Pridopidine in Amyotrophic Lateral Sclerosis
Authors: Douglas 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 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, Jonathan Glass, Christina N. Fournier, 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, Jeremy M. Shefner, Björn Oskarsson, Eric A. Macklin, Lori B. Chibnik, Melanie Quintana, Benjamin R. Saville, Michelle A. Detry, Matteo Vestrucci, Joe Marion, Anna McGlothlin, Terry Heiman-Patterson, Marianne Chase, Lindsay Pothier, Brittney A. Harkey, Hong Yu, Alexander V. Sherman, Meghan Hall, Gale Kittle, James D. Berry, Suma Babu, Jinsy Andrews, Derek D’Agostino, Eric Tustison, Erica Scirocco, Elisa Giacomelli, Gustavo Alameda, Eduardo Locatelli, Doreen Ho, Adam Quick, Senda Ajroud-Driss, 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, 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 A. Goyal, Jeffrey A. Cohen, Michael Benatar, Vovanti Jones, Jaimin Shah, Said R. Beydoun, James P. Wymer, Lindsay Zilliox, Shakti Nayar, Gary L. Pattee, Jennifer Martinez-Thompson, Melanie L. Leitner, Kelly Chen, Y. Paul Goldberg, Yael Cohen, Michal Geva, Michael R. Hayden, Sabrina Paganoni, Merit E. Cudkowicz
Journal: JAMA (2025)

Amyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention. To determine the effects of pridopidine, a σ1-receptor agonist, in ALS. Pridopidine was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind, platform trial. The study was conducted at 54 sites in the US from January 2021 to July 2022 (final follow-up, July 14, 2022). A total of 163 participants with ALS were randomized to receive pridopidine or placebo. An additional 122 concurrently randomized participants were assigned to receive placebo in other regimens and included in the analyses. Eligible participants were randomized 3:1 to receive oral pridopidine 45 mg twice daily (n = 121) or matching oral placebo (n = 42) for a planned duration of 24 weeks. The primary efficacy outcome was change from baseline through week 24 in ALS disease severity, analyzed using a bayesian shared parameter model, which has components for function (Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS-R]) and survival that were linked through an integrated estimate of treatment-dependent disease slowing across these 2 components. This was denoted as the disease rate ratio (DRR), with DRR less than 1 indicating a slowing in disease progression on pridopidine relative to placebo. There were 5 key secondary end points: time to 2-point or greater reduction in ALSFRS-R total score among participants with bulbar dysfunction at baseline, rate of decline in slow vital capacity among participants with bulbar dysfunction at baseline, percentage of participants with no worsening in the ALSFRS-R bulbar domain score, time to 1-point or greater change in the ALSFRS-R bulbar domain score, and time to death or permanent assisted ventilation. Among 162 patients (mean age, 57.5 years; 35% female) who were randomized to receive the pridopidine regimen and included in the primary efficacy analysis, 136 (84%) completed the trial. In the primary analysis comparing pridopidine vs the combined placebo groups, there was no significant difference between pridopidine and placebo in the primary end point (DRR, 0.99 [95% credible interval, 0.80-1.21]; probability of DRR <1, 0.55) and no differences were seen in the components of ALSFRS-R or survival. There was no benefit of pridopidine on the secondary end points. In the safety dataset (pridopidine, n = 121; placebo, n = 163), the most common adverse events were falls (28.1% vs 29.3%, respectively) and muscular weakness (24.0% vs 31.7%, respectively). In this 24-week study, pridopidine did not impact the progression of ALS. ClinicalTrials.gov Identifiers: NCT04297683, NCT04615923.