The primary outcome of the REVEAL/anacetrapib trial is MACE, not HDL. Change in HDL means nothing anymore for the future of anacetrapib. They need solid MACE data now. Based on the previous DEFINE /anacetrapib trial, the effect on MACE, if any, is expected to be modest and hence the need for a 30,000 patient, 4 year trial. They've already proven in Phase 2 and the earlier Phase 3 DEFINE, that anacetrapib raises HDL. But CETP inhibitors like anacetrapib raise HDL by affecting the normal HDL catabolic process. CETP catalyzes the reciprocal transfer of cholesterol ester from the HDL lipid core with triglyceride from triglyceride rich non HDL lipoproteins such as VLDL. So HDL cholesterol levels rise in response to CETP inhibitors by increasing the cholesterol ester content of each individual HDL particle without increasing the number of HDL particles and without increasing ApoA-I or HDL biogenesis. This is in contrast to RVX208, which increases ApoA-I gene expression/synthesis and generates new HDL particles. The majority opinion is that CETP inhibition leads to less functional HDL. Fortunately for RVX208, it raises HDL via a distinct mechanism and also has beneficial epigenetic effects on many other cardioprotective pathways.

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