Background and Aims: Previous CETP inhibitors were highly lipophilic with logP of 7.2–9.2, leading to adipose tissue accumulation in the case of anacetrapib. In contrast, obicetrapib is characterized by a logP of 4.9 and terminal half-life of ∼135 hours. Studies in monkeys and humans were undertaken to determine the definitive elimination of obicetrapib.

Methods: Obicetrapib was administered at doses up to 50 mg/kg/day in cynomolgus monkeys. A phase 1 trial administered doses of 1-25 mg to healthy humans, and 3 placebo-controlled, phase 2 studies in dyslipidemic humans administered obicetrapib (on background statin therapy) at 5 or 10 mg/d for 8 weeks (ROSE; n=120), 10 mg/d monotherapy or with ezetimibe for 12 weeks (ROSE2; n=119), and 2.5, 5, or 10 mg/d for 8 weeks (Japan; n=102). Plasma concentrations of obicetrapib were measured during the studies and post-treatment.

Results: In monkeys, obicetrapib was not detected in any adipose tissue. A period of 13 weeks was sufficient for complete elimination from systemic circulation. The terminal half-life of obicetrapib was 121-151 hours in healthy humans. Across phase 3 studies, the median plasma concentration of obicetrapib reached 384-472 μg/L and decreased by up to 93-99% by 4 to 15 weeks post-treatment.

Conclusions: Obicetrapib shows no evidence of accumulation in adipose tissue or delayed elimination from the systemic circulation supporting once daily, chronic dosing of 10 mg.