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Comment
. 2025 Feb 17;333(13):1128-1137.
doi: 10.1001/jama.2024.26429. Online ahead of print.

Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial

Writing Committee for the HEALEY ALS Platform Trial; Jeremy M Shefner  1 , Björn Oskarsson  2 , Eric A Macklin  3 , Lori B Chibnik  3 , Melanie Quintana  4 , Benjamin R Saville  4 , Michelle A Detry  4 , Matteo Vestrucci  4 , Joe Marion  4 , Anna McGlothlin  4 , Terry Heiman-Patterson  5 , Marianne Chase  3 , Lindsay Pothier  3 , Brittney A Harkey  3 , Hong Yu  3 , Alexander V Sherman  3 , Meghan Hall  1 , Gale Kittle  1 , James D Berry  3 , Suma Babu  3 , Jinsy Andrews  6 , Derek D'Agostino  3 , Eric Tustison  3 , Erica Scirocco  3 , Elisa Giacomelli  3 , Gustavo Alameda  7 , Eduardo Locatelli  7   8 , Doreen Ho  3 , Adam Quick  9 , Senda Ajroud-Driss  10 , Jonathan Katz  11 , Daragh Heitzman  12 , Stanley H Appel  13 , Sheetal Shroff  13 , Kevin Felice  14 , Nicholas J Maragakis  15 , Zachary Simmons  16 , Timothy M Miller  17 , Nicholas Olney  18 , Michael D Weiss  19 , Stephen A Goutman  20 , Joseph Americo Fernandes  21 , Omar Jawdat  22 , Margaret Ayo Owegi  23 , Laura A Foster  24 , Tuan Vu  25 , Hristelina Ilieva  26 , Daniel S Newman  27 , Ximena Arcila-Londono  27 , Carlayne E Jackson  28 , Shafeeq Ladha  1 , James B Caress  29 , Andrea Swenson  30 , Amanda Peltier  31 , Richard A Lewis  32 , Dominic Fee  33 , Matthew Elliott  34 , Richard Bedlack  35 , Edward J Kasarskis  36 , Lauren Elman  37 , Jeffrey Rosenfeld  38 , David Walk  39 , Courtney McIlduff  40 , Paul Twydell  41 , Eufrosina Young  42 , Kristin Johnson  43 , Kourosh Rezania  44 , Namita A Goyal  45 , Jeffrey A Cohen  46 , Michael Benatar  47 , Vovanti Jones  48 , Jaimin Shah  2 , Said R Beydoun  49 , James P Wymer  50 , Lindsay Zilliox  51 , Shakti Nayar  52 , Gary L Pattee  53 , Jennifer Martinez-Thompson  54 , Melanie L Leitner  55 , Kelly Chen  56 , Y Paul Goldberg  56 , Yael Cohen  56 , Michal Geva  56 , Michael R Hayden  56   57 , Sabrina Paganoni  3   58 , Merit E Cudkowicz  3 ; HEALEY ALS Platform Trial Study Group
Collaborators, Affiliations
Comment

Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial

Writing Committee for the HEALEY ALS Platform Trial et al. JAMA. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Shefner reported receiving grants from National Institute of Neurological Disorders and Stroke (NINDS), Mitsubishi Tanabe, Sean M. Healey & AMG Center for ALS, Sanofi, PTC, and NeuroSense; and personal fees from Novartis, PTC, NeuroSense, Amylyx, and Acurastem outside the submitted work. Dr Oskarsson reported receiving grants from Massachusetts General Hospital during the conduct of the study; grants from Columbia University/Tsumura, MediciNova, Biogen, Mitsubishi Tanabe, Cytokinetics, Calico, Sanofi, Ashvattha, Target ALS, and NINDS; and personal fees from uniQure and Amylyx outside the submitted work. Dr Macklin reported receiving grants from AI Therapeutics, Alector, Biohaven, Calico, Clene, Denali, ITB-MED, Lilly, Mitsubishi Tanabe, PharmAust, Revalesio Corporation, Seelos, and UCB/Ra Pharmaceuticals paid to institution; personal fees for serving on the advisory boards of Annexon Biosciences, BIAL, Cortexyme, Chase Therapeutics, Enterin, Hillhurst, Merck, nQ Medical, and Partner Therapeutics; personal fees for serving on the steering committees of Biogen, Stoparkinson, UCB, and argenx; and personal fees for being a data and safety monitoring board (DSMB) member of NeuroSense, Novartis, and Sanofi outside the submitted work. Dr Quintana reported receiving personal fees from Berry Consultants during the conduct of the study. Dr Saville reported being the owner of and receiving personal fees from various companies via Adaptix Trials outside the submitted work. Dr Detry reported consulting fees paid to Berry Consultants from Sean M. Healey & AMG Center for ALS during the conduct of the study. Dr Vestrucci reported consulting fees paid to Berry Consultants from Sean M. Healey & AMG Center for ALS during the conduct of the study. Dr Marion reported receiving personal fees from Berry Consultants during the conduct of the study. Dr McGlothlin reported consulting fees paid to Berry Consultants from Sean M. Healey & AMG Center for ALS during the conduct of the study. Dr Heiman-Patterson reported receiving grants from Sean M. Healey & AMG Center for ALS during the conduct of the study; grants from Mitsubishi Tanabe, Amylyx, ALS Association, Muscular Dystrophy Association, Samus, Alexion, and UCB; personal fees for serving on the medical advisory boards of Mitsubishi Tanabe, Amylyx, and Novartis; and personal fees from p-value group, Projects In Knowledge, and Vindico Medical Education outside the submitted work. Ms Chase reported receiving grants from UCB, Biohaven, and Clene during the conduct of the study. Mr Sherman reported receiving grants from US Food and Drug Administration (FDA), National Institutes of Health (NIH), Biogen, Mitsubishi Tanabe, Amylyx, and ALS Association outside the submitted work. Dr Berry reported receiving personal fees from Alexion, Amylyx, Biogen, Mitsubishi Tanabe, Roon, Regeneron, and Sanofi; and grants from Alexio, Amylyx, Mitsubishi Tanabe, Biogen, Rapa Therapeutics, BrainStorm Cell Therapeutics, and uniQure outside the submitted work. Dr Babu reported receiving grants from NIH/NINDS; research funding from Ionis, Biogen, Novartis, OrphAI, and Denali; consulting fees to institution from uniQure and MarvelBiome; and honoraria from NIH and American Academy of Neurology outside the submitted work. Dr Andrews reported receiving grants to institution from Biogen, Cytokinetics, Amylyx, NIH/NINDS, Calico, Denali, and Prilenia Therapeutics; personal fees for serving on the DSMBs of AL-S Pharma, Sanofi, and QurAlis; and personal fees for serving on the scientific advisory board of NeuroSense and AKAVA outside the submitted work. Dr Alameda reported receiving a principal investigator stipend from Sean M. Healey & AMG Center for ALS during the conduct of the study. Dr Ho reported receiving research funding from Ra Pharmaceuticals, Biohaven, Calico, Seelos, Denali, Biogen, Transposon, Sanofi, Neurodegenerative Alzheimer’s Disease and Amyotrophic Lateral Sclerosis basket trial, and Genentech; and personal fees for serving on the advisory boards of Sanofi, Alexion, and Biogen outside the submitted work. Dr Ajroud-Driss reported receiving personal fees from Amylyx and Biogen during the conduct of the study. Dr Heitzman reported receiving grants from Muscular Dystrophy Association and ALS Association; study support from NINDS, AbbVie, AbbVie/Calico, Anelixis, Amylyx, Biohaven, Cytokinetics, Denali, Abcuro, Immunovant, Clene, Mitsubishi Tanabe, Neurologix Foundation, Ra Pharmaceuticals, and Seelos; and personal fees from University of Texas and Amylyx outside the submitted work. Dr Shroff reported receiving personal fees from UCB, Alnylam, argenx, and AstraZeneca outside the submitted work. Dr Maragakis reported receiving grants from NIH/NINDS and US Department of Defense Amyotrophic Lateral Sclerosis Research Program during the conduct of the study; personal fees from Nura Bio, Novartis, and AKAVA; and nonfinancial support from Janssen and Secretome Therapeutics outside the submitted work. Dr Simmons reported receiving grants from Massachusetts General Hospital during the conduct of the study; personal fees from Biogen, Amylyx, Insmed, Corcept, and Columbia University; and grants from Sanofi and Clene outside the submitted work. Dr Miller reported receiving personal fees from Ionis Pharmaceuticals, Biogen, Arbor Biotechnologies, and BIOIO; licensing agreements from Ionis Pharmaceuticals and C2N; and honorarium from Denali outside the submitted work. Dr Weiss reported receiving personal fees from Biogen, Cytokinetics, Mitsubishi Tanabe, Amylyx, and Sanofi outside the submitted work. Dr Vu reported receiving reimbursement from University of South Florida Department of Neurology during the conduct of the study. Dr Ilieva reported receiving grants from ALS Association during the conduct of the study; and grants from TechVsALS outside the submitted work. Dr Arcila-Londono reported receiving grants from ALS Association outside the submitted work. Dr Ladha reported receiving personal fees from Sanofi, Biogen, Amylyx, and Genentech outside the submitted work. Dr Elliott reported receiving grants from Denali, Calico, AbbVie, Seelos, Biohaven, UCB, MediciNova, and ALS Association outside the submitted work. Dr Bedlack reported receiving grants from Duke during the conduct of the study. Dr Walk reported receiving personal fees from Mitsubishi Tanabe, Amylyx, and Clene outside the submitted work. Dr Johnson reported receiving personal fees from argenx outside the submitted work. Dr Goyal reported receiving grants from Abcuro, Amylyx, Annexon, Calico, Clene, Cytokinetics, Fulcrum, Janssen, Kezar, MediciNova, Mitsubishi Tanabe, PepGen, PTC, Roche, Sanofi, and Transposon outside the submitted work; and serving on the speakers’ bureau for argenx and CSL Behring. Dr Benatar reported receiving consulting fees from Prilenia Therapeutics, Alector, Biogen, Novartis, Bristol Myers Squibb, Woolsey, Eli Lilly, uniQure, and Arrowhead outside the submitted work. Dr Shah reported receiving grants from Abcuro, Muscular Dystrophy Association, and argenx outside the submitted work. Dr Beydoun reported receiving grants from University of Southern California during the conduct of the study; grants from Abcuro, Janssen, Sanofi, and Regeneron; and personal fees from argenx, Alnylam, AstraZeneca, Alexion, CSL Behring, UCB, and Takeda outside the submitted work. Dr Wymer reported receiving grants from Mitsubishi Tanabe outside the submitted work. Dr Nayar reported receiving personal fees from Sanofi outside the submitted work. Dr Leitner reported receiving personal fees from ALS Investment Fund outside the submitted work. Dr Goldberg reported owning shares in Prilenia Therapeutics. Dr Geva reported a patent (WO/2019/036358) issued. Dr Hayden reported being the Chief Executive Officer of Prilenia Therapeutics outside the submitted work; and owning patents (20240148708, 20230190724, 11406625, 20210030734, 20200179355). Dr Paganoni reported receiving grants from Amylyx, Eledon, Alector, Seelos, Calico, Denali, NIH, US Centers for Disease Control and Prevention, and US Department of Defense; consulting agreements from Amylyx, Revalesio Corporation, Bristol Myers Squibb, Clene, Prilenia Therapeutics, Eikonizo, Sola, and PharmAust; personal fees from Arrowhead, Biogen, Johnson & Johnson, Merck, and Cytokinetics; and being a speaker for PeerView, Medscape, and i3 Health outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Recruitment, Randomization, and Follow-Up for the Pridopidine Regimen
ALS indicates amyotrophic lateral sclerosis. aParticipants could have multiple reasons for exclusion from the master protocol. The most common reasons were not meeting the criteria for slow vital capacity of 50% or greater (46%), having a clinically significant unstable medical condition other than ALS (31%), and using investigational treatments for ALS within 5 half-lives (if known) or 30 days (whichever was longer) prior to the screening visit (17%).
Figure 2.
Figure 2.. Change in Disease Severity Over 24 Weeks Measured by Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) Scores and Survival
A, Boxplots of the ALSFRS-R score change from baseline over time for the active treatment, the regimen placebo, and the shared placebo. Points represent the raw mean values at each visit. The bottom of each box represents the 25th percentile of the ALSFRS-R score change from baseline values and the top of the box, the 75th percentile. The horizontal line within each box represents the median value. The whiskers extend to the most extreme data point, which is no further than 1.5 times the length of the box from the box, with outside values beyond this range represented as empty circles. The solid lines represent the model-estimated change in ALSFRS-R score over time, adjusting for covariates. The estimate for the regimen placebo shares information from placebo participants in other regimens. The numbers below the panel are the number of participants with known ALSFRS-R outcomes at each visit. The summary excludes all ALSFRS-R data from participants who died or had a death-equivalent event (permanent assisted ventilation [PAV]). B, Kaplan-Meier curves for death or PAV per group and the model-estimated exponential curves for the active treatment and pooled placebo groups. The numbers below the panel are the number of participants exposed and the number of deaths or PAV events per group.
See this image and copyright information in PMC

Comment in

  • Verdiperstat in Amyotrophic Lateral Sclerosis: Results From the Randomized HEALEY ALS Platform Trial.
    Writing Committee for the HEALEY ALS Platform Trial; Andrews J, Paganoni S, Macklin EA, Chibnik LB, Quintana M, Saville BR, Detry MA, Vestrucci M, Marion J, McGlothlin A, Young E, Chase M, Pothier L, Harkey B, Yu H, Sherman A, Shefner J, Hall M, Kittle G, Connolly MR, Berry JD, D'Agostino D, Tustison E, Giacomelli E, Scirocco E, Alameda G, Locatelli E, Ho D, Quick A, Heitzman D, Ajroud-Driss S, Appel SH, Shroff S, Katz J, Felice K, Maragakis NJ, Simmons Z, Goutman SA, Olney N, Miller T, Fernandes JA, Ilieva H, Jawdat O, Weiss MD, Foster L, Vu T, Ladha S, Owegi MA, Newman DS, Arcila-Londono X, Jackson CE, Swenson A, Heiman-Patterson T, Caress J, Fee D, Peltier A, Lewis R, Rosenfeld J, Walk D, Johnson K, Elliott M, Kasarskis EJ, Rutkove S, McIlduff CE, Bedlack R, Elman L, Goyal NA, Rezania K, Twydell P, Benatar M, Glass J, Cohen JA, Jones V, Zilliox L, Wymer JP, Beydoun SR, Shah J, Pattee GL, Martinez-Thompson J, Nayar S, Granit V, Donohue M, Grossman K, Campbell DJ, Qureshi IA, Cudkowicz ME, Babu S. Writing Committee for the HEALEY ALS Platform Trial, et al. JAMA Neurol. 2025 Apr;82(4):333-343. doi: 10.1001/jamaneurol.2024.5249. Epub 2025 Feb 17. JAMA Neurol. 2025. PMID: 40067754 Free PMC article. Clinical Trial.

Comment on

  • Platform Trials in ALS.
    Turnbull J. Turnbull J. JAMA. 2025 Feb 17. doi: 10.1001/jama.2025.0100. Online ahead of print. JAMA. 2025. PMID: 39960747 No abstract available.

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