EDP-297: A novel, farnesoid X receptor agonist-Results of a phase I study in healthy subjects.

EDP-297 is a farnesoid X receptor agonist under development for treating nonalcoholic steatohepatitis. The pharmacokinetic (PK), pharmacodynamic (PD), food effect, and safety were evaluated in a single ascending dose (SAD) and multiple ascending dose (MAD) phase I study. Healthy subjects received single EDP-297 doses of 20-600 μg or once daily doses of 5-90 μg for 14 days. Safety, PKs, and PDs were assessed, including fibroblast growth factor 19 (FGF-19) and 7-α-hydroxy-4-cholesten-3-one (C4). Among 82 subjects, EDP-297 was generally well-tolerated. Pruritus was observed in four subjects in the SAD phase and seven subjects in the MAD phase; four severe cases occurred at 90 μg in the MAD phase, including one that led to drug discontinuation. A grade 2 elevation in alanine aminotransferase occurred with 90 μg. Mean lipid values remained within normal range. Plasma exposures of EDP-297 increased with SADs and MADs, with mean half-life following multiple doses of 9-12.5 h. No food effect was observed. Mean FGF-19 increased and C4 decreased up to 95% and 92%, respectively. EDP-297 was generally well-tolerated up to 60 μg MAD, with linear PKs suitable for once daily oral dosing, target engagement, and no food effect.