351P Sevasemten, a fast myosin inhibitor, in adults with Becker muscular dystrophy results in reduced muscle damage biomarkers and functional stabilization.

Fast (Type II) muscle fibers are affected early and disproportionately in dystrophinopathies. Sevasemten (EDG-5506) is an orally administered, once daily, investigational product that modulates fast skeletal muscle myosin and, in DMD disease models, decreased muscle damage biomarkers and fibrosis while increasing muscle strength and activity. ARCH is a 24-month Phase 1b open-label study of sevasemten, assessing safety, pharmacokinetics, biomarkers of muscle damage and functional measures in adults with Becker. Twelve ambulatory adults with Becker received daily oral doses of sevasemten. At baseline, North Star Ambulatory Assessment (NSAA) ranged from 5 to 31 (mean 15.5). Decreased muscle mass was evident by low serum creatinine and DXA lean muscle mass. After 24 months, sevasemten was well tolerated without serious adverse events, withdrawals due to AEs, or dose modifications. Rapid (within 1-2 months) reductions in biomarkers of muscle damage were sustained to 24 months, including creatine kinase, myoglobin and fast skeletal muscle troponin I. Alongside acute and chronic biomarker changes, trends toward functional improvement were noted with NSAA with a mean change of -0.2 versus an expected decline of -2.4 or more as predicted from natural history (Bello 2016, Van de Velde 2021, De Wel 2024). The 100-meter timed test and grip strength were unchanged over 24 months. In summary, sevasemten was well tolerated with rapid and sustained reductions in biomarkers of muscle damage. Treatment resulted in acute and sustained reductions in muscle damage biomarkers. Functional improvements compared to the expected natural history decline in the NSAA score were observed. Phase 2 trials in BMD and DMD are ongoing (NCT05291091 and NCT05540860) including a pivotal cohort in Becker. [ABSTRACT FROM AUTHOR]