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Clinical Trial
. 2025 May 1;82(5):477-485.
doi: 10.1001/jamaneurol.2025.0241.

Reldesemtiv in Amyotrophic Lateral Sclerosis: Results From the COURAGE-ALS Randomized Clinical Trial

Jeremy M Shefner  1   2 , Merit E Cudkowicz  3 , Angela Genge  4 , Orla Hardiman  5 , Ammar Al-Chalabi  6 , Jinsy A Andrews  7 , Adriano Chio  8 , Philippe Corcia  9 , Philippe Couratier  10 , Mamede de Carvalho  11 , Terry Heiman-Patterson  12 , Robert D Henderson  13 , Caroline Ingre  14 , Wendy Johnston  15 , Albert Ludolph  16   17 , Nicholas J Maragakis  18 , Timothy M Miller  19 , Jesus S Mora  20 , Susanne Petri  21 , Zachary Simmons  22 , Leonard H van den Berg  23 , Lorne Zinman  24 , Stuart Kupfer  25 , Fady I Malik  25 , Lisa Meng  25 , Tyrell J Simkins  25 , Jenny Wei  25 , Andrew A Wolff  25 , Stacy A Rudnicki  25 ; COURAGE-ALS Study Group
Collaborators, Affiliations
Clinical Trial

Reldesemtiv in Amyotrophic Lateral Sclerosis: Results From the COURAGE-ALS Randomized Clinical Trial

Jeremy M Shefner et al. JAMA Neurol. .

Abstract

Importance: Treatment options for amyotrophic lateral sclerosis (ALS) remain suboptimal. Results from a phase 2 study of reldesemtiv in ALS suggested that it may slow disease progression.

Objective: To assess the effect of reldesemtiv vs placebo on functional outcomes in ALS.

Design, setting, and participants: A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (COURAGE-ALS) was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted at 83 ALS centers in 16 countries from August 2021 to July 2023. The first 24-week period was placebo controlled vs reldesemtiv. All participants received reldesemtiv during the second 24-week period with a 4-week follow-up. Two interim analyses were planned, the first for futility and the second for futility and possible resizing. This was a hybrid decentralized trial with approximately half the trial visits performed remotely and the remaining visits in the clinic. Eligible participants met criteria for definite, probable, or possible ALS with lower motor neuron signs by modified El Escorial Criteria, ALS symptoms for 24 months or less, ALS Functional Rating Scale-Revised (ALSFRS-R) total score of 44 or less, and forced vital capacity of greater than or equal to 65% of predicted.

Interventions: Oral reldesemtiv, 300 mg, or placebo twice daily.

Main outcomes and measures: The primary end point was change in ALSFRS-R total score from baseline to week 24.

Results: Of the 696 participants screened, 207 were screen failures. A total of 486 participants (mean [SD] age, 59.4 [10.9] years; 309 male [63.6%]) were randomized to reldesemtiv (n = 325) or placebo (n = 161); 3 randomized patients were not dosed. The second interim analysis at 24 weeks after randomization included 256 participants. The data monitoring committee recommended that the trial should end due to futility, and the sponsor agreed. The mean (SE) group difference in the ALSFRS-R score from baseline to week 24 was -1.1 (0.53; 95% CI, -2.17 to -0.08; P = .04, favoring placebo). Given excess missing data from early termination, the combined assessment assumed greater importance; it, too, failed to show a benefit from treatment with reldesemtiv (win probability was 0.44 for reldesemtiv and 0.49 for placebo, with a win ratio of 0.91; 95% CI of win ratio, 0.77-1.10; P = .11).

Conclusions and relevance: This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS.

Trial registration: ClinicalTrials.gov Identifier: NCT04944784.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Shefner reported receiving grants from Cytokinetics, National Institute of Neurological Disorders and Stroke (NINDS), MTP Pharma America, Amylyx, Sanofi, Healey Center for ALS, PTC Therapeutics, and Neurosense and personal fees from Amylyx, Sanofi, Novartis, PTC Therapeutics, Acurastem, Neurosense, Swanbio, and Vertex outside the submitted work. Dr Hardiman reported participating in the Cytokinetics steering committee, receiving grants from Science Foundation Ireland, and serving as editor in chief of Amyotrophic Lateral Sclerosis and the Frontotemporal Degenerations. Dr Al-Chalabi reported receiving nonfinancial support from the National Institute for Health and Care Research (NIHR); consultant fees from Amylyx, Clene Therapeutics, GenieUs, GSK, Eli Lilly, Mitsubishi Tanabe Pharma, Novartis, OrionPharma, Quralis, SanoGenetics, Sanofi, Voyager Therapeutics, and Wave Pharmaceuticals; and having a patent for use of CSF-neurofilament determinations and CSF-neurofilament thresholds of prognostic and stratification value with regards to response to therapy in neuromuscular and neurodegenerative diseases pending. Dr Andrews reported receiving personal/data safety monitoring board fees from AL-S Pharma, Biogen, Cytokinetics, Amylyx, Apellis, Wave Life Science, Revalasio, Quralis, Sanofi; grants from Amylyx, Biogen, Cytokinetics, Platform Trial [Ra/Biohaven/Clene/Prilenia/Calico], and National Institutes of Health (NIH)/NINDS research funding to the institution outside the submitted work. Dr Corcia reported receiving personal/consultant/data safety monitoring board fees from Cytokinetics, QurALIS, Mitsubishi Tanabe, Effik, Zambon, Vectory, Ferrer, and Amylyx outside the submitted work. Dr Heiman-Patterson reported receiving grants from Temple University Lewis Katz School of Medicine Trial compensation; advisory board fees from Mitsubishi Tanabe, Amylyx, and Novartis; data safety monitoring board fees from Healey expanded access program; and grants from Mitsubishi Tanabe and Amylyx outside the submitted work. Dr Johnston reported receiving personal fees from Cytokinetics and clinical trial funding to institution during the conduct of the study. Dr Ludolph reported receiving compensation fees from Cytokinetics during the conduct of the study. Dr Maragakis reported receiving grants from Cytokinetics, Massachusetts General Hospital, NIH/NINDS, Department of Defense Amyotrophic Lateral Sclerosis Research Program, and Maryland Stem Cell Research Fund; data monitoring committee/scientific advisory board/personal fees from Novartis, NuraBio, and Akava; and nonfinancial support from Secretome Therapeutics outside the submitted work. Dr Miller reported receiving personal fees/site payments from Cytokinetics, consulting/licensing fees from Ionis Pharmaceuticals, consulting fees from Biogen and Arbor Bio, licensing agreement from C2N, honorarium from Denali, and consulting fees from Bioio outside the submitted work. Dr Petri reported receiving payment to institution for patient visits within the clinical trial from Cytokinetics; grants from German Israeli Foundation, German Neuromuscular Society, and Neurodegenerative Research Inc, and personal/consulting/speaker/travel fees from Amylyx, PCT Therapeutics, Italfarmaco, Zambon, Biogen, Roche, Ferrer, and Cytokinetics outside the submitted work. Dr Simmons reported receiving grants from Penn State Hershey Medical Center, Clene, MT Pharma, and Sanofi and personal fees from Biogen, Amylyx, and Corcept outside the submitted work. Dr van den Berg reported receiving grants from Cytokinetics for executing the trial during the conduct of the study; Ferrer, Amylyx, Sanofi, Argenx, Biogen, Novartis, and Corcept outside the submitted work. Dr Kupfer reported being an employee of and receiving a salary and stock options from Cytokinetics outside the submitted work. Dr Malik reported being an employee of and shareholder in Cytokinetics during the conduct of the study. Drs Meng, Simkins, and Wolff reported being employees of Cytokinetics during the conduct of the study. Dr Wei reported being an employee of and owning stock in Cytokinetics. Dr Rudnicki reported being a consultant for, owning stock in, and being a previous employee of Cytokinetics. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Consolidated Standards of Reporting Trials Diagram of Participant Disposition
AE indicates adverse event; BID, twice daily.
Figure 2.
Figure 2.. Change From Baseline Through Week 24
A, Amyotrophic Lateral Sclerosis (ALS) Functional Rating Scale–Revised (ALSFRS-R). B, In-clinic percentage predicted forced vital capacity (FVC). C, Forty-item ALS Assessment Questionnaire (ALSAQ-40). D, Handgrip strength.
Figure 3.
Figure 3.. Change in Amyotrophic Lateral Sclerosis (ALS) Functional Rating Scale–Revised (ALSFRS-R) at Week 24 by Subgroup
FVC indicates forced vital capacity; LSM, least squares mean. aDetermined post hoc.
See this image and copyright information in PMC

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