Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis

作者：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, Robert Sufit, April Szymanski, Liberty Jenkins, A. D. Martin, Ericka Greene, Jason R. Thonhoff, Bing Liao, Charles H. Whitaker, Lora 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 M. Dimachkie, Robert H. Brown, 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 Rakočević, Sarah Jones, Guillermo Solórzano, Xiaoyan Li, Zabeen Mahuwala, Vishakhadatta Mathur Kumaraswamy, Colin Quinn, Michael Baer, David N. Borg, Karthikeyan Bhuvaneswaran, Jasdeep Kaur, Sam Maiser, Seward B. Rutkove, Andrew Mundwiler, Jenny Meyer, Pooja Rao, Betty Soliven, Raymond P. Roos, Ali A. Habib, Tahseen Mozaffar, Manisha Kak Korb, Jeffrey Mullen, Elijah W. Stommel, Nathaniel M. Robbins, Nathan Carberry, Volkan Granit, Raghav Govindarajan, Björn 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, L. R. 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 B. Small, Natalia Tarasenko, Mirna Thomas, Prasha Vigneswaran, Yusra Wahab, Isaac Whitworth, Spencer Wright, Mariah Connolly, Diana De Santiago, A. John William Felix, Karly Garrett, Jenny Hamilton, Kamran Khan, Marlee Lovett, Linda S. Nelson, Marissa Pabon, Diana Rede, Patrick Bolger, Ahmed Fetouh, Joan Woodcook, Cornelia Kamp, Julie Kennedy, Andrew McGarry, Margherita Torti · 发表于：JAMA Network Open · 年份：2025 · DOI：10.1001/jamanetworkopen.2024.59058 · 被引用次数：23 · 研究领域：Amyotrophic Lateral Sclerosis Research、Peripheral Neuropathies and Disorders、Multiple Sclerosis Research Studies

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...