Reldesemtiv

Reldesemtiv (CK-2127107) is a small-molecule fast skeletal muscle troponin activator (FSTA) that selectively binds the regulatory troponin complex in fast skeletal muscle fibers, slows the rate of calcium release from troponin C, and thereby sensitizes the sarcomere to calcium at submaximal stimulation frequencies. The compound was discovered at Cytokinetics, Inc. through property-based optimization of a high-throughput screening hit, yielding improved free exposure, in vivo muscle activation potency, and tolerability relative to the first-generation FSTA tirasemtiv, which had failed the Phase 3 VITALITY-ALS trial primarily because of dose-limiting tolerability (dizziness, nausea, weight loss, insomnia) and a 34.2 percent treatment discontinuation rate. Reldesemtiv does not activate slow skeletal or cardiac troponin complexes, providing a selectivity basis for its intended use in conditions characterized by fast skeletal muscle weakness secondary to attenuated neuronal input, including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and chronic obstructive pulmonary disease. In a Phase 1 pharmacodynamic study in 16 healthy volunteers, reldesemtiv amplified the tibialis anterior force-frequency response by approximately 60 percent at 10 Hz nerve stimulation at the highest plasma concentrations tested, confirming the mechanism of action in human skeletal muscle. Pharmacokinetics across five Phase 1 studies demonstrated dose-proportional exposure with a terminal half-life of approximately 5 to 14 hours depending on dose, a time to peak concentration of 2 to 3 hours, and similar pharmacokinetic profiles in young and elderly subjects. The Phase 2 FORTITUDE-ALS trial (n=458; 12 weeks; placebo, 150, 300, or 450 mg in the published literature) did not reach statistical significance on its primary endpoint of slow vital capacity change (p=0.11), though trends favoring reldesemtiv were observed across all three endpoints and a post hoc analysis of the ALSFRS-R functional scale reached nominal significance (p=0.01). The Phase 2 SMA study (n=70; 8 weeks; 150 or 450 mg in the published literature) reported statistically significant improvement in six-minute walk distance at week 4 (35.6 m, p=0.0037) and maximum expiratory pressure at week 8 (13.2 cmH2O, p=0.03) in the 450 mg group, with concentration-response relationships in the highest plasma concentration quartile reaching significance on both endpoints. The Phase 3 COURAGE-ALS trial (n=486; 24 weeks; 300 mg in the published literature versus placebo; 83 centers in 16 countries) was terminated for futility at the second planned interim analysis when conditional power for the primary endpoint (ALSFRS-R score change at 24 weeks) was 8.4 percent. The primary analysis showed a mean difference of negative 1.1 points (95 percent CI, negative 2.17 to negative 0.08; p=0.04), numerically favoring placebo. No preplanned subgroup favored reldesemtiv. The compound is not approved by any regulatory authority for any indication. This monograph reviews the chemistry, discovery, molecular pharmacology, pharmacokinetics, preclinical and clinical evidence, sourcing, handling, adverse events, and a comparative assessment of reldesemtiv against tirasemtiv, tofersen, riluzole, edaravone, and risdiplam on five competency standards.