] or acute deterioration of renal function, who may be at risk for nephrogenic systemic fibrosis.

[0423] treat

[0424] Study Treatment

[0425] Study drug and comparator drug

[0426] Each study site will be provided with study treatment in identical-looking packaging by Novartis. The study treatment packaging has a 2-part label. Each part of this label is printed with a unique randomization number that corresponds to either placebo or active treatment.

[0427] Figure 8 An overview of study treatment administration is shown. During Treatment Period 1 (Baseline to Week 56 Initial Dose), site staff will administer all secukinumab and placebo to participants. The Week 56 dose will also be administered at the site.

[0428] For dosing during Treatment Period 2 (Week 56 dosing to Week 108), participants may elect to administer at home starting at Week 60, provided that participants receive adequate training on the procedure. However, if participants wish to come to the site for study drug administration, they may do so. At Week 56, site staff will administer study treatment on site and dispense study drug product for home administration for the next two months of study treatment. All participants will have a site visit every 2-3 months from Week 56 until the end of the study.

[0429] The PFS is packaged in a double-blind fashion and requires no preparation. Study treatment will be labeled as follows:

[0430] Double-blind secukinumab and placebo prefilled syringes (PFS), labeled “AIN457 300 mg / 2 mL / placebo”.

[0431] Participants will also receive ≥20 mg / day of prednisone in an open-label fashion and a decreasing dose regimen of <20 mg / day in a double-blind fashion from baseline to Week 52. Site staff will provide participants with prednisone at the study site visit and provide them with enough prednisone to take at home during the study visit.

[0432] Table 0-3 Study and control drugs

[0433]

[0434] Additional study treatment

[0435] Prednisone from baseline

[0436] Participants will be offered prednisone as part of a GC taper regimen starting at baseline. Superencapsulated prednisone tablets of varying strengths (1 mg, 2.5 mg, 5 mg, 20 mg) and placebo tablets will be combined into blister packs (4 blisters per day) to meet the daily dose requirements of the taper prescribed based on the treatment group to which the participant was randomized (secukinumab or placebo). Superencapsulation allows for blinding of the daily prednisone dose, which will need to be initiated when the prednisone dose is <20 mg / day. Although superencapsulated tablets will also be combined into blister packs for a total daily dose ≥20 mg / day, the investigator and participant will be aware of the dose.

[0437] Treatment arm / group

[0438] Approximately 240 participants will be randomized in a 2:1 (secukinumab:placebo) ratio to one of the following 2 treatment arms.

[0439] Group 1: 300 mg of secukinumab (2 mL) subcutaneously + 26 weeks of prednisone taper

[0440] Group 2: Subcutaneous placebo (2 ml) + 52 weeks of prednisone reduction regimen

[0441] Stratification: To achieve a balanced distribution of baseline prednisone doses in each treatment arm, randomization will be stratified at baseline according to participant's GCA status (new-onset or recurrent GCA) and baseline prednisone dose (>30 mg / day and ≤30 mg / day prednisone).

[0442] Treatment Period 1 (Baseline to Week 56 Initial Dosing): Participants will receive secukinumab or placebo at baseline, Weeks 1, 2, 3, and then every four weeks starting at Week 4 through Week 52 at the study site.

[0443] Participants will receive a combination of prednisone and secukinumab or prednisone and placebo from baseline to week 52 according to a prespecified prednisone taper schedule (26 weeks in the secukinumab arm; 52 weeks in the placebo arm).

[0444] Participants who do not achieve clinical remission by Week 12 or who experience a clinical relapse of GCA after achieving clinical remission will enter an out-of-pocket therapy. Participants on out-of-pocket therapy will receive a GC (prednisone or prednisone equivalent) at a dose determined by the investigator based on standard of care and continue on their original randomized, double-blind study treatment. Alternatively, at the discretion of the investigator, participants may discontinue study treatment and receive rescue therapy (alternative treatment for GCA). Participants on out-of-pocket or rescue therapy will continue to attend all subsequent scheduled visits and assessments.

[0445] Treatment Period 2 (dosing from Week 56 to Week 108): Beginning at Week 56, during Treatment Period 2, participants will receive further treatment based on their clinical remission status as follows:

[0446] Participants in sustained clinical remission at Week 56 (defined as those who achieved clinical remission at Week 52 and did not relapse until Week 56) will continue to receive study treatment as follows until the end of Treatment Period 2 at Week 108

[0447] Participants initially randomized to receive secukinumab will be re-randomized in a 1:1 ratio to receive either 300 mg secukinumab or placebo subcutaneously q4w in a double-blind fashion.

[0448] Participants initially randomized to receive placebo will continue to receive placebo in a blinded manner.

[0449] If participants experience clinical relapse during Treatment Period 2, they will be offered 300 mg OL secukinumab subcutaneously. Treatment initiation with OL secukinumab will be similar to secukinumab treatment in Treatment Period 1, administered weekly (qw) for the first 4 weeks and then every 4 weeks (q4w) starting 4 weeks after the first dose. GC will be administered per standard of care, at a dose determined by the investigator.

[0450] Participants who experience clinical relapse and subsequently do not achieve clinical remission within 12 weeks after starting OL secukinumab or who experience clinical relapse while on OL secukinumab during Treatment Period 2 will discontinue OL secukinumab and attend the EOT and EOS visits. The investigator will determine further treatment based on standard of care.

[0451] Participants who do not achieve sustained clinical remission at Week 56 (including those receiving exit therapy) will receive 300 mg OL secukinumab subcutaneously starting at Week 56:

[0452] Treatment initiation for OL secukinumab will be similar to that for the secukinumab treatment group, administered weekly (qw) for the first 4 weeks, then every 4 weeks (q4w) starting 4 weeks after the first dose. Participants will also receive GC at a dose determined by the investigator based on standard of care.

[0453] Participants who do not achieve clinical remission within 12 weeks after starting OL secukinumab or who experience clinical relapse after starting OL secukinumab during Treatment Period 2 will discontinue OL secukinumab and attend the EOT and EOS visits. Further treatment will be determined by the investigator.

[0454] Duration of treatment

[0455] The planned maximum duration of study treatment in this study is 108 weeks, with the last dose in the study occurring at Week 104. Participants may discontinue study treatment early as described above or due to unacceptable toxicity, disease progression, and / or at the discretion of the investigator or participant.

[0456] Post-trial visit

[0457] Participants on blinded study treatment (secukinumab or placebo) at Week 108: Participants receiving blinded study treatment and in sustained clinical remission at Week 108 (i.e., study treatment alone without concomitant GC) will complete treatment (last dose at Week 104), complete the EOT visit at Week 108, and complete the EOS visit at Week 116. For participants who are deemed by the investigator to derive clinical benefit from post-trial secukinumab according to standard practice, every effort will be made to offer OL secukinumab in accordance with local laws and regulations. For participants who start OL secukinumab after completing study treatment, the Week 116 EOS visit will be waived.

[0458] Participants on OL Secukinumab at Week 108: Participants on OL Secukinumab at Week 108 will complete treatment (last dose at Week 104), complete the EOT visit at Week 108, and complete the EOS visit at Week 116. For participants who the investigator believes are still receiving clinical benefit from OL secukinumab, every effort will be made to continue to offer OL secukinumab in accordance with local laws and regulations. If post-trial access to OL secukinumab is offered, the Week 116 EOS visit will be waived. For participants who have not received 12 weeks of OL secukinumab, the investigator will assess whether the participant is receiving clinical benefit from OL secukinumab and should continue treatment in the post-trial access.

[0459] Other treatments

[0460] Concomitant therapy

[0461] All medications, procedures, and significant non-pharmacological therapies (including physical therapy and blood transfusions) administered to participants after they enter the study must be recorded on the appropriate Case Report Form (CRF).

[0462] Each concomitant medication must be individually evaluated for all exclusion criteria / contraindicated medications. If in doubt, the investigator should contact the Novartis Medical Monitor prior to randomizing a participant or allowing initiation of a new medication. If a participant is already enrolled, contact Novartis to determine if the participant should continue in the study.

[0463] Concomitant treatments permitted that require caution and / or action

[0464] Methotrexate (MTX)

[0465] Participants who were taking MTX (≤25 mg / week) at the start of the study could continue taking the medication provided they had been taking it for at least 3 months and maintained a stable dose for at least 4 weeks before randomization and throughout the study.

[0466] Participants taking MTX were required to take folic acid supplements before randomization and during the trial to minimize the potential for MTX-related toxicity.

[0467] Vitamin D

[0468] Given the use of corticosteroids in all treatment arms, vitamin D (daily dose of 1000 I.U.) and calcium supplementation were strongly recommended during the study period to prevent osteoporosis.

[0469] References

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Claims

1. A method for treating giant cell arteritis, comprising subcutaneously administering to a patient in need thereof about 150 mg to about 300 mg of an IL-17 antibody or an antigen-binding fragment thereof, wherein the IL-17 antibody or the 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 on one chain, and Tyr43, Tyr44, Arg46, Ala79, Asp80 on the other chain, wherein the IL-17 antibody or the antigen-binding fragment thereof has a K of about 100-200 pM for human IL-17 D , and wherein the IL-17 antibody or antigen-binding fragment thereof has an in vivo half-life of about 4 weeks.

2. The method of claim 1, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient as a loading dose.

3. The method of claim 1 or 2, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient as a weekly loading dose.

4. The method of claim 3, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient during weeks 0, 1, 2, 3, and 4.

5. The method of claim 1, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient every two weeks or every four weeks.

6. The method of claim 5, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient for a total treatment duration of at least 26 weeks, or at least 52 weeks, or at least 2 years.

7. The method of any one of the preceding claims, wherein the patient is administered an IL-17 antibody or antigen-binding fragment thereof as a weekly loading dose during weeks 0, 1, 2, 3 and 4 and every two weeks thereafter or every four weeks thereafter.

8. The method of claim 3, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient weekly during weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter.

9. The method of claim 8, wherein the IL-17 antibody or antigen-binding fragment thereof is administered to the patient during weeks 0, 1, 2, 3, 4, 8, and 12.

10. The method of claim 8, wherein the patient is administered an IL-17 antibody or antigen-binding fragment thereof weekly during weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter, for a total treatment duration of at least 26 weeks, at least 52 weeks, or at least 2 years.

11. The method of any of the above claims, wherein prior to treatment with the IL-17 antibody or antigen-binding fragment thereof, the patient has not responded, has had an inadequate response, or has been intolerant to a previous GCA treatment selected from the group consisting of treatment with a corticosteroid such as prednisone, prednisolone, or methylprednisolone, treatment with a TNF-α inhibitor, treatment with an IL-6 inhibitor, treatment with methotrexate, and combinations thereof.

12. The method of any of the above claims, wherein treatment with the IL-17 antibody or antigen-binding fragment thereof reduces the dose of corticosteroids sufficient to induce or maintain effective GCA treatment or GCA remission.

13. The method of any of the above claims, wherein the method comprises therapeutically effectively treating GCA without the use of corticosteroids; and / or wherein the method induces or maintains remission in GCA without the use of concomitant corticosteroid therapy.

14. The method of claim 13, wherein treatment with the IL-17 antibody or antigen-binding fragment thereof increases the time before a flare in the patient, wherein a flare is indicated by signs or symptoms of GCA and / or an erythrocyte sedimentation rate (ESR) ≥ 30 mm / hr and / or CRP ≥ 10 mg / L.

15. The method of any of the above claims, wherein the patient has a reduced cumulative corticosteroid dose after 28 weeks, or 52 weeks, or 2 years of treatment with the IL-17 antagonist compared to patients receiving treatment according to standard of care (SoC).

16. The method of any of the above claims, wherein the patient has active GCA, newly diagnosed GCA, or recurrent GCA.

17. The method of any of the above claims, wherein the use of the IL-17 antibody or antigen-binding fragment thereof and a corticosteroid dose equivalent to ≤ 5 mg / day of prednisolone is effective to treat the patient's GCA.

18. The method of claim 17, wherein treatment with the IL-17 antibody or antigen-binding fragment thereof induces an improvement in one or more clinical assessments selected from the group consisting of: Physician Global Assessment (PhGA) Visual Analog Scale (VAS); Patient Reported Outcomes (PROs); Patient Global Assessment (PGA) VAS; Functional Assessment of Chronic Disease Therapy-Fatigue (FACIT-Fatigue); Short Form 36 (SF36); and EuroQoL 5D (EQ-5D); and / or wherein the patient exhibits a reduction in vascular inflammation by ultrasound and / or MRI, e.g., wherein the reduction in vascular inflammation is greater than the reduction achieved without treatment with the IL-17 antibody or antigen-binding fragment thereof, greater than the reduction achieved with treatment with a corticosteroid alone or in combination with an IL-6 or TNF-α inhibitor, or greater than the reduction achieved with treatment with an IL-6 or TNF-α inhibitor.

19. The method according to any one of the above claims, wherein the IL-17 antibody or antigen-binding fragment thereof comprises: i) an immunoglobulin heavy chain variable domain (V H ); ii) an immunoglobulin light chain variable domain (V L ); iii) an immunoglobulin V comprising the amino acid sequence shown in SEQ ID NO: 8 H domain and an immunoglobulin V comprising the amino acid sequence shown in SEQ ID NO: 10 L Structural domain; iv) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 H Structural domain; v) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L Structural domain; vi) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H Structural domain; vii) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3 H Domains and immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L Structural domain; viii) an immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 11, SEQ ID NO: 12 and SEQ ID NO: 13 H Domains and immunoglobulin V comprising the hypervariable regions shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6 L Structural domain; ix) an immunoglobulin light chain comprising the amino acid sequence shown in SEQ ID NO: 14; x) an immunoglobulin heavy chain comprising the amino acid sequence shown in SEQ ID NO: 15; or xi) an immunoglobulin light chain comprising the amino acid sequence shown in SEQ ID NO: 14 and an immunoglobulin heavy chain comprising the amino acid sequence shown in SEQ ID NO:

15.

20. The method of claim 19, wherein the IL-17 antibody or antigen-binding fragment thereof is secukinumab.

21. A method of treating a patient with active GCA comprising administering to the patient about 300 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4 and every four weeks thereafter.

22. A method of treating a patient with active GCA comprising administering to the patient about 300 mg of secukinumab by subcutaneous injection at weeks 0, 1, 2, 3, and 4 and every four weeks thereafter for a total treatment duration of at least 52 weeks.

23. The method of any one of claims 1 to 22, wherein the patient is at least 50 years old.

24. The method of any one of claims 1 to 23, wherein, for example, prior to treatment, the patient has active GCA as indicated by: unequivocal cranial symptoms of GCA; a temporal artery biopsy (TAB) revealing features of GCA and / or a cross-sectional imaging study with evidence of vasculitis, such as ultrasound (e.g., cranial or axillary), MRA, CTA, or PET-CT.

25. The method of any one of claims 1 to 24, wherein the patient has an elevated erythrocyte sedimentation rate (ESR) of ≥30 mm / hr or a C-reactive protein (CRP) of ≥10 mg / L, e.g., prior to treatment, due to active GCA or active GCA shown on TAB or imaging studies.

26. The method of any one of claims 1 to 24, wherein the method comprises administering a corticosteroid (eg, prednisone or prednisolone) during the first 26 weeks of treatment.

27. The method of claim 26, wherein the method comprises gradually reducing the dose of the corticosteroid during the first 26 weeks of treatment.

28. The method of any one of claims 1 to 27, wherein the method comprises administering a loading dose of 150 mg of secukinumab once weekly at weeks 0, 1, 2, 3, and 4, and a maintenance dose of secukinumab monthly, every four weeks, or every two weeks thereafter.

29. The method of claim 28, wherein the maintenance dose is 150 mg of secukinumab.

30. The method of claim 28, wherein the maintenance dose is 150 mg of secukinumab administered every four weeks.

31. The method of any one of claims 1 to 27, wherein the method comprises administering a loading dose of 300 mg of secukinumab once weekly at weeks 0, 1, 2, 3, and 4, and a maintenance dose of secukinumab monthly, every four weeks, or every two weeks thereafter.

32. The method of claim 28, wherein the maintenance dose is 300 mg of secukinumab.

33. The method of claim 28, wherein the maintenance dose is 300 mg of secukinumab administered every four weeks.

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