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Cardiovascular Disease

Once More Into the CETP, Friends

So folks, let’s raise a bunch of money and pile back into CETP! You know, that great cardiovascular target that has been an absolute vale of tears for every big drug company that’s tried to develop it? What do you say?

Interestingly enough, someone is doing just that. I wrote last year about DalCor, a Montreal-based startup who had licensed Roche’s failed drug in this area, dalcetrapib. An analysis by Jean-Claude Tardif and co-workers of the dalcetrapib clinical data suggested that there actually were responders in the data set, specifically, people who were polymorphic for the ADCY9 gene. One genotype had a 39% lower rate of cardiovascular events in the drug treatment group, while another genotype had a 27% greater rate, and several other SNPs were associated with response to the drug as well. That would seem to be a pretty strong signal.

So what’s the gene? It codes for adenylate cyclase 9, a widely distributed form of the enzyme that’s been assoicated with several disease states, but not especially with cardiovascular problems. But there does appear to be some link with CETP inhibition, and there’s certainly enough evidence by now that our understanding of what’s going on with that therapy is. . .incomplete. Hundreds and hundreds of millions of dollars worth of incomplete, with trial after trial raising HDL, lowering LDL, and having no god efects whatsoever in cardiovascular outcomes.

The Montreal analysis was on carotid thickness, which is considered to be a pretty good marker for outcomes (better than lipoproteins, certainly). But you’re going to need about $250 million to put that idea to the test in the clinic, and that requires a goodly amount of nerve, considering the brutal history of this area. According to FiercePharma, DalCor is starting to recruit now for a 5,000-patient trial, though, and has raised perhaps $150 million of what they’ll need to get all the way through. Perhaps they’re hoping for some promising interim data to turbocharge the rest of the funding, and they might well be hoping to turn around and sign a deal with one of the large companies that have previously abandoned the field.

That’s going to require a good dose of those promising numbers. And it’s also going to require some promising figures on just how many patients will be able to take the drug. We already know that the broad population is not going to benefit (and odds are that Merck is going to tell everyone again next year, when their own CETP inhibitor trial reports at last). But how many variants of ADCY9 are going to show significant effects, and how many people have them? About 20% of the Roche dalcetrapib trial seem to have fallen into this category, so if that holds, you have to run the numbers with one-fifth of the expected patient population. On the other hand, those patients will be pretty close to guaranteed to experience a real benefit, assuming the trial works the way it’s theorized to, and you can identify them up front with a simple genetic marker. (A mechanism would be nice, too, but isn’t essential). So it might work, and there are plenty of companies with plenty of people who can run just those sorts of analyses. We shall see. . .

16 comments on “Once More Into the CETP, Friends”

  1. ksr15 says:

    Nice article! Never knew so much about drug discovery in my life!
    Quick typo: I assume you meant “good” instead of “god” towards the end of the third paragraph

  2. bk says:

    Good for God
    I bet he’s got a very hard job

  3. Glen says:

    I gladly send them my best wishes. I’ll not send them my money.

  4. An Open Heart article, whose work is discussed this week by Larry Husten, theorizes that for people taking statins you can look at current lifespan data this way: ” 93% will have no gain in lifespan, but 7% will have an enormous gain of 99 months.” Interesting to ponder the dalcetrapib results in this way?

  5. Anchor says:

    @ Kwalwasser-Do you have reference to this article?

    1. Dolph says:

      It’s bullshit anyway, because it’s a “milk-maid”-calculation as we say in Germany. Fact is that each and every(!) patient on a statin drug will show stabilized plaque, delipidation of plaque and a reduced risk of future events. People don’t understand the concept of risk, that’s the problem. You can’t tell beforehand who will win the lottery and you can’t tell beforehand whos plaque will rupture.

  6. Twelve says:

    If the ADCY9 finding is real, and if it’s mechanism-based, then in principle the other CETP inhibitors should show the same effect. If fact, since dalcetrapib was the least potent of any of the clinical compounds, it’s even possible that the others might show greater efficacy in this cohort. Of course, this assumes that the plasma samples are still available and the sponsors have the right to do this sort of genotyping – and that they care enough to try.

    It also assumes that the finding isn’t just the result of trolling through thousands of meaningless genetic variants until this one, by chance, popped up out of the rubble.

  7. Daniel Barkalow says:

    My first thought is to wonder what the dead fish (of “Neural Correlates of Interspecies Perspective Taking in the Post-Mortem Atlantic Salmon”) thinks of this analysis. I guess it’s still worth following up on it, since it’s more likely to have an interesting connection than a random pair of disease and gene would, but I wouldn’t exactly expect to find anything.

  8. bhip says:

    I know I should understand this stuff more than I do but wouldn’t one look to see if ADCY9 protein expression changes? Some (all?) of these SNP are synonymous i.e. the protein structure is unaffected? I believe that synonymous SNP can effect transcription efficiency but if that is the case, then the ADCY9 expression would be altered. I would want a little more meat on the bone before offering cash money….

  9. Barry says:

    It’s always tempting to rescue a Phase III failure by changing the endpoint or subdividing the clinical population. It can even lead to new hypotheses and greater understanding. But without a testable mechanism for ADCY9 to interact with CETP blockade, you’d be a fool to throw new money down this rat-hole. Pfizer and Merck gave it good shots. The target is as close to invalidated as $2billion of R&D can make it

    1. Mol Biologist says:

      You always can find small population where it will work (20 patients or so). In a Phase 2 clinical trial of the immunotherapy drug pembrolizumab (Keytruda) as a first-line therapy for advanced Merkel cell carcinoma (MCC) — a rare, aggressive type of skin cancer — patients had a durable response similar to that seen with chemotherapy.
      http://www.dddmag.com/news/2016/04/mercks-keytruda-shows-promise-merkel-cell-carcinoma

      1. Barry says:

        if you can identify a marker for responders in the Phase II trial, you’d be foolish to launch a Phase III trial without refining the clinical population. If you get a finding of efficacy in the restricted indication, it will pay for a second Clinical trial for a broader indication. This was all the difference between the Tarceva and Iressa trials.

        1. Mol Biologist says:

          Cancer caused by viral invasion is good indication. Although in the case of HPV mediated cancer it does not require expensive new drugs since it can be treatable by others. I am wondering if it would next a rare, aggressive type of cancer.
          https://www.collective-evolution.com/2016/04/12/lead-developer-of-hpv-vaccines-comes-clean-to-warn-parents-young-girls/

  10. MTK says:

    Why would you go directly into a 5,000 person trial?

    Wouldn’t you first conduct a smaller trial?

    I guess that means the ROI on successful Phase III is higher than on a successful POC study. Of course, you’re risking a lot more but it’s go big or go home I guess.

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