Despite rumors to the contrary the story of the CETP inhibitors isn’t quite over. Merck today announced that the REVEAL trial will continue. After a series of disappointing and often spectacular failures, REVEAL is the last remaining phase 3 trial of a CETP inhibitor still underway.
REVEAL is a 30,000 patient trial studying Merck’s anacetrapib. In the announcement Merck said the decision to continue the trial was based on a planned review of unblinded data by the study’s independent data monitoring committee. The review “included an assessment of futility.”
Three previous CETP inhibitors have failed. First, and most spectacularly, Pfizer’s torcetrapib, which the company had hoped would preserve its cholesterol franchise, was found to have off target negative effects. Expectations for the CETP inhibitor class were further damaged by the failure of Roche’s dalcetrapib and, more recently, Lilly’s evacetrapib. With this string of failures many experts gave up hope for the drugs and many speculated that Merck would end development of anacetrapib and terminate REVEAL.
Initial interest in CETP inhibitors was based on their ability to raise HDL levels. In observational studies HDL has been consistently associated with reduced cardiovascular risk, but a cause and effect relationship has never been demonstrated, and more recent genetic studies have put additional stress on the HDL hypothesis.
The failure of the trials has prompted many experts to question the value of the HDL hypothesis. (Some experts argue that simply raising HDL may not be enough; instead it may be necessary to enhance the purported benefit of HDL’s “reverse cholesterol transport” mechanism.)
One point of confusion and possible ray of light for Merck’s anacetrapib is that there appear to be important differences in the activity of the different CETP inhibitors. In particular, Merck may be pinning its hopes not on the HDL-raising properties of the drug but on its LDL-lowering properties. Some think REVEAL could be successful based solely on the LDL lowering properties of the drug.