Associate Scientist Edgewise Therapeutics Boulder, Colorado, United States
Background: Sevasemten (EDG-5506) is a novel, orally bioavailable, small molecule investigational agent designed to selectively modulate type II fast skeletal myosin with the goal of protecting dystrophic muscle from contraction induced damage. Sevasemten in clinical development for the treatment of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Methods: In this first-in-human, randomized, double-blind, placebo-controlled phase 1 study, we evaluate the safety and tolerability and pharmacokinetics of sevasemten in 57 and 40 healthy subjects (HS) in single and multiple ascending dose cohorts and 7 patients with BMD. Results: We observed that sevasemten was well tolerated in HS and adults with BMD, with no serious adverse events or adverse events leading to trial discontinuation. Following single dose administration in HS, sevasemten (5-135mg), was rapidly absorbed, with a median tmax ranging between 0.52 and 0.77 hours and a long half-life, with a mean value of 531.8 hours (22 days). Data was similar in the multiple ascending dose cohorts. C24 was still increasing after 14 days of dosing, suggesting steady state was not reached. Adults with BMD had approximately 2-fold higher plasma concentrations of sevasemten compared to HS and a half-life of approximately 168 hours (7 days). Evaluation of sevasemten levels in both healthy and dystrophic muscle after 15 days of dosing demonstrated delivery of drug to the target, fast myosin muscle, with concentrations in the range of approximately 1300 to 6600 ng/g. Muscle sevasemten concentrations were 2-3-fold higher in HS compared to BMD patients. Conclusion: Contraction-induced damage of fast skeletal muscle is a common pathology for DMD and BMD. By selectively limiting contraction of fast skeletal muscle fibers to protect dystrophic muscle without compromising contractile strength, sevasemten has the potential to be a disease-modifying, mutation-agnostic treatment. These data support continued clinical development of sevasemten for the treatment of muscular dystrophies.
