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)