Pridopidine in Amyotrophic Lateral Sclerosis
Douglas Hayden, Po-Ying Lai, Rachel A. Donahue, H.Y. 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, Jonathan D. Glass, Christina Fournier, Leila Darki, Rodrigo Rodriguez, Miguel Chuquilin, Whitney McNeely, Montserrat Diaz‐Abad, Peter H. Jin, Chandana Chauhan
Abstract
Importance: Amyotrophic lateral sclerosis (ALS) is a fatal disease. The sigma-1 (σ1) receptor emerged as a target for intervention. Objective: To determine the effects of pridopidine, a σ1-receptor agonist, in ALS. Design, Settings, and Participants: 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. Interventions: 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. Main Outcomes and Measures: 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. Results: 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). Conclusions and Relevance: In this 24-week study, pridopidine did not impact the progression of ALS. Trial Registration: ClinicalTrials.gov Identifiers: NCT04297683, NCT04615923.