including clinical trial updates for reldesemtiv in neuromuscular and non-neuromuscular conditions. In addition to reldesemtiv, the companies are advancing another fast skeletal muscle troponin activator (FSTA) into Investigational New Drug (IND)-enabling studies and continuing their joint research program through 2019. Cytokinetics has been developing reldesemtiv as a potential treatment for people with Spinal Muscular Atrophy (SMA), Amyotrophic Lateral Sclerosis (ALS), and other debilitating neuromuscular diseases and conditions associated with skeletal muscle weakness and/or fatigue. In parallel, Astellas has been conducting non-neuromuscular clinical trials with reldesemtiv to investigate a potential path forward for the next generation FSTA in patients with Chronic Obstructive Pulmonary Disease (COPD) and Frailty. Cytokinetics and Astellas are also conducting joint research to discover and advance additional small molecule activators of skeletal muscle, which may be developed as drug candidates for a broad array of diseases associated with skeletal muscle weakness and fatigue.
Spinal Muscular Atrophy (SMA)
- In June, Cytokinetics announced data from a Phase 2 double-blind, randomized, placebo-controlled clinical study in patients with SMA which was designed to determine potential pharmacodynamic effects of a suspension formulation of reldesemtiv following 8 weeks of oral dosing in each of two cohorts of 36 patients with Type II, Type III, or Type IV disease. Secondary objectives were to evaluate the safety, tolerability and pharmacokinetics of reldesemtiv. The study showed statistically significant concentration-dependent increases in changes from baseline in Six Minute Walk Distance (6MWD), a sub-maximal exercise test of aerobic capacity and endurance. The study also showed statistically significant increases for Maximal Expiratory Pressure (MEP), a measure of strength of respiratory muscles. Other assessments, including the Hammersmith Functional Motor Score – Extended, (a functional motor scale that was assessed in the development program that led to the FDA approval of the first therapy for patients with SMA), Revised Upper Limb Module, Timed Up-and-Go, Forced Vital Capacity, and the SMA Health Index (SMA-HI), a patient reported outcome measure (PROM) developed to comply with FDA standards for PROMs, did not demonstrate differences between reldesemtiv versus placebo. Adverse events were similar between groups receiving reldesemtiv and placebo.
- Additional results presented at the 2018 Muscle Study Group Scientific Meeting in Oxford, U.K. showed sustained increases in 6MWD and MEP four weeks after discontinuation of study drug (i.e., Follow-up). The mean increase versus placebo in the change from baseline in 6MWD on 450 mg twice daily was 24.89 m after 8 weeks of treatment (p = 0.0584) and 30.81 m at Follow-up (p = 0.0381). Similarly, the mean increase versus placebo in the change from baseline in MEP on 450 mg twice daily was 13.15 cm H2O after 8 weeks of treatment (p = 0.0298) and 9.47 cm H2O at Follow-up (p = 0.1344).
- A post-hoc analysis also showed that changes from baseline in the 6MWD at 450 mg twice daily were significantly correlated with changes from baseline on certain domains of the SMA-HI intended to reflect improved endurance, especially Fatigue (correlation coefficient [r] = -0.90, p = 0.01) and Activity Participation (r = -0.82, p = 0.05). Of note, decreases in SMA-HI scores reflect reduced disease burden as measured by that PROM; therefore, the negative correlation coefficients indicate that as 6MWD increases, disease burden assessed by that domain of the SMA-HI is reduced.
- Cytokinetics recently convened an expert advisor meeting to discuss the Phase 2 clinical study of reldesemtiv in patients with SMA and received encouraging and constructive feedback as well as recommendations to inform potential next steps.
- Cytokinetics will be seeking a Type C regulatory interaction with the FDA this year regarding the acceptability of 6MWD as an endpoint for a potential registration program for reldesemtiv in patients with SMA.