Well, maybe. I have to admit that my first reaction was disbelief. Merck has come out this morning with a statement that its long-running outcomes trial with anacetrapib, their cholesteryl ester transfer protein (CETP) inhibitor, had positive results. Specifically, they say that the trial. . .
. . .met its primary endpoint, significantly reducing major coronary events (defined as the composite of coronary death, myocardial infarction, and coronary revascularization) compared to placebo in patients at risk for cardiac events who are already receiving an effective LDL-C lowering regimen. The safety profile of anacetrapib in the early analysis was generally consistent with that demonstrated in previous studies of the drug, including accumulation of anacetrapib in adipose tissue, as has been previously reported. Merck plans to review the results of the trial with external experts, and will consider whether to file new drug applications with the U.S. Food and Drug Administration (FDA) and other regulatory agencies. The results of the REVEAL study will be presented at the European Society of Cardiology meeting on Aug. 29, 2017.
This area has been an expensive wasteland for drug development since 2006, when Pfizer’s torcetrapib (the company’s biggest drug development effort ever, at the time) unexpectedly failed in Phase III. In the years since then, every single other CETP inhibitor has failed as well. They didn’t all raise cardiovascular mortality like Pfizer’s compound, but they sure didn’t lower it, either. Merck persevered with their compound, though, in the face of all these results, and the REVEAL study is a real cardiovascular whopper: 30,000 patients, with the first participants dosed back in 2011, all of them diagnosed with cardiovascular disease and all of them given a statin for LDL lowering. Some of them have been getting anacetrapib on top of that statin dose and others have been getting statin and added placebo.
So this is really the first positive outcomes result ever seen in CETP, thus my surprise and the surprise of most observers. But it’s not time to declare victory yet, because there are a lot of things to think about in that Merck statement:
- You will note that the company says it will “consider” whether to file an NDA. On the one hand, that’s appropriately cautious language, but at the same time, companies usually announce that they’re marching ahead to NDA filing after announcing positive results. This makes a person wonder what the magnitude of these positive results might have been. It’s certainly possible that the trial came out nominally positive, but not positive enough to give anacetrapib a chance in the (crowded) cardiovascular market. It’s all about effect size.
- Some observers this morning have wondered if the positive trial outcome is due to the compound’s effects on HDL (which is raises) or on LDL (which it lowers). I think that’s impossible to say at this point, but it’s worth noting that Eli Lilly’s compound did both of those and had no effect at all on cardiovascular outcomes. Since all these patients were already on atorvastatin, you also have to wonder how much effect on LDL anacetrapib could pile on, and what the clinical implications of that would be. But it’s certainly still possible that the HDL-raising effects, which are the main reason that everyone piled into CETP in the first place, aren’t doing anything.
- Note the statement on the safety of the drug. “Generally consistent” is appropriate language, although not a ringing endorsement, and it’s interesting that the statement specifically mentions the accumulation of the drug in adipose tissue. CETP inhibitors are famously greasy molecules, and it’s not surprising that they would do something like this, but it’s not a desirable feature.
So we’re going to have to wait to see if this clinical trial turns into anything more than an eventual trivia question. Merck might well be finding themselves in the position of King Pyrrhus (“Another victory of this sort and we will be completely undone”). I wondered back in 2011 if that might not be the outcome, and I certainly wasn’t alone. Merck’s stock went up in premarket trading on this announcement, but I think that’s premature. The history of this target should tell us that no one should count a CETP victory until every last bit of the news is in.