Dosage and Administration of Anti-C5 Antibodies for Treating Dermatomyositis (DM)

Abstract

Dosages and methods are provided for the clinical treatment of dermatomyositis (DM), particularly severe and / or refractory DM, in human patients with an anti-C5 antibody or antigen-binding fragment thereof, such as ravulizumab (ULTOMIRIS®).

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 210,280, filed June 14, 2021, the contents of which are incorporated by reference herein in their entirety.

[0002] Sequence Listing This application has been submitted electronically in ASCII format and contains a Sequence Listing, which is incorporated herein by reference in its entirety. Said ASCII copy, created on April 22, 2022, is named 0662WO_SL.txt and is 54,103 bytes in size. [Background technology]

[0003] Complement-mediated injury has been implicated in the pathology of dermatomyositis (DM), a disorder characterized by a distinct skin rash and muscle weakness (see, e.g., Dalakas MC, N. Engl. J. Med. 2015; 372(18): 1734-1747; Isak V, et al., J. Dermatolog. Treat. 2018; 29(5): 450-459; and Mahil S. et al., Br. J. Hosp. Med. (Lond). 2012; 73(2): C18-22). Patients with DM typically present with proximal muscle weakness and skin signs that develop over months or years (see, e.g., Selva-O'Callaghan A, et al., The Lancet Neurology, 2018; 17(9): 816-828). Muscle biopsies from patients with DM have revealed the presence of membrane attack complexes (MACs) on endothelial cells of endomysial capillaries (see, e.g., Dalakas MC, et al., Nat. Rev. Neurol. 2020;16(11):601-617 and Kissel JT, et al., N. Engl. J. Med. 1986;314(6):329-334). Currently, there are only three therapies approved for the treatment of DM: azathioprine, corticotropin injections, and glucocorticoids. However, despite therapy, approximately one-third of patients with DM remain mildly to severely disabled (see, e.g., Dalakas MC, et al., Lancet. 2003; 362(9388): 971-982), and half of patients considered stable do not return to their previous level of performance (see, e.g., Marie I, et al., J. Rheumatol. 2001; 28(10): 2230-2237). It is therefore an object of the present disclosure to provide improved methods for treating patients with DM. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Dalakas MC, N. Engl. J. Med. 2015; 372(18): 1734 - 1747

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Summary of the Invention

Means for Solving the Problems

[0005] The present disclosure is based, in part, on the insight that treating patients with ravulizumab (ALXN1210; ULTOMIRIS) achieves inhibition of terminal complement (C5) and concomitantly reduces terminal complement-mediated damage to skin tissue. The inventors' insight is based, in part, on knowledge of the pharmacodynamic (PD) effect of ravulizumab on terminal complement in vivo and the identification of the involvement of the membrane attack complex (MAC) in the pathophysiology of dermatomyositis (DM). The present disclosure specifically relates to a new therapeutic role of ravulizumab in improving clinical signs of DM in patients, in particular the efficacy of ravulizumab in reducing muscle weakness and / or skin signs in patients with severe and / or refractory DM. Provided herein are compositions and methods for treating dermatomyositis (DM) in a human patient (e.g., an adult patient) comprising administering to the patient an anti-C5 antibody or antigen-binding fragment thereof, where the anti-C5 antibody or antigen-binding fragment thereof is administered (or is for administration) according to a specific clinical dosing regimen (e.g., at a specific dose according to a specific dosing schedule). The compositions and methods of the present disclosure are particularly useful for treating severe and / or refractory dermatomyositis.

[0006] An exemplary anti-C5 antibody is ravulizumab (ULTOMIRIS®), which comprises heavy and light chains having the sequences set forth in SEQ ID NOs: 14 and 11, respectively, or antigen-binding fragments and variants thereof. In other embodiments, the antibody comprises the heavy and light chain complementarity determining regions (CDRs) or variable regions (VRs) of ravulizumab. Thus, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the heavy chain variable (VH) region of ravulizumab having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the light chain variable (VL) region of ravulizumab having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises the CDR1, CDR2 and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and the CDR1, CDR2 and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5 and 6, respectively. In another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively. In another embodiment, the antibody comprises the heavy chain constant region set forth in SEQ ID NO:13.

[0007] In another embodiment, the antibody comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, of native human IgG Fc constant region according to EU numbering convention.

[0008] In another embodiment, the antibody comprises the CDR1, CDR2 and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and the CDR1, CDR2 and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5 and 6, respectively, and a mutant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the mutant human Fc CH3 constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, of native human IgG Fc constant region according to EU numbering convention.

[0009] In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see U.S. Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody (see U.S. Patent No. 9,765,135). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody (clovalimab). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the REGN3918 antibody (pozelimab). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of the LFG316 antibody (tesidormab). In another embodiment, the anti-C5 antibody comprises the heavy and light chain CDRs or variable regions of eculizumab or a biosimilar antibody thereof (e.g., ABP959; SB12 or Elizaria).

[0010] In one embodiment, the dose of anti-C5 antibody or antigen-binding fragment thereof is based on the patient's weight. In one embodiment, for example, 900 mg, 1200 mg, 2400 mg, 2700 mg, 3000 mg, 3300 mg, or 3600 mg of anti-C5 antibody or antigen-binding fragment thereof is administered based on the patient's weight. In another embodiment, 900 mg and / or 2100 mg of anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing <30 kg. In another embodiment, 1200 mg and / or 2700 mg of anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧30 to <40 kg. In another embodiment, 2400 mg and / or 3000 mg of anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧40 to <60 kg. In another embodiment, 2700 mg and / or 3300 mg of anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧60 to <100 kg. In another embodiment, 3000 mg and / or 3600 mg of anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧100 kg. In certain embodiments, the dosing regimen is adjusted to provide the optimal desired response (e.g., an effective response).

[0011] In another embodiment, a method of treating a human patient with DM is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises: (a) in patients weighing <30 kg, a loading dose of 900 mg, followed after 2 weeks by a maintenance dose of 2100 mg, then once every 8 weeks thereafter; (b) for patients weighing ≥30 to <40 kg, a loading dose of 1200 mg, followed after 2 weeks by a maintenance dose of 2700 mg, then once every 8 weeks thereafter; (c) for patients weighing ≥40 to <60 kg, a loading dose of 2400 mg, followed after 2 weeks by a maintenance dose of 3000 mg, then once every 8 weeks thereafter; (d) for patients weighing ≥ 60 to < 100 kg, a loading dose of 2700 mg, followed after 2 weeks by a maintenance dose of 3300 mg, then once every 8 weeks thereafter; or (e) Patients weighing ≧100 kg will be administered a loading dose of 3000 mg, followed two weeks later by a maintenance dose of 3600 mg, then once every eight weeks thereafter.

[0012] In another embodiment, a method of treating a human patient with DM is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises: (a) for patients weighing <30 kg, a loading dose of 900 mg on day 1, followed by a maintenance dose of 2100 mg on day 15, then once every 8 weeks thereafter; (b) for patients weighing ≥30 to <40 kg, a loading dose of 1200 mg on day 1, followed by a maintenance dose of 2700 mg on day 15, then once every 8 weeks thereafter; (c) for patients weighing ≥40 to <60 kg, a loading dose of 2400 mg on day 1, followed by a maintenance dose of 3000 mg on day 15, then once every 8 weeks thereafter; (d) for patients weighing ≥ 60 to < 100 kg, a loading dose of 2700 mg on day 1, followed by a maintenance dose of 3300 mg on day 15, then once every 8 weeks thereafter; or (e) Patients weighing ≧100 kg will be administered a loading dose of 3000 mg on day 1, followed by a maintenance dose of 3600 mg on day 15, then once every 8 weeks thereafter.

[0013] In another embodiment, a method of treating a human patient with DM is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of a native human IgG Fc constant region, wherein the anti-C5 antibody or antigen-binding fragment thereof is: (a) in patients weighing <30 kg, a loading dose of 900 mg, followed after 2 weeks by a maintenance dose of 2100 mg, then once every 8 weeks thereafter; (b) for patients weighing ≥30 to <40 kg, a loading dose of 1200 mg, followed after 2 weeks by a maintenance dose of 2700 mg, then once every 8 weeks thereafter; (c) for patients weighing ≥40 to <60 kg, a loading dose of 2400 mg, followed after 2 weeks by a maintenance dose of 3000 mg, then once every 8 weeks thereafter; (d) for patients weighing ≥ 60 to < 100 kg, a loading dose of 2700 mg, followed after 2 weeks by a maintenance dose of 3300 mg, then once every 8 weeks thereafter; or (e) Patients weighing ≧100 kg will be administered a loading dose of 3000 mg, followed two weeks later by a maintenance dose of 3600 mg, then once every eight weeks thereafter.

[0014] In another embodiment, a method of treating a human patient with DM is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of a native human IgG Fc constant region, wherein the anti-C5 antibody or antigen-binding fragment thereof is: (a) for patients weighing <30 kg, a loading dose of 900 mg on day 1, followed by a maintenance dose of 2100 mg on day 15, then once every 8 weeks thereafter; (b) for patients weighing ≥30 to <40 kg, a loading dose of 1200 mg on day 1, followed by a maintenance dose of 2700 mg on day 15, then once every 8 weeks thereafter; (c) for patients weighing ≥40 to <60 kg, a loading dose of 2400 mg on day 1, followed by a maintenance dose of 3000 mg on day 15, then once every 8 weeks thereafter; (d) for patients weighing ≥ 60 to < 100 kg, a loading dose of 2700 mg on day 1, followed by a maintenance dose of 3300 mg on day 15, then once every 8 weeks thereafter; or (e) Patients weighing ≧100 kg will be administered a loading dose of 3000 mg on day 1, followed by a maintenance dose of 3600 mg on day 15, then once every 8 weeks thereafter.

[0015] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing <30 kg at a loading dose of 900 mg, followed two weeks later by a maintenance dose of 2100 mg, and then once every eight weeks thereafter.

[0016] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing ≧30 to <40 kg at a loading dose of 1200 mg, followed two weeks later by a maintenance dose of 2700 mg, and then once every eight weeks thereafter.

[0017] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing ≧40 to <60 kg at a loading dose of 2400 mg, followed two weeks later by a maintenance dose of 3000 mg, and then once every 8 weeks thereafter.

[0018] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing ≧60 to <100 kg at a loading dose of 2700 mg, followed two weeks later by a maintenance dose of 3300 mg, and then once every eight weeks thereafter.

[0019] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing > 100 kg at a loading dose of 3000 mg on day 1, followed by a maintenance dose of 3600 mg on day 15, then once every 8 weeks thereafter.

[0020] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing <30 kg at a loading dose of 900 mg on day 1, followed by a maintenance dose of 2100 mg on day 15, then once every 8 weeks thereafter.

[0021] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing ≧30 to <40 kg at a loading dose of 1200 mg on day 1, followed by a maintenance dose of 2700 mg on day 15, and then once every 8 weeks thereafter.

[0022] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing ≧40 to <60 kg at a loading dose of 2400 mg on day 1, followed by a maintenance dose of 3000 mg on day 15, and then once every 8 weeks thereafter.

[0023] In another embodiment, a method is provided for treating a human patient with DM in which an anti-C5 antibody is administered to a patient weighing ≧60 to <100 kg at a loading dose of 2700 mg on day 1, followed by a maintenance dose of 3300 mg on day 15, and so on once every 8 weeks thereafter.

[0024] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing > 100 kg at a loading dose of 3000 mg, followed by a maintenance dose of 3600 mg on day 15, then once every 8 weeks thereafter.

[0025] In one embodiment, the patient has not been previously treated with eculizumab, hi another embodiment, the patient has been previously treated with eculizumab.

[0026] In another aspect, the described treatment regimen is sufficient to maintain a particular serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof. In one embodiment, for example, the treatment regimen is sufficient to maintain a particular serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof for 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 78 maintains a serum trough concentration of 25, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 μg / mL or greater. In one embodiment, the treatment regimen maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof of 100 μg / mL or greater, 150 μg / mL or greater, 200 μg / mL or greater, 250 μg / mL or greater, or 300 μg / mL or greater. In another embodiment, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen-binding fragment thereof of between 100 μg / mL and 200 μg / mL. In another embodiment, the treatment maintains a serum trough concentration of anti-C5 antibody or antigen-binding fragment thereof of about 175 μg / mL.

[0027] In another embodiment, to obtain an effective response, the anti-C5 antibody is administered at least 50 μg, 55 μg, 60 μg, 65 μg, 70 μg, 75 μg, 80 μg, 85 μg, 90 μg, 95 μg, 100 μg, 105 μg, 110 μg, 115 μg, 120 μg, 125 μg, 130 μg, 135 μg, 140 μg, 145 μg, The patient is administered an amount and frequency to maintain 150 μg, 155 μg, 160 μg, 165 μg, 170 μg, 175 μg, 180 μg, 185 μg, 190 μg, 195 μg, 200 μg, 205 μg, 210 μg, 215 μg, 220 μg, 225 μg, 230 μg, 235 μg, 240 μg, 245 μg, 250 μg, 255 μg, or 260 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain 50 μg to 250 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency to maintain 100 μg to 200 μg of antibody per milliliter of blood. In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains the patient at about 175 μg of antibody per milliliter of blood.

[0028] In another embodiment, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains a minimum free C5 concentration to obtain an effective response. In one embodiment, for example, the anti-C5 antibody is administered to the patient in an amount and frequency that maintains a free C5 concentration of 0.5 μg / mL or less (e.g., 0.4 μg / mL, 0.3 μg / mL, 0.2 μg / mL, or 0.1 μg / mL or less).

[0029] The anti-C5 antibody or antigen-binding fragment thereof can be administered to the patient by any suitable means. In one embodiment, the antibody is formulated for intravenous administration.

[0030] The efficacy of the therapeutic methods provided herein can be assessed using any suitable means. In one embodiment, the treatment results in a shift in soluble C5b-9 towards normal levels.

[0031] In another embodiment, treatment results in a shift in myositis-specific autoantibodies (e.g., anti-melanoma differentiation-associated protein 5 antibodies (anti-MDA5 antibodies), anti-nuclear matrix protein 2 antibodies (anti-NXP2 / MJ antibodies), and / or anti-synthetase / Jo1 antibodies) to normal levels.

[0032] In another embodiment, treatment results in a shift in muscle enzymes (e.g., creatine kinase (CK), aldolase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)) to normal levels.

[0033] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by the International Myositis Assessment and Clinical Trials Total Improvement Scale (IMACS-TIS). In one embodiment, the treatment results in a Total Improvement Score (TIS) of at least > 20, 25, 30, 35, 40, 45, 50, 55, or 60 points compared to baseline as assessed by the IMACS-TIS score.

[0034] In another embodiment, treatment results in an improvement in the patient compared to baseline as assessed by the Dermatomyositis Skin Disease Area and Severity Index (CDASI).

[0035] In another embodiment, the treatment results in a ≧7, 8, 9, 10, 11, or 12 point improvement in the patient compared to baseline as assessed by the CDASI.

[0036] In another embodiment, the treatment results in an improvement in the patient as assessed by the European Quality of Life-Health 5-item Questionnaire Dimension 5 Level (EQ-5D-5L) score compared to baseline.

[0037] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by Patient-Reported Outcomes Measurement Information System (PROMIS).

[0038] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by the Short-Form Health Survey (36-question version) (SF36).

[0039] In another embodiment, treatment results in an improvement in the patient compared to baseline as assessed by the Dermatomyositis Disease Symptom Questionnaire (DM-DSQ).

[0040] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by the 30 second chair stand test (30sCST).

[0041] In another embodiment, the treatment results in a reduction in the patient's detectable rash compared to baseline as assessed by photographic analysis, hi one embodiment, the treatment results in a 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% reduction in the patient's detectable rash compared to baseline as assessed by photographic analysis.

[0042] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by the 5D Itch Scale.

[0043] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by handheld dynamometry performance analysis.

[0044] In another embodiment, the treatment provides an improvement in the patient compared to baseline as assessed by the Functional Assessment of Chronic Therapy (FACIT)-Fatigue score.

[0045] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by an 8-muscle manual muscle testing subset (MMT8).

[0046] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by the Myositis Disease Activity Assessment Tool (MDAAT).

[0047] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by Physician Global Activity Assessment.

[0048] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by Patient Global Activity Assessment.

[0049] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by a Health Assessment Questionnaire (HAQ).

[0050] In another embodiment, the treatment provides an improvement in the patient compared to baseline as assessed by Physician's Global Assessment of Dermatomyositis Skin Activity.

[0051] In another embodiment, treatment results in a reduction or cessation of the patient's rash and / or muscle weakness.

[0052] In another embodiment, the treatment provides terminal complement inhibition.

[0053] In another embodiment, treatment results in a reduction in adverse events.

[0054] In another embodiment, the patient has, prior to treatment, MMT-8≦142 / 150 and two or more of the following: a) Patient Global Activity Assessment of ≥ 2.0 cm on a 10 cm VAS b) Physician global activity assessment of ≥2.0 cm on a 10 cm VAS c) HAQ disability index ≥ 0.25 d) at least one muscle enzyme is elevated ≥ 1.3 times the upper limit of normal (ULN); and / or e) Global Extramuscular Disease Activity Score of ≥ 2.0 cm on a 10 cm visual analog scale (VAS) has.

[0055] In one embodiment, the global extramuscular disease activity score is based on assessment of activity scores on the total body, skin, skeletal, gastrointestinal, pulmonary, and cardiac scales of the MDAAT.

[0056] In another embodiment, the patient, prior to treatment, has one or more of the following: a) Muscle or skin biopsy with evidence of active pathology of DM within the past 6 months prior to or at the time of treatment initiation; b) electromyography evidence of active myositis within the past 6 months prior to or at the time of treatment initiation; c) muscle evidence of active myositis on magnetic resonance imaging (MRI) within the past 6 months prior to or at the time of treatment initiation; d) at least one muscle enzyme (e.g., CK, aldolase, LDH, ALT, and / or AST) in the IMACS panel ≥2x the ULN prior to or at the start of treatment; and / or e) Active DM rash characterized by inflammatory changes (CDASI activity score ≥ 7) before or at the start of treatment has.

[0057] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof is administered alone. In other embodiments, the anti-C5 antibody or antigen-binding fragment thereof is administered in combination (e.g., simultaneously or separately) with one or more additional therapeutic agents. In one embodiment, the treatment further comprises administering azathioprine. In another embodiment, the treatment further comprises administering cyclosporine. In another embodiment, the treatment further comprises administering a glucocorticoid. In another embodiment, the treatment further comprises administering an intramuscular glucocorticoid. In another embodiment, the treatment further comprises administering hydroxychloroquine. In another embodiment, the treatment further comprises administering leflunomide. In another embodiment, the treatment further comprises administering methotrexate. In another embodiment, the treatment further comprises administering mycophenolate mofetil / mycophenolic acid. In another embodiment, the treatment further comprises administering sulfasalazine. In another embodiment, the treatment further comprises administering an antihistamine. In another embodiment, the treatment further comprises administering ibuprofen. In another embodiment, the treatment further comprises administering acetaminophen. In another embodiment, the treatment further comprises administering an anti-pruritic agent. In another embodiment, the treatment further comprises administering a topical steroid. In another embodiment, the treatment further comprises administering vitamin B12. In another embodiment, the treatment further comprises administering vitamin E. In another embodiment, the treatment further comprises administering creatine. In another embodiment, the treatment further comprises administering coenzyme Q10. In another embodiment, the treatment further comprises administering a biotin supplement.

[0058] In one embodiment, the patient has not previously taken or is not currently taking any of the following at the start of or during treatment: intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), IV glucocorticoids, corticotropin injections, cyclophosphamide, rituximab, infliximab, adalimumab, etanercept, tofacitinib, ruxolitinib, or anakinra.

[0059] Further provided are kits comprising a pharmaceutical composition comprising a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof, such as ravulizumab, adapted for use in the methods described herein, and a pharma- ceutical acceptable carrier, optionally together with background therapy. In one embodiment, the kit comprises (a) a dose of an anti-C5 antibody or antigen-binding fragment thereof, comprising the CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8, and (b) instructions for using the anti-C5 antibody or antigen-binding fragment thereof in any of the methods described herein.

[0060] Also provided herein is an anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the sequence shown in SEQ ID NO: 12, and CDR1, CDR2, and CDR3 domains of a light chain variable region having the sequence shown in SEQ ID NO: 8, wherein the anti-C5 antibody or antigen-binding fragment thereof is (a) in patients weighing <30 kg, a loading dose of 900 mg, followed after 2 weeks by a maintenance dose of 2100 mg, then once every 8 weeks thereafter; (b) for patients weighing ≥30 to <40 kg, a loading dose of 1200 mg, followed after 2 weeks by a maintenance dose of 2700 mg, then once every 8 weeks thereafter; (c) for patients weighing ≥40 to <60 kg, a loading dose of 2400 mg, followed after 2 weeks by a maintenance dose of 3000 mg, then once every 8 weeks thereafter; (d) for patients weighing ≥ 60 to < 100 kg, a loading dose of 2700 mg, followed after 2 weeks by a maintenance dose of 3300 mg, then once every 8 weeks thereafter; or (e) Patients weighing ≧100 kg will be administered a loading dose of 3000 mg, followed two weeks later by a maintenance dose of 3600 mg, then once every eight weeks thereafter.

[0061] In some embodiments, the present disclosure relates to a composition, e.g., a pharmaceutical composition or a medicament, comprising an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR) comprising the HCDR1, HCDR2 and HCDR3 sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and a light chain complementarity determining region (LCDR) comprising the LCDR1, LCDR2 and LCDR3 sequences set forth in SEQ ID NOs: 4, 5 and 6, respectively, for use in treating DM in a human patient, the composition optionally including background therapy for treating DM. Specifically, provided herein is a composition comprising an effective amount of ravulizumab (ULTOMIRIS®) or an antigen-binding fragment thereof for treating DM in a human patient. In some embodiments, the effective amount includes the use of dosing and scheduling as described for anti-C5 antibodies, e.g., ravulizumab.

[0062] In further embodiments, the disclosure relates to the use of an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR) comprising HCDR1, HCDR2 and HCDR3 sequences as set forth in SEQ ID NOs: 19, 18 and 3, respectively, and a light chain complementarity determining region (LCDR) comprising LCDR1, LCDR2 and LCDR3 sequences as set forth in SEQ ID NOs: 4, 5 and 6, respectively, in the manufacture of a composition, e.g., a pharmaceutical composition or medicament, for treating DM in a human patient, the composition optionally including background therapy for the treatment of DM. Specifically, provided herein is the use of an effective amount of ravulizumab (ULTOMIRIS®) or an antigen-binding fragment thereof, in the manufacture of a composition, e.g., a pharmaceutical composition or medicament, for treating DM in a human patient, the composition optionally including background therapy for the treatment of DM. In some embodiments, the effective amount includes using the dosage and schedule described for an anti-C5 antibody, e.g., ravulizumab, optionally together with the dosage and schedule of background therapy. [Brief description of the drawings]

[0063] [Figure 1] FIG. 1 is a schematic showing the overall study design. [Diagram 2] A sample Physician Global Activity Assessment (IMACS Form 02). [Diagram 3] Sample Patient / Parent Global Activity Assessment (IMACS Form 03). [Figure 4] A sample Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire is shown. [Diagram 5] A sample Dermatomyositis Disease Symptom Questionnaire (DM-DSQ) is shown. [Figure 6-1] The timeline of activities for Part A (from screening to the end of the randomized control period) is shown. [Figure 6-2] Same as above. [Figure 6-3] Same as above. [Figure 6-4] Same as above. [Figure 6-5] Same as above. [Figure 6-6] Same as above. [Figure 7-1] Shows the timeline of Part B activities (from screening to the end of the randomized control period). [Figure 7-2] Same as above. [Figure 7-3] Same as above. [Figure 7-4] Same as above. [Figure 7-5] Same as above. [Figure 7-6] Same as above. [Figure 8-1] The timeline of activities for the open-label extension periods of Parts A and B is shown. [Figure 8-2] Same as above. [Figure 8-3] Same as above. [Figure 8-4] Same as above. [Figure 8-5] Same as above. [Figure 8-6] Same as above. [Figure 8-7] Same as above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0064] I. Definition As used herein, the term "subject" or "patient" refers to a human patient (eg, a patient with DM).

[0065] As used herein, the term "pediatric" patient is a human patient who has been classified by a physician or caregiver as belonging to a non-adult category and can include, for example, neonates (both preterm and full term), infants, children, and adolescents. Typically, a pediatric patient is a patient under the age of 18 (<18 years old).

[0066] As used herein, the term "adult" patient is a human patient who has been classified by a physician or caregiver based on, e.g., age, developmental state, physiological characteristics, etc., as someone who is not, e.g., a neonate, infant, child, or adolescent. Typically, an adult patient is a patient who is 18 years of age or older (≧18 years of age).

[0067] As used herein, dermatomyositis (DM) is an autoimmune idiopathic inflammatory disease characterized by a distinct skin rash and muscle weakness (see, e.g., Bendewald MJ, et al., Archives of dermatology. 2010; 146(1):26-30; Bohan A, et al., N. Engl. J. Med. 1975; 292(7):344-347; Dalakas MC, N. Engl. J. Med. 2015; 372(18):1734-1747; Isak V. et al., J. Dermatolog. Treat. 2018; 29(5):450-459; and Mahil S, et al., Br. J. Hosp. Med. (Lond). 2012; 73(2):C18-22). Patients with DM typically present with proximal muscle weakness and skin signs that develop over months or years (see, e.g., Selva-O'Callaghan A, et al., The Lancet Neurology. 2018; 17(9): 816-828). DM affects both children (juvenile DM) and adults, and more women than men (see, e.g., Dalakas MC, et al., Lancet; 2003; 362(9388): 971-982). In the United States, the incidence of DM is estimated to be 9.63 / million, with a bimodal distribution peaking at ages 5-15 and 50-60 (see, e.g., Bendewald MJ, et al., Archives of dermatology. 2010;146(1):26-30; Bohan A, Peter JB., N. Engl. J. Med. 1975;292(7):344-347; Isak V, et al., J. Dermatolog. Treat. 2018;29(5):450-459).Patients with DM typically develop gradual muscle weakness that makes it difficult to perform everyday tasks such as buttoning or holding things, combing their hair, getting up from a chair, climbing stairs, or lifting objects (see, e.g., Dalakas MC., N. Engl. J. Med. 2015;372(18):1734-1747; and Dalakas MC, Lancet. 2003;362(9388):971-982).

[0068] Organ systems such as the vascular, pulmonary, gastrointestinal, and cardiac systems can be involved, and rare cases of interstitial lung disease can be fatal (see, e.g., Ernste FC, et al., Mayo. Clin. Proc. 2013; 88(1):83-105). Adult patients with DM have a 9%-32% increased risk of cancer in the first 3-5 years after DM diagnosis (see, e.g., Dalakas MC., N. Engl. J. Med. 2015; 372(18):1734-1747). The most common cancers in women with DM are breast and ovarian cancer; whereas lung and prostate cancers are most common in men with DM (see, e.g., Ernste FC, et al., Mayo. Clin. Proc. 2013; 88(1):83-105).

[0069] Currently, azathioprine is approved for the treatment of DM in the EU. In the United States, glucocorticoids and corticotropin injections (Acthar® Gel) are the only available medications approved for the treatment of DM (see, e.g., Isak V, et al., J. Dermatolog Treat. 2018; 29(5): 450-459). Management of DM consists of glucocorticoids alone or in combination with immunosuppressive / immunomodulatory therapy (IST), including rituximab and IV immunoglobulin (IVIg) (see, e.g., Dalakas MC., N. Engl. J. Med. 2015; 372(18): 1734-1747). Long-term use of corticosteroids can lead to adverse complications such as osteoporosis, compression fractures, and avascular necrosis, and use of IST can increase the risk of serious infections and is associated with tolerance issues and even liver toxicity (see, e.g., Chandra T, et al., Expert Opin. Emerg. Drugs. 2020:1-16; and Ernste FC, et al., Mayo. Clin. Proc. 2013;88(1):83-105). Moreover, despite therapy, approximately one-third of patients with DM remain mildly to severely disabled (see, e.g., Dalakas MC, et al., Lancet. 2003; 362(9388): 971-982), and half of patients considered stable do not return to their previous level of performance (see, e.g., Marie I, et al., J Rheumatol. 2001; 28(10): 2230-2237). With available therapies, 5-year mortality has been reduced but remains approximately 25% (see, e.g., Rider LG, et al., JAMA. 2011a; 305(2): 183-190).

[0070] In summary, due to the currently limited number of treatment options available for patients with DM (especially those with severe and / or refractory DM), many clinical treatment decisions are made empirically and without adequate clinical data. Thus, there remains a high unmet medical need for effective and safe treatment options for this disease.

[0071] Chronic activation of the immune system by environmental risk factors in genetically predisposed individuals is believed to be the underlying cause of DM (see, e.g., Rider LG, et al., JAMA. 2011a; 305(2): 183-190). Environmental exposures including streptococci, echoviruses, human growth hormone, interferon-α, interferon-γ, bovine collagen implants, physical exertion, and ultraviolet light have been implicated in the development of DM. Genetic risk factors associated with an individual's susceptibility to DM include gene polymorphisms (e.g., polymorphisms in human leukocyte antigen [HLA] and cytokine and immunoglobulin genes) that are known to modulate the later response to environmental factors.

[0072] The pathogenesis of DM is thought to be triggered when autoantibodies against the endothelium of endomysial capillaries activate complement component 3 (C3) damage (see, e.g., Dalakas MC, et al., Lancet. 2003;362(9388):971-982), leading to complement-mediated damage to endothelial cells in myopathy (see, e.g., Dalakas MC, et al., Lancet. 2003;362(9388):971-982; and Mahil S, et al., Br. J. Hosp. Med. (Lond). 2012;73(2):C18-22), as well as MAC deposition in skin and muscle tissue (see, e.g., Magro CM, et al., J. Cutan. Pathol. 1997;24(9):543-552). This hypothesis is supported by the activation of the complement system as an early disease manifestation of DM (see, e.g., Pinal-Fernandez I, et al., J Rheumatol. 2015;42(8):1448-1454).

[0073] The complement pathways (classical, alternative, and lectin) all converge on C5. Activation of C5 cleaves this protein into complement components 5a and 5b (C5a and C5b); ravulizumab robustly inhibits this activation. C5a is one of the most powerful chemoattractants and pro-inflammatory modulators (see, e.g., Harris CL, et al., Mol. Immunol. 2018;102:89-119), recruiting B and T cells, macrophages, and other immune cells to the site of inflammation. These inappropriately activated immune cells release cytokines to further enhance the aberrant immune response with autoantibody formation and further tissue damage. In DM, it has been shown that activated complement C5a can lead to cytokine induction by upregulating adhesion molecule expression after binding to endothelial cells (see, e.g., Sallum AM, et al., Autoimmun. Rev. 2006;5(2):93-100).

[0074] C5b is involved in the formation of the terminal complement (C5b-9) MAC (see, e.g., Tegla CA, et al., Immunol. Res. 2011; 51(1): 45-60). The MAC is deposited on capillaries and induces perivascular inflammation in muscle fibers (see, e.g., Dalakas MC., N. Engl. J. Med. 2015; 372(18): 1734-1747; and Dalakas MC, et al., Lancet. 2003; 362(9388): 971-982). MAC in DM leads to necrosis, reduced density of endomysial capillaries, ischemia, and myofiber destruction (see, e.g., Dalakas MC., N. Engl. J. Med. 2015; 372(18): 1734-1747; and Pinal-Fernandez I, et al., J Rheumatol. 2015; 42(8): 1448-1454). Microscopic lesions of myofibers result in reduced blood flow and perifascicular atrophy (see, e.g., Dalakas MC., N. Engl. J. Med. 2015; 372(18): 1734-1747), making it a highly specific feature in patients with DM (specificity > 90%) (see, e.g., Suarez-Calvet X, et al., Arthritis. Res. Ther. 2017; 19(1): 174).

[0075] As used herein, "effective treatment" refers to treatment that results in a beneficial effect, e.g., an improvement in at least one symptom of a disease or disorder. The beneficial effect can take the form of an improvement over a baseline, e.g., an improvement over a measurement or observation made before the start of treatment by the method. Effective treatment can refer to the alleviation of at least one symptom of DM (e.g., a blue-purple or dusky red rash that most commonly occurs on the face, eyelids, knuckles, elbows, knees, chest, and back) and / or muscle weakness (e.g., progressive muscle weakness of the muscles closest to the trunk, such as the hips, thighs, shoulders, upper arms, and neck muscles). Effective treatment can refer to the alleviation of at least one symptom of DM (e.g., a discernible rash and / or muscle weakness).

[0076] The term "effective amount" refers to an amount of an agent that provides a desired biological, therapeutic and / or prophylactic result. The result may be reduction, amelioration, palliation, relief, delay and / or alleviation of one or more signs, symptoms or causes of a disease, or any other desired change in a biological system. In one example, an "effective amount" is an amount of an anti-C5 antibody or antigen-binding fragment thereof that has been clinically proven to alleviate at least one symptom of DM (e.g., a discernible rash and / or muscle weakness). An effective amount may be administered in one or more administrations.

[0077] As used herein, the term "loading dose" refers to the first dose administered (eg, in a dosing cycle).

[0078] As used herein, the terms "maintenance" and "maintenance phase" are used interchangeably and refer to the second phase of treatment. In certain embodiments, treatment is continued as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.

[0079] As used herein, the term "serum trough level" refers to the lowest level at which a drug (e.g., an anti-C5 antibody or antigen-binding fragment thereof) or medication is present in the serum. In contrast, "peak serum level" refers to the highest level of drug in the serum. "Mean serum level" refers to the average level of drug in the serum over time.

[0080] The term "antibody" describes a polypeptide comprising at least one antibody-derived antigen-binding site (e.g., VH / VL region or Fv, or CDR). Antibodies include known forms of antibodies, for example, the antibody may be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody. The antibody may also be a Fab, Fab'2, ScFv, SMIP, Affibody®, nanobody, or single domain antibody. The antibody may also be of any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, IgE, or a combination thereof. The antibody may be a naturally occurring antibody or an antibody modified by protein engineering techniques (e.g., by mutation, deletion, substitution, conjugation to a non-antibody moiety). The antibody may comprise one or more variant amino acids (compared to a naturally occurring antibody) that, for example, alter the properties (e.g., functional properties) of the antibody. Many such modifications are known in the art that affect, for example, the half-life, effector functions, and / or the immune response to the antibody in a patient. The term antibody also includes artificial or engineered polypeptide constructs that contain at least one antibody-derived antigen-binding site.

[0081] II. Anti-C5 antibody The anti-C5 antibodies described herein bind to complement component C5 (e.g., human C5) and inhibit cleavage of C5 into fragments C5a and C5b. As noted above, such antibodies also have improved pharmacokinetic properties compared to, for example, other anti-C5 antibodies used for therapeutic purposes (e.g., eculizumab).

[0082] Anti-C5 antibodies (or VH / VL domains derived therefrom) suitable for use in the methods described herein can be generated using methods known in the art. Alternatively, art-recognized anti-C5 antibodies can be used. Antibodies that compete with any of these art-recognized antibodies or those described herein for binding to C5 can also be used.

[0083] An exemplary anti-C5 antibody is ravulizumab, or antigen-binding fragments and variants thereof, comprising heavy and light chains having the sequences set forth in SEQ ID NOs: 14 and 11, respectively. Rabulizumab (also known as ULTOMIRIS®, BNJ441, and ALXN1210) is described in WO 2015134894 and U.S. Patent No. 9,079,949, the entire teachings of which are incorporated herein by reference. The terms ravulizumab, BNJ441, and ALXN1210 may be used interchangeably throughout this specification, but all refer to the same antibody. Rabulizumab selectively binds to the human complement protein C5 and inhibits its cleavage into C5a and C5b during complement activation. This inhibition prevents the release of the proinflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC) C5b-9, while preserving the proximal or early components of complement activation (e.g., C3 and C3b) that are essential for microbial opsonization and immune complex clearance.

[0084] In other embodiments, the antibody comprises the heavy and light chain CDRs or heavy and light chain variable regions (VH / VL) of ravulizumab. Thus, in one embodiment, the antibody comprises the CDR1, CDR2, and CDR3 domains of the VH region of ravulizumab having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2, and CDR3 domains of the VL region of ravulizumab having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises heavy chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and light chain CDR1, CDR2, and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively. In another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively. In another embodiment, the antibody comprises a heavy chain having the amino acid sequence set forth in SEQ ID NO: 14. In another embodiment, the antibody comprises a heavy chain constant region having the amino acid sequence set forth in SEQ ID NO: 15. In another embodiment, the antibody comprises a heavy chain constant region having the amino acid sequence set forth in SEQ ID NO:16.

[0085] Another exemplary anti-C5 antibody is the antibody BNJ421, or antigen-binding fragments and variants thereof, comprising heavy and light chains having the sequences set forth in SEQ ID NOs: 20 and 11, respectively. BNJ421 (also known as ALXN1211) is described in WO2015134894 and U.S. Patent No. 9,079,949, the entire teachings of which are incorporated herein by reference.

[0086] In other embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Thus, in one embodiment, the antibody comprises the CDR1, CDR2 and CDR3 domains of the VH region of BNJ421 having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the VL region of BNJ421 having the sequence set forth in SEQ ID NO: 8. In another embodiment, the antibody comprises the heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and the light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5 and 6, respectively. In another embodiment, the antibody comprises the VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively. In another embodiment, the antibody comprises the heavy chain constant region having the amino acid sequence set forth in SEQ ID NO: 9.

[0087] In another embodiment, the antibody comprises a heavy chain having the amino acid sequence set forth in SEQ ID NO:10.

[0088] Another exemplary anti-C5 antibody is the 7086 antibody described in U.S. Patent Nos. 8,241,628 and 8,883,158. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see U.S. Patent Nos. 8,241,628 and 8,883,158). In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:24, 25 and 26, respectively. In another embodiment, the antibody or antigen-binding fragment thereof comprises the VH region of the 7086 antibody having the sequence set forth in SEQ ID NO:27, and the VL region of the 7086 antibody having the sequence set forth in SEQ ID NO:28.

[0089] Another exemplary anti-C5 antibody is the 305LO5 antibody described in U.S. Patent No. 9,765,135. In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody. In another embodiment, the antibody or antigen-binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:29, 30 and 31, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:32, 33 and 34, respectively. In another embodiment, the antibody comprises the VH region of the 305LO5 antibody having the sequence set forth in SEQ ID NO:35, and the VL region of the 305LO5 antibody having the sequence set forth in SEQ ID NO:36.

[0090] Another exemplary anti-C5 antibody is the SKY59 antibody (Fukuzawa, T. et al., Sci. Rep., 7:1080, 2017). In one embodiment, the antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody (clovalimab). In another embodiment, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising SEQ ID NO:37 and a light chain comprising SEQ ID NO:38.

[0091] In some embodiments, the anti-C5 antibody comprises the heavy and light chain variable regions or the heavy and light chains of the REGN3918 antibody (pozelimab) (see U.S. Pat. No. 10,633,434). In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a heavy chain variable region sequence set forth in SEQ ID NO:39 and a light chain variable region comprising the sequence set forth in SEQ ID NO:40. In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof comprises a heavy chain sequence set forth in SEQ ID NO:41 and a light chain sequence set forth in SEQ ID NO:42.

[0092] In some embodiments, the anti-C5 antibody comprises the heavy and light chain CDRs or the heavy and light chains of the LFG316 antibody (tesidolumab).

[0093] In some embodiments, the anti-C5 antibody comprises the heavy and light chain CDRs or the heavy and light chains of eculizumab or a biosimilar antibody thereof (e.g., ABP959; SB12 or Elizaria).

[0094] In some embodiments, the antibody comprises a complementarity determining region (CDR) comprising a variable heavy CDR (VHCDR1-3) and a variable light CDR (VLCDR1-3). The exact boundaries of the CDRs are defined differently according to different methods. In some embodiments, the location of the CDR or framework region in a light or heavy chain variable domain is as defined by Kabat et al. [(1991) "Sequences of Proteins of Immunological Interest." NIH Publication No. 91 3242, USDepartment of Health and Human Services, Bethesda, MD]. In such cases, the CDRs may be referred to as "Kabat CDRs" (e.g., "Kabat LCDR2" or "Kabat HCDR1"). In some embodiments, the location of the CDRs of a light or heavy chain variable domain is as defined by Chothia et al. (Nature, 342:877-83, 1989). These regions may therefore be referred to as "Chothia CDRs" (e.g., "Chothia LCDR2" or "Chothia HCDR3"). In some embodiments, the positions of the CDRs of the light and heavy chain variable regions may be defined by the combined Kabat-Chothia definition. In such embodiments, these regions may be referred to as "combined Kabat-Chothia CDRs". Thomas, C. et al. (Mol. Immunol., 33:1389-401, 1996) illustrates the identification of CDR boundaries according to the Kabat and Chothia numbering schemes.

[0095] In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain CDR1 that comprises, or consists of, the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19). In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain CDR2 that comprises, or consists of, the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO: 18). In some embodiments, the anti-C5 antibodies described herein comprise a heavy chain CDR2 that comprises, or consists of, the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO: 18). [ka]

[0096] In some embodiments, the anti-C5 antibodies described herein comprise a light chain variable region comprising the following amino acid sequence: [ka]

[0097] The anti-C5 antibodies described herein, in some embodiments, can comprise a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn) with higher affinity than that of the native human Fc constant region from which the variant human Fc constant region is derived. The Fc constant region can comprise, for example, one or more (e.g., 2, 3, 4, 5, 6, 7, or 8 or more) amino acid substitutions compared to the native human Fc constant region from which the variant human Fc constant region is derived. The substitutions can increase the binding affinity of an IgG antibody comprising a variant Fc constant region to FcRn at pH 6.0 while maintaining the pH dependency of the interaction. Methods for testing whether one or more substitutions in an antibody's Fc constant region increase the affinity of the Fc constant region for FcRn at pH 6.0 are known in the art and are illustrated in the Examples. See, for example, WO2015134894 and U.S. Pat. No. 9,079,949, the disclosures of each of which are incorporated herein by reference in their entirety.

[0098] Substitutions that enhance the binding affinity of antibody Fc constant regions to FcRn are known in the art and include, for example, (1) M252Y / S254T / T256E triple substitutions (Dall'Acqua, W. et al., J. Biol. Chem., 281:23514-24, 2006); (2) M428L or T250Q / M428L substitutions (Hinton, P. et al., J. Biol. Chem., 279:6213-6, 2004; Hinton, P. et al., J. Immunol., 176:346-56, 2006); and (3) N434A or T307 / E380A / N434A substitutions (Petkova, S. et al., J. Immunol., 176:346-56, 2006). al., Int. Immunol., 18:1759-69, 2006), and additional substitution pairs: P257I / Q311I, P257I / N434H, and D376V / N434H (Datta-Mannan, A. et al., J. Biol. Chem., 282:1709-17, 2007), the disclosures of each of which are incorporated herein by reference in their entirety.

[0099] Anti-C5 antibodies suitable for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 14 and / or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11. Alternatively, anti-C5 antibodies for use in the methods described herein, in some embodiments, comprise a heavy chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 20 and / or a light chain polypeptide comprising the amino acid sequence set forth in SEQ ID NO: 11.

[0100] In one embodiment, the antibody has an affinity dissociation constant (K) of at least 0.1 (e.g., at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875, 0.9, 0.925, 0.95 or 0.975) nM at pH 7.4 and 25° C. (otherwise under physiological conditions). DIn one embodiment, the antibody binds to C5 with an affinity dissociation constant (K) of about 0.5 nM at pH 7.4 and 25° C. (otherwise under physiological conditions). D In some embodiments, the K of the anti-C5 antibody or antigen-binding fragment thereof D is 1 nM or less (e.g., 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, or 0.2 or less). In some embodiments, the antibody has a K of about 22 nM at pH 6.0 and 25° C. (otherwise under physiological conditions). D Then it binds to C5.

[0101] In another embodiment, the K of an antibody against C5 at pH 6.0 at 25° C. D ) / (K of antibody against C5 at pH 7.4 at 25C D )] is greater than 21 (e.g., 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 24 0, 250, 260, 270, 280, 290, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500 or greater).

[0102] Methods for determining whether an antibody binds to a protein antigen and / or the affinity of an antibody for a protein antigen are known in the art. Binding of the antibody to the protein antigen can be detected and / or quantified using a variety of techniques, including, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) detection (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, NJ), or enzyme-linked immunosorbent assay (ELISA; Benny KC Lo (2004) "Antibody Engineering: Methods and Protocols," Humana Press (ISBN: 1588290921); Johne, B. et al., J. Immunol. Meth., 160:191-8, 1993; Jonsson, U. et al., Ann. Biol. Clin., 51:19-26, 1993; Jonsson, U. et al., Biotechniques, 11:620-7, 1991). Additionally, methods for measuring affinity (eg, dissociation and association constants) are described in the Examples.

[0103] As used herein, the term "k a " refers to the rate constant for the association of an antibody to an antigen. d " refers to the rate constant for dissociation of an antibody from the antibody / antigen complex. D " refers to the equilibrium dissociation constant of an antibody-antigen interaction. The equilibrium dissociation constant is the ratio of the rate constants, K D =K a / K d Such determinations can be made, for example, at 25C or 37C (see Examples). The kinetics of antibody binding to human C5 can be determined, for example, using Fc capture to immobilize the antibody and via SPR on a BIAcore 3000 instrument at pH 8.0, 7.4, 7.0, 6.5 and 6.0.

[0104] In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof blocks the cleavage of C5 into C5a and C5b, which inhibits, for example, the proinflammatory effects of C5a and the generation of the C5b-9 membrane attack complex (MAC) at the cell surface.

[0105] Methods for determining whether a particular antibody described herein inhibits C5 cleavage are known in the art. Inhibition of human complement component C5 can reduce the cytolytic ability of complement in a subject's body fluid. Such reduction in the cytolytic ability of complement present in a body fluid can be measured by methods known in the art, such as hemolysis assays (Kabat and Mayer (eds.), "Experimental Immunochemistry, 2001, 14:131-135). nd Edition," 135-240, Springfield, IL, CC Thomas (1961), pp. 135-139) or a conventional variation of that assay, such as the chicken erythrocyte hemolysis method (Hillmen, P. et al., N. Engl. J. Med., 350:552-9, 2004). Methods for determining whether a candidate compound inhibits the cleavage of human C5 into the forms C5a and C5b are known in the art (Evans, M. et al., Mol. Immunol., 32:1183-95, 1995). The concentration and / or biological activity of C5a and C5b in body fluids can be measured, for example, by methods known in the art. For C5b, a hemolytic assay or an assay for soluble C5b-9 discussed herein can be used. Other assays known in the art can also be used. These or other suitable types of assays can be used to screen candidate agents capable of inhibiting human complement component C5.

[0106] Immunological techniques, such as, but not limited to, ELISA, can be used to measure protein concentrations of C5 and / or its cleavage products to determine the ability of anti-C5 antibodies or antigen-binding fragments thereof to inhibit conversion of C5 to biologically active products. In some embodiments, C5a generation is measured. In some embodiments, a C5b-9 neoepitope-specific antibody is used to detect MAC formation.

[0107] To determine the inhibitory activity of anti-C5 antibody or its antigen-binding fragment on complement activation, a hemolysis assay can be used. To determine the effect of anti-C5 antibody or its antigen-binding fragment on classical complement pathway-mediated hemolysis in serum test solution in vitro, for example, sheep red blood cells coated with hemolysin or chicken red blood cells sensitized with anti-chicken red blood cell antibody are used as target cells. The percentage of lysis is normalized by considering 100% lysis as equivalent to the lysis occurring in the absence of inhibitor. In some embodiments, the classical complement pathway is activated by human IgM antibody, for example, as utilized in Wieslab® classical pathway complement kit (Wieslab® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with anti-C5 antibody or its antigen-binding fragment in the presence of human IgM antibody. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-linked anti-C5b-9 antibody and a fluorogenic substrate and measuring absorbance at an appropriate wavelength. As a control, test serum is incubated in the absence of anti-C5 antibody or antigen-binding fragment thereof. In some embodiments, the test serum is C5-deficient serum reconstituted with C5 polypeptide.

[0108] To determine the effect of anti-C5 antibodies or antigen-binding fragments thereof on alternative pathway-mediated hemolysis, non-sensitized rabbit or guinea pig red blood cells can be used as target cells. In some embodiments, the serum test solution is C5-deficient serum reconstituted with C5 polypeptide. The percentage of lysis is normalized by considering 100% lysis as equivalent to the lysis occurring in the absence of inhibitors. In some embodiments, the alternative complement pathway is activated by lipopolysaccharide, for example, as utilized in the Wieslab® alternative pathway complement kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with anti-C5 antibodies or antigen-binding fragments thereof in the presence of lipopolysaccharide. The amount of C5b-9 produced is measured by contacting the mixture with an enzyme-linked anti-C5b-9 antibody and a fluorogenic substrate and measuring the fluorescence at an appropriate wavelength. As a control, the test serum is incubated in the absence of anti-C5 antibodies or antigen-binding fragments thereof.

[0109] In some embodiments, C5 activity or its inhibition is quantified using a CH50eq assay. The CH50eq assay is a method for measuring total classical complement activity in serum. This test is a lysis assay that uses antibody-sensitized red blood cells as activators of the classical complement pathway and determines the amount required to obtain 50% lysis (CH50) using various dilutions of test serum. Percent hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measurement of terminal complement complex (TCC) formation, since TCC itself is directly involved in the hemolysis being measured. This assay is known to those skilled in the art and is commonly performed. Briefly, to activate the classical complement pathway, undiluted serum samples (e.g., reconstituted human serum samples) are added to microassay wells containing antibody-sensitized red blood cells, thereby generating TCC. The activated serum is then diluted in microassay wells coated with a capture reagent (e.g., an antibody that binds to one or more components of TCC). TCC present in the activated sample binds to the monoclonal antibody that coats the surface of the microassay wells. The wells are washed and a detectably labeled detection reagent that recognizes the bound TCC is added to each well. The detectable label can be, for example, a fluorescent label or an enzyme label. Assay results are expressed in CH50 unit equivalents per milliliter (CH50 U Eq / mL).

[0110] Inhibition, e.g., with respect to terminal complement activity, includes at least a 5 (e.g., at least 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60)% decrease in terminal complement activity, e.g., in a hemolytic assay or CH50eq assay, compared to the effect of a control antibody (or antigen-binding fragment thereof) under similar conditions and at equimolar concentration. Substantial inhibition, as used herein, refers to an inhibition of a given activity (e.g., terminal complement activity) of at least 40 (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, or 95 or more)%. In some embodiments, the anti-C5 antibodies described herein contain one or more amino acid substitutions relative to the CDRs of eculizumab (i.e., SEQ ID NOs:1-6) but still retain at least 30 (e.g., at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95)% of the complement inhibitory activity of eculizumab in a hemolytic assay or a CH50eq assay.

[0111] The anti-C5 antibodies described herein have a serum half-life in humans of at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or 55) days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of at least 40 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of about 43 days. In another embodiment, the anti-C5 antibodies described herein have a serum half-life in humans of 39-48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, the anti-C5 antibodies or antigen-binding fragments thereof described herein have a serum half-life that is at least 20 (e.g., at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 400 or 500)% greater than the serum half-life of eculizumab, e.g., as measured in one of the mouse model systems described in the Examples (e.g., a C5-deficient / NOD / scid mouse or an hFcRn transgenic mouse model system).

[0112] In one embodiment, the antibody competes for binding with the antibody described herein and / or binds to the same epitope on C5. With respect to two or more antibodies, the term "binds to the same epitope" means that the antibodies bind to the same section of amino acid residues as determined by a given method. Techniques for determining whether an antibody binds to the same epitope on C5 as the antibody described herein include, for example, epitope mapping methods, such as x-ray analysis of crystals of antigen:antibody complexes, and hydrogen / deuterium exchange mass spectrometry (HDX-MS). Other methods monitor the binding of the antibody to peptide antigen fragments or mutants of the antigen, where loss of binding due to modification of amino acid residues within the antigen sequence is often considered an indication of epitope content. Additionally, computational combinatorial methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from combinatorial phage display peptide libraries. Antibodies with the same VH and VL or the same CDR1, CDR2 and CDR3 sequences are expected to bind to the same epitope.

[0113] An antibody that "competes with another antibody for binding to a target" refers to an antibody that inhibits (partially or completely) the binding of the other antibody to a target. Whether two antibodies compete with each other for binding to a target, i.e., whether and to what extent one antibody inhibits the binding of the other antibody to a target, can be determined using known competition experiments. In certain embodiments, an antibody competes with another antibody and inhibits the binding of the other antibody to a target by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%. The level of inhibition or competition can vary depending on which antibody is the "blocking antibody" (i.e., the antibody that is first incubated with the target). Competing antibodies can, for example, bind to the same epitope, overlapping epitopes, or adjacent epitopes (e.g., as evidenced by steric hindrance).

[0114] The anti-C5 antibodies or antigen-binding fragments thereof described herein used in the methods described herein can be produced using a variety of techniques recognized in the art. Monoclonal antibodies can be obtained by a variety of techniques well known to those skilled in the art. Briefly, spleen cells from animals immunized with a desired antigen are immortalized, typically by fusion with myeloma cells (Koehler, G. & Milstein, C., Eur. J. Immunol., 6:511-9, 1976). Methods of immortalization include transformation with Epstein-Barr virus, oncogenes, or retroviruses, or other methods known in the art. Colonies arising from a single immortalized cell can be screened for production of antibodies with the desired specificity and affinity for the antigen, and the yield of monoclonal antibodies produced by those cells can be enhanced by a variety of techniques, including injection into the peritoneal cavity of a vertebrate host. Alternatively, DNA sequences encoding monoclonal antibodies or binding fragments thereof may be isolated by screening DNA libraries from human B cells (Huse, W. et al., Science, 246:1275-81, 1989).

[0115] In some embodiments, the anti-C5 antibody is eculizumab (SOLIRIS®) or an antigen-binding fragment thereof (e.g., the heavy and light chain complementarity determining regions (HCDRs) of eculizumab, respectively). 1-3 and LCDR 1-3 In some embodiments, the anti-C5 antibody is not a biosimilar of eculizumab (SOLIRIS®), such as the ABP 959 antibody (Amgen Inc., USA), ELIZARIA® (Generium JNC, Russia), or SB12 (Samsung Bioepis, Incheon, Korea).

[0116] III. Composition Compositions comprising an anti-C5 antibody or an antigen-binding fragment thereof are also provided herein. In one embodiment, the composition comprises an anti-C5 antibody comprising CDR1, CDR2 and CDR3 domains in a heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and CDR1, CDR2 and CDR3 domains in a light chain variable region having the sequence set forth in SEQ ID NO: 8. In another embodiment, the anti-C5 antibody comprises a heavy chain and a light chain having the sequences set forth in SEQ ID NOs: 14 and 11, respectively. In another embodiment, the anti-C5 antibody comprises a heavy chain and a light chain having the sequences set forth in SEQ ID NOs: 20 and 11, respectively.

[0117] The composition can be formulated as a pharmaceutical solution for administration to a subject, for example, for the treatment of DM. Pharmaceutical compositions generally include a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" refers to and includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The composition can include pharmaceutically acceptable salts, such as acid or base addition salts, sugars, carbohydrates, polyols, and / or tonicity adjusters.

[0118] The compositions can be formulated according to standard methods. Pharmaceutical formulation is a well-established technique (see, e.g., Gennaro (2000) "Remington: The Science and Practice of Pharmacy," 2006). th Edition, Lippincott, Williams & Wilkins (ISBN:0683306472); Ansel et al. (1999) “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 7 th Edition, Lippincott Williams & Wilkins Publishers (ISBN:0683305727); and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association,” 3 rd(See, for example, ISBN:091733096X). In some embodiments, the compositions can be formulated, for example, as a buffer solution of appropriate concentration suitable for storage at 2-8C (e.g., 4C). In some embodiments, the compositions can be formulated for storage at temperatures below 0C (e.g., -20C or 80C). In some embodiments, the compositions can be formulated for storage at 2-8C (e.g., 4C) for up to 2 years (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1.5 years, or 2 years). Thus, in some embodiments, the compositions described herein are stable upon storage at 2-8C (e.g., 4C) for at least 1 year.

[0119] Pharmaceutical compositions can be in various forms. These forms include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends, in part, on the intended mode of administration and therapeutic application. Compositions, including compositions intended for systemic or local delivery, can be in the form of, for example, injectable or infusible solutions. Thus, compositions can be formulated for administration by parenteral modes (e.g., intravenous, subcutaneous, intraperitoneal or intramuscular injection). "Parenteral administration", "parenterally administered" and other grammatically equivalent phrases, as used herein, refer to modes of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intranasal, intraocular, intrapulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid, and intrasternal injection and infusion.

[0120] In some embodiments, the disclosure relates to a composition, e.g., a pharmaceutical composition or medicament, comprising an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and a light chain complementarity determining region (LCDR) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, for use in treating DM in a human patient, wherein the effective amount is an amount of the anti-C5 antibody or antigen-binding fragment thereof that is: (a) in patients weighing <30 kg, a loading dose of 900 mg, followed after 2 weeks by a maintenance dose of 2100 mg, then once every 8 weeks thereafter; (b) for patients weighing ≥30 to <40 kg, a loading dose of 1200 mg, followed after 2 weeks by a maintenance dose of 2700 mg, then once every 8 weeks thereafter; (c) for patients weighing ≥40 to <60 kg, a loading dose of 2400 mg, followed after 2 weeks by a maintenance dose of 3000 mg, then once every 8 weeks thereafter; (d) for patients weighing ≥ 60 to < 100 kg, a loading dose of 2700 mg, followed after 2 weeks by a maintenance dose of 3300 mg, then once every 8 weeks thereafter; or (e) For patients weighing ≧100 kg, a loading dose of 3000 mg, followed two weeks later by a maintenance dose of 3600 mg, then once every eight weeks thereafter.

[0121] In other embodiments, the disclosure relates to a composition, e.g., a pharmaceutical composition or medicament, comprising an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising a heavy chain complementarity determining region (HCDR) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and a light chain complementarity determining region (LCDR) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, for use in treating DM in a human patient, wherein the effective amount is an amount of the anti-C5 antibody or antigen-binding fragment thereof that is: (a) for patients weighing <30 kg, a loading dose of 900 mg on day 1, followed by a maintenance dose of 2100 mg on day 15, then once every 8 weeks thereafter; (b) for patients weighing ≥30 to <40 kg, a loading dose of 1200 mg on day 1, followed by a maintenance dose of 2700 mg on day 15, then once every 8 weeks thereafter; (c) for patients weighing ≥40 to <60 kg, a loading dose of 2400 mg on day 1, followed by a maintenance dose of 3000 mg on day 15, then once every 8 weeks thereafter; (d) for patients weighing ≥ 60 to < 100 kg, a loading dose of 2700 mg on day 1, followed by a maintenance dose of 3300 mg on day 15, then once every 8 weeks thereafter; or (e) For patients weighing ≧100 kg, a loading dose of 3000 mg on day 1, followed by a maintenance dose of 3600 mg on day 15, then once every 8 weeks thereafter.

[0122] In some embodiments, the present invention provides a method for the treatment of DM in a human patient comprising administering to a subject a therapeutically effective amount of HCDR SEQ ID NOs: 19, 18 and 3. 1-3 and LCDRs comprising SEQ ID NOs: 4, 5 and 6 1-3 wherein the anti-C5 antibody further comprises a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), the variant human Fc constant region comprising Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in the EU numbering of native human IgG Fc constant region. In particular, the present specification relates to a composition, e.g., a pharmaceutical composition or a medicament, comprising an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, comprising: 1-3 and LCDR 1-3 The present invention relates to a pharmaceutical composition or drug product comprising an effective amount of ravulizumab (ULTOMIRIS®) or an antigen-binding fragment thereof, comprising:

[0123] IV. Method Provided herein are methods for treating DM in a human patient, comprising administering to the patient an anti-C5 antibody or antigen-binding fragment thereof, where the anti-C5 antibody or antigen-binding fragment thereof is administered (or is for administration) according to a particular clinical dosage regimen (e.g., at a particular dose, according to a particular dosing schedule).

[0124] In one embodiment, the dose of anti-C5 antibody or antigen-binding fragment thereof is based on the patient's weight. In one embodiment, for example, 900 mg, 1200 mg, 2400 mg, 2700 mg, 3000 mg, 3300 mg, or 3600 mg of anti-C5 antibody or antigen-binding fragment thereof is administered based on the patient's weight. In another embodiment, 900 mg and / or 2100 mg of anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing <30 kg. In another embodiment, 1200 mg and / or 2700 mg of anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧30 to <40 kg. In another embodiment, 2400 mg and / or 3000 mg of anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧40 to <60 kg. In another embodiment, 2700 mg and / or 3300 mg of anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧60 to <100 kg. In another embodiment, 3000 mg and / or 3600 mg of anti-C5 antibody or antigen-binding fragment thereof is administered to a patient weighing ≧100 kg. In certain embodiments, the dosing regimen is adjusted to provide the optimal desired response (e.g., an effective response).

[0125] In another embodiment, a method of treating a human patient with DM is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises: (a) in patients weighing <30 kg, a loading dose of 900 mg, followed after 2 weeks by a maintenance dose of 2100 mg, then once every 8 weeks thereafter; (b) for patients weighing ≥30 to <40 kg, a loading dose of 1200 mg, followed after 2 weeks by a maintenance dose of 2700 mg, then once every 8 weeks thereafter; (c) for patients weighing ≥40 to <60 kg, a loading dose of 2400 mg, followed after 2 weeks by a maintenance dose of 3000 mg, then once every 8 weeks thereafter; (d) for patients weighing ≥ 60 to < 100 kg, a loading dose of 2700 mg, followed after 2 weeks by a maintenance dose of 3300 mg, then once every 8 weeks thereafter; or (e) Patients weighing ≧100 kg will be administered a loading dose of 3000 mg, followed two weeks later by a maintenance dose of 3600 mg, then once every eight weeks thereafter.

[0126] In another embodiment, a method of treating a human patient with DM is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and the CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or antigen-binding fragment thereof comprises: (a) for patients weighing <30 kg, a loading dose of 900 mg on day 1, followed by a maintenance dose of 2100 mg on day 15, then once every 8 weeks thereafter; (b) for patients weighing ≥30 to <40 kg, a loading dose of 1200 mg on day 1, followed by a maintenance dose of 2700 mg on day 15, then once every 8 weeks thereafter; (c) for patients weighing ≥40 to <60 kg, a loading dose of 2400 mg on day 1, followed by a maintenance dose of 3000 mg on day 15, then once every 8 weeks thereafter; (d) for patients weighing ≥ 60 to < 100 kg, a loading dose of 2700 mg on day 1, followed by a maintenance dose of 3300 mg on day 15, then once every 8 weeks thereafter; or (e) Patients weighing ≧100 kg will be administered a loading dose of 3000 mg on day 1, followed by a maintenance dose of 3600 mg on day 15, then once every 8 weeks thereafter.

[0127] In another embodiment, a method of treating a human patient with DM is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of a native human IgG Fc constant region, wherein the anti-C5 antibody or antigen-binding fragment thereof is: (a) in patients weighing <30 kg, a loading dose of 900 mg, followed after 2 weeks by a maintenance dose of 2100 mg, then once every 8 weeks thereafter; (b) for patients weighing ≥30 to <40 kg, a loading dose of 1200 mg, followed after 2 weeks by a maintenance dose of 2700 mg, then once every 8 weeks thereafter; (c) for patients weighing ≥40 to <60 kg, a loading dose of 2400 mg, followed after 2 weeks by a maintenance dose of 3000 mg, then once every 8 weeks thereafter; (d) for patients weighing ≥ 60 to < 100 kg, a loading dose of 2700 mg, followed after 2 weeks by a maintenance dose of 3300 mg, then once every 8 weeks thereafter; or (e) Patients weighing ≧100 kg will be administered a loading dose of 3000 mg, followed two weeks later by a maintenance dose of 3600 mg, then once every eight weeks thereafter.

[0128] In another embodiment, a method of treating a human patient with DM is provided, the method comprising administering to the patient an effective amount of an anti-C5 antibody or antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, and a variant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the variant human Fc constant region comprises Met429Leu and Asn435Ser substitutions at residues corresponding to methionine 428 and asparagine 434, respectively, in EU numbering, of a native human IgG Fc constant region, wherein the anti-C5 antibody or antigen-binding fragment thereof is: (a) for patients weighing <30 kg, a loading dose of 900 mg on day 1, followed by a maintenance dose of 2100 mg on day 15, then once every 8 weeks thereafter; (b) for patients weighing ≥30 to <40 kg, a loading dose of 1200 mg on day 1, followed by a maintenance dose of 2700 mg on day 15, then once every 8 weeks thereafter; (c) for patients weighing ≥40 to <60 kg, a loading dose of 2400 mg on day 1, followed by a maintenance dose of 3000 mg on day 15, then once every 8 weeks thereafter; (d) for patients weighing ≥ 60 to < 100 kg, a loading dose of 2700 mg on day 1, followed by a maintenance dose of 3300 mg on day 15, then once every 8 weeks thereafter; or (e) Patients weighing ≧100 kg will be administered a loading dose of 3000 mg on day 1, followed by a maintenance dose of 3600 mg on day 15, then once every 8 weeks thereafter.

[0129] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing <30 kg at a loading dose of 900 mg, followed two weeks later by a maintenance dose of 2100 mg, and then once every eight weeks thereafter.

[0130] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing ≧30 to <40 kg at a loading dose of 1200 mg, followed two weeks later by a maintenance dose of 2700 mg, and then once every eight weeks thereafter.

[0131] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing ≧40 to <60 kg at a loading dose of 2400 mg, followed two weeks later by a maintenance dose of 3000 mg, and then once every 8 weeks thereafter.

[0132] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing ≧60 to <100 kg at a loading dose of 2700 mg, followed two weeks later by a maintenance dose of 3300 mg, and then once every eight weeks thereafter.

[0133] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing > 100 kg at a loading dose of 3000 mg on day 1, followed by a maintenance dose of 3600 mg on day 15, then once every 8 weeks thereafter.

[0134] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing <30 kg at a loading dose of 900 mg on day 1, followed by a maintenance dose of 2100 mg on day 15, then once every 8 weeks thereafter.

[0135] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing ≧30 to <40 kg at a loading dose of 1200 mg on day 1, followed by a maintenance dose of 2700 mg on day 15, and then once every 8 weeks thereafter.

[0136] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing ≧40 to <60 kg at a loading dose of 2400 mg on day 1, followed by a maintenance dose of 3000 mg on day 15, and then once every 8 weeks thereafter.

[0137] In another embodiment, a method is provided for treating a human patient with DM in which an anti-C5 antibody is administered to a patient weighing ≧60 to <100 kg at a loading dose of 2700 mg on day 1, followed by a maintenance dose of 3300 mg on day 15, and so on once every 8 weeks thereafter.

[0138] In another embodiment, a method of treating a human patient with DM is provided in which an anti-C5 antibody is administered to a patient weighing > 100 kg at a loading dose of 3000 mg, followed by a maintenance dose of 3600 mg on day 15, then once every 8 weeks thereafter.

[0139] In some embodiments, the anti-C5 antibody or antigen-binding fragment thereof is administered alone. In other embodiments, the anti-C5 antibody or antigen-binding fragment thereof is administered in combination (e.g., simultaneously or separately) with one or more additional therapeutic agents. In one embodiment, the treatment further comprises administering azathioprine. In another embodiment, the treatment further comprises administering cyclosporine. In another embodiment, the treatment further comprises administering a glucocorticoid. In another embodiment, the treatment further comprises administering an intramuscular glucocorticoid. In another embodiment, the treatment further comprises administering hydroxychloroquine. In another embodiment, the treatment further comprises administering leflunomide. In another embodiment, the treatment further comprises administering methotrexate. In another embodiment, the treatment further comprises administering mycophenolate mofetil / mycophenolic acid. In another embodiment, the treatment further comprises administering sulfasalazine. In another embodiment, the treatment further comprises administering an antihistamine. In another embodiment, the treatment further comprises administering ibuprofen. In another embodiment, the treatment further comprises administering acetaminophen. In another embodiment, the treatment further comprises administering an anti-pruritic agent. In another embodiment, the treatment further comprises administering a topical steroid. In another embodiment, the treatment further comprises administering vitamin B12. In another embodiment, the treatment further comprises administering vitamin E. In another embodiment, the treatment further comprises administering creatine. In another embodiment, the treatment further comprises administering coenzyme Q10. In another embodiment, the treatment further comprises administering a biotin supplement.

[0140] In one embodiment, the patient has not previously taken or is not currently taking any of the following at the start of or during treatment: intravenous immunoglobulin (IVIg), subcutaneous immunoglobulin (SCIg), IV glucocorticoids, corticotropin injections, cyclophosphamide, rituximab, infliximab, adalimumab, etanercept, tofacitinib, ruxolitinib, or anakinra.

[0141] In one embodiment, the patient has not been previously treated with eculizumab, hi another embodiment, the patient has been previously treated with eculizumab.

[0142] In another embodiment, the patient has, prior to treatment, MMT-8≦142 / 150 and two or more of the following: a) Patient Global Activity Assessment of ≥ 2.0 cm on a 10 cm VAS b) Physician global activity assessment of ≥2.0 cm on a 10 cm VAS c) HAQ disability index ≥ 0.25 d) at least one muscle enzyme is elevated ≥ 1.3 times the upper limit of normal (ULN); and / or e) Global Extramuscular Disease Activity Score of ≥ 2.0 cm on a 10 cm visual analog scale (VAS) has.

[0143] In one embodiment, the global extramuscular disease activity score is based on assessment of activity scores on the total body, skin, skeletal, gastrointestinal, pulmonary, and cardiac scales of the MDAAT.

[0144] In another embodiment, the patient, prior to treatment, has one or more of the following: a) Muscle or skin biopsy with evidence of active pathology of DM within the past 6 months prior to or at the time of treatment initiation; b) electromyography evidence of active myositis within the past 6 months prior to or at the time of treatment initiation; c) muscle evidence of active myositis on magnetic resonance imaging (MRI) within the past 6 months prior to or at the time of treatment initiation; d) at least one muscle enzyme (e.g., CK, aldolase, LDH, ALT, and / or AST) in the IMACS panel ≥2x the ULN prior to or at the start of treatment; and / or e) Active DM rash characterized by inflammatory changes (CDASI activity score ≥ 7) before or at the start of treatment has.

[0145] In some embodiments, the present disclosure relates to a composition, e.g., a pharmaceutical composition or a medicament, comprising an effective amount of an anti-C5 antibody or an antigen-binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR) comprising the HCDR1, HCDR2, and HCDR3 sequences set forth in SEQ ID NOs: 19, 18, and 3, respectively, and a light chain complementarity determining region (LCDR) comprising the LCDR1, LCDR2, and LCDR3 sequences set forth in SEQ ID NOs: 4, 5, and 6, respectively, for use in treating DM in a human patient, the composition optionally including background therapy for treating DM. Specifically, provided herein is a composition comprising an effective amount of ravulizumab (ULTOMIRIS®) or an antigen-binding fragment thereof for treating DM in a human patient. In some embodiments, the effective amount includes using the dosing and scheduling described herein for the anti-C5 antibody, e.g., ravulizumab.

[0146] In further embodiments, the disclosure relates to the use of an effective amount of an anti-C5 antibody or antigen-binding fragment thereof, comprising a heavy chain complementarity determining region (HCDR) comprising HCDR1, HCDR2, and HCDR3 sequences as set forth in SEQ ID NOs: 19, 18, and 3, respectively, and a light chain complementarity determining region (LCDR) comprising LCDR1, LCDR2, and LCDR3 sequences as set forth in SEQ ID NOs: 4, 5, and 6, respectively, in the manufacture of a composition, e.g., a pharmaceutical composition or medicament, for treating DM in a human patient, optionally including background therapy for the treatment of DM. Specifically provided herein is the use of an effective amount of ravulizumab (ULTOMIRIS®) or an antigen-binding fragment thereof, in the manufacture of a composition, e.g., a pharmaceutical composition or medicament, for treating DM in a human patient. In some embodiments, the effective amount includes the use of the dosing and scheduling described herein for an anti-C5 antibody, e.g., ravulizumab, optionally with the dosing and scheduling of background therapy.

[0147] V. Outcomes Provided herein are methods of treating DM in a patient, comprising administering to the patient an anti-C5 antibody.

[0148] Symptoms of DM include, but are not limited to, a rash (e.g., a blue-purple or dusky red rash that most commonly occurs on the face, eyelids, knuckles, elbows, knees, chest, and back) and / or muscle weakness (e.g., progressive muscle weakness in the muscles closest to the trunk, such as the hips, thighs, shoulders, upper arms, and neck muscles).

[0149] In one embodiment, a patient treated according to the disclosed methods maintains a serum trough concentration of an anti-C5 antibody or antigen-binding fragment thereof of at least 150, 155, 160, 165, 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 g / mL or greater. In one embodiment, a patient treated according to the disclosed methods maintains a serum trough concentration of anti-C5 antibody or antigen-binding fragment thereof of at least 175 μg / mL or greater.

[0150] In one embodiment, a patient treated according to the disclosed methods has a free C5 concentration of 0.5 μg / mL or less (e.g., 0.4 μg / mL, 0.3 μg / mL, 0.2 μg / mL, or 0.1 μg / mL or less).

[0151] The efficacy of the treatment methods provided herein can be assessed using any suitable means. In one embodiment, the treatment results in a shift in soluble C5b-9 towards normal levels.

[0152] In another embodiment, treatment results in a shift in myositis-specific autoantibodies (e.g., anti-melanoma differentiation-associated protein 5 antibodies (anti-MDA5 antibodies), anti-nuclear matrix protein 2 antibodies (anti-NXP2 / MJ antibodies), and / or anti-synthetase / Jo1 antibodies) to normal levels.

[0153] In another embodiment, treatment results in a shift in muscle enzymes (e.g., creatine kinase (CK), aldolase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)) to normal levels.

[0154] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by the International Myositis Assessment and Clinical Trials Total Improvement Scale (IMACS-TIS). In one embodiment, the treatment results in a Total Improvement Score (TIS) of at least > 20, 25, 30, 35, 40, 45, 50, 55, or 60 points compared to baseline as assessed by the IMACS-TIS score.

[0155] In another embodiment, treatment results in an improvement in the patient compared to baseline as assessed by the Dermatomyositis Skin Disease Area and Severity Index (CDASI).

[0156] In another embodiment, the treatment results in a ≧7, 8, 9, 10, 11, or 12 point improvement in the patient compared to baseline as assessed by the CDASI.

[0157] In another embodiment, the treatment results in an improvement in the patient as assessed by the European Quality of Life-Health 5-item Questionnaire Dimension 5 Level (EQ-5D-5L) score compared to baseline.

[0158] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by Patient-Reported Outcomes Measurement Information System (PROMIS).

[0159] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by the Short-Form Health Survey (36-question version) (SF36).

[0160] In another embodiment, treatment results in an improvement in the patient compared to baseline as assessed by the Dermatomyositis Disease Symptom Questionnaire (DM-DSQ).

[0161] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by the 30 second chair stand test (30sCST).

[0162] In another embodiment, the treatment results in a reduction in the patient's detectable rash compared to baseline as assessed by photographic analysis, hi one embodiment, the treatment results in a 25%, 30%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, or 100% reduction in the patient's detectable rash compared to baseline as assessed by photographic analysis.

[0163] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by the 5D Itch Scale.

[0164] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by handheld dynamometry performance analysis.

[0165] In another embodiment, the treatment provides an improvement in the patient compared to baseline as assessed by the Functional Assessment of Chronic Therapy (FACIT)-Fatigue score.

[0166] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by an 8-muscle manual muscle testing subset (MMT8).

[0167] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by the Myositis Disease Activity Assessment Tool (MDAAT).

[0168] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by Physician Global Activity Assessment.

[0169] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by Patient Global Activity Assessment.

[0170] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by a Health Assessment Questionnaire (HAQ).

[0171] In another embodiment, the treatment results in an improvement in the patient compared to baseline as assessed by the Dermatomyositis Physician Global Assessment of Skin Activity (CD-IGA).

[0172] In another embodiment, treatment results in a reduction or cessation of the patient's rash and / or muscle weakness.

[0173] In another embodiment, the treatment provides terminal complement inhibition.

[0174] In another embodiment, treatment results in a reduction in adverse events.

[0175] VI. Kits and Unit Dosage Forms Also provided herein is a kit comprising a pharmaceutical composition comprising an anti-C5 antibody or an antigen-binding fragment thereof, such as ravulizumab or BNJ421, and a pharma- ceutically acceptable carrier in a therapeutically effective amount adapted for use in the aforementioned method. The kit may also optionally comprise instructions, including, for example, an administration schedule, for allowing a practitioner (e.g., a doctor, a nurse, or a patient) to administer the composition contained therein to a patient with DM. The kit may also comprise a syringe.

[0176] Optionally, the kit comprises multiple packages of single-dose pharmaceutical compositions, each of which comprises an effective amount of anti-C5 antibody or its antigen-binding fragment for single administration according to the method provided above.The instruments or devices required for administering the pharmaceutical compositions may also be included in the kit.For example, the kit may provide one or more pre-filled syringes that contain a certain amount of anti-C5 antibody or its antigen-binding fragment.

[0177] In one embodiment, a kit for treating DM in a human patient comprises: (a) a dose of an anti-C5 antibody or antigen-binding fragment thereof comprising the CDR1, CDR2 and CDR3 domains of a heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and the CDR1, CDR2 and CDR3 domains of a light chain variable region having the sequence set forth in SEQ ID NO: 8; and (b) instructions for using the anti-C5 antibody or antigen-binding fragment thereof according to any of the methods described herein. In one embodiment, the anti-C5 antibody or antigen-binding fragment thereof is: (a) in patients weighing <30 kg, a loading dose of 900 mg, followed after 2 weeks by a maintenance dose of 2100 mg, then once every 8 weeks thereafter; (b) for patients weighing ≥30 to <40 kg, a loading dose of 1200 mg, followed after 2 weeks by a maintenance dose of 2700 mg, then once every 8 weeks thereafter; (c) for patients weighing ≥40 to <60 kg, a loading dose of 2400 mg, followed after 2 weeks by a maintenance dose of 3000 mg, then once every 8 weeks thereafter; (d) for patients weighing ≥ 60 to < 100 kg, a loading dose of 2700 mg, followed after 2 weeks by a maintenance dose of 3300 mg, then once every 8 weeks thereafter; or (e) Patients weighing ≧100 kg will be administered a loading dose of 3000 mg, followed two weeks later by a maintenance dose of 3600 mg, then once every eight weeks thereafter.

[0178] The following examples are merely illustrative and should not be construed as limiting the scope of the disclosure, since many variations and equivalents will become apparent to those skilled in the art upon reading this disclosure. The contents of all references, Genbank entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference. EXAMPLES

[0179] Example 1: A Phase 2 / 3, Double-Blind, Randomized, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of ULTOMIRIS in Adult Participants with Dermatomyositis 1. Purpose a. Phase 2 objectives The primary objective of the study is to determine the effect of ULTOMIRIS compared with placebo in treating DM based on improvement in Total Improvement Score (TIS) according to the 2016 ACR / EULAR Myositis Response Criteria for Adults with DM (also known as IMACS) (e.g., as assessed by the proportion of participants having a ≥ 20-point improvement response on the IMACS TIS (TIS20) at week 26 of the randomized controlled period).

[0180] Secondary objectives are to evaluate the efficacy of ULTOMIRIS compared to placebo in the treatment of DM based on improvement in efficacy endpoints (e.g., (a) mean TIS at week 26, (b) mean change from baseline in CDASI activity score at week 26, (c) change from baseline in each of the IMACS core set scales at week 26, (d) time to first CDASI activity score improvement (minimal clinically important difference [MCID] = 7-point improvement), (e) proportion of participants with CDASI MCID improvement at week 26, (f) change in CD-IGA at week 26, (g) proportion of participants with TIS20 at each visit, (h) proportion of participants with TIS40 at each visit, (i) proportion of participants with TIS60 at each visit, (j) time to first response in each of TIS20, TIS40, or TIS60, and / or (k) time to first IMACS Myositis Core Set scale improvement (see MCID for each core set scale).

[0181] Additional objectives are to characterize the PK / PD and immunogenicity of ULTOMIRIS in adult participants with DM (e.g., as assessed by serum ULTOMIRIS concentrations over the study period, changes in serum free and total C5 concentrations over the study period, and the presence and titer of ADAs over the study period).

[0182] Another objective is to characterize the overall safety of ULTOMIRIS in participants with DM (e.g., via incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and TEAEs leading to discontinuation of the study intervention).

[0183] Exploratory objectives include: (1) the effect of ULTOMIRIS on overall health-related quality of life (HR-QoL) and participant-centered and participant-reported outcomes in DM (e.g., as assessed by change from baseline in EQ5D5L at each visit, change from baseline in PROMIS29v2.1 domains over time, change from baseline in SF-36 over time, change from baseline in DM symptoms captured by the DM-DSQ over time, and change from baseline in patient self-assessment of disease activity (last question on the DM-DSQ) over time) and (2) the effect of ULTOMIRIS on complement, inflammatory, autoimmune, and other soluble biomarkers in adult participants with DM (e.g., the presence of myositis-specific autoantibodies in the blood (e.g., anti-MDA5, anti-NXP2 / MJ, and anti-synthetase / Jo-1) and the change from baseline in one / more specific autoantibodies over the study period). (3) changes in visible clinical skin signs in participants with DM who are concurrently taking ULTOMIRIS (e.g., as assessed by change from baseline in areas with detectable rash using specialized photo analysis at each visit); and (4) the efficacy of ULTOMIRIS in treating DM based on other efficacy endpoints throughout the study (e.g., as assessed by change from baseline using a pruritus measurement scale (5D itch scale) at each visit, proportion of participants meeting clinical worsening criteria, change from baseline in handheld dynamometry performance at each visit, change from baseline in 30-second chair stand test (30sCST) at each visit, and change from baseline in FACIT-Fatigue score over time).

[0184] b. Phase 3 objectives The primary Phase 3 objective is to determine the effect of ULTOMIRIS compared with placebo in the treatment of DM based on improvement in TIS according to the 2016 IMACS (e.g., as assessed by the proportion of participants with a ≥ 20-point improvement response on the IMACS-TIS at Week 50 (TIS20) according to a defined composite evaluand in the randomized controlled period).

[0185] Key secondary objectives are to evaluate the efficacy of ULTOMIRIS compared to placebo in the treatment of DM based on improvement in components of IMACS and other myositis activity measures (e.g., as assessed by mean TIS at week 50, mean change from baseline in MMT-8 at week 50, mean change from baseline in extramuscular disease activity based on MDAAT at week 50, and mean change from baseline in CDASI activity score at week 50).

[0186] Secondary objectives are to evaluate the efficacy of ULTOMIRIS compared to placebo in the treatment of DM based on other efficacy endpoints (e.g., (a) mean change from baseline in Patient Global Activity Assessment at Week 50, (b) mean change from baseline in Physician Global Activity Assessment at Week 50, (c) mean change from baseline in HAQ at Week 50, (d) mean change from baseline in muscle enzyme levels at Week 50, (e) mean TIS at each visit from Week 2 to Week 50, (f) mean change from baseline in DM at each visit from Week 2 to Week 50, (g) mean change from baseline in DM at each visit from Week 2 to Week 50, (h) mean change from baseline in DM at each visit from Week 2 to Week 50, (i) mean change from baseline in DM at each visit from Week 2 to Week 50, (j) mean change from baseline in DM at each visit from Week 2 to Week 50, (k) mean change from baseline in DM at each visit from Week 2 to Week 50, (l ... (g) proportion of participants with a TIS 20 at each visit; (h) proportion of participants with a TIS 60 at each visit; (i) time to first response of TIS 20, TIS 40, or TIS 60, respectively; (j) time to first IMACS Myositis Core Set scale improvement (see MCID for each Core Set scale); (k) time to T = first CDASI activity score improvement (minimal clinically important difference [MCID] = 7 point improvement); (l) proportion of participants with CDASI MCID improvement at week 50; and (m) proportion of participants with CD-IGA change at week 50.

[0187] Additional objectives are to characterize the PK / PD and immunogenicity of ULTOMIRIS in adult participants with DM (e.g., as assessed by serum ULTOMIRIS concentrations over the study period, changes in serum free and total C5 concentrations over the study period, and the presence and titer of ADAs over the study period).

[0188] Another objective is to characterize the overall safety of ULTOMIRIS in participants with DM (e.g., as assessed by the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and TEAEs leading to discontinuation of the study intervention).

[0189] Exploratory objectives are: (1) the effect of ULTOMIRIS compared with placebo on overall health-related quality of life (HR-QoL) and participant-centered and participant-reported outcomes in DM (e.g., as assessed by change from baseline in EQ5D5L at each visit, change from baseline in PROMIS29v2.1 domains over time, change from baseline in SF36 over time, change from baseline in DM symptoms captured by the DM-DSQ over time, and change from baseline in patient self-assessment of disease activity (last question on the DM-DSQ) over time) and (2) the effect of ULTOMIRIS compared with placebo on overall health-related quality of life (HR-QoL) and participant-centered and participant-reported outcomes in DM (e.g., as assessed by change from baseline in EQ5D5L at each visit, change from baseline in PROMIS29v2.1 domains over time, change from baseline in SF36 over time, change from baseline in DM symptoms captured by the DM-DSQ, and change from baseline in patient self-assessment of disease activity (last question on the DM-DSQ) over time) in adult participants with DM; (3) changes in visible clinical skin signs in participants with DM who are concurrently taking ULTOMIRIS (e.g., as assessed by change in areas with detectable rash using specialized photographic analysis); and (4) the efficacy of ULTOMIRIS compared to placebo in treating DM based on other efficacy endpoints throughout the study (e.g., as assessed by change from baseline using a pruritus measurement scale (5D itch scale) at each visit, proportion of participants meeting disease worsening criteria, change from baseline in handheld dynamometry performance at each visit, change from baseline in 30-second chair stand test (30sCST) at each visit, and change from baseline in FACIT-Fatigue score over time).

[0190] c. Unblinded extension purpose The objectives of the open-label extension study include: (1) to evaluate the long-term efficacy of ULTOMIRIS in treating DM based on other efficacy endpoints throughout the study (e.g., via change from baseline using the pruritus measurement scale (5D itch scale) at each visit, change from baseline in CDASI activity score at each visit, change in CD-IGA at week 78, percentage of participants meeting disease worsening criteria, change from baseline in handheld dynamometry performance at each visit, change from baseline in 30-second chair stand test (30sCST) at each visit, and change from baseline in FACIT-Fatigue score at each visit), as well as the long-term use of DM treatments in participants with DM who are concurrently taking ULTOMIRIS (e.g., via percentage of participants on steroid-free or minimal maintenance dose of 5 mg or less at the end of the OLE period, cumulative steroid dose from baseline, number of rescue therapy events and time to first rescue therapy treatment, percentage of participants who changed tolerated DM treatment and time to first DM treatment change).

[0191] Exploratory objectives were: (1) to evaluate the long-term effect of ULTOMIRIS treatment in participants with DM based on improvement in IMACS components (e.g., via mean TIS at week 78, change from baseline in MMT-8 at each visit, change from baseline in Physician Global Activity Assessment at each visit, change from baseline in extramuscular disease activity based on the MDAAT at each visit, and change from baseline in HAQ at each visit); (2) to evaluate the long-term effect of ULTOMIRIS on overall health-related quality of life (HR-QoL) and participant-centered and participant-reported outcomes in DM (e.g., change from baseline in EQ-5D-5L at each visit, change from baseline in PROMIS29v2.1 domains at each visit, change from baseline in SF-36 at each visit, change from baseline in DM symptoms captured by the DM-DSQ at each visit, and change from baseline in Patient Global Assessment of Disease Activity (last question on the DM-DSQ) at each visit). (3) characterizing the long-term safety of ULTOMIRIS in participants with DM (e.g., via incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), and TEAEs leading to discontinuation of the study intervention); (4) characterizing the long-term PK / PD and immunogenicity of ULTOMIRIS in adult participants with DM (e.g., via change in serum ULTOMIRIS concentrations over the study period, change in serum free and total C5 concentrations over the study period, and presence and titer of ADAs over the study period); and (5) evaluating complement, inflammatory, autoimmune, and other soluble biomarkers in adult participants with DM (e.g., via change from baseline in specific autoantibody (e.g., anti-MDA5, anti-NXP2 / MJ, and anti-synthetase / Jo-1) titers over the study period (only in subjects who were positive at baseline), and change from baseline in plasma complement activation (e.g., sC5b-9, etc.) over the study period).

[0192] 2. Major Estimand Part A of the study is exploratory in nature and the primary endpoint is not predefined.

[0193] In Part B, the primary evaluand is the difference in response rates (TIS20) between ULTOMIRIS and placebo at the end of the randomized controlled period in participants with DM, as defined by the study entry criteria. The primary evaluand is based on a combination strategy based on the following:

[0194] Participants with any of the following intervening events were considered treatment failures for purposes of the primary evaluand during the randomized controlled period: (1) prematurely discontinued the study due to safety, tolerability, or efficacy reasons related to ULTOMIRIS; (2) study intervention due to safety, tolerability, or efficacy concerns during the randomized controlled period; (3) increased dose or started new DM treatment (glucocorticoids and / or IST) for any reason during the randomized controlled period; or (4) received prohibited medications / therapy at any time during the randomized controlled period.

[0195] All participants without any intercurrent events will have their IMACS-TIS rating used for primary evaluative purposes.

[0196] Any individual who discontinues the study intervention but has not withdrawn consent will be allowed to remain in the study and complete scheduled assessments.

[0197] Participants with any of the following intercurrent events will be considered treatment failures for the purposes of the primary evaluand during the randomized controlled period: premature discontinuation from the study due to safety, tolerability, or efficacy reasons related to ULTOMIRIS.

[0198] 3. Study Design Study ALXN1210-DM-310 is a Phase 2 / 3, double-blind, randomized, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy, safety, PK, PD, and immunogenicity of ULTOMIRIS in adult participants with DM. An overview of the study is shown in Figure 1. The study will be conducted in two parts: Part A (Phase 2) and Part B (Phase 3). For the purposes of this protocol, information provided that is applicable only to Part A or Part B will be clearly demarcated. Information that is not specifically indicated as pertaining to either Part A or Part B is applicable to both parts.

[0199] a. Part A (Phase 2) Part A of the study has three periods: a screening period, a randomized controlled period, and an OLE period. Participants will be screened for eligibility for up to 4 weeks during the screening period. Approximately 48 eligible participants will be randomized in a 2:1 ratio to receive a weight-based IV infusion of either ravulizumab or matching placebo during the double-blind randomized controlled period. Upon completing the final assessment of the randomized controlled period at week 26, participants may subsequently enter the OLE period.

[0200] For each participant, the randomized controlled period ends and the OLE period begins at week 26. During the OLE period, participants in the ULTOMIRIS arm will continue to receive ULTOMIRIS treatment and participants in the placebo arm will switch to receive ULTOMIRIS treatment. Participants will receive ULTOMIRIS until ULTOMIRIS is registered or approved (subject to country-specific regulations) or for up to 74 weeks (approximately 1.5 years), whichever comes first.

[0201] Participants in the randomized controlled period who discontinue the study intervention early for any reason and agree to remain in the study will receive follow-up for safety and efficacy assessments for the duration of the randomized controlled period. If the decision to discontinue the study intervention is outside of the study visit, the participant will be expected to make the earliest possible unscheduled re-visit within 1 week. Participants in the randomized controlled period who discontinue the study intervention early and do not agree to continue in the study will be expected to complete a study visit (if scheduled at the site) or the earliest possible unscheduled re-visit within 1 week and an ET visit 8 weeks after the participant's last dose of study intervention. In addition, a follow-up phone call will be conducted 20 weeks after the participant's last dose of study intervention to collect concomitant medications, non-pharmacological therapies and procedures, and AEs. Participants who discontinue the study intervention during the randomized controlled period will not be eligible for the OLE period.

[0202] Eight weeks after administration of the final dose of study intervention during the OLE period, all enrolled participants will return for the Week 100 EOS visit, where final study assessments will be conducted. Participants during the OLE period who discontinue study intervention early will be expected to complete a study visit (if scheduled at site) or an ET visit as soon as possible within one week for an unscheduled visit 8 weeks after the participant's final dose of study intervention. In addition, a follow-up phone call will be conducted 20 weeks after the participant's final dose of study intervention to collect concomitant medications, non-pharmacological therapies and procedures, and AEs.

[0203] Safety follow-up should be attempted in all participants for 8 weeks after the last dose of study intervention.

[0204] One interim analysis planned for Part A for dosing purposes. The interim analysis will be conducted conservatively when approximately 50% of participants complete the pre-dose Week 26 visit or prematurely discontinue the randomized controlled period of Part A. Independent statistics will be established to perform the unblinded interim analysis.

[0205] Participants from Part A will not be enrolled in Part B (Phase 3) of the trial and therefore will not contribute to the formal statistical hypothesis testing of Part B.

[0206] b. Part B (Phase 3) Part B of the study will have three periods: a screening period, a randomized-controlled period, and an OLE period. Approximately 132 eligible participants will be stratified by region (North America, Europe, and Asia Pacific) and skin manifestations (Dermatomyositis Skin Disease Area and Severity Index [CDASI] activity score ≦14 and >14) and randomized 1:1 to receive either ravulizumab IV infusion or placebo IV infusion.

[0207] For each participant, the randomized controlled period ends and the OLE period begins at week 50. During the OLE period, participants in the ULTOMIRIS arm continue to receive ULTOMIRIS and participants in the placebo arm switch to receive ULTOMIRIS. Participants will receive ULTOMIRIS until ULTOMIRIS is registered or approved (subject to country-specific regulations) or for up to 74 weeks (approximately 1.5 years), whichever comes first.

[0208] Participants in the randomized controlled period who discontinue the study intervention early and agree to remain in the study will receive follow-up for safety and efficacy assessments for the duration of the randomized controlled period. If the decision to discontinue the study intervention occurs outside of a study visit, participants will be expected to return for the earliest possible unscheduled visit within 1 week.

[0209] Participants in the randomized controlled period who discontinue the study intervention early and do not consent to continuing in the study are expected to complete a study visit (if scheduled at the site) or a return visit for an unscheduled visit as soon as possible within 1 week, and an ET visit 8 weeks after the participant's last dose of study intervention. In addition, a follow-up phone call will be conducted 20 weeks after the participant's last dose of study intervention to collect concomitant medications, non-pharmacological therapies and procedures, and adverse events (AEs). Participants who discontinue the study intervention during the randomized controlled period are not eligible for the OLE period. Eight weeks after administration of the last dose of study intervention during the OLE period, all enrolled participants will return for an EOS visit at week 124, where the final study evaluation will be conducted. Participants in the OLE period who discontinue the study intervention early are expected to complete a study visit (if scheduled at the site) or a return visit for an unscheduled visit as soon as possible within 1 week, and an ET visit 8 weeks after the participant's last dose of study intervention. In addition, a follow-up telephone call will be conducted 20 weeks after the participant's final dose of study intervention to collect concomitant medications, non-pharmacological therapies and procedures, and AEs.

[0210] All participants will be followed up for safety for 8 weeks after the final dose of study intervention.

[0211] One interim analysis is planned for sample size re-estimation for Part B. The unblinded interim analysis will be conducted by an independent Data Monitoring Committee (DMC). Treatment assignment during the randomized controlled period will remain blinded throughout the study. The interim analysis for sample size re-estimation will be conducted prudently when approximately 30% of participants complete the pre-dose Week 50 visit or prematurely discontinue Part B.

[0212] C. Clinical deterioration In this protocol, clinical deterioration is defined as the presence of one of the following criteria on two consecutive visits approximately 4 weeks apart: a. Physician global activity visual analog scale (VAS) worsening ≥ 2 cm and 8-muscle manual muscle testing subset (MMT-8) worsening ≥ 20% compared to baseline; b. Myositis Disease Activity Assessment Tool (MDAAT) VAS global extramuscular activity worsening ≥ 2 cm compared to baseline; and / or c. ≥30% deterioration in any three of the five Core Set Scales (CSM) (excluding muscle enzymes) compared to baseline.

[0213] Exacerbation will be determined using the criteria provided above. An unscheduled visit will occur 4 weeks after the visit where the participant showed the first signs of exacerbation. At the unscheduled visit, the investigator will check the above criteria to determine if the participant continues to show signs of exacerbation. If the participant meets the definition of clinical exacerbation, glucocorticoid rescue therapy may be administered.

[0214] Participants may take rescue medication, which may be an increased dose of medication currently being used to treat DM symptoms or a newly initiated DM treatment (glucocorticoids and / or IST), and the study intervention will be discontinued.

[0215] Participants in the randomized controlled period who, for any reason, discontinue the study intervention early and agree to remain in the study will be followed up for safety and efficacy assessments for the duration of the randomized controlled period. If the decision to discontinue the study intervention is outside of a study visit, participants will be expected to return for the earliest possible unscheduled visit within 1 week.

[0216] Participants in the randomized controlled period who discontinue the study intervention early and do not consent to continuing in the study are expected to complete a study visit (if scheduled at the site) or a return visit for an unscheduled visit as soon as possible within 1 week and an ET visit 8 weeks after the participant's last dose of study intervention. In addition, a follow-up telephone call will be conducted 20 weeks after the participant's last dose of study intervention to collect concomitant medications, non-pharmacological therapies and procedures, and AEs. The investigator will determine whether participants who meet the definition of clinical deterioration should remain on the study intervention. Participants who discontinue the study intervention during the randomized controlled period are not eligible for the OLE period.

[0217] Clinical deterioration criteria will be checked at both visits during the randomized control period and the OLE period.

[0218] d. Completion of treatment Participants are considered to have completed study treatment during the randomized controlled period if they do not permanently discontinue the study intervention before the Week 26 (Part A) or Week 50 (Part B) visit. All participants who discontinue the study intervention during the randomized controlled period will be followed up for safety and efficacy assessments until the end of the randomized controlled period, withdrawal of consent, or loss to follow-up, whichever occurs first.

[0219] Participants are considered to have completed study treatment during the OLE period if they do not discontinue ULTOMIRIS treatment before the EOS visit at Week 100 (Part A) or Week 24 (Part B), or before the participant stops study early due to study cessation or transition to an approved product.

[0220] Participants were considered to have completed the randomized controlled period of the study if they completed the last scheduled visit specified in the schedule of activities for that period.

[0221] 4. Study population Selection Criteria Participants were eligible for inclusion in the study only if they met all of the following criteria: 1. 18 years of age or older at the time of signing informed consent. 2.Weight ≥ 30 kg at screening. 3. Male or female. 4. Diagnosis: Meets the 2017 ACR / EULAR classification criteria for definite or probable DM (see Lundberg IE, et al., Arthritis Rheumatol. 2017;69(12):2271-2282). 5. Participant has had an inadequate response or is intolerant to two or more DM treatments, either in combination or as monotherapy, including systemic glucocorticoids or IST (e.g., azathioprine, methotrexate, rituximab, IVIg). 6. Glucocorticoid- and / or IST-treated participants who receive and may remain on stable therapy as described in Table 5 throughout the randomized control period, or who have completed the appropriate washout period for these treatments prior to the Day 1 visit as described in Table 12 (e.g., 6-month washout period for rituximab; 3-month washout period for IVIg or subcutaneous immunoglobulin [SCIg]). 7. Disease Severity: Participants demonstrating disease severity using the following criteria at screening: MMT-8 of ≦142 / (out of a maximum of 150) and 2 additional IMACS CSMs of 5 at screening, e.g.: (a) Patient Global Activity Assessment of ≧2.0 cm on a 10 cm VAS; (b) Physician Global Activity Assessment of ≧2.0 cm on a 10 cm VAS; (c) HAQ Disability Index of ≧0.25; (d) at least one of the muscle enzymes (including creatine kinase [CK], aldolase, lactate dehydrogenase [LDH], alanine aminotransferase [ALT], and aspartate aminotransferase [AST]) elevated to ≧1.3 times the upper limit of normal (ULN); and / or (e) Global Extramuscular Disease Activity Score of ≧2.0 cm on a 10 cm VAS (this measure is a physician composite assessment and is based on assessment of activity scores on the MDAAT total body, skin, skeletal, gastrointestinal, pulmonary, and cardiac scales). 8. Disease Activity: Participants must meet one of the criteria below to ensure enrollment for active disease and not weakness due to muscle damage. An Independent Adjudication Committee (IAC) will be used to assess the eligibility of participants who do not meet the criteria listed below but who, in the opinion of the Investigator, qualify for the study. a. Muscle or skin biopsy with evidence of active pathology of DM within the past 6 months prior to screening or at the time of screening; b. Electromyography evidence of active myositis within the past 6 months prior to screening; c. Magnetic resonance imaging (MRI) muscle evidence of active myositis within the past 6 months prior to screening; d. At least one muscle enzyme (CK, LDH, aldolase, AST, ALT) of the IMACS panel at screening is ≥2x the ULN; and / or e. Active DM rash characterized by inflammatory changes (CDASI activity score ≥ 7) at screening. 9. Vaccinate against N meningitidis within 3 years prior to starting ULTOMIRIS according to national and local guidelines. Participants must be vaccinated at least 2 weeks prior to the first study intervention. National and local guidelines for prophylactic antibiotics will also be followed. 10. Participants diagnosed with cancer within the past 3 years must have an adequate negative cancer screen according to local standard of care within 6 months prior to screening (basal or squamous cell skin cancer or carcinoma in situ of the cervix must have been excised and cured at least 3 months prior to screening). 11. Female and male participants of childbearing potential must follow contraceptive guidance as specified in the protocol. 12. Capable of giving signed informed consent as described in the protocol, including compliance with the requirements and limitations listed in the Informed Consent Form (ICF) and the protocol.

[0222] b. Exclusion criteria Participants will be excluded from the study if any of the following criteria apply: 1. Cancer-associated myositis defined as a diagnosis of myositis within 3 years of a cancer diagnosis (excluding basal or squamous cell skin cancer or carcinoma in situ of the cervix that has been excised and healed at least 3 months prior to screening). 2. Active malignancy or evidence of malignancy (including hematologic malignancies and solid tumors) diagnosed within the past 5 years (excluding basal or squamous cell skin cancer or carcinoma in situ of the cervix that has been excised and healed for at least 3 months prior to screening). 3. Other forms of myositis: Participants with a clinical diagnosis of inclusion body myositis, polymyositis, necrotizing myositis, drug-induced myositis / myopathy, DM non-concomitant antisynthetase syndrome, cancer-associated myositis (myositis diagnosed within 3 years either prior to or after diagnosis of a malignancy except for cutaneous squamous cell carcinoma, basal cell carcinoma, carcinoma in situ lesion of any location, or cervical intraepithelial carcinoma), myositis with overlapping connective tissue disease such as SLE, rheumatoid arthritis, or systemic sclerosis. Participants with secondary Sjogren's syndrome are permitted. 4. Participant with significant muscle damage according to the investigator's opinion (e.g., severe muscle atrophy, end-stage muscle disease, MRI with concomitant severe atrophy or fibrofatty replacement). 5. History of meningococcal (N meningitidis) infection. 6. Human immunodeficiency virus (HIV) infection (evidenced by HIV type 1 or 2 antibody titers). 7. History of infection of unknown origin. 8. Active systemic bacterial, viral, or fungal infection within 14 days prior to ULTOMIRIS administration. 9. Presence of fever ≥ 38°C (100.4°F) within 7 days prior to administration of study intervention on Day 1. 10. History of hypersensitivity to murine proteins or one of the excipients in ravulizumab. 11. Participant with advanced clinical symptomatic interstitial lung disease (in the opinion of the investigator) as supported by a history of fibrosis on chest x-ray, a history of interstitial lung disease on lung computed tomography (CT) scan, or a confirmed history of forced vital capacity percent predicted <80% associated with DM. 12. Any medical condition (e.g., diagnosis of cardiac, pulmonary, renal, oncologic, psychiatric, or fibromyalgia) that, in the opinion of the Investigator, may interfere with the participant's participation in the trial, impose any additional risk on the participant, or confound the participant's evaluation. This includes participants with severe arthritis or severe diffuse calcinosis that limits range of motion or other conditions that would interfere with quantitative muscle strength testing. 13. History of drug and / or alcohol abuse (according to the Diagnostic and Statistical Manual of Mental Disorders [DSM] 5) within 1 year prior to the Screening Visit that may limit the participant's participation in the study as determined by the Investigator. 14. Participant is unwilling or unable to complete any appropriate washout period of prohibited medications prior to the Day 1 visit. 15.Has taken ≥ 1 mg / kg / day of prednisone or equivalent within 8 weeks prior to randomization or is currently taking a maintenance dose of > 20 mg / day of prednisone or equivalent. 16. Previously treated or currently being treated with a complement inhibitor. 17. Participation in any other investigational drug trial or exposure to an investigational drug or device within 30 days of screening or within 5 half-lives of an investigational drug, whichever is greater. 18. Participant begins a new muscle-strengthening exercise program (e.g., physical therapy [PT]) for myositis or changes their current exercise regimen for up to 4 weeks in the last 4 weeks prior to the visit on Day 1. Participants should not start any new exercise program or change their current exercise regimen throughout the randomized phase of the trial. 19. Pregnancy, lactation, or intent to conceive during the study period. 20. Unable or unwilling to comply with protocol requirements.

[0223] 5. Study Intervention A study intervention is defined as any investigational intervention, commercial product, placebo, or medical device intended to be administered to study participants according to the study protocol.

[0224] ULTOMIRIS IV is formulated at 10 mg / mL and 100 mg / mL concentrations with pH 7.0 and 7.4, respectively. Both formulations are presented as sterile, preservative-free solutions and supplied in single-use vials for IV administration.

[0225] The placebo comparator drug will be formulated as a compatible, sterile, clear, colorless solution with the same buffer components but without the active ingredient.

[0226] Details regarding the ravulizumab IV formulation are shown in Table 1.

[0227] [Table 1]

[0228] At the scheduled dosing visit, the study intervention infusion should be performed after all other tests and procedures have been completed, except for post-dose blood sampling for PK / PD.

[0229] The ravulizumab or placebo dose for each participant will be administered as an IV infusion based on body weight. The dosing regimen will consist of a loading dose followed by a maintenance dose administered q8w (see Table 2). Maintenance doses will begin 2 weeks after the loading dose administration. Table 3 is a reference chart for weight-based dosing.

[0230] [Table 2]

[0231] [Table 3-1]

[0232] [Table 3-2]

[0233] Part A For each participant in Part A, the total treatment period will be up to 100 weeks, consisting of a randomized controlled period (26 weeks) and an OLE period (up to 74 weeks).

[0234] The randomized control period is a double-blind, randomized, placebo-controlled period. Eligible participants will be randomized 2:1 to receive a blinded dose of ravulizumab or placebo beginning on Day 1 and ending after a pre-dose evaluation at Week 26. Participants in the ravulizumab group will receive a blinded loading dose of ravulizumab (10 mg / mL formulation) via IV infusion on Day 1, followed by blinded maintenance doses at Weeks 2, 10, and 18. Participants in the placebo group will receive a blinded matching placebo via IV infusion on Day 1, followed by blinded matching placebo at Weeks 2, 10, and 18. Participants who discontinue the study intervention will be followed for key efficacy and safety assessments until the end of the randomized control period, consent withdrawal, or loss to follow-up, whichever occurs first.

[0235] The randomized controlled period will end after all pre-dose assessments are completed at the Week 26 visit. The Open-Blind Extension Period (OLE) period will begin when participants who elect to continue treatment receive their Week 26 study intervention infusion. Participants in both the placebo and ravulizumab groups will receive a blinded dose of ravulizumab as follows: Participants in the placebo group will switch to receive a blinded loading dose of ravulizumab (10 mg / mL formulation) at Week 26 (Table 3). Participants in the ravulizumab group will receive a 900 mg blinded ravulizumab dose (10 mg / mL formulation) at Week 26. The 900 mg dose at Week 26 will be chosen to maintain full C5 inhibition for a period of 2 weeks until the next scheduled maintenance dose. This administration will maintain the treatment randomization blind of the randomized controlled period. Beginning at week 28, all participants will receive an open-label ULTOMIRIS maintenance dose (10 mg / mL or 100 mg / mL formulation) q8w until the end of the OLE period (see Table 3).

[0236] b. Part B For each participant in Part B, the total treatment period will be up to 124 weeks, consisting of a randomized controlled period (50 weeks) and an OLE period (up to 74 weeks).

[0237] The randomized control period is a double-blind, randomized, placebo-controlled period. Eligible participants will be randomized 1:1 to receive a blinded dose of ravulizumab or placebo beginning on Day 1 and ending after the pre-dose evaluation at Week 50. Participants in the ravulizumab group will receive a blinded loading dose of ravulizumab (10 mg / mL formulation) via IV infusion on Day 1, followed by a blinded maintenance dose at Week 2 and q8w thereafter until Week 42 (Table 3). Participants in the placebo group will receive a blinded matching placebo via IV infusion on Day 1, followed by a blinded matching placebo at Week 2 and q8w thereafter until Week 42 (Table 3). Participants who discontinue the study intervention will be followed for key safety and efficacy assessments until the end of the randomized control period, consent withdrawal, or loss to follow-up, whichever occurs first.

[0238] The randomized controlled period will end after all pre-dose assessments are completed at the Week 50 visit. The OLE period will begin when eligible participants who elect to continue treatment receive their Week 50 study intervention infusion. Participants in both the placebo and ravulizumab groups will receive a blinded dose of ravulizumab as follows: Participants in the placebo group will switch to receive a blinded loading dose of ravulizumab (10 mg / mL formulation) at Week 50 (Table 3). Participants in the ravulizumab group will receive a 900 mg blinded ravulizumab dose (10 mg / mL formulation) at Week 50. The 900 mg dose at Week 50 will be chosen to maintain full C5 inhibition for a period of 2 weeks until the next scheduled maintenance dose. This administration will maintain the treatment randomization blind of the randomized controlled period. Beginning at week 52, all participants will receive an open-label ULTOMIRIS maintenance dose (10 mg / mL or 100 mg / mL formulation) q8w until the end of the OLE period (Table 3).

[0239] c. Preparation / Handling / Storage / Accountability Upon arrival of the study intervention at the study site, the study intervention kit will be removed from the shipping container and stored in its original carton under refrigerated conditions at 2°C to 8°C (35°F to 47°F) and protected from light. The study intervention will not be frozen. The study intervention must be stored in a secure, limited-access storage area with daily temperature monitoring. Study intervention injections will be prepared using aseptic technique. Ravulizumab and placebo will be further diluted in a 1:1 ratio with compatible diluents. Ravulizumab and placebo will be filtered through a 0.2 micron filter at the time of injection.

[0240] 6. Combination Therapy Any medications (including over-the-counter or prescription medications, vitamins, and / or herbal supplements), vaccines, or other specific target categories the participant is taking at enrollment or will take during the study must be recorded with the following: (1) reason for use, (2) dates of administration, including start and end dates, and (3) dosage information, including dose and frequency.

[0241] Participants continuing on an accepted DM treatment as concomitant therapy are required to have been on that treatment for at least the amount of time listed in Table 4 prior to the Day 1 visit and are required to maintain a stable dose during the randomized control period. The maximum accepted stable dose is listed in Table 4. In some cases, the stable dose of accepted DM treatment may be reduced due to safety and / or tolerability issues.

[0242] During the OLE period, doses of allowed DM treatments may be changed or discontinued. New allowed DM treatments may be initiated during the OLE period. Medications listed in Table 5 are prohibited during the OLE period. Any changes in medications will be properly documented on the CRF.

[0243] [Table 4]

[0244] Alternatively, participants may choose to discontinue prior DM treatment prior to the Day 1 visit, but will be required to complete the appropriate washout period as described in Table 5.

[0245] [Table 5]

[0246] The following medications may be taken as needed, but should not be administered within 72 hours prior to the study visit: antihistamines (oral and topical), ibuprofen, acetaminophen, antipruritics, and topical steroids (1% hydrocortisone).

[0247] Vitamin B12, Vitamin E, Creatine, Coenzyme Q10, and Biotin supplements are permitted in this study. Participants taking any or all of these supplements should begin on a stable dose 14 days prior to the first dose of the study intervention and maintain a stable dose for the duration of the randomized controlled period of the study unless a dose modification is deemed medically necessary. All other vitamins and supplements are permitted in this study. Participants are encouraged to maintain a stable dose for the duration of the randomized controlled period of the study.

[0248] The following medications and therapies are prohibited at the time of the study: (1) the treatments listed in Table 6 (participants must complete the appropriate washout periods for these treatments prior to the Day 1 visit), (2) eculizumab or other complement inhibitors, and (3) any off-label use of approved products currently under investigational use for the treatment of DM at the time of the study.

[0249] [Table 6]

[0250] Participants who require prohibited medication at any time during the study will discontinue the study intervention.

[0251] To allow sufficient time for the study medication to take effect, participants are encouraged not to receive any rescue therapy during the first 10 weeks of receiving the study intervention during the randomized controlled period. If at any time during the randomized controlled period the participant requires rescue therapy in the form of a dose escalation or initiation of a new DM treatment (glucocorticoids and / or IST), the participant will discontinue the study intervention.

[0252] Participants in the randomized controlled period who, for any reason, discontinue the study intervention early and agree to remain in the study will be followed up for safety and efficacy assessments for the duration of the randomized controlled period. If the decision to discontinue the study intervention is outside of a study visit, participants will be expected to return for the earliest possible unscheduled visit within 1 week.

[0253] Participants in the randomized controlled period who discontinue the study intervention early and do not consent to continuing in the study are expected to complete a study visit (if scheduled at the site) or a return visit for an unscheduled visit as soon as possible within 1 week and an ET visit 8 weeks after the participant's last dose of study intervention. In addition, a follow-up telephone call will be conducted 20 weeks after the participant's last dose of study intervention to collect concomitant medications, non-pharmacological therapies and procedures, and AEs. Patients who discontinue the study intervention during the randomized controlled period are not eligible for the OLE period. Glucocorticoid tapering will be allowed as needed throughout the OLE period.

[0254] 7. Test Evaluation Procedures Study procedures and their timing are summarized in the Schedule of Activities. The Schedule of Activities for Part A (from screening to the end of the randomized controlled period) is shown in Figures 6A-6F. The Schedule of Activities for Part B (from screening to the end of the randomized controlled period) is shown in Figures 7A-7F. The Schedule of Activities for the open-label extension period of Parts A and B is shown in Figures 8A-8G.

[0255] No protocol waivers or exemptions will be permitted. All screening assessments must be completed and reviewed to ensure potential participants meet all eligibility criteria. The investigator will maintain a screening log to record details of all participants screened and to confirm eligibility or record reasons for screening failure, if applicable. Procedures performed as part of the participant's routine clinical management (e.g., blood counts) and accomplished prior to signing of the Informed Consent Form (ICF) may be used for screening or baseline purposes, provided the procedures meet the criteria specified in the protocol and are performed within the time frame defined in the Schedule of Activities.

[0256] Efficacy evaluation All efficacy assessments not completed by the participants themselves should preferably be conducted by the same study staff members throughout the study. Below are example efficacy assessments:

[0257] i. International Myositis Assessment and Clinical Trials (IMACS) Core Set Scale (CSM) The IMACS group developed consensus on outcome measures and definitions of improvement to be used in clinical trials for DM (see Aggarwal R, et al., Arthritis Rheumatol. 2017;69(5):898-910). The CSM is described in the following subsections.

[0258] ii.8-Muscle Manual Muscle Testing Group (MMT-8) The purpose of the MMT-8 is to measure muscle strength as part of a health check. It includes eight muscle groups: neck flexors, deltoids, biceps, wrist extensors, gluteus maximus and medius, quadriceps, and a subset of ankle dorsiflexors (Rider LG, et al., Measures of adult and juvenile dermatomyositis, polymyositis, and inclusion body myositis: Physician and Patient / Parent Global Activity, Manual Muscle Testing (MMT), Health Assessment Questionnaire (HAQ) / Childhood Health Assessment Questionnaire (C-HAQ), Childhood Myositis Assessment Scale (CMAS), Myositis Disease Activity Assessment Tool (MDAAT), Disease Activity Score (DAS), Short Form 36 (SF-36), Child Health Questionnaire (CHQ), physician global damage, Myositis Damage Index (MDI), Quantitative Muscle Testing (QMT), Myositis Functional Index-2 (FI-2), Myositis Activities Profile (MAP), Inclusion Body Myositis Functional Rating Scale (IBMFRS), Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), Cutaneous Assessment Tool (CAT), Dermatomyositis Skin Severity Index (DSSI), Skindex, and Dermatology Life Quality Index (DLQI). Arthritis Care Res (Hoboken). 2011b;63 Suppl 11:S118-157).MMT-8 will be administered at the time points listed in the Schedule of Evaluations.

[0259] iii. Physician Global Activity Assessment The Physician Global Activity Assessment provides an overall rating of disease activity associated with myositis. Disease activity is judged by the physician based on all information available at the time of assessment, including the participant's appearance, medical history, physical examination, laboratory tests, and prescribed medical therapy. The Global Disease Activity Score is recorded on a 10 cm VAS with fixed endpoints and midpoints. The Physician Global Activity Assessment is completed at the time points listed in the Schedule of Assessments. An exemplary Physician Global Activity Assessment is shown in FIG. 2.

[0260] iv. Patient Global Activity Assessment The Patient Global Activity Assessment provides an overall rating of disease activity related to myositis from the participant's perspective. Participants are asked to consider any active inflammation in their muscles, skin, joints, intestines, heart, lungs, or other parts of the body that may be improved with treatment. The Patient Global Disease Activity Score is recorded on a 10 cm VAS that contains a smiley face at the 0 cm fixation point and a sad face at the 10 cm fixation point to help participants understand the scale (see Rider LG, et al., Arthritis Care Res (Hoboken). 2011b; 63 Suppl 11: S118-157). The Patient Global Activity Assessment is completed at the time points listed in the schedule of activities. An exemplary Patient Global Activity Assessment is shown in FIG. 3.

[0261] v. Health Assessment Questionnaire (HAQ) The HAQ is a brief self-report questionnaire that assesses physical function for activities of daily living in various domains (see Rider LG, et al., Arthritis Care Res (Hoboken). 2011b;63 Suppl 11:S118-157). The full 5-dimensional HAQ includes the following domains: disability, discomfort and pain, adverse drug reactions, and dollar cost. In this study, the HAQ Disability Index is completed at the time points listed in the schedule of activities.

[0262] vi. Muscle Enzymes As part of the IMACS CSM, laboratory tests will be performed to measure serum activity of muscle-related enzymes, including CK, ALT and AST, LDH, and aldolase. The most abnormal serum muscle enzyme value at baseline will be used (Aggarwal R, et al., 2016 American College of Rheumatology / European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis: An International Myositis Assessment and Clinical Studies Group / Paediatric Rheumatology International Trials Organisation Collaborative Initiative. Arthritis Rheumatol. 2017;69(5):898-910). Muscle enzymes will be assessed at the time points listed in the schedule of activities.

[0263] vii. Myositis Disease Activity Assessment Tool (MDAAT) The MDAAT assesses disease activity in extramuscular organ systems and muscle in patients with DM. It is a combination tool that includes the Myositis Disease Activity Assessment VAS (MYOACT) and the Myositis Intent to Treat Activity Index (MITAX). The MITAX assesses specific signs in seven organs / systems: systemic, skin, skeletal, gastrointestinal, pulmonary, cardiac, and muscular. It consists of the MYOACT, a 10 cm VAS for each organ system and globally. The MDAAT is administered by the patient and completed by a clinician (see Rider LG, et al., Arthritis Care Res (Hoboken). 2011b;63 Suppl 11:S118-157). The MDAAT is completed at the time points listed in the Schedule of Assessments.

[0264] viii. Dermatomyositis Skin Disease Area and Severity Index (CDASI) The CDASI is an instrument that measures activity and damage separately on the skin of DM patients. It is a one-page instrument that contains three activity scales (erythema, scaling, and erosion / ulceration) and two damage scales (poikiloderma and calcification). The CDASI is completed by a clinician or clinician-investigator while examining the participant (see Rider LG, et al., Arthritis Care Res (Hoboken). 2011b; 63 Suppl 11:S118-157). The CDASI is completed at the time points listed in the schedule of activities.

[0265] ix. Physician Global Assessment of Dermatomyositis Skin Activity (CD-IGA) The CD-IGA is a scale developed to measure disease severity in patients with skin disease. It is a 5-point scale (0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe) with morphological descriptors for each score. The CD-IGA is completed by the investigator and describes the overall appearance of the lesions at given time points. The CD-IGA is completed at the time points listed in the schedule of assessments.

[0266] x.EuroQoL5-dimensional (EQ-5D-5L) The European Quality of Life and Health 5-item Questionnaire Dimension 5 Level (EQ5D5L) is a self-assessed standardized instrument measuring health-related quality of life and has been used across a wide range of health conditions (Schrag A, et al., Journal of neurology, neurosurgery, and psychiatry. 2000;69(1):67-73). The EQ5D5L consists of two pages: the EQ-5D-5L descriptor and the EQVAS. The EQ-5D-5L is completed at timepoints specified in the schedule of assessments, or the EQ-5D-5L can be assessed via telephone if participants are unable to make the scheduled onsite visit.

[0267] xi.EQ-5D-5L description system The descriptor system is a five-component scale that includes mobility, self-care, daily activities, pain / discomfort, and anxiety / depression. Each level is graded on a scale that describes the degree of problem in that area.

[0268] xii.EQ Visual Analog Scale The EQVAS is a global health status scale in which participants select a number from 0 to 100 to describe their health status, with 100 being "the best health you can imagine" and 0 being "the worst health you can imagine."

[0269] This information can be used as a quantitative measure of health outcomes judged by individual responders. Published trials by EuroQol group members have demonstrated preliminary evidence of the instrument's feasibility, reliability, and validity.

[0270] xiii.5D Itch Scale The 5D Itch Scale is a multidimensional questionnaire that includes five dimensions: severity, duration, direction, interference, and distribution (see, e.g., Elman et al., Br. J. Dermatol. 2010 Mar;162(3):587-93). The 5D Itch Scale is completed by participants at time points described in the schedule of activities.

[0271] xiv. Patient-Reported Outcomes Measurement Information System (PROMIS) 29 v2.1 Tool The PROMIS29v2.1 profile assesses pain intensity using a single 0-10 numeric rating scale and seven health domains (physical function, fatigue, pain interference, depression, anxiety, ability to engage in social roles and activities, and sleep disturbance) with four items per domain (see, e.g., Hays et al., Qual. Life Res. 2018 Jul;27(7):1885-1891). PROMIS29v2.1 is completed by participants at time points described in the schedule of activities.

[0272] xv. Short-Form Health Survey (36-question version) (SF-36) The SF-36 (Version 2.0) is a 36-item self-report of health-related quality of life (see Stewart AL,et al.,Med Care.1988;26(7):724-735; and Ware et al.,Med Care.1992;30(6):473-483). It contains eight subscales that measure different domains of health-related quality of life: physical functioning, role limitations due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitations due to emotional problems, and mental health. The SF-36 is administered at screening and at time points specifically indicated for each schedule of activities. The two summary scores are the Physical Component Summary and the Mental Component Summary. There is no single overall score for the SF-36.

[0273] xvi. Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) The FACIT-Fatigue scale (Version 4) is a brief 13-item self-report easy-to-administer tool that measures an individual's fatigue level during normal daily activities over the past week (see, e.g., Tennant, K., Supportive Care in Cancer 23.5(2015):1355-1364). Fatigue level is measured on a 5-point Likert-type scale (0=not fatigued at all, 1=a little fatigued, 2=some fatigued, 3=a lot of fatigued, and 4=extreme fatigued). All items contribute equally weighted to the sum score. The FACIT-Fatigue is completed at time points specified in the schedule of activities. An exemplary FACIT-Fatigue is shown in FIG. 4.

[0274] xvii. Dermatomyositis Disease Symptom Questionnaire (DM-DSQ) The Dermatomyositis Disease Symptom Questionnaire (DM-DSQ) version 1.0 is a 14-item PRO instrument designed to assess symptoms related to patients' experience of DM in the past 24 hours. Each item was generated based on a corresponding concept extracted from published qualitative literature (interviews or focus groups with patients) or from direct patient input (minutes of meetings with patients describing their disease and video testimonials from patients from the Myositis Society). There are 13 symptom questions graded according to severity on a 5-point response scale (asymptomatic, mild, moderate, severe, and very severe) and one overall question regarding disease activity graded on a 5-point response scale (not at all active, mildly active, moderately active, very active, extremely active). The DM-DSQ is completed at time points specified in the schedule of activities. An exemplary DM-DSQ is shown in FIG. 5.

[0275] xviii. 30-second chair stand test (30sCST) The 30sCST is a procedure to assess proximal muscle function (see Agarwal S, Kiely PD, Rheumatology (Oxford). 2006; 45(7): 874-879; and Rider LG, et al., Nat. Rev. Rheumatol. 2018; 14(5): 303-318). During the test, participants are asked to rise and sit down from a standard-height chair as many times as possible in 30 seconds. The 30sCST is assessed at time points specified in the schedule of activities.

[0276] xix. Handheld Dynamometry Handheld dynamometry (see Rider LG, et al., Nat. Rev. Rheumatol. 2018;14(5):303-318) is a procedure for quantitative strength testing. This testing will be performed by the Investigator or any designee who is appropriately trained for quantitative muscle strength assessment. It is highly recommended that all assessments be performed by the same assessor, if possible. Muscle strength testing will be performed on pre-specified muscles on both sides of the upper and lower extremities and force measurements will be recorded. Handheld dynamometry will be assessed at screening and at time points specified in the schedule of activities.

[0277] xx. Skin rash photo High-resolution digital images of the skin lesions are taken at time points specified in the schedule of activities.

[0278] xxi. Home Electronic Patient-Reported Outcomes In Part A, participants will be asked to complete the following PROs: DM-DSQ, HAQ, PROMIS29v2.1, FACIT-Fatigue, and SF-36 at the frequency stated in the schedule of activities.

[0279] These PROs are completed using an electronic device (e.g., an iPad®). Further details of selected PROs and the processes associated with completing the PROs are included in a separate electronic PRO (ePRO) manual.

[0280] b. Safety evaluation Planned timepoints for all safety evaluations are provided in the Schedule of Activities.

[0281] As with any complement C5 inhibition, the use of ravulizumab increases participants' susceptibility to meningococcal infection (N meningitidis). To reduce the risk of meningococcal infection, all participants must be vaccinated against meningococcal infection within 3 years prior to or at the start of the study intervention. Participants must be vaccinated at least 2 weeks prior to the first study intervention. Participants must be vaccinated or revaccinated according to current national vaccination guidelines or local norms for vaccination use with complement inhibitors (e.g., eculizumab, ravulizumab). To prevent common pathogenic meningococcal serotypes, vaccines against serotypes A, C, Y, W135, and B are recommended, where available. Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given to official guidance and local norms regarding the appropriate use of antibacterial agents. All participants should be monitored for early signs of meningococcal infection and, if infection is suspected, should be promptly evaluated and, if necessary, treated with appropriate antibiotics.

[0282] A complete physical examination will include, at a minimum, evaluation of the following organs / body systems: skin, head, ears, eyes, nose, throat, neck, lymph nodes, chest, heart, abdomen, limbs, and musculoskeletal. A prescribed physical examination will, at a minimum, include body system-related examinations based on investigator judgment and participant symptoms. Examiners should pay special attention to clinical signs associated with prior serious illness. To ensure consistency, every effort should be made to have the physical examination performed by the same certified study staff at each study visit. Additional physical examinations may be performed at the investigator's discretion if medically indicated at the time of the study.

[0283] Weight is measured in pounds or kilograms. Height is measured in inches or centimeters.

[0284] Temperature (° C. or° F.), pulse rate, respiratory rate, and systolic and diastolic blood pressure (mmHg), and pulse oximetry will be assessed.

[0285] Blood pressure and pulse measurements are assessed in a seated position with fully automated equipment, manual techniques are used only if automated equipment is not available.

[0286] Blood pressure and pulse measurements should be taken with the participant resting for at least 5 minutes in a quiet setting without distractions (e.g., television, cell phone). Ideally, the same arm should be used for each participant. O2 saturation (%) will be collected using pulse oximetry.

[0287] A single 12-lead electrocardiogram (ECG) will be provided using an ECG machine at the visit specified in the schedule of activities protocol to obtain measures of heart rate and PR, QRS, QT, and QT intervals. Participants will lie supine and remain supine approximately 5-10 minutes prior to ECG collection, but must be awake at the time of ECG collection.

[0288] The clinical tests shown in Table 7 will be performed by a central laboratory. Additional tests may be performed at any time during the study if deemed necessary by the investigator or required by local regulations.

[0289] [Table 7]

[0290] The Investigator must review the laboratory reports, document this review, and record any clinically relevant changes occurring during the study in the Adverse Events section of the eCRF. Laboratory reports must be filed with the original documentation. Clinically significant abnormal laboratory findings are not related to an underlying disease unless judged by the Investigator to be more severe than would be expected for the participant's condition.

[0291] All laboratory tests with values ​​considered clinically significantly abnormal at the time of entry into the study or within 8 weeks after the last dose of study intervention should be repeated until the values ​​return to normal or baseline or are no longer considered clinically significant.

[0292] Pregnancy testing should be performed in all females of childbearing potential.

[0293] 8. Adverse Events (AEs) and Serious Adverse Events (SAEs) Adverse events are reported by the participant (or by the caregiver, representative, or legally authorized representative of the participant, as appropriate) to the investigator. An AE is defined as any untoward medical occurrence in a participant or clinical trial participant to whom a medicinal product has been administered, which does not necessarily have to have a causal relationship to this treatment (ICH E2A). Thus, an AE can be any adverse and unintended sign (including abnormal laboratory findings), symptom, or disease [new or worsening] temporally related to the use of the study intervention, whether or not it is considered related to the study intervention.

[0294] The following events meet the definition of an adverse event: 1. Any abnormal clinical laboratory results (hematology, clinical chemistry, or urinalysis) or other safety assessments (e.g., electrocardiogram, radiology scan, vital sign measurements), including any deterioration from baseline, that are considered clinically significant (i.e., not associated with progression of the underlying disease) in the medical and scientific judgment of the investigator. 2. An exacerbation of a chronic or intermittent pre-existing condition, including an increase in the frequency and / or intensity of the condition. 3. Any new condition that may have been present before the start of the study but is detected or diagnosed after administration of the study intervention. 4. Signs, symptoms, or clinical sequelae of a suspected drug-drug interaction. 5. Signs, symptoms, or clinical sequelae suspected of overdose of the study intervention or concomitant medication. Overdose itself is not reported as an AE / SAE unless it is an intentional overdose with possible suicidal / self-harming behavior. Such overdoses should be reported regardless of sequelae.

[0295] The following events do not meet the definition of an adverse event: 1. Medical or surgical procedure (e.g., endoscopy, appendectomy): A condition leading to this procedure is an AE. A condition that did not result in an adverse medical occurrence (e.g., hospitalization for elective surgery, hospitalization for social reasons or convenience if scheduled before signing the ICF). 2. Anticipated day-to-day variation of a pre-existing disease or condition present or detected at the start of the study that does not worsen. 3. Medication errors (including intentional misuse, abuse, or overdosing of an investigational product) or use other than as defined in the protocol will not be considered an AE unless there is an adverse medical occurrence as a result of the medication error. 4. Cases of pregnancy occurring during maternal or paternal exposure to the investigational intervention will be reported within 24 hours of the Investigator / Institution's knowledge. Data regarding fetal outcome and lactation will be collected for regulatory reporting and safety evaluation. 5. Clinically significant abnormal laboratory findings or other abnormal safety assessments related to the underlying disease, unless judged by the Investigator to be more severe than expected for the participant's condition. 6. The disease / disorder being studied, or the expected progression, signs, or symptoms of the disease / disorder being studied, unless it is more severe than expected for the participant's condition. 7. Situations in which no adverse medical occurrence occurred (social and / or convenience admission to hospital). 8. "Lack of efficacy" or "failure to achieve expected pharmacological effect" per se is not reported as an AE or SAE. Such instances are captured in the efficacy evaluation. However, signs, symptoms, and / or clinical sequelae resulting from lack of efficacy are reported as AEs or SAEs if they meet the definition of an AE or SAE.

[0296] If an event is not an AE according to the above definition, it cannot be a Serious Adverse Event (SAE) even if it meets the seriousness criteria (e.g., hospitalization due to signs / symptoms of the disease under study, death due to disease progression). An SAE is defined as any untoward medical occurrence at any dose that results in: 1. Leads to death. 2. Life-threatening. The term "life-threatening" in the definition of "serious" refers to an event in which the participant was at risk of death at the time of the event. It does not refer to an adverse event that could hypothetically have caused death if it had become more severe. 3. Requires hospitalization of the patient or extension of current hospitalization. In general, hospitalization means admitting the participant to a hospital or emergency room for observation and / or treatment that would not have been appropriate in a clinic or outpatient setting (usually involving at least an overnight stay). A complication occurring during hospitalization is an AE. An event is serious if the complication extends hospitalization or meets any other serious criteria. An AE should be considered serious when there is doubt whether "hospitalization" was performed or necessary. Hospitalization for elective treatment of an existing condition that did not worsen from baseline is not considered an AE. 4. Resulting in persistent impairment / incapacity. The term impairment means substantial disruption of a person's ability to carry out normal life functions. This definition is not intended to include the experience of relatively minor medically significant conditions, such as uncomplicated headaches, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or impede daily life functions but are not substantial disruption. 5. Congenital anomalies / birth defects. 6. Other Situations: In other situations, such as major medical events that are not immediately life-threatening or likely to result in death or hospitalization, but which may endanger the participant or require medical or surgical intervention to prevent one of the other outcomes listed in the definition above, medical or scientific judgment should be used in determining whether an SAE report is appropriate. These events should generally be considered serious. Examples of such events include invasive or malignant cancer, allergic bronchospasm that does not result in hospitalization, blood disorders, or intensive care in the emergency room or at home due to seizures, or the development of drug dependence or abuse.

[0297] A suspected unexpected serious adverse reaction (SUSAR) is defined as an event assessed by the investigator as serious that is not listed in the appropriate reference safety information (IB) and where the investigator assesses that there is at least a reasonable likelihood that the event is related to the investigator drug. Suspected unexpected serious adverse reactions will be reported promptly to national regulatory authorities, IRB / IEC, and the investigator, in accordance with local regulatory reporting requirements, where applicable.

[0298] It is the investigator's responsibility to review all documentation related to the event (e.g., hospital progress notes, laboratory reports, and diagnostic reports) for recording of AEs and / or SAEs. The investigator then records all relevant AE / SAE information in the eCRF. The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and / or other clinical information. Whenever possible, the diagnosis (not the individual signs / symptoms) will be confirmed as an AE / SAE.

[0299] Investigators will provide an intensity rating for each AE and SAE reported during the study and assign it to one of the following categories from the National Cancer Institute CTCAE v5.0 published November 27, 2017: Grade 1: mild (noticeable signs or symptoms but easily tolerated), Grade 2: moderate (sufficient discomfort to cause interference with normal activities), Grade 3: severe (incapacitating and unable to perform normal activities), Grade 4: life-threatening, and Grade 5: fatal. An event is defined as "serious" when it meets at least one of the predefined consequences described in the SAE definition, but is not graded as severe.

[0300] The investigator is required to assess the relationship of each AE or SAE to the study intervention. The investigator's causality assessment must be provided for all AEs (both non-serious and serious). This assessment must be recorded in the eCRF in any additional form, as appropriate. The definitions in the causality assessment are as follows: (1) Unrelated: There is no reasonable possibility that the study intervention caused the AE. The AE is more likely to have an alternative etiology; it may be due to an underlying or intercurrent illness, a comorbid condition, a concomitant treatment, or the effect of another concomitant medication. The event does not follow a reasonable temporal relationship to the administration of the study intervention. (2) Related: There is a reasonable possibility that the study intervention caused the AE. The AE has a temporal relationship to the administration of the study intervention. The event is not likely to have an alternative etiology. The event corresponds to the known pharmacological profile of the study intervention. There is improvement on discontinuation and / or recurrence on rechallenge.

[0301] The investigator will use clinical judgment to determine the relationship. Alternative causes such as underlying disease, concomitant medications, and other risk factors, as well as the temporal relationship between the event and administration of the study intervention, will be considered and examined. The investigator will also review the IB and / or product information for the marketed product in their assessment. For each AE / SAE, the investigator must document in the medical record that he / she has reviewed the AE / SAE and provided an assessment of causality. There may be situations where an SAE occurs and the investigator has minimal information to include in the initial report. The investigator may change his / her opinion about causality in light of follow-up information and will send an SAE follow-up report with an updated causality assessment. The causality assessment is one of the criteria used when determining regulatory reporting requirements.

[0302] 9. Pharmacokinetics and Pharmacodynamics Blood samples for determination of serum drug concentrations and serum free and total C5 will be collected before and after administration of the study intervention at the time points specified in the Schedule of Activities. Instructions for collection and handling of biological samples will be provided. The actual date and time (24-hour time) of each sample will be recorded on the eCRF and the Central Laboratory Request Form. Samples collected for analysis of ULTOMIRIS serum concentrations may also be used to evaluate aspects of safety or efficacy related to concerns arising during or after the study. Baseline and trough PK / PD blood samples will be collected pre-dose and within 90 minutes prior to study intervention administration at visits specified in the Schedule of Activities. Pre-dose blood samples may be collected prior to dose administration via the venous access created for dose infusion. Post-dose PK / PD blood samples will be collected post-dose and within 60 minutes after completion of study intervention infusion. Post-dose blood samples will be drawn from the participant's contralateral non-injected arm. PK / PD blood samples collected at ET / EOS visits and unscheduled visits may be collected at any time point. In the event of unscheduled visits, PK / PD blood samples can be drawn at any time.

[0303] 10. Biomarkers Blood (serum and plasma) samples for biomarker studies will be collected from all participants at time points specified in the schedule of activities.

[0304] Biomarkers measured may include, but are not limited to, assessment of complement pathway dysregulation (e.g., soluble C5b-9, etc.) and myositis-specific autoantibodies (e.g., anti-melanoma differentiation-associated protein 5 [anti-MDA5], anti-nuclear matrix protein 2 (anti-NXP2 / MJ), anti-synthetase / Jo1, etc.).

[0305] Remaining samples from PK, PD, immunogenicity, and biomarker studies will be banked for further method development of assays (e.g., prognostics and / or companion diagnostics related to the study intervention target, disease process, pathways associated with a disease state, other complement-related diseases, and / or mechanism of action of ULTOMIRIS).

[0306] Samples will be retained to allow for further analysis of ULTOMIRIS, but for up to five years after study cessation or other period in accordance with local requirements.

[0307] 11. Immunogenicity Assessment Antibodies to ULTOMIRIS (i.e., ADA) will be assessed in serum samples collected pre-dose (90 minutes prior to the start of infusion of study intervention) from all participants according to the schedule of activities. In addition, serum samples should also be collected at the final visit from participants who discontinue the study intervention or withdraw from the study.

[0308] Serum samples are screened for antibodies that bind ULTOMIRIS and titers of confirmed positive samples are reported. Other analyses may be performed to further characterize the immunogenicity of ULTOMIRIS.

[0309] Detection and characterization of antibodies to ULTOMIRIS will be performed using a validation / qualification assay. Antibodies may be further characterized and / or evaluated for their ability to neutralize the activity of the study intervention. Samples may be stored for a maximum period following the last visit of the last participant in accordance with local regulations to allow further analysis of the immune response to ULTOMIRIS.

[0310] 12.Statistical considerations Part A is exploratory in nature and there is no formal statistical hypothesis testing planned.

[0311] For Part B, the primary hypothesis is that ULTOMIRIS is superior to placebo in the primary endpoint. The hypotheses evaluating superiority in terms of the proportion of responders are as follows: H0:p rav -p pbo ≦0;H1:p rav -p pbo >0 (In the formula, p rav and p pbo are the proportions of responders to ravulizumab and placebo, respectively).

[0312] For Part A, a total of 48 participants will be randomized in a 2:1 (ravulizumab:placebo) allocation ratio to detect a 35% treatment difference in IMACS-TIS minimal response (IMACS-TIS ≥ 20) with a one-sided type I error of 0.1, assuming a 40% placebo response rate and a dropout rate of approximately 15%. Sample size was calculated by EAST 6.5 using a 2-sample test for the difference in proportions with a nonpooled variance estimate for the primary endpoint (IMACS-TIS ≥ 20).

[0313] For Part B, a total of 132 participants will be randomized in a 1:1 (ravulizumab:placebo) allocation ratio to detect a 30% treatment difference in IMACS-TIS minimal response (IMACS-TIS ≥ 20) with a one-sided type I error of 0.025, assuming a 40% placebo response rate and approximately 20% dropout rate. Sample size was calculated with EAST 6.5 using a 2-sample test for the difference in proportions with unpooled variance estimates.

[0314] Unblinded sample size re-estimation is planned in Part B to potentially increase the sample size to a maximum of 174 participants.

[0315] For analysis purposes, the following analysis sets are defined separately for each of Part A and Part B in Table 8. Unless otherwise stated, the same definitions will be used for the statistical analyses of Part A and Part B, where applicable.

[0316] [Table 8]

[0317] Statistical analysis includes participant listing and numerical summary data tabulation, inferential analysis. Summary statistics for continuous variables include, but are not limited to, number of participants, mean, standard deviation, minimum, median, and maximum. For categorical variables, frequencies and percentages will be presented.

[0318] All efficacy analyses will be based on the full analysis set (FAS). Additional per-protocol analyses for the primary and secondary efficacy endpoints will be performed on the per-protocol set (PPS) in the same manner as was done for the FAS. Safety analyses will be performed on the safety set (SS).

[0319] Baseline values ​​and reporting for analysis will be based on the last nonmissing measurement on or before the first administration of study intervention unless otherwise stated.

[0320] Analyses are performed using SAS® software version 9.4 or higher.

[0321] For Part A, all data collected during the initial 26-week randomized controlled period of Part A will be analyzed independently of Part B and will not be included in the formal hypothesis testing in Part B. In general, statistical tests in Part A will be exploratory in nature and will be performed with a two-sided type I error of 0.2. For endpoints where such exploratory hypothesis tests are performed, two-sided p-values, estimated differences between ULTOMIRIS and placebo, and two-sided 80% confidence intervals (CIs) of the treatment differences will be presented.

[0322] In part A, comparisons of treatment groups for the primary endpoint were based on the Mantel-Haenszel test for the difference between two proportions and FAS with a two-sided type I error of 0.2. Estimated Mantel-Haenszel risk differences were summarized with two-sided 80% CIs using Mantel-Haenszel strata weighting (see Mantel N, Haenszel W., J. Natl. Cancer Inst. 1959;22(4):719-748) and the Sato variance estimator (see Sato T., letter to the editor. Biometrics. 1989;45:1323-1324).

[0323] All secondary efficacy endpoints will be analyzed using FAS. To compare treatment differences between two independent samples, a mixed-effects repeated measures model will be used for continuous efficacy endpoints, the Mantel-Haenszel test will be used for binary efficacy endpoints, and the Kaplan-Meier method will be used for survival (time to event) efficacy endpoints.

[0324] For Part B, all data collected during the initial 50-week randomized controlled period of Part B will be analyzed independently from Part A. Formal statistical hypothesis testing for Part B will be performed with a two-sided type I error of 0.05.

[0325] The primary null hypothesis is that the effect of ULTOMIRIS is not different from placebo on TIS20 response. The alternative hypothesis is that there is a treatment difference from placebo in favor of ULTOMIRIS based on TIS20 response.

[0326] Comparison of treatment groups for the primary endpoint was based on a two-sided Mantel-Haenszel test of the difference between two proportions stratified by randomization stratification factors and FAS with a type I error of 0.05. Two-sided p-values ​​and estimated Mantel-Haenszel risk differences are presented with two-sided 95% CIs using Mantel-Haenszel strata weights (Mantel, 1959) and the Sato variance estimator (Sato, 1989).

[0327] If the null hypothesis is rejected in favor of ULTOMIRIS at the two-sided statistical significance level of 0.05, the trial will be considered to have met its primary efficacy objective.

[0328] The next supportive analysis will be performed on the primary efficacy endpoint to examine the robustness of the IMACS-TIS results from the primary efficacy analysis due to intercurrent events. Further supportive analyses may also be performed using a rational penalized strategy for post-intercurrent event data.

[0329] In this analysis, data after any intercurrent event are assumed to follow the trajectory of event-free participants from the control treatment arm who continued to their next visit (control-based) using a multiple imputation approach. Imputations are performed on the IMACS-TIS data and a binary outcome of response (TIS20) is derived from the imputed TIS data.

[0330] Tipping Point Analysis: In this sensitivity analysis of the delta-adjusted stress test method (tipping point analysis), data from participants after any intercurrent event are assumed to experience a worsening in the remainder of the randomized controlled period, with the worsening defined by a pre-specified adjustment (delta) in the TIS score, compared to participants in the same treatment group who continue in the study and reach their next visit without any intercurrent event. The pre-specified delta value is a negative quantity, as a higher TIS score (0 100) represents a better improvement. A two-way tipping point analysis via multiple imputation is performed by using a different delta adjustment for each treatment group. Binary responses are derived from the imputed TIS data and analyzed using the same primary analysis method as for the primary endpoint.

[0331] A treatment effect will be determined for each combination of delta values ​​for ULTOMIRIS and placebo, and the delta value at which the nominal two-sided p-value crosses 0.05 will be considered the "tipping point," i.e., the positive conclusion from the primary analysis will be reversed when participant dropouts are assumed to experience this fixed deterioration after discontinuation.

[0332] Supportive analyses of the primary endpoint will also be performed using a treatment policy estimand strategy. In this analysis, the same analysis method will be used for the binary outcome (TIS20) from participants regardless of whether they experienced any intercurrent events. Missing data due to early discontinuation will be imputed to match the treatment policy estimand.

[0333] In the binary primary composite estimand (TIS20), participants with missing TIS data from early discontinuation after experiencing any intercurrent event are considered treatment failures (non-responders). Missing TIS data from participants who discontinued early without experiencing any intercurrent event are imputed using a multiple imputation missing at random (MAR) strategy and are assumed to follow the trajectory of participants without intercurrent events from the same treatment arm who continued to their next visit. Binary TIS response data from the imputed TIS data will be analyzed using statistical methods for the primary endpoint.

[0334] For the key continuous secondary endpoint (IMACS-TIS), missing TIS data from participants who discontinue early after experiencing any intercurrent event are imputed using a missing at random (MNAR) strategy via multiple imputation to meet the primary composite estimand. Missing TIS data from participants who discontinue early without experiencing any intercurrent event are imputed using a missing at random (MAR) strategy via multiple imputation and are assumed to follow the trajectory of participants without intercurrent events from the same treatment group who continue to their next visit. Continuous TIS data are analyzed using statistical methods described herein.

[0335] For Part B, the comparison of treatment groups for the mean IMACS-TIS at week 50 of the randomized controlled period is based on the FAS. To meet the primary composite estimand, a control-based multiple imputation strategy is employed. In this approach, data from participants after experiencing any intercurrent event are assumed to follow the trajectory of event-free participants from the control treatment group who continued to their next visit using a multiple imputation approach.

[0336] Mixed-effects repeated measures models are used for statistical analysis of the impute TIS data. The model includes the response variable, fixed categorical effects of treatment, study visit, and its interaction with study visit, as well as region, at each prespecified time point as the dependent variable, as well as important baseline covariates. Treatment effects are assessed via contrasts on treatment-visit terms at week 50. An unstructured covariance matrix is ​​used to model correlations between repeated measures within each participant. If convergence problems arise, other covariance structures are implemented.

[0337] Two-sided p-values, estimated least squares mean differences between ravulizumab and placebo, along with two-sided 95% CIs of the differences from the model are presented.

[0338] Survival (time to event) endpoints were analyzed using the Kaplan-Meier method and compared using the log-rank test stratified by region and skin manifestation. Hazard ratios and risk reductions are summarized from Cox proportional hazards models stratified by region and skin manifestation. CIs (95%) are presented for survival estimates based on complementary log-log transformations. Kaplan-Meier curves are generated for both treatment arms.

[0339] The final primary hypothesis related to the primary endpoint will be tested with a two-sided type I error of 0.05 with the final test statistic adjusted for planned adaptive sample size reestimation to control for overall type I error in Part B. Hypothesis testing related to key secondary endpoints will proceed only if the null hypothesis related to the primary endpoint is rejected.

[0340] The safety and tolerability of ULTOMIRIS will be evaluated based on AE reports, clinical laboratory findings, ECG, and vital sign findings. Safety analyses will be performed in the SS population.

[0341] Analysis and reporting of AEs will be based on TEAEs, including treatment-emergent serious adverse events (TESAEs) and treatment-emergent adverse events (TEAEs) leading to drug discontinuation, defined as AEs with onset at or after the first dose of study intervention during the randomized controlled period. TEAEs and TESAEs and TEAEs leading to drug discontinuation will be summarized in the Medical Dictionary for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term by severity and by relationship to the study intervention. Participant age-adjusted event rates will be generated to characterize the long-term safety profile.

[0342] Laboratory measurements and, where applicable, changes from baseline and shifts from baseline at each visit will be summarized descriptively. Significant findings related to ECG and vital signs will also be summarized using descriptive analysis.

[0343] Individual serum concentration data for all participants who received at least one dose of study intervention and have at least one post-dose PK sample will be used to derive PK parameters for ULTOMIRIS.

[0344] A graph of the mean serum concentration-time profile is constructed. Graphs of the serum concentration-time profiles of individual participants may also be provided.

[0345] Descriptive statistics will be calculated for serum concentration data at each sampling time, as appropriate. Population-PK assessments can be considered using data from this study or in combination with data from other studies.

[0346] Descriptive statistics will be presented for all ULTOMIRIS PD endpoints at each sampling time. The effect of IV ULTOMIRIS PD will be evaluated by assessing absolute free and total C5 serum concentrations and change over time and percent change from baseline, as appropriate. Box plots of absolute free and total C5 serum concentrations will be constructed for each study visit. Evaluation of ULTOMIRIS PK / PD relationships may be explored using data from this study or in combination with data from other studies.

[0347] Immunogenicity analysis was based on SS.

[0348] The presence of ADAs to ULTOMIRIS in serum will be evaluated over the course of the study. Further characterization of antibody responses, including titers of neutralizing antibodies and confirmed positive samples, may be performed as appropriate. Immunogenicity results will be analyzed by compiling the number and percentage of participants who develop confirmed positive ADAs. Associations between ADAs and ULTOMIRIS concentrations, PD parameters, efficacy, and TEAEs may be explored as appropriate.

[0349] Analyses of exploratory biomarkers are described in a separate analysis plan.

[0350] For Part A, an interim analysis may be performed for dosing purposes. The interim analysis will be conducted on a contingent basis when a total of approximately 24 (50%) participants reach the pre-dose Week 26 visit or discontinue prematurely. Comparative primary and key efficacy as well as safety data will be evaluated in this interim analysis. As there are no plans to alter the Part A study design, no type I error adjustment will be required for the final statistical analysis. The interim analysis will be performed by an independent DMC to maintain blinding.

[0351] The primary efficacy endpoint as well as safety data will be evaluated in this interim analysis. Further enrollment may be halted if futility criteria are met or if the benefit / risk is not deemed favorable.

[0352] For Part B, one interim analysis may be performed for sample size re-estimation. An interim analysis for unblinded sample size re-estimation will be performed prudently when approximately 30% of participants complete the pre-dose Week 50 visit or prematurely discontinue Part B. Sample size will be increased to a maximum of 174 participants using a conditional power approach. Weighted stage-wise statistical combination tests will be used in the final statistical analysis to control for type I error due to planned adaptive sample size increase. Interim analyses will be performed by an independent DMC to maintain study integrity and blinding.

[0353] [Table 9-1]

[0354] [Table 9-2]

[0355] [Table 9-3]

[0356] [Table 9-4]

Claims

A composition for use in the treatment of human patients with dermatomyositis (DM), comprising an anti-C5 antibody or an antigen-binding fragment thereof comprising CDR1, CDR2, and CDR3 heavy chain sequences shown in SEQ ID NOs: 19, 18, and 3, respectively, and CDR1, CDR2, and CDR3 light chain sequences shown in SEQ ID NOs: 4, 5, and 6, respectively, wherein the anti-C5 antibody or its antigen-binding fragment is administered to the patient: (a) to patients weighing < 30 kg, as a loading dose of 900 mg, followed by after 2 weeks, and then once every 8 weeks thereafter, as a maintenance dose of 2100 mg; (b) to patients weighing ≧ 30 to < 40 kg, as a loading dose of 1200 mg, followed by after 2 weeks, and then once every 8 weeks thereafter, as a maintenance dose of 2700 mg; (c) to patients weighing ≧ 40 to < 60 kg, as a loading dose of 2400 mg, followed by after 2 weeks, and then once every 8 weeks thereafter, as a maintenance dose of 3000 mg; (d) to patients weighing ≧ 60 to < 100 kg, as a loading dose of 2700 mg, followed by after 2 weeks, and then once every 8 weeks thereafter, as a maintenance dose of 3300 mg; or (e) to patients weighing ≧ 100, as a loading dose of 3000 mg, followed by after 2 weeks, and then once every 8 weeks thereafter, as a maintenance dose of 3600 mg A composition, characterized in that it is administered as such. Claim 2. The anti-C5 antibody or its antigen-binding fragment is: (a) to patients weighing < 30 kg, as a loading dose of 900 mg on day 1, followed by on day 15, and then once every 8 weeks thereafter, as a maintenance dose of 2100 mg; (b) to patients weighing ≧ 30 to < 40 kg, as a loading dose of 1200 mg on day 1, followed by on day 15, and then once every 8 weeks thereafter, as a maintenance dose of 2700 mg; (c) to patients weighing ≧ 40 to < 60 kg, as a loading dose of 2400 mg on day 1, followed by on day 15, and then once every 8 weeks thereafter, as a maintenance dose of 3000 mg; (d) In patients with a body weight of ≧60 to <100 kg, an initial dose of 2700 mg on day 1, followed by 3300 mg maintenance dose on day 15 and then once every 8 weeks thereafter; or (e) In patients with a body weight of ≧100, an initial dose of 3000 mg on day 1, followed by 3600 mg maintenance dose on day 15 and then once every 8 weeks thereafter The composition according to claim 1, characterized in that it is administered.

3. The anti-C5 antibody or antigen-binding fragment thereof is: (i) further comprises a mutant human Fc constant region that binds to the human neonatal Fc receptor (FcRn), wherein the mutant human Fc constant region, numbered according to EU numbering, contains Met429Leu and Asn435Ser substitutions at the residues corresponding to methionine 428 and asparagine 434 of the native human IgG Fc constant region; (ii) comprises a heavy chain variable region shown in SEQ ID NO: 12 and a light chain variable region shown in SEQ ID NO: 8; (iii) further comprises a heavy chain constant region shown in SEQ ID NO: 13; (iv) comprises a heavy chain polypeptide containing the amino acid sequence shown in SEQ ID NO: 14 and a light chain polypeptide containing the amino acid sequence shown in SEQ ID NO: 11; (v) binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) in the range of 0.1 nM ≦ KD ≦ 1 nM (for example, about 0.5 nM); and / or (vi) binds to human C5 at pH 6.0 and 25°C with KD ≧ 10 nM (for example, about 22 nM), The composition according to claim 1 or 2.

4. The composition according to claim 1, wherein the treatment maintains a serum trough concentration of the anti-C5 antibody of 100 μg / mL or more or 200 μg / mL or more.

5. The composition according to claim 1, characterized in that the anti-C5 antibody is administered intravenously.

6. The treatment is (i) a shift to normal levels of soluble C5b-9; (ii) A shift to normal levels of myositis-specific autoantibodies, optionally wherein said autoantibodies are anti-melanoma differentiation-associated protein 5 antibody (anti-MDA5 antibody), anti-nuclear matrix protein 2 antibody (anti-NXP2 / MJ antibody), or anti-synthetase / Jo1 antibody; and / or (iii) A shift to normal levels of muscle enzymes The composition according to claim 1, which brings about.

7. The composition according to claim 1, wherein the treatment results in improvement in the patient compared to baseline when evaluated by the International Myositis Assessment and Clinical Studies Total Improvement Scale (IMACS-TIS), for example, a total improvement score (TIS) of at least ≧20 points compared to baseline when evaluated by the IMACS-TIS score, a TIS of at least ≧40 points compared to baseline when evaluated by IMACS-TIS, or a TIS of at least ≧60 points compared to baseline when evaluated by IMACS-TIS.

8. The treatment is (i) Improvement in the patient compared to baseline when evaluated by the Cutaneous Dermatomyositis Area and Severity Index (CDASI); (ii) An improvement of ≧7 points in the patient compared to baseline when evaluated by CDASI; (iii) Improvement in the patient compared to baseline when evaluated by the EuroQol 5-Dimension 5-Level (EQ-5D-5L) score; (iv) Improvement in the patient compared to baseline when evaluated by the Patient-Reported Outcomes Measurement Information System (PROMIS); (v) Improvement in the patient compared to baseline when evaluated by the Short Form Health Survey (36-question version) (SF36); (vi) Improvement in the patient compared to baseline when evaluated by the Dermatomyositis Disease Symptom Questionnaire (DM-DSQ); (vii) improvement in said patient as evaluated by the 30 - second chair stand test (30sCST) compared to baseline; (viii) a decrease in detectable rash in said patient compared to baseline as evaluated by photographic analysis; (ix) improvement in said patient as evaluated by the 5 - D itch scale compared to baseline; (x) improvement in said patient as evaluated by hand - held dynamometry performance analysis compared to baseline; (xi) improvement in said patient as evaluated by the Functional Assessment of Chronic Illness Therapy (FACIT) - fatigue score compared to baseline; (xii) improvement in said patient as evaluated by the 8 - muscle manual muscle test subset (MMT8) compared to baseline; (xiii) improvement in said patient as evaluated by the Myositis Disease Activity Assessment Tool (MDAAT) compared to baseline; (xiv) improvement in said patient as evaluated by physician global activity assessment compared to baseline; (xv) improvement in said patient as evaluated by patient global activity assessment compared to baseline; (xvi) improvement in said patient as evaluated by the Health Assessment Questionnaire (HAQ) compared to baseline; (xvii) improvement in said patient as evaluated by the physician's global assessment of cutaneous activity in dermatomyositis (CD - IGA) compared to baseline; and / or (xviii) a decrease or cessation of rash and / or muscle weakness in said patient The composition according to claim 1, which brings about the above.

9. The patient has, before treatment, MMT - 8 ≤ 142 / 150 and the following: a) Patient global activity assessment of ≥ 2.0 cm on a 10 - cm VAS b) Physician global activity assessment of ≥ 2.0 cm on a 10 - cm VAS c) HAQ disability index ≥ 0.25 d) An increase to ≥ 1.3-fold the upper limit of normal (ULN) of at least one muscle enzyme, optionally, said at least one muscle enzyme being selected from the group consisting of creatine kinase (CK), aldolase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST); and / or e) A global extra-muscular disease activity score ≥ 2.0 cm on a 10 cm visual analog scale (VAS), optionally, said global extra-muscular disease activity score being based on the evaluation of the activity scores on the systemic, skin, skeletal, gastrointestinal, lung, and heart scales of said MDAAT, global extra-muscular disease activity score The composition according to claim 1, having two or more of the above.

10. Before treatment, the patient has the following: a) A muscle or skin biopsy having evidence of active pathological findings of DM within the past 6 months before the start of treatment or at the start of treatment; b) Evidence of electromyogram examination of active myositis within the past 6 months before the start of treatment or at the start of treatment; c) Evidence of muscle on magnetic resonance imaging (MRI) of active myositis within the past 6 months before the start of treatment or at the start of treatment; d) At least one muscle enzyme in the IMACS panel before the start of treatment or at the start of treatment being ≥ 2-fold the ULN, optionally, said at least one muscle enzyme being selected from the group consisting of creatine kinase (CK), aldolase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST); and / or e) An active DM rash characterized by inflammatory changes (CDASI activity score ≥ 7) before the start of treatment or at the start of treatment The composition according to claim 1, having one or more of the above.

11. The treatment is as follows: a) Azathioprine; b) Cyclosporine; c) Glucocorticoids; d) Intramuscular glucocorticoids; e) Hydroxychloroquine; f) Leflunomide; g) Methotrexate, h) Mycophenolate mofetil / mycophenolic acid; and / or i) Sulfasalazine The composition according to claim 1, further comprising administering one or more of the following.

12. The treatment is as follows: a) Antihistamines; b) Ibuprofen; c) Acetaminophen; d) Antipruritics; e) Topical steroids; f) Vitamin B12; g) Vitamin E, h) Creatine, i) Coenzyme Q10, and / or j) Biotin supplement The composition according to claim 1, further comprising administering one or more of the following.

13. At the start or during the treatment, the patient is as follows: a) Intravenous immunoglobulin (IVIg); b) Subcutaneous immunoglobulin (SCIg); c) IV glucocorticoids; d) Corticotropin injection; e) Cyclophosphamide, f) Rituximab; g) Infliximab; h) Adalimumab; i) Etanercept; j) Tofacitinib; k) Ruxolitinib; or l) Anakinra The composition according to claim 1, wherein the patient has not previously ingested any of them and is not currently ingesting any of them.

14. The composition according to claim 1, wherein the treatment results in terminal complement inhibition and / or a reduction in adverse events.

15. The composition according to claim 1, wherein the human patient is an adult patient.

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