Evacetrapib (DB11655): A Definitive Report on a Promising CETP Inhibitor and Its Instructive Failure

Executive Summary

Evacetrapib (investigational name LY2484595) was a potent, selective, small-molecule inhibitor of cholesteryl ester transfer protein (CETP) developed by Eli Lilly and Company.[1] It was rationally designed as a second-generation agent to test the hypothesis that raising high-density lipoprotein cholesterol (HDL-C) could reduce cardiovascular risk, while specifically avoiding the off-target toxicities that led to the failure of its predecessor, torcetrapib. Pre-clinical and early-phase clinical studies confirmed Evacetrapib's "clean" safety profile and its profound pharmacodynamic effects on lipid biomarkers.

The pivotal Phase 3 cardiovascular outcomes trial, ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes), demonstrated the drug's remarkable ability to remodel the lipid profile. In over 12,000 high-risk patients, Evacetrapib produced unprecedented and highly statistically significant changes, increasing HDL-C by approximately 130% while concurrently lowering low-density lipoprotein cholesterol (LDL-C) by approximately 37%.[7] Despite this dramatic and seemingly beneficial impact on these surrogate markers, the trial revealed a complete absence of clinical efficacy. There was no reduction in the primary composite endpoint of major adverse cardiovascular events (MACE).[9]