Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of INT‐787, a Novel Farnesoid X Receptor Agonist, in Healthy Volunteers: A Phase 1 Trial

Abstract

ABSTRACT

Aberrant farnesoid X receptor (FXR) signaling is implicated in cholestatic, inflammatory, and fibrotic liver diseases. In preclinical/clinical studies, semisynthetic bile acid‐derived FXR agonists markedly improved hepatic function in various conditions. INT‐787, a novel hydrophilic semisynthetic bile acid FXR agonist, has demonstrated a reduction in inflammatory and fibrotic markers and regulation of bile acid/lipid metabolism. This first‐in‐human, randomized, placebo‐controlled phase 1 study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of INT‐787 and its equipotent metabolites in healthy volunteers by evaluating single ascending doses (SAD), multiple ascending doses (MAD), and food effect. Participants (n = 130) across all study portions were similar in age, race, and body mass index. In the SAD and MAD portions, the maximum plasma concentration (C_max) and area under the curve (AUC) for total INT‐787 generally increased with dose. In the Food Effect portion, the mean C_max of total INT‐787 was almost 2‐fold higher under fasted conditions compared with fed conditions; AUC_0‐inf was unchanged. Steady state for total INT‐787 was reached by Day 7. In cohorts receiving ≥ 50 mg doses, the half‐life of total INT‐787 ranged from 21 to 55 h. INT‐787 metabolites exhibited increased concentrations after mealtimes despite morning dosing, consistent with endogenous bile acid behavior. Following single and multiple doses of INT‐787, decreases in C4 and increases in FGF‐19 levels were observed. Single and multiple oral doses were generally well tolerated; 4 adverse events of mild, transient pruritus not requiring interventions were reported at higher doses. These results warrant further investigation of INT‐787 in patients with liver‐related disorders.