PII-054 - A PHASE 1, OPEN-LABEL STUDY IN HEALTHY MALE SUBJECTS OF THE ABSORPTION, METABOLISM, EXCRETION, AND PHARMACOKINETICS OF SEVASEMTEN

M. Madden¹, S. Collins², J. Lane¹, J. Donovan¹, J. Silverman¹; ¹Edgewise Therapeutics, Boulder, CO, United States, ²Edgewise Therapeutics, Riviere du Rempart, Mauritius.

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 is in clinical development for the treatment of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD).

Methods: In this fasted, open-label study, we evaluate the oral absorption, metabolism, and excretion (cohort 1) and absolute bioavailability (cohort 2) in healthy adult male subjects. The first cohort contained 8 subjects and were given a single oral administration of sevasemten of 20 mg containing approximately 500 μCi [14C]-EDG-5506. Cohort 2 contained 7 subjects who received a single 20 mg oral dose of sevasemten, followed 2 hours later by a single dose of [14C]-EDG-5506 administered as a single ≤100 μg IV bolus containing approximately 1 μCi of [14C]-EDG-5506 over approximately 2 minutes. Samples were collected up to 35 days.

Results: Sevasemten was well tolerated with no serious adverse events or adverse events leading to trial discontinuation. Oral sevasemten appeared rapidly in plasma, with a median time of the maximum observed concentration (tmax) of 0.375 hour and was eliminated with a geometric mean apparent terminal elimination half-life (t1/2) of approximately 495 hours. Apparent total clearance and renal clearance values for EDG-5506 were 12.0 L/h (50.8%) and 0.0526 L/h (37.5%), respectively. Urinary excretion was the predominant route of elimination for [14C]-EDG-5506. Approximately 52% of the administered dose was eliminated in urine and 9% was eliminated in feces. The absolute bioavailability was 90.8%. EDG-5506 was eliminated primarily by metabolism. Metabolism of EDG- 5506 was mediated by O-dealkylation, hydroxylation, N-dealkylation, and oxidation. The major circulating plasma components were EDG-006078 and EDG-5506, accounting for 66.3 and 17.1% of the total circulating radioactivity. The major urinary metabolite was EDG-006380 and is ~36.7% of the dose.

Conclusion: Sevasemten was characterized by a rapid absorption phase in plasma, reaching a median tmax of 0.5 hours and a slow and steady terminal elimination phase between 16.1 and 20.6 days.