The phase III trial of reldesemtiv did not meet its primary endpoint in amyotrophic lateral sclerosis (ALS).
Reldesemtiv also demonstrated no effect on key secondary endpoints.
The trial was stopped for futility.
The phase III trial COURAGE-ALS of investigational reldesemtiv, a fast skeletal troponin activator, did not meet its primary endpoint in amyotrophic lateral sclerosis (ALS), but its findings shed light on ALS clinical research.
From baseline to week 24, the mean group difference on the 48-point ALS Functional Rating Scale-Revised (ALSFRS-R) was -1.1 (95% CI -2.17 to -0.08, P=0.04, favoring placebo), reported Jeremy Shefner, MD, PhD, of the Barrow Neurological Institute in Phoenix, and co-authors.
COURAGE-ALS was stopped for futility. With missing data from the trial's early termination, the combined assessment of function and survival (CAFS) assumed greater importance, the researchers said in JAMA Neurology.
That assessment also failed to show benefit; the CAFS win probability was 0.44 for reldesemtiv and 0.49 for placebo (win ratio 0.91, P=0.11).
Reldesemtiv demonstrated no effect on key secondary endpoints including change in predicted forced vital capacity (FVC), health-related quality of life, or handgrip strength.
"In the COURAGE-ALS randomized clinical trial, the overall development of fast skeletal troponin activators evaluated an important clinical hypothesis with great rigor," Shefner and colleagues wrote.
"The results reported here parallel findings from other clinical trials testing agents intended to improve skeletal muscle function, including levosimendan and ozanezumab," the researchers pointed out.
"Although muscle-directed strategies may prove effective in static or slowly progressive processes, our data and those of others suggest this is unlikely to be an effective strategy in ALS or other conditions with ongoing denervation," they stated.
Reldesemtiv is a second-generation fast skeletal troponin activator that increases the contractility of skeletal muscle. Tirasemtiv, a first-generation fast skeletal troponin activator, also was studied in ALS but its tolerability was poor.
The phase II FORTITUDE-ALS study of reldesemtiv reported trends favoring the drug but did not achieve statistical significance on primary or secondary endpoints. However, a post hoc analysis suggested the drug might improve outcomes in ALS patients with fast disease progression.
COURAGE-ALS was a double-blind, placebo-controlled trial of 486 patients conducted at 83 ALS centers from August 2021 to July 2023. Participants met criteria for definite, probable, or possible ALS with lower motor neuron signs, and had ALS symptoms for 24 months or less, ALSFRS-R total scores of 44 or less, and FVC greater than or equal to 65%.
The mean age of participants was 59.4. The trial randomized 325 people to 300 mg of oral reldesemtiv and 161 to placebo.
The study was designed with two planned interim analyses of unblinded data by the Data Monitoring Committee. At the second interim analysis, the Data Monitoring Committee recommended the discontinuation of the clinical trial due to futility.
At the time the trial was stopped, 486 patients had started treatment with reldesemtiv or placebo and 276 had completed dosing through 24 weeks. Subgroup analysis showed that participants with a faster disease progression rate did not experience a greater treatment effect from reldesemtiv, contrary to the findings of the FORTITUDE-ALS post hoc analyses.
Overall, 12.6% in the reldesemtiv group and 15.5% in the placebo group experienced a serious adverse event, and 79.4% versus 77.6%, respectively, experienced one or more treatment-emergent adverse event. The most common adverse events were falls, skin and subcutaneous tissue disorder, and COVID-19 infections.
Higher alanine transaminase (ALT) and aspartate transaminase (AST) levels occurred more frequently in patients treated with reldesemtiv than placebo. ALT elevations were found in 6.5% of the reldesemtiv group and 1.9% of the placebo group; AST elevations occurred in 5.5% and 0.6%, respectively.
Reldesemtiv treatment was discontinued in 2023 for all ALS patients, including those in the COURAGE-ALS open-label extension. The drug's development was terminated, the trial sponsor said.
Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow
Disclosures
COURAGE-ALS was conducted and funded by Cytokinetics, with co-funding from Astellas Pharma.
Shefner reported receiving grants from Cytokinetics, NIH, 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.
Co-authors reported relationships with nonprofit groups and pharmaceutical companies.
Primary Source
JAMA Neurology
Source Reference: Shefner JM, et al "Reldesemtiv in amyotrophic lateral sclerosis: results from the COURAGE-ALS randomized clinical trial" JAMA Neurol 2025, DOI: 10.1001/jamaneurol.2025.0241.