AB1287 DESIGN OF A GLOBAL PHASE 2/3 RANDOMIZED, PLACEBO-CONTROLLED TRIAL EVALUATING THE EFFICACY AND SAFETY OF RAVULIZUMAB IN ADULTS WITH DERMATOMYOSITIS

Abstract

BackgroundDermatomyositis (DM) is a rare and life-altering chronic immune-mediated disease characterized by distinct skin rash and/or progressive muscle weakness and other systemic manifestations. Many patients are refractory and/or experience serious adverse effects when treated with currently prescribed medications, including high-dose systemic steroids and immunosuppressive therapies1-3, which are often prescribed off-label. Therefore, there is a need for new DM treatment options that offer more favorable risk-benefit profiles.The classical complement pathway is implicated in DM pathophysiology, including a close correlation between endothelial deposition of the C5b-9 membrane attack complex (MAC) and organ damage.4 Treatment with the long-acting anti-C5 monoclonal antibody ravulizumab is associated with immediate, complete, and sustained inhibition of the complement protein C5, which prevents its cleavage to form MAC, and it has proven to be a safe and effective therapeutic approach for multiple complement-mediated diseases.5ObjectivesGiven the continued unmet need in DM and the evidence implicating the terminal complement pathway in the disease pathophysiology, a global, multi-center double-blind, randomized, placebo-controlled Phase 2 (Part A)/Phase 3 (Part B) trial was designed to evaluate the efficacy and safety of the C5 inhibitor ravulizumab compared with placebo in adults with DM (ALXN1210-DM-310; NCT04999020; EudraCT2021-001200-15).MethodsA total of 180 adult patients with DM6 who have active disease with muscle weakness and inadequate responses or intolerances to two or more DM treatments including glucocorticoids will be randomized to receive either intravenous ravulizumab or placebo, delivered as loading dose followed by maintenance administration once every eight weeks. Different patients will be enrolled in Parts A and B, which each consist of a screening period, a randomized, controlled period (Part A; 26 weeks; Part B: 50 weeks), and an open-label extension period. The primary endpoints are the proportion of patients with a minimal improvement from baseline on the ACR/EULAR Myositis Response Criteria Total Improvement Score (TIS20) at 26 weeks (Part A) and 50 weeks (Part B). In addition, a wide range of key secondary and exploratory outcome measures will be evaluated, including the mean change from baseline in the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score and a novel participant-reported outcome measure, the Dermatomyositis-Disease Symptoms Questionnaire (DM-DSQ). Safety will be assessed by analyzing the incidence of treatment-related adverse events (TEAEs), including those classified as serious and/or leading to intervention discontinuation.ResultsThe ALXN1210-DM-310 trial is currently enrolling patients.ConclusionALXN1210-DM-310 is the first global, multi-center, randomized, placebo-controlled Phase 2/3 interventional trial designed to evaluate the safety and efficacy of a C5 inhibitor in adult patients with DM who continue to have active disease despite treatment with standard medications.References[1]Joffe MM, Love LA, Leff RL, et al. Am J Med.1993; 94:379.[2]Zieglschmid-Adams ME, Pandya AG, Cohen SB, et al. J Am Acad Dermatol. 1995; 32:754.[3]Kissel JT, Levy RJ, Mendell JR, Griggs RC. Neurology 1986; 36:35.[4]Yang SH, Chang C, Lian Z-X. J Transl Autoimmun. 2019;2:100018.[5]https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761108s012lbl.pdf. Accessed January 26, 2022.[6]Lundberg IE, Tjarnlund A, Bottai M, et al. Arthritis Rheumatol. 2017;69(12):2271-2282.Disclosure of InterestsLorenzo Cavagna: None declared, Rohit Aggarwal Consultant of: Alexion and AstraZeneca, Pfizer, Octapharma, Csl Behring, BMS, Argenx, Corbus, EMD, Janssen, Kezar, Kyverna, Roivant, and Mallinckrodt, Grant/research support from: Pfizer, BMS, Q32, EMD Serono, and Mallinckrodt, Noriko Iikuni Shareholder of: AstraZeneca, Employee of: Alexion/AstraZeneca Rare Disease, Pfizer, Eli Lilly, Sanjay Rakhade Shareholder of: AstraZeneca, Employee of: Alexion/AstraZeneca Rare Disease, Sanofi Genzyme