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

ImportanceThe etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression.ObjectiveTo determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS.Design, Setting, and ParticipantsZilucoplan 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.InterventionsEligible 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 MeasuresThe 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;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).ResultsAmong 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT04297683