DEVELOPING A MUSCLE-DIRECTED THERAPY FOR NEUROMUSCULAR DISEASES
Cytokinetics is developing reldesemtiv, a fast skeletal muscle troponin activator (FSTA), as a potential treatment for people living with debilitating diseases and conditions associated with muscular weakness, and/or muscle fatigue, including ALS and SMA.
Reldesemtiv is an investigational drug candidate intended to slow the rate of calcium release from the regulatory troponin complex of fast skeletal muscle fibers. Contraction of skeletal muscles is driven by the sarcomere, the fundamental unit of muscle contraction, which contains myosin, a protein which converts chemical energy into mechanical force through its interaction with another protein, actin. This interaction is regulated by other proteins including troponin and tropomyosin, and is dependent on changes in calcium. By slowing the rate of calcium release, reldesemtiv sensitizes the sarcomere to calcium, leading to an increase in muscle contractility.
Reldesemtiv was the subject of a Phase 2, hypothesis-generating clinical study in patients with Type 2, Type 3 and Type 4 SMA. The study showed increases in the distance patients could walk in six minutes, a validated measure of endurance consistent with the mechanism of action in patients treated with reldesemtiv.
Reldesemtiv was also the subject of FORTITUDE-ALS (Functional Outcomes in a Randomized Trial of Investigational Treatment with CK-2127107 to Understand Decline in Endpoints – in ALS), a Phase 2, double-blind, randomized, dose-ranging, placebo-controlled, parallel group study of reldesemtiv in patients with ALS that enrolled 458 patients with ALS in the US, Canada, Europe and Australia. The trial did not achieve statistical significance for its primary endpoint of change from baseline in slow vital capacity (SVC) after 12 weeks of dosing, but all patients on all doses of reldesemtiv declined less than patients on placebo for SVC and ALSFRS-R, with clinically meaningful differences emerging over time. For the full results from the trial, click here.