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Tropifexor (LJN452) is a potent, orally available, non–bile acid farnesoid X receptor agonist under clinical development for chronic liver diseases. Here, we present results from a first‐in‐human study of tropifexor following single‐ and multiple‐ascending doses (SAD/MAD) and food effect substudy in healthy volunteers. The SAD study included 6 fasted cohorts receiving 10‐ to 3000‐µg tropifexor or placebo and 1 cohort receiving 300‐µg tropifexor with a high‐fat meal. The MAD study included 4 lean cohorts receiving 10 to 100 µg and 1 obese cohort receiving 30‐µg once‐daily doses or placebo for 14 days. Pharmacodynamic assessment of fibroblast growth factor 19 and fasting plasma lipids was performed after dosing. Overall, 95 volunteers received at least 1 tropifexor or placebo dose. Tropifexor was well tolerated up to 3000 µg and 100 µg in the SAD and MAD studies, respectively; however, 2 subjects discontinued the MAD study due to asymptomatic elevation of liver transaminases. At single doses, tropifexor showed a moderate rate of absorption (median time to maximum concentration, 4 hours), dose‐proportional increases in exposure, and elimination half‐life of 13.5 to 21.9 hours. When taken with food, tropifexor exposure increased by ∼60%. With multiple dosing, steady state was reached on day 4 with <2‐fold accumulation. Single and multiple doses showed dose‐dependent increases in fibroblast growth factor 19. No changes in serum lipids were observed in tropifexor‐ vs placebo‐treated obese subjects. In conclusion, tropifexor was well tolerated, had a pharmacokinetic profile suitable for once‐daily dosing and showed dose‐dependent target engagement without altering plasma lipids in healthy volunteers.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel Non–Bile Acid FXR Agonist Tropifexor (LJN452) in Healthy Volunteers