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

Myeloperoxidase 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. To determine the safety, tolerability, and efficacy of verdiperstat, a selective myeloperoxidase inhibitor, in ALS. Verdiperstat 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. Eligible 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. The 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. A 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 <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. Results demonstrate that treatment with verdiperstat was unlikely to alter disease progression in ALS. Clinical Trial Identifiers: NCT04297683 and NCT04436510.