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Cardiovascular Disease

Hold On, Merck’s CETP Inhibitor Actually Works?

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:

  1. 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.
  2. 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.
  3. 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.

Update: Merck has indeed dropped the program. . .

15 comments on “Hold On, Merck’s CETP Inhibitor Actually Works?”

  1. dearieme says:

    “Eli Lilly’s compound did both of those and had no effect at all on cardiovascular outcomes.”

    Golly, it’s them darned paradoxes again.

  2. Barry says:

    Would it be petty to observe that while Merck’s cmpd ” reducing major coronary events (defined as the composite of coronary death, myocardial infarction, and coronary revascularization)” they don’t claim that it changed (or reduced) overall mortality? Torcetrapib–if memory serves–succeeded on the surrogate endpoints of raising HDL and lowering LDL, but failed for mortality.

    1. Derek Lowe says:

      That might not turn out to be petty. Coronary death is in the composite endpoint, of course, but overall mortality might well be different, especially if the primary endpoint was a narrow statistical win.

  3. Janex says:

    Given the difference in response with every other inhibitor which hits this target, perhaps it’s efficacy isn’t do to its CETP activity but to some other activity (or perhaps a combination of activity at CETP and the secondary target).

  4. Anon says:

    Makes me wonder whether this is a meaningless result based on random sampling. After all, with a p-Value cut-off of 0.05, 5% of drug trials will give a “statistically significant” result by chance alone, and we must have had about 20 failed CETP inhibitor trials by now…

  5. tnr says:

    It will be interesting to see the detailed results. The language is strange. Why would Merck ‘consider’ filing if the primary endpoint came up statistically significant? The only thing I can speculate is that one of the components of the primary endpoint, like cv deaths actually looks bad for the drug, but gets washed out when you combine with other components.

    1. Diver Dude says:

      The language screams “we’re putting a brave face on this but we don’t think we’ve got enough positives to outweigh the negatives and so it’s dead but we don’t want to say so out loud just yet” to me.

      1. tangent says:

        The way they mention bioaccumulation also reads as odd to me. Putting the two oddities together, maybe they believe they have a worthwhile treatment effect, but they have unknowns in long-term toxicity, and they’re arguing about whether to bet they can make more money than they’ll lose in a giant class-action lawsuit down the road.

        1. john adams says:

          As an ex-Merckie (Murkie?) I think you can take that line of thought to the bank (or not) !

  6. anon says:

    So, the Teflon molecule really sticks, or not?

  7. DrugMaker_2017 says:

    Three CF3 groups, 10 F atoms total. Pfizer’s compound has also three CF3 groups.
    Some so called “MediChem Guru” will once more emphasize how bad this kind of molecules would be, in terms of blah blah blah…..

  8. Calvin says:

    I doubt there’s much happening at Merck today….I’m told the whole place is shut due to the issue with ransomware. Entire US shut down.

  9. MFernflower says:

    It’s a pretty interesting structure to say the least (10 F atoms, isopropylbiphenyl, 1,3-oxazolidin-2-one) …. I would be concerned with environmental accumulation and possible long term liver damage from this stuff however!

    I cannot wait for the NDA to be looked at by the FDA and for an FDA report on this stuff to be written up *grabs popcorn*

  10. Simon says:

    Merck is doing a good a job in these area of drugs. But from attack of Petya ransomware attack, i recommend that the team embrace IT/cybersecurity

  11. Cytirps says:

    It’s too bad for the clinical people that the ransomware shut down the entire Merck computer network

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