†Obicetrapib Does Not Accumulate in Adipose Tissue: Results from Studies in Man and Non-human Primates

Abstract

Study Funding

NewAmsterdam Pharma.

Background/Synopsis

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.

Objective/Purpose

Studies in cynomolgus monkeys and humans were undertaken to determine the definitive elimination of obicetrapib from these organisms.

Methods

In a 9-month toxicology study in cynomolgus monkeys, obicetrapib was administered at doses up to 50 mg/kg/day. 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 dosing/treatment and up to 15-weeks post-treatment.

Results

In monkeys, obicetrapib was not detected in any adipose tissue samples and a recovery period of 13 weeks was sufficient for complete elimination from systemic circulation. The terminal half-life of obicetrapib was between 121 and 151 hours in healthy humans. In ROSE, median plasma obicetrapib in the 10 mg/d group was 384 mg/L at week 8 and decreased by 93, 98, and 99% at 4-, 8-, and 15-weeks post-treatment. In ROSE2, median plasma obicetrapib at week 12 was 387 mg/L in the 10 mg/d monotherapy group and decreased by 94% at 4-weeks post-treatment. In the Japan phase 2 study, median plasma obicetrapib at week 8 was 472 mg/L for the 10 mg/d group and decreased by 96% at 4-weeks post-treatment.

Conclusions

In dedicated pre-clinical experiments and in clinical trials, obicetrapib shows no evidence of accumulation in adipose tissue or delayed elimination from the systemic circulation supporting once daily, chronic dosing of 10 mg.