Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis
Sabrina Paganoni, Christina Fournier, Eric A. Macklin, Lori B. Chibnik, Melanie Quintana, Benjamin R. Saville, Michelle A. Detry, Matteo Vestrucci, Joe Marion, Anna McGlothlin, Senda Ajroud‐Driss, Marianne Chase, Lindsay Pothier, Brittney Harkey, Hong Yu, Alexander Sherman, Jeremy M. Shefner, Meghan Hall, Gale Kittle, James D. Berry, Suma Babu, Jinsy Andrews, Derek D’Agostino, Eric Tustison, Elisa Giacomelli, Erica Scirocco, Gustavo Alameda, Eduardo Locatelli, Doreen Ho, Adam Quick, Jonathan Katz, Daragh Heitzman, Stanley H. Appel, Sheetal Shroff, Kevin J. Felice, Nicholas J. Maragakis, Zachary Simmons, Timothy M. Miller, Nicholas Olney, Michael D. Weiss, Stephen A. Goutman, Joseph Americo Fernandes, Omar Jawdat, Margaret Owegi, Laura A. Foster, Tuan Vu, Hristelina Ilieva, Daniel S. Newman, Ximena Arcila-Londono, Carlayne E. Jackson, Shafeeq Ladha, Terry Heiman‐Patterson, James B. Caress, Andrea Swenson, Amanda Peltier, Richard A. Lewis, Dominic Fee, Matthew Elliott, Richard Bedlack, Edward J. Kasarskis, Lauren Elman, Jeffrey Rosenfeld, David Walk, Courtney McIlduff, Paul Twydell, Eufrosina Young, Kristin Johnson, Kourosh Rezania, Namita Goyal, Jeffrey A. Cohen, Michael Benatar, Vovanti Jones, Jonathan D. Glass, Jaimin Shah, Said R. Beydoun, James Wymer, Lindsay Zilliox, Shakti Nayar, Gary L. Pattee, Jennifer M. Martinez‐Thompson, Brittany Harvey, Shital Patel, Paul Mahoney, Petra W. Duda, Merit Cudkowicz, HEALEY ALS Platform Trial Study Group, Douglas * deceased Hayden, Po-Ying Lai, Rachel A. Donahue, Hao-Wun Chen, Jianing Wang, Nithya Mathai, Gabriela Lopes, Alexandra McCaffrey, Jennifer Scalia, Sarah Luppino, Clotilde Lagier‐Tourenne, Ghazaleh Sadri‐Vakili, Stephen J. Kolb, Sarah Heintzman
Abstract
Importance: The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective: To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants: Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions: Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures: The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results: Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance: In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration: ClinicalTrials.gov Identifier: NCT04297683.