Human Disposition, Metabolism, and Excretion of Sevasemten (EDG-5506), a Selective Modulator of Fast Myosin in Healthy Volunteers.

Sevasemten (EDG-5506) is a novel, orally bioavailable, investigational small molecule designed to selectively modulate type II fast skeletal myosin with the goal of protecting dystrophic muscle from contraction-induced injury. Sevasemten is in clinical development for the treatment of Becker and Duchenne muscular dystrophy. In the current Phase 1 study (NCT05730842), eight participants were dosed with a 20 mg single oral suspension dose of sevasemten containing approximately 500 µCi [14C] sevasemten. Blood and urine samples were collected to evaluate the pharmacokinetics (PK), oral absorption, metabolism, and excretion (AME) of sevasemten and its metabolites. A second cohort of seven participants received a single 20 mg oral dose of sevasemten, followed 2 h later by a single dose of [14C] sevasemten administered as a single intravenous (IV) bolus with approximately 1 µCi [14C] sevasemten to determine absolute bioavailability. Sevasemten was excreted primarily in urine (52.1%) subsequent to CYP3A-mediated metabolism, and 8.89% was eliminated in the feces, for a total of 61.0% recovered over 840 h post-dose. Most of the recoverable radioactivity was excreted by 576 h (24 days). However, sevasemten total radioactivity in plasma and whole blood was characterized by a very slow elimination phase of 16.1-20.6 days; total recovery of radioactivity was not achieved. Sevasemten was well tolerated, with no serious adverse events or adverse events leading to study discontinuation. Sevasemten has favorable PK properties for once daily administration and continues to be investigated for the treatment of Becker and Duchenne muscular dystrophies.