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Cardiovascular Disease

CETP Failure: Now It’s Lilly’s Turn

It’s been a while since CETP came up on this site as a drug target. This has been many companies’ best shot at an HDL-raising therapy, to go along with the LDL-lowering effects of the statins (and now the PCSK9 inhibitors). The prospect of a two-front attack on cardiovascular disease (and the cardiovascular disease market) has led to a vast amount of time, effort, and investment over the years (late-stage trials in this area are almost always gigantic and costly). But looming over the whole CETP landscape is the dust cloud caused by the failure, back in 2006, of Pfizer’s torcetrapib, which was the most advanced drug in the class. That was a terrible shock, for sure – looking back, there were some warning signs in the earlier clinical data, but no one expected the drug to crater as badly as it did in Phase III.

In the years since, the companies pushing hardest to make a success out of a CETP inhibitor have included Merck and Lilly. (Roche gave up on their entry in 2012). And now Lilly is out this morning with news that their drug, evacetrapib, has failed in Phase III. In this case, it wasn’t toxicity, as with Pfizer’s compound, which showed a slightly higher death rate in the treatment group. But it was sheer lack of efficacy. The data monitoring committee decided that there was basically no chance that the compound would make its primary endpoints, the way things were going, and recommended a complete halt.

When torcetrapib failed, there were a number of rationales advanced for how that could have happened. The drug seemed to cause some electrolyte imbalances, and raised blood pressure a bit on its own, for example. Given the experiences since then, though, it would seem that these could account for the swing to actual harm, as opposed to just doing no good. But it’s also looking harder and harder to deny that inhibiting CETP is just that: an intervention that does nothing useful. Every single company so far that has ventured into this area has had cause to regret it. And there have been many, since many of them didn’t even make it to the clinic, which in retrospect makes them fortunate, I’d say.

All this makes a person wonder, very very much, about Merck’s anacetrapib. As far as I know, they’re officially pushing on with it, but that took nerve even after Pfizer’s failure. Now after Roche, and now after Lilly, what do they have? Either CETP inhibitors are a much more varied lot than you’d ever think, or they’re probably going down the same chute as everyone else. . .

Update: Lilly’s stock has been taking a beating this morning, an unusually large move for a company its size. And Merck’s stock is feeling the pressure as well, as the pessimism spreads.

17 comments on “CETP Failure: Now It’s Lilly’s Turn”

  1. Me says:

    Wow! Another sink-hole for Lilly to put their cash to try to convince investors of their ‘potential’ filled….

  2. James Edwards says:

    I would not discount Anacetrapib just yet. It has demonstrated tremendous efficacy in HDL-elevation AND LDL-lowering. I would not be surprised is the leads to success in outcomes trials monitoring for overall cardiovascular events and arterial plaque regression. To my knowledge, despite its high lipophilicity, no other CETP inhibitor has demonstrated quite the efficacy profile that Anacetrapib has so far.

  3. PharmaHeretic says:

    The most important part of that article is:

    “In this case, it wasn’t toxicity, as with Pfizer’s compound, which showed a slightly higher death rate in the treatment group. But it was sheer lack of efficacy. The data monitoring committee decided that there was basically no chance that the compound would make its primary endpoints, the way things were going, and recommended a complete halt.”

    Given that Dalcetrapib was dropped by Roche in 2012 for lack of therapeutic efficacy, perhaps CETP inhibition is not therapeutically relevant in humans.

  4. Rock says:

    James, HDL elevation and LDL lowering are not “efficacy” endpoints themselves. That is why the companies need to run M&M studies. The LDL effect will be washed out because these trials are run against SOC (likely Lipitor) as was done with torcetrapib. I believe that HDL is beneficial, but I have never bought in to the CETP inhibitor mechanism to raise it. What you want is to create more HDL particles, not just fill up the particles you have with more cholesterol. Defeats the beneficial effects of HDL in the first place.

  5. Andy II says:

    @Rock. Thanks for the education. Checked Clintrial.gov for the primary endpoint. It says that ACCELERATE study is to evaluate the efficacy and safety of evacetrapib in participants with high-risk vascular disease (HRVD) compared to placebo for “Time to First Occurrence of the Composite Endpoint of Cardiovascular (CV) Death, Myocardial Infarction (MI), Stroke, Coronary Revascularization, or Hospitalization for Unstable Angina (UA) [ Time Frame: Baseline to Study Completion (estimated to be up to 4 years) ] (https://clinicaltrials.gov/ct2/show/NCT01687998). And, you are right, Rock, lipitor treatment is required. BTW. What is the “M&M study”?
    Inclusion Criteria:
    – Diagnosis of high risk vascular disease (HRVD) (that is, meet at least one of the disease diagnostic criteria of: 1)History of acute coronary syndrome (ACS) (that is, ≥30 days through 365 days after discharge for ACS) 2)cerebrovascular atherosclerotic disease 3)peripheral arterial disease 4)diabetes mellitus with documented coronary artery disease and are clinically stable (as judged by the responsible physician).
    – Must be treated with a statin for at least 30 days prior to screening. If not treated with a statin must have documented statin intolerance, or contraindication to statin
    – Have a screening high-density lipoprotein cholesterol (HDL-C) ≤80 milligram per deciliter (mg/dL) (≤2.1 millimole per liter [mmol/L])
    – Have screening triglycerides (TG) ≤400 mg/dL (≤4.5 mmol/L)
    – Meet 1 of the following criteria:
    – screening low-density lipoprotein cholesterol (LDL-C) no more than 10 mg/dL (0.3 mmol/L) above the target chosen by the investigator (either LDL-C <100 mg/dL [<2.6 mmol/L] or LDL-C <70 mg/dL [<1.8 mmol/L]), OR
    – if LDL-C is greater than target, the patient participant must be on maximum tolerated statin dose (for at least 30 days), have documented statin intolerance, or contraindication to statin

  6. anchor says:

    It’s a game of poker and when everyone folds Merck is thinking they won! But, is it? Lincoln was right, can’t fool all the people all the time!

    1. Derek Lowe the pitcher says:

      @anchor

      Merck hasn’t won yet; they need to demonstrate the efficacy of their compound. That’s the hardest part, not whether have your competitor’s compounds fail.

  7. nitricoxide99 says:

    Amgen apparently thinks that CETP inhibition still holds blockbuster potential based on their recent $1.25 billion acquisition of Dezima and their CETP inhibitor TA-8995:

    TA-8995, an oral, once-daily cholesteryl ester transfer protein (CETP) inhibitor. In a Phase 2b clinical trial for dyslipidemia, TA-8995 reduced low-density lipoprotein cholesterol (LDL-C) by 45 to 48 percent compared to baseline. LDL-C reduction was consistent when TA-8995 was administered as monotherapy or in combination with statins.

    see: http://www.dezimapharma.com/amgen-to-acquire-privately-held-dezima-pharma

  8. a. nonymaus says:

    From reading the wikipedia page on CETP, it seems like loss-of-function mutations in humans are associated with higher higher severity of cardiovascular disease. Even the I405V mutation increases cardiovascular disease in patients with hypertrigyceridemia. Inhibiting CETP might be useful in healthy patients with low triglycerides, but even that seems to be unlikely to me.

    If anything, CETP may need to be induced to comproportionate HDL and VLDL but this may be just rearranging deck chairs on the Titanic. Hypothesis: a high HDL/LDL ratio is an indicator that there are low levels of triglycerides for CETP to transfer around, and that the underlying problem when HDL is low is hypertrigyceridemia.

  9. HFM says:

    Came here to say what nonymaus did. This target has more than a whiff of cargo cult to it.

  10. Andy II says:

    Well, this clinical halt was not due to the safety concern, someone (Hedge Fund people) may be looking for licensing to repeat another Biotech Bonanza…Axovant acquired a drug for Alzheimer’s from GSK for $5 million and flipping it into an IPO initially worth more than $2 billion in June 2015. VTv got another abandoned Altzheimer’s drug, azeliragon, from Pfizer and raised $117 millions in July 2015.

  11. Magrinho says:

    Outcomes trials means enormous costs to test a hypothesis.

    To the true believers: torcetrapib = toxic (and PFE should have known), dalcetrapib = crap (and Roche should have known), evacetrapib = not good enough

    To the skeptics: the HDL hypothesis is bunko.

    Another $1+ billion will give us two more data points.

  12. HDL consulting? says:

    Think there are still a number of important issues to consider with respects to CETPi’s and raising HDL in general.

    1. The failures so far have been due to off-target effects, inferior HDL raising and testing a drug in a cohort of patients that is probably less than idea. Giving a drug to raise HDL in people that have had a acute coronary event is likely asking to much of the drug to see an outcome as by this stage the disease is far to complex.

    2. Merk’s CETPi still has a good chance as (stated above) it dramatically raises HDL levels, while also lowering LDL. There was also a small signal for reduction in cardiovascular events in their safety studies. Merk has probably selected a better patient population to test its drug in – people with high cholesterol at risk of an event, but have not yet had one (this is important). The only problem they face is that the control group (by chance) has lower LDL levels on average, which may skew findings. There is never a perfect clinical trial in cardiovascular disease……

    3. Its important to lets these drugs run the course as if one does have a positive effect on reducing cardiovascular disease (or other diseases) then it is a major advance in human health.

    4. If the mechanism of raising HDL is incorrect, then there are still other drugs out there which work via completely different pathways that may work – but perhaps there are other diseases that HDL raising is better?

    lets see…!

  13. The problem lies with the assumption in the first place that LDL and HDL are causative in atherosclerosis. The HR’s associated with them are marginal and therefore likely to be confounding. Immunological processes regarding handling of LDL and recycling apoptotic cells are likely where the possibility of prevention lie.

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