Cytokinetics Announces COURAGE-ALS Met Criteria for Futility at Second Interim Analysis
Company Plans to Discontinue the Phase 3 Clinical Trial of Reldesemtiv
After Data Monitoring Committee Found No Effect on Primary or Key Secondary Endpoints
The DMC reviewed unblinded data from COURAGE-ALS and recommended the discontinuation of the clinical trial due to futility, as it found no evidence of effect in patients treated with reldesemtiv relative to placebo on the primary endpoint of change from baseline to 24 weeks in ALSFRS-R or in key secondary endpoints. Given these results, study conduct in COURAGE-ALS will be concluding. In addition,
“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,” said
The second interim analysis was triggered 24 weeks after at least one third of the planned sample size was randomized in COURAGE-ALS. At the interim analysis, approximately 460 patients had been randomized and over 200 had reached the 24-week assessment of the trial endpoints. This interim analysis assessed the primary and key secondary endpoints for potential futility as well as provided for a potential fixed increase in total enrollment, if it had been deemed necessary to augment the statistical power of the trial, or to continue the trial to its conclusion as planned.
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COURAGE-ALS & COURAGE-ALS OLE: Trial Design
COURAGE-ALS was a Phase 3, multi-center, double-blind, randomized, placebo-controlled trial of reldesemtiv designed to enroll approximately 555 patients with ALS. Patients were randomized 2:1 to receive 300 mg of reldesemtiv or matching placebo dosed orally twice daily for 24 weeks, followed by a 24-week period in which all patients received 300 mg of reldesemtiv twice daily. Eligible patients were within the first two years of their first symptom of muscle weakness, had a vital capacity of ≥65% predicted, and a screening ALS Functional Rating Scale – Revised (ALSFRS-R) ≤44. Patients taking stable doses of edaravone and/or riluzole were permitted to enroll, and randomization was stratified accordingly. The primary efficacy endpoint was change from baseline to 24 weeks in ALSFRS-R. Secondary endpoints included combined assessment of ALSFRS-R total score, time to onset of respiratory insufficiency and survival time up to week 24 using a joint rank test; change from baseline to 24 weeks for vital capacity; ALSAQ-40; and bilateral handgrip strength. The trial included two planned unblinded interim analyses conducted by the Data Monitoring Committee. The first interim analysis assessed for futility, 12 weeks after approximately one-third or more of the planned sample size were randomized. The second interim analysis assessed for futility with the option for a fixed increase in total enrollment, if it had been deemed necessary, to augment the statistical power of the trial.
An open-label extension trial, COURAGE-ALS OLE, has enrolled people who completed participation in COURAGE-ALS. In COURAGE-ALS OLE, participants received 300 mg of reldesemtiv dosed orally twice daily for 48 weeks after which they were eligible to transition into the Managed Access Program, a program designed to provide access to reldesemtiv for patients diagnosed with ALS who have completed a prior
Skeletal muscle contractility is driven by the sarcomere, the fundamental unit of skeletal muscle contraction and a highly ordered cytoskeletal structure composed of several key proteins. Skeletal muscle myosin is the motor protein that converts chemical energy into mechanical force through its interaction with actin. A set of regulatory proteins, which includes tropomyosin and the troponin complex, make the actin-myosin interaction dependent on changes in intracellular calcium levels. Reldesemtiv is an investigational, selective, small molecule fast skeletal muscle troponin activator (FSTA) arising from Cytokinetics’ skeletal muscle contractility program. Reldesemtiv was designed to slow 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 development program for reldesemtiv assessed its potential for the treatment of ALS and includes FORTITUDE-ALS, a completed Phase 2 trial, and COURAGE-ALS, the Phase 3 clinical trial designed to evaluate the effect of treatment with reldesemtiv compared to placebo on measures of disease progression, functional outcomes and survival.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that afflicts approximately 27,000 people in
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Source: Cytokinetics, Incorporated