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

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.