A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial OfReldesemtivIn Patients With ALS

Objective To evaluate safety, dose response, and preliminary efficacy ofreldesemtivover 12 weeks in patients with amyotrophic lateral sclerosis (ALS).Methods:Patients (<= 2 years since diagnosis) with slow upright vital capacity (SVC) of >= 60% were randomized 1:1:1:1 toreldesemtiv150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score.Results:Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R,p = 0.09; muscle strength mega-score,p = 0.31). Post hoc analyses pooling all activereldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)).Reldesemtivwas well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation.Conclusions:Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoringreldesemtivfor all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact ofreldesemtivon patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898)

Automated summary

This study evaluated the safety, dose response, and preliminary efficacy of reldesemtiv in patients with ALS. Although the primary efficacy analysis did not demonstrate statistical significance, post hoc analyses showed trends favoring reldesemtiv in all endpoints, with good tolerability.