Cytokinetics Presents Data at the Virtual 33rd International Symposium on ALS/MND
Analysis from FORTITUDE-ALS Shows Predicted Survival Risk Score Strongly Correlated with Decline in ALSFRS-R
Findings Suggest Inclusion Criteria for COURAGE-ALS Will Enrich for the Enrollment of Faster Progressors
“This analysis from FORTITUDE-ALS helps to build our understanding of disease progression in ALS, which is complex and heterogenous, and is an important element in the conduct of clinical research and the design of our clinical trials,” said
Predicted Survival Risk Score for Participants in FORTITUDE-ALS Strongly Correlated with Decline in ALSFRS-R
In a previously presented post-hoc analysis of disease progression in FORTITUDE-ALS, patients were grouped into tertiles according to their pre-study rate of decline in the ALS Functional Rating Scale Revised (ALSFRS-R) total score. The largest treatment effect from reldesemtiv was observed in the intermediate and fast progressing tertiles. Most patients in these two tertiles had experienced symptoms for ≤24 months and had a baseline ALSFRS-R total score ≤44 (referred to as the 24/44 criteria). In this analysis, the ENCALS survival model was used to calculate a predicted survival risk score for all participants in FORTITUDE-ALS. The ENCALS survival model calculates the risk score based on several factors, including age at onset, onset site, cognition, vital capacity, El Escorial classification, diagnostic delay, C9orf72 expansion repeat, and decline in ALSFRS-R total score. Based on their risk score, participants were assigned to one of five risk groups based on predicted survival: very short (G1), short (G2), intermediate (G3), long (G4), and very long (G5). Among participants in FORTITUDE-ALS, the mean ENCALS risk score at baseline was similar for patients receiving reldesemtiv and for those receiving placebo, and there was no statistically significant difference in the distribution of risk groups for those randomized to reldesemtiv compared to those randomized to placebo. When participants who met the 24/44 criteria (n=272) and those who did not (n=184) were categorized according to their ENCALS risk score, those who met the criteria were primarily in the G1, G2 or G3 groups associated with fast or intermediate progression and shorter predicted survival, whereas those who did not meet the criteria were primarily in the G4 and G5 risk groups associated with slow progression and longer survival. These findings suggest that ENCALS risk scores are strongly correlated with the rate of decline in the ALSFRS-R.
In the ongoing Phase 3 trial of reldesemtiv, COURAGE-ALS (Clinical Outcomes Using Reldesemtiv on ALSFRS-R in a Global Evaluation in ALS), in order to enhance the ability to detect a treatment effect, participants must meet the 24/44 criteria to enroll in the trial. Findings from the current analysis of FORTITUDE-ALS suggest that implementing the 24/44 inclusion criteria will enrich for the enrollment of participants with more rapidly progressing disease, while minimizing, but not excluding, participants with more slowly progressing disease.
COURAGE-ALS & COURAGE-ALS OLE: Trial Design
COURAGE-ALS, a Phase 3, multi-center, double-blind, randomized, placebo-controlled trial of reldesemtiv is expected to enroll approximately 555 patients with ALS. Patients are 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 will receive 300 mg of reldesemtiv twice daily. Eligible patients are within the first two years of their first symptom of muscle weakness, have a vital capacity of ≥65% predicted, and a screening ALS Functional Rating Scale – Revised (ALSFRS-R) ≤44. Patients currently taking stable doses of Radicava® (edaravone) and/or Rilutek® (riluzole) are permitted to enroll, and randomization is stratified accordingly. In countries where the combination drug of sodium phenylbutyrate and taurursodiol is approved, Albrioza® (
An open-label extension trial, COURAGE-ALS OLE, is open to people who have completed participation in COURAGE-ALS. Following enrollment in COURAGE-ALS OLE, participants continue to receive 300 mg of reldesemtiv dosed orally twice daily for 48 weeks after which they may transition into the Managed Access Program. The primary endpoint is the incidence of adverse events. Secondary endpoints include the time to the first occurrence of respiratory insufficiency or death, time to the first hospitalization, combined assessment of change in ALSFRS-R total score, time to onset of respiratory insufficiency, and survival time, changes in ALSFRS-R total score, and the slope of changes in ALSFRS-R total score. Additional information on COURAGE-ALS OLE can be found at www.clinicaltrials.gov.
About Reldesemtiv
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 is assessing its potential for the treatment of ALS and includes FORTITUDE-ALS, a completed Phase 2 trial, and COURAGE-ALS, the ongoing 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.
About ALS
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that afflicts approximately 27,000 people in
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