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Cardiovascular Disease

Pushing Onwards with CETP: The Big Money and the Big Risks

Remember torcetrapib? Pfizer always will. The late Phase III failure of that CETP inhibitor wiped out their chances for an even bigger HDL-raising follow-up to LDL-lowering Lipitor, the world’s biggest drug, and changed the future of the company in ways that are still being played out.
But CETP inhibition still makes sense, biochemically. And the market for increasing HDL levels is just as huge as it ever was, since there’s still no good way to do it. Merck is pressing ahead with anacetrapib, Roche with dalcetrapib, and Lilly is out with recent data on evacetrapib. All three companies have tried to learn as much as they could from Pfizer’s disaster, and are keeping a close eye on the best guesses for why it happened (a small rise in blood pressure and changes in aldosterone levels). So far, so good – but that only takes you so far. Those toxicological changes are reasonable, but they’re only hypotheses for why torcetrapib showed a higher death rate in the drug treatment group than it did in the controls. And even that only takes you up to the big questions.
Which are: will raising HDL really make a difference in cardiovascular morbidity and mortality? And if so, is inhibiting CETP the right way to do it? Human lipidology is not nearly as well worked out as some people might think it is, and these are both still very open questions. But such drugs, and such trials, are the only way that we’re going to find out the answers. All three companies are risking hundreds of millions of dollars (in an area that’s already had one catastrophe) in an effort to find out, and (to be sure) in the hope of making billions of dollars if they’re correct.
Will anyone make it through? Will they fail for tox like Pfizer did, telling us that we don’t understand CETP inhibitors? Or will they make it past that problem, but not help patients as much as expected, telling us that we don’t understand CETP itself, or HDL? Or will all three work as hoped, and arrive in time to split up the market ferociously, making none of them as profitable as the companies might have wanted? If you want to see what big-time drug development is like, I can’t think of a better field to illustrate it.

18 comments on “Pushing Onwards with CETP: The Big Money and the Big Risks”

  1. barry says:

    There remain the results with administering ApoA1-Milano, in which researchers were surprised to see acute reversal of chronic arterial disease. That still inspires a lot of hope. Can someone bring ApoA1-Milano itself to market? Would you get enough compliance with an injectable? Projected cost of goods and expected compliance are both much better for an oral, small molecule therapeutic if it can be done.

  2. anon says:

    “…Such trials, are the only way that we’re going to find out the answers”. I keep hearing people say this, but is it really true? If you told researchers they couldn’t put CETP into the clinic for 5 years, are you telling me they would have to sit on their hands because they don’t know how else to advance their understanding of this area? I don’t believe that, and I think the potential for big profit is blinding people from the folly of pressing forward in an area that is not understood as well as it needs to be.

  3. Ben says:

    I am rather uninformed about this subject, but I remember reading that CETP is responsible for the transport of vitamin E into lipoproteins – that would be a hypothesis that’d explain the desastrous results of CETP inhibitors..

  4. @#2,
    Yup! Big trials are the only way to know for sure, at least to the standards that the FDA will accept.
    Pre-clinical studies can only go so far for a few reasons:
    1. You’re often doing studies with non-human models (thinking cells here) or animals. Not a great model for how they work in humans.
    2. You can often look at only one or two effects in models; i.e. receptor interactions, metabolism. Things get infinitely more complicated once you dose in a living system.
    3. Often toxicological effects are due to individual differences. So you could screen a compound and see no obvious toxicity, but then when you give it to 10,000 humans, 5 of them drop dead from some previously unknown mechanism.
    That’s why Derek is right. If the goal is an effective, safe therapy, there is no substitute for large, phase III clinical trials. Sure you can do a lot of pre-clinical work to gain a better understanding of a drug, but it doesn’t replace the empirical evidence you gather in a clinical trial.
    Mike

  5. dearieme says:

    “will raising HDL really make a difference in cardiovascular morbidity and mortality? …Human lipidology is not nearly as well worked out as some people might think it is”: I hope you’ll take a chance to expound on those points at some time in the next few months.

  6. Lester Freamon says:

    Well, we know from the big Niaspan/HDL trial that raising HDL might not do a damn thing to improve cardiovascular outcome. Anacetrapib raised HDL 138% in the DEFINE trial, but it’s effect on LDL is similar to that of statins.

  7. pete says:

    “If you want to see what big-time drug development is like, I can’t think of a better field to illustrate it.”
    Clash of the titans, it would seem. If PIII news is positive, then it’s Thundering Battle for Primacy. If the news is negative, then it’s…oh boy, there goes the neighborhood.

  8. luysii says:

    #5 Agree — remember that HDL is only a biologic marker. A social marker, such as yacht ownership would likely also be associated with reduced vascular mortality, due to the status of those with enough money to afford one (better access to health care, etc. etc.). Giving people yachts is unlikely to help prevent vascular disease.
    However, there is (hopefully) something to the excitement about HDL. My parents lived to 94 and 100 (HDL status unknown) and mine ranges between 85 and 100. As my late father used so say when asked about his longevity — “I chose my parents carefully”.

  9. molecular architect says:

    #8 As scientists, we should do the experiment. Someone give me a yacht and let’s see if I get heart disease!

  10. anchor says:

    Coming to Merck’s ongoing trial (Phase 3, CETP), I believe that when it comes to the management once you made the decision (to run the trial) you stick with the decision and let the trial run its course for whatever it is worth. I think that is what Merck is doing. It is good to keep the perspective on both Abbott and Pfizer trials and see what transpires. Yanking the trial at this point could do even more damage for Merck and its employees. As is Roche is touting that their compound is better than Merck and just few days back Lilly informed us they too have a compound that is as good as Merck’s CETP analog.

  11. Derek Lowe says:

    #2 Anon: as #4 says, it’s not like people couldn’t make any headway without clinical data. But there are a lot of key questions that can only be answered in humans, and those by small molecule drugs. Our lipid handling is different enough from other species that you can never quite be sure until you get to the real system, although various animal models have gotten closer and more useful.
    #5 Dearieme: I hope to do just that. In the meantime, Gary Taubes’ book on dietary fat has some good illustrations of the point, though. And in fact, comment #6 is one example right there.

  12. Blue Maharajah says:

    The issue here feels less about the target, more the Industry approach to it.
    ‘Blockbuster or Bust’ has served neither the science nor the patient… nor ultimately Big Pharma (vide supra). CETP could provide its tombstone.

  13. Anonymous says:

    Here’s the Roche CETP inhibitor.
    http://en.wikipedia.org/wiki/Dalcetrapib
    Doesn’t this compound smell of “high risk” even to the most liberal of med chemists?? Humm…a Thioester?? Looks like it may have originated from a pharma co who “polished the turd” and sold it back to them at a premium!!!

  14. Nick K says:

    #13: Something is very odd in that Wikipedia stub. The compound looks to be achiral with a plane of symmentry, and yet the name begins with (S).

  15. Anonymous says:

    The reason PFE rushed forward with torceptrapib (in knowledge of the potential issues) and didn’t progress a backup was timing. Unless it could be brought out in time to co-formulate with Lipitor (in oder to build on and extend the Lipitor franchise) it was deemed that you would not make a positive ROI on a CETP inhibitor.
    Why? Because most patients will now be put on generic Zocor/Lipitor where their cholesterol levels will be adequately controlled. Physicians will only use a CEPT inhibitor as an add on for a relatively small number of patients and that will take a lot of expensive data to show that has a positive benefit on CV outcomes. Perhaps after 10 years more data has been gathered they may use it earlier and more aggressively but that will be after Merck et al have lost patent coverage.
    I actually think PFE made a wise decision (a rare thing indeed!) to leave the CETP field. The arguments about whether this appraoch will be successful scientifically then seem a little moot.

  16. Fred says:

    “I actually think PFE made a wise decision (a rare thing indeed!) to leave the CETP field. The arguments about whether this appraoch will be successful scientifically then seem a little moot.”
    A cynical decision. They chose to screw over those patients for whom Lipitor is insufficient. Another triumph of the bean counters vs the public good.

  17. Ed says:

    #14 I read that S meaning sulfur, not as an (S) stereochemical designator

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