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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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May 7, 2012

The CETP Saga Continues (And It's Not Getting More Entertaining)

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Posted by Derek

Roche has halted trials of its CETP inhibitor dalcetrapib. Many will remember the Pfizer compound in this class, torcetrapib, which went down catastrophically in Phase III back in 2006. In that case, deaths in the treatment group were higher than the placebo group, which will bring you to a screeching halt every time. The generally accepted story is that the compound's effects on blood pressure (and possibly electrolyte balance) negated its beneficial effects on lipoproteins. But was torcetrapib actually working? It certainly raised HDL levels - but is that enough?

You have to wonder. Dalcetrapib wasn't taken out by toxicity - it was dropped because of "a lack of clinically meaningful efficacy". Analysis of several Phase II trials seems to have shown no beneficial outcome in cardiovascular mortality and mobidity. So what is it that we don't know about CETP, about HDL, and about lipoprotein roles in cardiovascular disease in general? Quite a bit, is my guess.

Two companies that are very, very much pondering that question are Merck and Eli Lilly, both with competing CETP inhibitors in the clinic. Expect statement from each of them that they continue to have confidence in their clinical candidates. But behind the scenes, expect a lot of very intense re-evaluation.

Comments (32) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials


COMMENTS

1. luysii on May 7, 2012 9:00 AM writes...

"So what is it that we don't know about CETP, about HDL, and about lipoprotein roles in cardiovascular disease in general? Quite a bit, is my guess."

Exactly, and this is why big pharma is shedding organic chemists right and left. We are mucking about with a system we only dimly understand.

For other 22 other examples of our ignorance see ttps://luysii.wordpress.com/category/aargh-big-pharma-sheds-chemists-why/

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2. PharmaHeretic on May 7, 2012 9:35 AM writes...

I guess people could admit that dyslipidemias are just another symptom of whatever causes atherosclerosis than its 'real' cause. But that would be so embarrassing.. would it not?

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3. PPedroso on May 7, 2012 9:41 AM writes...

@1 But are they internalizing anyone else? Perhaps, someone that can help them understand the system and after that re-hire new chemists for the same work but on proven/known ground?

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4. Ric Locke on May 7, 2012 9:43 AM writes...

I used to take statins to control my cholesterol. I quit doing so because I objected to the side effects, particularly as regards cognitive abilities.

Results such as you describe confirm my prejudice -- and it is a prejudice, not a reasoned judgement based on scientific evidence, because I'm neither a medical professional, a biomedical investigator, nor a chemist. That prejudice is: Cholesterol levels are a symptom, not a cause; researchers don't know enough about the metabolic pathways to reach for the actual cause. Cholesterol control, as it stands, is roughly equivalent to treating a wound by trying to control blood supply to it rather than sewing it up.

Regards,
Ric Locke

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5. bmartinmd on May 7, 2012 9:45 AM writes...

The CETP-inhibitor data seen so far may be the result of a kind of Goldilocks effect. And therefore, it may not be wise to abandon the class entirely. Pfizer's torcetrapib, which significantly raised HDL and lowered LDL in clinical trials, seems to have had an over-exuberant (and therefore deleterious) effect on the renin-angiotensin-aldosterone system. Roche's dalcetrapib was much more modest in action, raising HDL about 30% but having little effect on LDL (or blood pressure, aldosterone, and serum electrolytes, for that matter). Merck's anacetrapib may be just right--by raising HDL more significantly than dalcetrapib; by considerably lowering LDL; and by having no effect on the renin-angiotension-aldosterone system. But we won't know for a while, I guess. The first of Merck's phase 3 studies won't be completed in 2014.

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6. NoDrugsNoJobs on May 7, 2012 9:46 AM writes...

I believe folks who understood this area well also understood the risks. The phenotypes with high CETP and/or Hpatic lipase activity were just not that strong. If one looks at the whole machinery, the gears must sort of work together - meshed in their efficiency and simply slowing down HDL breakdown might not help where you have a statin helping the liver to suck up all the LDL that is contained within. I might have thought to go the other way, speed up the breakdown together with a statin. In other words, accelerate CETP, speed HDL breakdown and coupled with a statin pulling in the ldl at the liver, the parts might work better. In any event, would have been nice if they worked!

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7. Curious Wavefunction on May 7, 2012 9:55 AM writes...

It's remarkable that we still know so little about cardiovascular disease and lipid metabolism, even after billions of dollars and dozens of Nobel Prizes. The end of science is not quite near.

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8. barry on May 7, 2012 12:05 PM writes...

One datum that seems secure in this whole unsettled field is the efficacy of ApoA-1 Milano in reversing cardiovascular disease http://en.wikipedia.org/wiki/ApoA-1_Milano

Pfizer owns the patent on ApoA-1 Milano as a (biologic, non-orally available) drug but hasn't figured out how to sell the market on an expensive injectable.
Paradoxically, administration of expogenous ApoA-1 Milano causes elevation of circulating triglycerides and depression of measured HDL in circulation.
Who has the stomach for a a gene-therapy trial in 2012?

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9. ScientistSailor on May 7, 2012 1:11 PM writes...

We know a lot about how to treat these metabolic/CV disorders: don't eat so !@#$ much lard, and get off your butt and do some exercise. We spent >$1B on these trials, we would have had a much larger positive effect on society if we had spent those $$ on smoking cessation.

To save itself, the pharma industry should focus on diseases for which there are no treatments, and yes that probably means the industry will get smaller.

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10. Landlubber on May 7, 2012 2:02 PM writes...

ScientistSailor, the same advice could be used to dramatically reduce cancer rates as well. Should we stop working on Oncology too?

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11. johnnyboy on May 7, 2012 2:26 PM writes...

@4 Ric Locke: the results Derek mentions concern CETP inhibitors, whose purpose was to increase HDL-cholesterol levels, which has been hypothesized to have a beneficial effect on atherosclerosis (hypothesis which may or may not be true). What you were prescribed were statins, whose purpose is to lower LDL-cholesterol; the beneficial effect of lowering LDL-cholesterol is not a hypothesis, it has been shown over and over in clinical trials and observational studies, for atherosclerosis, survival, myocardial infarcts, etc... Yes elevated cholesterol is a symptom, and taking statins is treating a symptom and not the underlying cause; that doesn't mean that treating that symptom is useless. I suspect that if you have a headache, you take aspirin or tylenol, ie. you treat the symptom, even though you don't know the cause of your headache, and even though medicine cannot fully explain why aspirin will alleviate your headache.
No one is forcing you to take statins, especially if they have untoward side effects for you, but the fact that medicine does not have the whole atherosclerosis mechanism completely sorted out yet changes nothing to the fact that statins are useful and can save lives.

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12. ScientistSailor on May 7, 2012 4:40 PM writes...

@10
The same could be said for Alzheimer's as well, and I don't believe we should be working on that.

and I am considering leaving my oncology research position for one in infectious disease...

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13. anonymous on May 7, 2012 6:44 PM writes...

Call this BS if you like, but the second (long ago it seems) that I saw the structure / thioester moiety in dalcetrapib I said to myself "no f'in way will this make it all the way".... Sorry to say, but what idiot would spend PhIII $$$$ on this structure in this day and age? Guess I should be running Roche!!!

For what it's worth, I do believe anacetrapib will test the hypothesis, for better or for worse!

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14. dearieme on May 7, 2012 6:45 PM writes...

The cholesterol sceptics may be onto something.

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15. Anonymous on May 7, 2012 7:48 PM writes...

7, Curious Wavefunction:

When someone claims they know-all, it's time to run away. (Reminds me when pundents of the stock claim that the rules of economics have change.)

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16. Anonymous on May 7, 2012 8:19 PM writes...

@13
"Sorry to say, but what idiot would spend PhIII $$$$ on this structure in this day and age?"

It's the same idiot that lays off talent (based on politics)and retains ineptitude. Yes, you hit the mark on this one. There are big problems over there in Nutley. Just look at the morale in the Med. Chem. dept. People are just hanging on waiting for the axe to come down. If I were a Nutley NJ employee I'd be updating my CV NOW! Remember what went down at Pfizer after Torcetrapib??? The writing is on the wall especially based on the fact that Nutley USED to be working in the Metabolic area. They will inevitably take the fall for this fiasco. Mark my words...

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17. Anonymous on May 7, 2012 8:40 PM writes...

Will Merck and Lilly be able to stomach "the risk" in taking their compounds forward?? Big pharma is getting more risk averse by the day. Given the "state of the union" in the big pharma industry, I believe we're going to see some more fall out from this....it's not over yet...

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18. Clueless on May 7, 2012 9:07 PM writes...

The pharma industry needs to have a fundmental change in structuring clinical trials. Currently it's way too expensive to test a hypothesis.  A disease cause could be heterogenous, patients are heterogenous, so it could be too early/too simple to conclude there is no efficacy and move away. It could still show efficacy in a subgroup or in combination with future drug candidates one day. 

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19. BCP on May 7, 2012 10:36 PM writes...

The optimistic me wants to point out that Torcetrapib was an imperfect test of the CETP hypothesis by virtue of it's off target BP activities, while dalcetrapib didn't have a big enough effect HDL to make a real difference in outcomes.

The pessimistic me wants to consider that perhaps we need to have HDL circulating at elevated levels for a number of years to regress plaques that take decades to be deposited and see differences in endpoints.

The hard ass me wants to say, it's a dud target, duh.

Permalink to Comment

20. experienced chemist on May 8, 2012 12:01 AM writes...

What does the failure from Roche's clinical trial mean? There was an extraordinary section at recent ACS in San Diego covering the CETP topic. The first speaker is from Argone National Laboratory. He mainly talked about biology of CEPT. Following his speech, a guy from Pfizer showed a detailed presentation about the failed compound. That compd caused QT prolongation even in primate. As you might be aware, the Pfizer's management was desparate to find something to fill the hole left by the Lipitor's patent expiration. They were willing to gamble even if with the patients' life. At present environment, there is no chance for this type of compd to enter into clinical trial. Guess what happened. The QT prolongation manifested in human, leading to more death than placebo group. I remember this was just like a bomber when Pfizer released the result. Now Merck is also gambling on this even on a much bigger scale. At the ACS meeting, the senior research fellow from Merck gave an excellent presentation. He mainly highlighted two points: one is Merck's compd doesn't cause any cardiotoxicity, the other is this compd is efficacious in terms of raising HDL and lowering LDL. So Merck is doing the largest ever Ph III clinical trial with the hope this will be a blockbuster. Now Roche just made another headline. Its compound doesn't have cardiotoxicity issue, but it has no efficacy. I couldn't remember the exact structure of this compd. But I assume it is close to Merck's compd. So this really cause me to raise my eyebrow. Does Merck's compd really have a good chance? As of Lilly's compd, it is significantly different from other competitor's compds. It is a late comer in the game. The only chance for them is to have a totally different structure. There was also a talk at the ACS meeting. The guy was the last speaker. I recall that the SAR for Lilly's series is different from other series. Does this has a better chance?

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21. CETP GUY on May 8, 2012 12:18 AM writes...

@20,
dalcetrapib's structure is NOT close to Merck's anacetrapib.

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22. CETP GUY on May 8, 2012 12:31 AM writes...

just curious about Merck's anacetrapib. It has 10 fluorine atoms and MW over 630. Better chance too?

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23. Vince on May 8, 2012 6:25 AM writes...

Experienced Chemist said: That compd caused QT prolongation even in primate. As you might be aware, the Pfizer's management was desparate to find something to fill the hole left by the Lipitor's patent expiration. They were willing to gamble even if with the patients' life

That doesn't seem fair.

Pfizer found torcetrapib to cause a 3.3msec prolongation in QTc. Circadian variation itself is on the order of 15-20mseconds, with the peak prolongation right around dawn.

The mean QTc prolongation of antipyschotic molecules, which I'm more familiar with, are demonstrably higher. I'd point you toward Pfizer's 054 Study which looked at baseline changes in 6 marketed drugs. It found the avg prolongation around 15ms, the largest being in Thioridazine -- notorious for cardiotoxicity. Only it's mean QTc shift was 33.3ms, or 10X what you're claiming is 'gambling with patient's lives.'

At the end of the day, anytime you write a script you're playing a probabilistic game. It's a question of informed trade-offs: net expected benefit, net expected cost. The same goes with drug development -- and 3ms isn't exactly a deal breaker.

That said, IMHO, your comment imputing malicious intent was completely inappropriate. Pharma-bashing might be en vogue in certain venues, but do it with facts.

Permalink to Comment

24. CR on May 8, 2012 7:18 AM writes...

@12, ScientistSailor:
"@10
The same could be said for Alzheimer's as well, and I don't believe we should be working on that.

and I am considering leaving my oncology research position for one in infectious disease..."

Why do research in infectious diseases? According to your logic, we should just all buy bubbles and live in them, problem solved.

Permalink to Comment

25. ScientistSailor on May 8, 2012 12:58 PM writes...

@24
CR, That's not the logical conclusion from my position, any more than the logical conclusion from your position is that we should be working on drugs to make smoking safer.

There is a spectrum of personal responsibility for every disease, from none in diseases like ALS and lupis to complete in smoking-related illnesses. I would say that MRSA and bird-flu are closer to the former than the latter, no? We all know that the industry is getting smaller, where should we focus our remaining effort? Vivus just got another PDE5 inhibitor approved, is that really a good use of resources? Versus developing a new drug so that if a kid gets a scratch, they don't die, and still have their whole life ahead of them. Cancer is some where in between. We know there are people who will get cancer through no fault of their own, and others who's choices put them at greater risk.

I'm voting with my feet.

Hey Derek, How about a thread on this: what diseases should we focus on in the few years the industry has left?

Permalink to Comment

26. CR on May 8, 2012 1:08 PM writes...

Nope, I sum up the logical conclusion in your first two posts in my post. Why work on AD? People get old, f-them, that is their fault. People get fat, f-them, it's just simply they need more exercise and less food. People that get sick after getting a scratch? F-them, if they are in a bubble that wouldn't happen.

You're not voting with your feet, your trying to determine who should get medicines.

If you believe the industry only has a few years left, then we shouldn't focus on anything - a few years is not long enough to make serious inroads in any disease area - so just ride out whatever profits are left, give out big executive bonuses and then close shop.

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27. ScientistSailor on May 8, 2012 4:15 PM writes...

Wrong, it's not possible to live life in a bubble, it is possible not to smoke and not to get fat, thus your logic is wrong...

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28. ScientistSailor on May 8, 2012 5:42 PM writes...

...and another thought: every system makes decisions about how to distribute scarce resources. Our system has decided that people with ALS get no drugs, and people who actively contribute to their own illness get lots of drugs. Are you happy with that decision? I'm not, and I am trying to change it.

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29. Anonymous on May 9, 2012 12:13 PM writes...

1) "Don't do what I think is harmful" has worked out so well for sex, and other things. I can't see why it won't work here. (snicker)

2) If you were to actually make useful drugs for obesity or smoking cessation, for example, you might actually make enough money to generate drugs for the indications you believe should be medicated. [DTC ads in pharma generated money - they just made a lot of other costs that (may have) hurt pharma.] Of course, if that's not possible, well, then you're probably screwed anyway, because your business has a massive mismatch between what people will pay for and what it can actually do. Whether governments can or will fill that gap seems like an open question (but with an answer that is most likely "no").

3) Waiting around for complete information is probably a fool's game - there's plenty of room in human experience for humility, but not enough time in it for despair.

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30. MedChem on May 9, 2012 4:23 PM writes...

Anon #13:

Not so fast buddy. Roche's cmpd did not fail due to tox, it failed due to lack of efficacy. The thing is perfectly safe, as perfectly as these things can be.

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31. Anonymous on May 9, 2012 7:17 PM writes...

@30
If the compound was "perfectly safe" then they would have been able to push the dose as far as they wanted. That's not the case with that compound. Every drug is toxic to some degree...it all comes down to therapeutic index.

Permalink to Comment

32. PPedroso on May 17, 2012 8:31 AM writes...

Dear Derek,

I think this is worth a post:

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)60312-2/fulltext

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