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

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 &amp;lt;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