Effect of Varying Degrees of Hepatic Impairment on the Pharmacokinetics of Ervogastat, a Diacylglycerol Acyltransferase 2 (DGAT2) Inhibitor, and Clesacostat, an Acetyl-CoA Carboxylase (ACC) Inhibitor.

Abstract

Ervogastat, a diacylglycerol-O-acyltransferase-2 inhibitor, and clesacostat, an acetyl-CoA carboxylase inhibitor, are in clinical development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). Study 1 and Study 2 were open-label, Phase 1 trials that assessed the pharmacokinetics (PK) of a single dose of ervogastat (100 mg) and clesacostat (25 mg), respectively, in participants (n = 6/cohort) with mild, moderate, or severe hepatic impairment (HI) and compared to those without HI (reference). Plasma samples were analyzed for both total and unbound concentrations in Study 2 as clesacostat is highly protein bound. In Study 1, compared to participants without HI, ervogastat exposure (AUC_inf) was 56%, 65%, and 52% higher in participants with mild, moderate, and severe HI, respectively. However, when excluding PK data from a participant with unexplained low exposures in reference group, ervogastat exposures were similar between those with/without HI. In Study 2, total clesacostat exposure was 36%, 24%, and 19% higher for mild, moderate, and severe HI, respectively, as compared to reference group. Unbound clesacostat exposures were 70%, 83%, and 166% higher for mild, moderate, and severe HI cohorts, respectively, with clesacostat plasma protein binding shown to decrease with increasing HI severity. Ervogastat and clesacostat were well tolerated with no clinically significant laboratory abnormalities or changes in vital signs and/or electrocardiograms observed. Observed exposures in HI studies were consistent with simulated exposures in MASH population. Taking into consideration the safety margins at the highest doses evaluated in Phase 2, no dose adjustment of ervogastat or clesacostat is currently warranted for patients with hepatic impairment. NCT: NCT04091061, NCT03309202.