Effects of sevasemten (EDG-5506) on safety, biomarkers, and functional measures in adults with Becker muscular dystrophy: results of a phase 1b, open-label study.

Abstract

Sevasemten (EDG-5506) is an orally administered, investigational small molecule that selectively modulates fast muscle fibre contraction by inhibiting fast myosin ATPase. In animal models of Duchenne and Becker muscular dystrophy (DMD and BMD, respectively), sevasemten reduced the muscle contraction injury that leads to inflammation, fibrosis and muscle loss without affecting function. The aim of this study was to evaluate the long-term safety, tolerability, and pharmacokinetics (PK)/pharmacodynamics of sevasemten in adult participants with BMD who had already experienced a decline in function and would be anticipated to continue to decline based on natural history. This open-label, dose escalation, phase 1 b study (NCT05160415) was conducted at a single site and enrolled ambulatory adults with BMD aged 18-55 years; the study is completed. Eligible participants received 10 mg of sevasemten once daily (QD) for 8 weeks, followed by 15 mg QD for 4 months, 20 mg QD for 9 months, and 10 mg QD for 9 months. The primary objective was to assess the safety and tolerability of sevasemten in adults with BMD; endpoints included adverse events (AEs), PK, change from baseline in circulating biomarkers of muscle injury, as well as physical function measures. The study enrolled 12 adults with BMD. Sevasemten was well tolerated; all AEs were mild or moderate in severity and there were no serious AEs or AEs leading to discontinuation. Treatment with sevasemten was associated with reductions in circulating biomarkers of muscle injury that were evident within 4 weeks and sustained for up to 24 months. Physical function, as assessed by North Star Ambulatory Assessment (NSAA), was stable over 24 months. Sevasemten treatment for up to 24 months in adults with BMD was well tolerated and associated with durable reductions in muscle injury biomarkers, consistent with preclinical studies and near maximal with the 10 mg dose, as well as functional stabilisation. Further clinical development is ongoing. Edgewise Therapeutics, Inc.