Obicetrapib Alone and in Combination with Ezetimibe Reduces Atherosclerotic Lesion Prevalence, Size and Severity in ApoE*3-Leiden.CETP Mice

Abstract

Background and Aims: Obicetrapib is a selective, potent, cholesteryl ester transfer protein (CETP) inhibitor in clinical development for the treatment of hypercholesterolemia and reduction of cardiovascular risk. It strongly reduces apolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) and increases plasma high-density lipoprotein cholesterol (HDL-C). Ezetimibe is a potent, selective inhibitor of biliary and dietary cholesterol absorption from the small intestine, also reducing LDL-C levels. The current study evaluated the effect of obicetrapib monotherapy and in combination with ezetimibe on atherosclerosis development in a 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 (on average 0.6 mg/kg/day), or the combination of obicetrapib and ezetimibe. After 28 weeks of treatment, atherosclerosis development was measured in the aortic roots.

Results: Obicetrapib, ezetimibe, and the combination reduced total plasma cholesterol levels (-31%, -19% and -53%), mainly attributed to a decrease in non-HDL-C levels (-53%, -19% and -75%). Obicetrapib and combination treatment nearly completely blocked CETP activity (-98% and -98%). Obicetrapib, ezetimibe, and the combination reduced atherosclerotic lesion size (-90%, -50% and -98%) and reduced severe lesions (-82%, -31% and -98%). The percentage of unaffected segments was increased by obicetrapib and the combination treatment (+347%, +442%).

Conclusions: Obicetrapib alone and the combination with ezetimibe robustly lowers non-HDL-C levels and impedes atherosclerosis development through a large decrease in atherosclerotic lesion size and severity.