Journal article
Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial
JAMA : the journal of the American Medical Association, Vol.333(13), pp.1128-1137
04/01/2025
DOI: 10.1001/jama.2024.26429
PMCID: PMC11833658
PMID: 40067755
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
Details
- Title: Subtitle
- Pridopidine in Amyotrophic Lateral Sclerosis: The HEALEY ALS Platform Trial
- Creators
- Jeremy M Shefner - Barrow Neurological InstituteBjörn Oskarsson - Mayo Clinic in FloridaEric A Macklin - Harvard UniversityLori B Chibnik - Harvard UniversityMelanie QuintanaBenjamin R SavilleMichelle A DetryMatteo VestrucciJoe MarionAnna McGlothlinTerry Heiman-Patterson - Temple UniversityMarianne Chase - Harvard UniversityLindsay Pothier - Harvard UniversityBrittney A Harkey - Harvard UniversityHong Yu - Harvard UniversityAlexander V Sherman - Harvard UniversityMeghan Hall - Barrow Neurological InstituteGale Kittle - Barrow Neurological InstituteJames D Berry - Massachusetts General HospitalSuma Babu - Harvard UniversityJinsy Andrews - Columbia UniversityDerek D’Agostino - Harvard UniversityEric Tustison - Harvard UniversityErica Scirocco - Harvard UniversityElisa Giacomelli - Harvard UniversityGustavo Alameda - Holy Cross HospitalEduardo Locatelli - Holy Cross HospitalDoreen Ho - Harvard UniversityAdam Quick - The Ohio State UniversitySenda Ajroud-Driss - Northwestern UniversityJonathan Katz - California Pacific Medical CenterDaragh Heitzman - Texas NeurologyStanley H Appel - Houston MethodistSheetal Shroff - Houston MethodistKevin Felice - Hospital for Special CareNicholas J Maragakis - Johns Hopkins UniversityZachary Simmons - Penn State Milton S. Hershey Medical CenterTimothy M MillerNicholas Olney - Oregon ClinicMichael D Weiss - University of WashingtonStephen A Goutman - University of MichiganJoseph Americo Fernandes - University of Nebraska Medical CenterOmar Jawdat - University of Kansas Medical CenterMargaret Ayo Owegi - University of Massachusetts Chan Medical SchoolLaura A Foster - University of Colorado Anschutz Medical CampusTuan Vu - University of South FloridaHristelina IlievaDaniel S Newman - Henry Ford HospitalXimena Arcila-Londono - Henry Ford HospitalCarlayne E Jackson - The University of Texas at San Antonio Health Science CenterShafeeq Ladha - Barrow Neurological InstituteJames B Caress - Wake Forest UniversityAndrea Swenson - University of IowaAmanda Peltier - Vanderbilt University Medical CenterRichard A Lewis - Cedars-Sinai Medical CenterDominic Fee - Medical College of WisconsinMatthew Elliott - University of VirginiaRichard Bedlack - Duke UniversityEdward J Kasarskis - University of KentuckyLauren Elman - University of PennsylvaniaJeffrey Rosenfeld - Loma Linda UniversityDavid Walk - University of MinnesotaCourtney McIlduff - Beth Israel Deaconess Medical CenterPaul Twydell - Corewell Health Blodgett HospitalEufrosina Young - SUNY Upstate Medical UniversityKristin Johnson - Ochsner Health SystemKourosh Rezania - University of ChicagoNamita A Goyal - University of California, Irvine Medical CenterJeffrey A Cohen - Dartmouth–Hitchcock Medical CenterMichael Benatar - University of MiamiVovanti Jones - University of MissouriJaimin Shah - Mayo Clinic in FloridaSaid R Beydoun - University of Southern CaliforniaJames P Wymer - University of FloridaLindsay Zilliox - University of Maryland, BaltimoreShakti Nayar - Georgetown UniversityGary L PatteeJennifer Martinez-Thompson - Mayo ClinicMelanie L LeitnerKelly ChenY. Paul GoldbergYael CohenMichal GevaMichael R Hayden - University of British ColumbiaSabrina Paganoni - Harvard UniversityMerit E Cudkowicz - Massachusetts General Hospital
- Resource Type
- Journal article
- Publication Details
- JAMA : the journal of the American Medical Association, Vol.333(13), pp.1128-1137
- DOI
- 10.1001/jama.2024.26429
- PMID
- 40067755
- PMCID
- PMC11833658
- NLM abbreviation
- JAMA
- ISSN
- 0098-7484
- eISSN
- 1538-3598
- Publisher
- American Medical Association
- Grant note
- AMG Charitable FoundationTackle ALSALS AssociationALS Finding a CureMuscular Dystrophy AssociationALS ONEArthur M. Blank Family FoundationI AM ALSTambourine ALS Collaborative CohortPrilenia Therapeutics
The HEALEY ALS Platform Trial was supported and made possible by the AMG Charitable Foundation, Tackle ALS, The ALS Association, ALS Finding a Cure, Muscular Dystrophy Association, ALS ONE, Arthur M. Blank Family Foundation, I AM ALS, Tambourine ALS Collaborative Cohort, and many other community fundraising initiatives and donors. The study drug and partial funding were provided by Prilenia Therapeutics. For more information, please visit the HEALEY ALS Platform Trial at https://www. massgeneral.org/assets/mgh/pdf/neurology/als/healey_platform_trial_publication%20policy.pdf.
- Language
- English
- Electronic publication date
- 02/17/2025
- Date published
- 04/01/2025
- Academic Unit
- Neurology
- Record Identifier
- 9984792365002771
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