Verdiperstat in Amyotrophic Lateral Sclerosis
Authors:   Writing Committee for the HEALEY ALS Platform Trial, 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 , 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 , Walk David , Maiser Sam , Mundwiler Andrew , Meyer Jenny A. , Soliven Betty , Roos Raymond , Mozaffar Tahseen , Korb Manisha Kak , Mullen Jeffrey , Stommel Elijah , Robbins Nathaniel M , Carberry Nathan , Govindarajan Raghav , Fournier Christina N. , 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 , 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 , Andrews Jinsy , Paganoni Sabrina , Macklin Eric A. , Chibnik Lori B. , Quintana Melanie , Saville Benjamin R. , Detry Michelle A. , Vestrucci Matteo , Marion Joseph , McGlothlin Anna , Young Eufrosina , Chase Marianne , Pothier Lindsay , Harkey Brittney , Yu Hong , Sherman Alex , Shefner Jeremy , Hall Meghan , Kittle Gale , Connolly Mariah R. , Berry James D. , D’Agostino Derek , Tustison Eric , Giacomelli Elisa , Scirocco Erica , Alameda Gustavo , Locatelli Eduardo , Ho Doreen , Quick Adam , Heitzman Daragh , Ajroud-Driss Senda , Appel Stanley H. , Shroff Sheetal , Katz Jonathan , Felice Kevin , Maragakis Nicholas J. , Simmons Zachary , Goutman Stephen A. , Olney Nicholas , Miller Timothy , Fernandes Joseph Americo , Ilieva Hristelina , Jawdat Omar , Weiss Michael D , Foster Laura , Vu Tuan , Ladha Shafeeq , Owegi Margaret Ayo , Newman Daniel S. , Arcila-Londono Ximena , Jackson Carlayne E. , Swenson Andrea , Heiman-Patterson Terry , Caress James , Fee Dominic , Peltier Amanda , Lewis Richard , Rosenfeld Jeffrey , Walk David , Johnson Kristin , Elliott Matthew , Kasarskis Edward J. , Rutkove Seward , McIlduff Courtney E. , Bedlack Richard , Elman Lauren , Goyal Namita A. , Rezania Kourosh , Twydell Paul , Benatar Michael , Glass Jonathan , Cohen Jeffrey A. , Jones Vovanti , Zilliox Lindsay , Wymer James P. , Beydoun Said R. , Shah Jaimin , Pattee Gary L. , Martinez-Thompson Jennifer , Nayar Shakti , Granit Volkan , Donohue Mary , Grossman Katheryn , Campbell Daniel J , Qureshi Irfan A , Cudkowicz Merit E. , Babu Suma ,   HEALEY ALS Platform Trial Study Group
Published: February 2025

ImportanceMyeloperoxidase is one of the most abundant peroxidase enzymes in activated myeloid cells. Myeloperoxidase inhibitors may have a clinical benefit in amyotrophic lateral sclerosis (ALS) by slowing neurodegeneration via reduced neuroinflammation and oxidative stress.ObjectiveTo determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS.Design, Settings, and ParticipantsVerdiperstat was tested as a regimen of the HEALEY ALS Platform Trial, a multicenter, double-blind, perpetual platform design, randomized clinical trial, with sharing of trial infrastructure and placebo data across multiple regimens. The study was conducted at 54 ALS referral centers across the US from July 2020 to April 2022. Adult participants with a diagnosis of clinically possible, probable, laboratory-supported probable, or definite ALS defined by the revised El Escorial criteria were randomized to verdiperstat or regimen-specific placebo. An additional group of participants concurrently randomized to placebo from other regimens was included in the analyses.InterventionsEligible participants were randomized in a 3:1 ratio to receive oral verdiperstat, 600 mg, twice daily or matching placebo for a planned placebo-controlled duration of 24 weeks.Main Outcomes and MeasuresThe primary efficacy outcome was change from baseline through week 24 in disease severity, as measured by a joint model of ALS Functional Rating Scale–Revised and survival, with the treatment effect quantified by the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression of verdiperstat relative to placebo.ResultsA total of 167 participants (mean [SD] age, 58.5 [11.4] years; 59 [35.3%] female; 108 [64.6%] male) were randomized to either verdiperstat (126 [75.4%]) or to placebo (41 [25.6%]). Among the participants randomized to the verdiperstat regimen, 130 (78%) completed the trial. The estimated DRR was 0.98 (95% credible interval, 0.77-1.24; posterior probability = 0.57 for slowing of disease progression [DRR &amp;lt;1]). Verdiperstat was estimated to slow progression by 2% vs placebo (95% credible interval, −23% to 24%; posterior probability 0.57). Verdiperstat was overall safe and well tolerated. Common adverse events in the verdiperstat group were nausea, insomnia, and elevated thyrotropin levels.Conclusions and RelevanceResults demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS.Trial RegistrationClinical Trial Identifiers: NCT04297683 and NCT04436510