Third Strike For CETP Inhibitors: Lilly Halts Big Evacetrapib Trial

For the third time a large trial testing a CETP inhibitor drug has gone down the tubes. On Monday morning Eli Lilly announced that it had terminated ACCELERATE, its large phase 3 trial of the drug evacetrapib. The company said the trial was stopped “due to insufficient efficacy” and that the company planned to discontinue development of the drug.

Lilly said that the full results of ACCELERATE will be presented at a future scientific meeting. Steve Nissen, the study chairman, told Forbes that the trial was large enough to demonstrate an effect. “The drug didn’t work,” he said.

This is the third strike for this class of drugs. Pfizer’s torcetrapib and Roche’s dalcetrapib, were unsuccessful, leading many to lower their expectations for ACCELERATE. But Lilly believed that its drug might prove successful, as it didn’t appear to have the off-target effects of torcetrapib and to be more effective than dalcetrapib. A fourth trial, REVEAL, with a Merck drug, anacetrapib, continues. Many supporters of anacetrapib have pinned their hopes not on the HDL-raising properties of the drug but on its LDL-lowering properties.

Initial hopes for CETP inhibitors were based on the observation that the drugs raised HDL. High HDL levels have been consistently shown in observational studies to be 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.

Responding to the news, Sanjay Kaul wrote me that “Association is not causation! That is why we do randomized controlled trials to bust myths derived from epidemiological associations. Although CETP inhibitors are not a pure test of the HDL hypothesis (because other lipid factors are also modified), it would be difficult to remain enthusiastic about it with this news.”

In a tweet, Sekar Kathiresan said that he believed that “there is now sufficient evidence to retire both the HDL & CETP hypotheses.” Previous genetic work by Kathiresan and others suggests that future progress in  understanding and treating heart disease will depend less on lipid research and more on vessel wall biology. Kathiresan told me that “the holy grail for therapeutics is non-lipid mechanisms. We really need to understand the causal genes and mechanism at the 80% of CAD gene regions that are non-lipid…. Identifying non-lipid causal factors could open the door to a new series of treatments.”