Zilucoplan in immune-mediated necrotising myopathy: a phase 2, randomised, double-blind, placebo-controlled, multicentre trial.

Background: Immune-mediated necrotizing myopathy (IMNM) is an autoimmune myopathy characterised by proximal muscle weakness, high creatine kinase (CK) values, and autoantibodies recognizing 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) or the signal recognition particle (SRP). There are currently no approved therapies for IMNM and many patients experience active disease despite off-label treatment with intravenous immunoglobulin, glucocorticoids, and immunosuppressants. Detection of complement-activating anti-HMGCR and anti-SRP autoantibodies and the presence of complement deposition on the sarcolemma of non-necrotic myofibers led to the hypothesis that complement activation may be pathogenic in IMNM, therefore zilucoplan, a complement component 5 (C5) inhibitor, could be a potential therapy.
Methods: IMNM01, a phase 2, multicenter, randomised, double-blind, placebo-controlled study (NCT04025632) at 15 sites (four countries) evaluated efficacy, safety, and tolerability of zilucoplan in adult participants with anti-HMGCR or anti-SRP autoantibody-positive IMNM. Participants were randomised 1:1 to receive daily subcutaneous zilucoplan (0·3mg/kg) or placebo for eight weeks; with optional enrolment in the study open-label extension. Primary efficacy endpoint was percent change from baseline to Week 8 in CK levels. Secondary endpoints included safety.
Findings: Between 07 November 2019 and 07 January 2021, 27 participants (13 female and 14 male) received zilucoplan (n=12) or placebo (n=15) and completed the 8-week main study. At Week 8 there were no clinically relevant or statistically significant differences, despite target engagement based on mode of action, between treatment arms in mean percent change (standard deviation) of CK levels versus baseline (-9·86% [26·06] versus -20·72% [31·22] in zilucoplan [n=10] and placebo arms [n=14], p=0·46, respectively) and no clinically relevant improvement over time within the treatment arm. There were no unexpected adverse safety or tolerability findings. Treatment emergent adverse events (TEAEs) and serious TEAEs were reported in n=9 (75·0%) vs n=13 (86·7%) and n=0 (0%) and n=3 (20·0%) participants, respectively. The most frequent TEAEs were headache (n=4 in both groups [33·3% and 26·7%, respectively]) and nausea (n=3 in both groups [25·0% and 20·0%, respectively]).
Interpretation: C5 inhibition does not appear to be an effective treatment modality for IMNM. Rather than driving myofiber necrosis, complement activation may be secondary to muscle injury.
Funding: Study funded by Ra Pharmaceuticals (now part of UCB Pharma).
Competing Interests: Declaration of interests ALM is a patent author for the anti-HMGCR test. AAA has participated in medical advisory boards/acted as a consultant for Argenx, Ra Pharmaceuticals, Alexion, EMD Serono, OnoPharma, Horizon Therapeutics, Takeda, Johnson & Johnson (COVID-19 vaccination program) MD has served or recently served as a consultant for Amazentis, ArgenX, Catalyst, Cello, Covance/Labcorp, CSL-Behring, EcoR1, Janssen, Kezar, Medlink, Momenta, NuFactor, Octapharma, RaPharma/UCB, Roivant Sciences Inc, RMS Medical, Sanofi Genzyme, Shire Takeda, Scholar Rock, Spark Therapeutics, Abata/Third Rock, UCB Biopharma, and UpToDate. Dr. Dimachkie received research grants or contracts or educational grants from Alexion, Alnylam Pharmaceuticals, Amicus, Biomarin, Bristol-Myers Squibb, Catalyst, Corbus, CSL-Behring, FDA/OOPD, GlaxoSmithKline, Genentech, Grifols, Kezar, Mitsubishi Tanabe Pharma, MDA, NIH, Novartis, Octapharma, Orphazyme, Ra Pharma/UCB, Sanofi Genzyme, Sarepta Therapeutics, Shire Takeda, Spark Therapeutics, UCB Biopharma / RaPharma, Viromed/Healixmith & TMA. HC has received personal compensation for activities with Novartis, UCB, Lilly, Biogen, Orphazyme, Astra Zeneca as a speaker, advisory board member or consultancy, grants via The University of Manchester from Novartis, UCB and MedImmune, and has received travel support from Abbvie and Janssen. JBL has received speakers fees, travel support, and/or consultancy fees from Sanofi Genzyme, Roche, and Biogen. Yves Allenbach: has received personal compensation for activities with Lilly, and CSL-Berhing as a speaker or consultancy. Mark Vanderkelen: Employee and stockholder of UCB Pharma Eumorphia Delicha: Contractor of UCB Pharma Ramin Farzaneh-Far: was an employee of Ra Pharma at the time of the study BB, HK, PWD, CS* and OB are employees and stockholders of UCB Pharma IPF and YH have no competing interests to declare *Employee at the time to the study