Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis
Authors: Sabrina Paganoni, Christina N. 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 A. Harkey, Hong Yu, Alexander V. Sherman, Jeremy M. Shefner, Meghan Hall, Gale Kittle, James D. Berry, Suma Babu, Jinsy Andrews, Derek Dagostino, Eric Tustison, Elisa Giacomelli, Erica Scirocco, Gustavo Alameda, Eduardo Locatelli, Doreen Ho, Adam Quick, Jonathan Katz, Daragh Heitzman, Stanley H. Appel, Sheetal Shroff, Kevin Felice, Nicholas J. Maragakis, Zachary Simmons, Timothy M. Miller, Nicholas Olney, Michael D. Weiss, Stephen A. Goutman, Joseph Americo Fernandes, Omar Jawdat, Margaret Ayo 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 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 A. Goyal, Jeffrey A. Cohen, Michael Benatar, Vovanti Jones, Jonathan Glass, Jaimin Shah, Said R. Beydoun, James P. Wymer, Lindsay Zilliox, Shakti Nayar, Gary L. Pattee, Jennifer Martinez-Thompson, Brittany Harvey, Shital Patel, Paul Mahoney, Petra W. Duda, Merit E. Cudkowicz, 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 Kolb, Sarah Heintzman, Robert Sufit, April Szymanski, Liberty Jenkins, Alan Martin, Ericka (Simpson) Greene, Jason R. Thonhoff, Bing Liao, Charles  * deceased Whitaker, Lora L. Clawson, Alpa Uchil, Kristen M. Riley, JinAe Arneklev, James Grogan, Xiaowei Su, Mansoureh Mamarabadi, Amber Malcolm, Tracy Bazan, Nassim Rad, Leo H. Wang, Eva L. Feldman, Ezequiel Piccione, Pariwat Thaisetthawatkul, Constantine Farmakidis, Duaa Jabari, Jeffrey Statland, Mamatha Pasnoor, Mazen Dimachkie, Robert H. Brown, Jr., Mehdi Ghasemi, Hajar Houmani, Catherine Douthwright, Kate Daniello, Niraja Suresh, Jerrica Farias, I-Hweii A. Chen, Piera Pasinelli, Kara Steijlen, Ratna Bhavaraju-Sanka, Bill Jacobsen, Jourdan Milliard, Robert Bowser, Anahita Deboo, Michael S. Cartwright, Christopher Nance, Ludwig Gutmann, Julia Yasek, Matthew Harms, Matthew Burford, Frank Diaz, David Shrilla, Goran Rakocevic, Sarah Jones, Guillermo Solorzano, Xiaoyan Li, Zabeen Mahuwala, Vishakhadatta (Vish) Mathur Kumaraswamy, Colin Quinn, Michael Baer, David Borg, Karthikeyan Bhuvaneswaran, Jasdeep Kaur, Sam Maiser, Seward B. Rutkove, Andrew Mundwiler, Jenny A. Meyer, Pooja Rao, Betty Soliven, Raymond Roos, Ali A. Habib, Tahseen Mozaffar, Manisha Kak Korb, Jeffrey Mullen, Elijah Stommel, Nathaniel M Robbins, Nathan Carberry, Volkan Granit, Raghav Govindarajan, Bjorn Oskarsson, Leila Darki, Rodrigo Rodriguez, Miguel Chuquilin, Whitney McNeely, Montserrat Diaz-Abad, Peter H. Jin, Chandana Chauhan, James Bobenhouse, Nathan P. Staff, Ghazala Hayat, Luisa Arroyave, Abbey Bailey, Jesse Bailey, Victoria Barlow, Allison Bulat, Genevive Changkuon, Melissa Cirino, Cristina Deignan, Emma Deirmendjian, Annette De Mattos, Sofia DiStefano, Kristin Drake, Michaela Estes, Kenneth Faulconer, Precious Figueroa-Szostek, Tessa Garozzo, Meredith Gibbons Hasenoehrl, Jennifer Henrique, Natalie Henrique, Samuel Hurwitz, Courtney Igne, Liam Irwin, Katie Jentoft, Boglarka Jordan, Igor Katsovskiy, Olga Kharakozova, Taylor Kolvek, Alexander Korin, Thuong La, Haining Li, Joey Nguyen, Ilya Novak, Ricardo Ortiz, Joe Ostrow, Jaclyn Pagliaro, Jack Palillo, Payal Patel, Janae Patterson, Minh Phan, Najla Popel, Serena Proueng, Jesse Rosenthal, Catherine Small, Natalia Tarasenko, Mirna Thomas, Prasha Vigneswaran, Yusra Wahab, Isaac Whitworth, Spencer Wright, Mariah Connolly, Diana De Santiago, Adrian Felix, Karly Garrett, Jenny Hamilton, Kamran Khan, Marlee Lovett, Linda Nelson, Marissa Pabon, Diana Rede, Patrick Bolger, Ahmed Fetouh, Joan Woodcook, Cornelia Kamp, Julie Kennedy, Andrew McGarry, Margherita Torti
Journal: JAMA Network Open (2025)

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; &amp;amp;lt;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