Obicetrapib Alone and with Ezetimibe Reduces Non-HDL-C by Enhanced LDL-Receptor-Mediated VLDL Clearance and Increased Net Fecal Sterol Excretion

Abstract

Study Funding

NewAmsterdam Pharma.

Background/Synopsis

Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor currently in clinical development for the treatment of hypercholesterolemia and reduction of cardiovascular risk that strongly reduces apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) and concomitantly increases plasma high-density lipoprotein cholesterol (HDL-C). Ezetimibe reduces absorption of biliary and dietary cholesterol from the small intestine, thereby reducing LDL-C levels.

Objective/Purpose

The current study was carried out to elucidate the mechanism of action responsible for the observed decrease in non-HDL-C by obicetrapib monotherapy and in combination with ezetimibe in a translational mouse model for hyperlipidemia and atherosclerosis.

Methods

Female ApoE*3-Leiden.CETP transgenic mice were fed a Western diet with 0.05% w/w cholesterol (equivalent to daily human intake) or this diet containing obicetrapib alone (2 mg/kg/day), ezetimibe alone (1 mg/kg/day) or the combination of obicetrapib and ezetimibe.

Results

Obicetrapib, ezetimibe and the combination thereof reduced total plasma cholesterol levels (-42%, -23% and -62%), mainly attributed to a decrease in non-HDL-C levels (-61%, -24% and -80%). Obicetrapib alone and in combination with ezetimibe nearly completely blocked CETP activity (-99% and -100%) resulting in increased HDL-C (+260% and +245%) and ApoA1 levels (98% and 81%). Obicetrapib, ezetimibe and to a larger extent the combination thereof enhanced clearance of VLDL-like particles (half-life: -44%, -23% and -57%) and enhanced hepatic LDL receptor expression (+63% and +74%). Fecal analysis demonstrated increased bile acid excretion in obicetrapib-treated mice (+41%) and increased neutral sterol excretion in ezetimibe-treated mice, which was even more pronounced in combination with obicetrapib (+68% and +100%), resulting in a net fecal sterol loss.

Conclusions

Obicetrapib alone and the combination with ezetimibe reduce non-HDL-C levels by increased VLDL lipolysis, increased VLDL clearance and elevated LDL receptor levels accompanied by an enhanced fecal bile acid and neutral sterol excretion.