Cautious Optimism Welcomes New CETP Inhibitor, Evacetrapib

November 15, 2011

November 15, 2011 (Orlando, Florida) —A new cholesteryl ester transfer protein (CETP) inhibitor, evacetrapib (Lilly, Indianapolis, Indiana), has shown encouraging results in a phase 2 trial and appears safe [1]. It is hoped that the drug will soon begin a phase 3 study, joining two other CETP inhibitors that are already in such trials, said Dr Stephen J Nicholls (Cleveland Clinic, OH), who presented the findings during a late-breaking clinical-trial session at the American Heart Association (AHA) 2011 Scientific Sessions today. The results were also published in the Journal of the American Medical Association.

However, it will still be some time before it becomes clear whether these agents can reduce cardiovascular events, Nicholls said. "In the course of the next five years, hopefully we are going to have the answer to this question," he told heartwire .

Discussant of the study, Dr Daniel J Rader (University of Pennsylvania, Philadelphia), called the lipid results with evacetrapib "impressive" and the safety analysis "reassuring," although he cautioned that this was a small, relatively short-term study.

"I think the real importance here is that another apparently safe CETP inhibitor is entering into what we hope will be clinical-outcomes trials. This affords the opportunity to test some additional key questions that are not being fully addressed" with the current studies of the CETP inhibitors dalcetrapib (Roche, Pleasanton, CA) and anacetrapib (Merck, Whitehouse Station, NJ), he noted.

In an editorial accompanying the publication of Nicholls et al's data [2], Dr Christopher P Cannon (Brigham and Women's Hospital, Boston, MA) observes that the CETP-inhibitor class had "a difficult start" with torcetrapib, and these evacetrapib results "represent early experience with this agent." He cites several limitations of the new study, including the fact that only 42 patients were treated with the highest, 500-mg, dose of the drug, and notes that longer-term safety data are required.

Evacetrapib Raises HDL and Lowers LDL and LDL on Top of Statins

Nicholls's trial randomized almost 400 patients with elevated LDL-C or low HDL-C to one of 10 treatment groups for 12 weeks: placebo; evacetrapib monotherapy 30 mg/day, 100 mg/day, or 500 mg per day; or statin therapy (simvastatin 40 mg/day, atorvastatin 20 mg/day or rosuvastatin 10 mg/day) with or without evacetrapib 100 mg/day; Nicholls emphasized several times during his presentation that the 100-mg dose of evacetrapib was "submaximal."

There were two primary efficacy end points, percentage change in HDL-C and LDL-C. "Evacetrapib produced a dose-dependent increase in HDL-C from 53.6% to 128.8%," Nicholls noted. And there was a dose-dependent reduction in LDL-C in the range of 13.6% to 35.9%, plus when the submaximal dose of evacetrapib was added on top of statins, the LDL lowering was in the range of 46.1% to 52.3%.

Evacetrapib causes profound increases in HDL and it lowers LDL cholesterol.

"Evacetrapib causes profound increases in HDL cholesterol--we can more than double HDL--and it lowers LDL cholesterol in the range of commonly prescribed doses of statins, and then, if you give it on top of a statin, it lowers LDL even more," Nicholls told heartwire .

He added that a "comprehensive" safety evaluation was performed. "This is critical with CETP inhibitors in light of the torcetrapib experience. We saw absolutely no adverse effect on BP or increased incidence of liver, muscle, or kidney biochemical abnormalities. And critical for the CETP-inhibitor story, we see no adverse effect on either aldosterone or salivary cortisol levels, which were clearly factors that were implicated in the torcetrapib failure."

What Dose to Trial? Is There a "Sweet Spot" for CETP Inhibition?

However, Nicholls agreed with Rader that there were many unanswered questions with regard to CETP inhibitors that only time would help to unravel.

"One key question for the field is the issue of the degree of CETP inhibition in relationship to cardiovascular risk reduction," observed Rader. "CETP is complicated. It's not entirely clear that there is a linear association between the magnitude of CETP inhibition and CV risk reduction. If you accept that's a possibility, you may have to accept some 'sweet spot' for CETP inhibition that may not be the maximal CETP inhibition you can achieve, so having another CETP inhibitor allows more opportunity to test this relationship."

He noted that the three doses of evacetrapib that were used in this study--30 mg/day, 100 mg/day, and 500 mg/day--inhibited CETP "by about 50%, 70%, and 90%, respectively.

"I think that is why we need these trials, and frankly this is why it's so important that evacetrapib is entering the scene, because it gives us yet another opportunity to really investigate this issue," he added.

"Best" Patient for Phase 3 Still Unclear

Another question is "who are the patients most likely to benefit from CETP inhibition?" Rader wondered.

"Both trials that are currently going on with dalcetrapib and anacetrapib require that people have LDLs below 100 mg/dL to even get into the trial, so they are excluding anybody who is over 100, and also they did not select based on HDL. Even though these are HDL-raising drugs, they are letting anyone, regardless of HDL, into the trial."

CETP is complicated. It's not entirely clear that there is a linear association between the magnitude of CETP inhibition and the CV risk reduction.

He added that a case could be made that CETP inhibitors that also lower LDL--anacetrapib and evacetrapib--might be most effective in people whose LDLs are on the higher side. "So one possibility that evacetrapib affords is the important question of testing it in people whose LDLs are actually a bit higher and not already optimally controlled."

Nicholls agrees: "We treat patients with statins, but a lot of patients still have clinical events even when we treat them. We saw today with SATURN that even a third of patients [on high-dose statins] continue to progress; it tells us there is still a lot going on, that a lot of patients will require additional therapies.

"It makes sense that at least the first foray into clinical trials with these compounds are in patients at the highest residual risk of a CV event despite ongoing treatment," he added. "Evacetrapib is very effective in raising HDL but also in lowering LDL, so it seems reasonable that it could be tested in both patients who have low levels of HDL and patients who don't have low levels of HDL."

But he noted that no decisions have been made yet with regard to the patient population for a phase 3 trial of evacetrapib or the dose to be tested, noting that these decisions "are up to the sponsor."

"The jury will be out with CETP inhibitors until we have definitive outcomes studies; we all remain very encouraged that this may be the strategy moving forward, but we have to wait and see."

The phase 3 trial of dalcetrapib, dal-OUTCOMES, has finished enrollment, with results expected in the next couple of years, he said, whereas the equivalent trial with anacetrapib, REVEAL HPS-3 TIMI-55, has only just begun enrolling patients.

The study was sponsored by Eli Lilly. Nicholls reports research support from AstraZeneca, Anthera, Eli Lilly, Novartis, Resverlogix, Roche, and LipoScience and consulting honoraria from AstraZeneca, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Aventis, CSL Bering, Esperion, and Boehringer Ingelheim. Disclosures for the coauthors are listed in the paper.