Over a 24-week treatment period, reldesemtiv failed to show a significant effect vs placebo on the primary end point of ALS Functional Scale-Revised, as well as other key secondary end points.
Following a planned interim analysis meeting, the Data Monitoring Committee for the phase 3 COURAGE-ALS trial (NCT04944784) concluded that reldesemtiv had no functional benefit as a treatment for patients with amyotrophic lateral sclerosis (ALS). Cytokinetics, the drug manufacturer, noted the trial will conclude, and all patients, including those in the open-label extension study, will discontinue treatment immediately.
"We are extremely disappointed with this outcome and would like to thank the people with ALS, caregivers, investigators and clinical trial staff for their participation in COURAGE-ALS," Robert I. Blum, chief executive officer and president, Cytokinetics, said in a statement. "Cytokinetics has been committed to the ALS community for more than a decade and recognizes the urgency to bring new potential medicines to the forefront for this grievous disease. In the coming months, we will assess next steps relating to our neuromuscular development programs."
Reldesemtiv, a next-generation fast skeletal muscle troponin activator (FSTA), slows the rate of calcium release from the regulatory troponin complex of fast skeletal muscle fibers, which sensitizes the sarcomere to calcium, leading to an increase in skeletal muscle contractility. The drug has previously demonstrated pharmacological activity that may lead to new therapeutic options for diseases associated with muscle weakness and fatigue.
COURAGE-ALS was a double-blind, placebo-controlled trial that included 555 patients with ALS who were randomly assigned 2:1 to either 300-mg reldesemtiv or matching placebo dosed twice daily for 24 weeks, followed by a 24-week period in which all patients receive study drug twice daily. The trial was designed to have 2 unblinded interim analyses, the first of which assessed the futility of the drug 12 weeks after approximately one-third or more of the planned sample size was randomized, and the second after 24 weeks.
At the interim analysis, approximately 460 patients had been randomized and over 200 had reached the 24-week assessment of the trial end points, of which included the ALS Functional Rating Scale-Revised (ALSFRS-R) scale. Eligible patients were within 2 years of their first symptom of muscle weakness, had a vital capacity of less than 65% predicted, and had ALSFRS-R scores of less than 44. The cohort of patients were on stable doses of edaravone (Radicava; MT Pharma) or riluzole (Rilutek).
Reldesemtiv also failed to show an effect on secondary end points, which included combined assessment of the ALSFRS-R total score, time to onset of respiratory insufficiency and survival time up to week 24 using a joint rank test. Other end point such as change in vital capacity, ALS Assessment Questionnaire (ALSAQ-40), and bilateral handgrip strength, were not significantly with active treatment.
The development program for reldesemtiv assessing its benefit in ALS also includes FORTITUDE-ALS, a completed phase 2 trial (NCT03160898) that also did not achieve statistical significance in its primary end point. That double-blind, randomized, dose-ranging, placebo-controlled parallel group study included 458 patients with ALS who were assessed on change from baseline in percent predicted slow vital capacity, a measure of respiratory function, over a 12-week period.
Similar analyses of ALSFRS-R and slope of Muscle Strength Mega-Score, key secondary end points, yielded P values of 0.09 and 0.31, respectively. Investigators did note that patients across all dose groups (150 mg, 300 mg, and 450 mg) declined less than patients on placebo for SVC and ALSFRS-R, with larger and clinically meaningful differences emerging over time. A post-hoc analysis of FORTITUDE-ALS showed that the differences between reldesemtiv and placebo on SVC and ALSFRS-R total score following the 12-week study period remained evident at follow-up, 4 weeks after the last dose of the study drug.