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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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December 21, 2012

Merck's Tredaptive Comes to a Halt

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Posted by Derek

Merck's Tredaptive (formerly Cordaptive) has had a long and troubled history. It's a combination of niacin and Laropiprant, which is there to try to reduce the cardiovascular (flushing) side effects of large niacin doses, which otherwise seem to do a good job improving lipid profiles. (Mind you, we don't seem to know how that works, and there's a lot of reason to wonder how well it works in combination with statins, but still).

The combination was rejected by the FDA back in 2008, but approved in Europe. Merck has been trying to shore up the drug ever since, and since the FDA told them that they would not approve without more data, the company has been running a 25,000-patient trial (oh, cardiovascular disease. . .) combining Tredaptive with statin therapy. In light of the last link in the paragraph above, one might have wondered how that was going to work out, since the NIH had to stop a large niacin-plus-statin study of their own. Well. . .

The European Medicines Agency has started a review of the safety and efficacy of Tredaptive, Pelzont and Trevaclyn, identical medicines that are used to treat adults with dyslipidaemia (abnormally high levels of fat in the blood), particularly combined mixed dyslipidaemia and primary hypercholesterolaemia.

The review was triggered because the Agency was informed by the pharmaceutical company Merck, Sharp & Dohme of the preliminary results of a large, long-term study comparing the clinical effects of adding these medicines to statins (standard medicines used to reduce cholesterol) with statin treatment alone. The study raises questions about the efficacy of the medicine when added to statins, as this did not reduce the risk of major vascular events (serious problems with the heart and blood vessels, including heart attack and stroke) compared with statin therapy alone. In addition, in the preliminary results a higher frequency of non-fatal but serious side effects was seen in patients taking the medicines than in patients only taking statins.

So much for Tredaptive, and (I'd say) so much for the idea of taking niacin and statins together. And it also looks like the FDA was on target here when they asked for more evidence from Merck. Human lipid biology, as we get reminded over and over, is very complicated indeed. The statin drugs, for all their faults, do seem to be effective, but (to repeat myself!) they also seem, more and more, to be outliers in that regard.

Comments (13) + TrackBacks (0) | Category: Cardiovascular Disease | Clinical Trials | Toxicology


COMMENTS

1. Anonymous on December 21, 2012 12:02 PM writes...

Any chance it's the laropiprant, rather than the niacin? Wouldn't be the first time something messing with prostaglandins has had 'unexpected' side effects...

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2. John on December 21, 2012 12:21 PM writes...

What fraction of statin use in the US is treating lifestyle? 80%? 90%?

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3. John Wayne on December 21, 2012 12:29 PM writes...

@2: Depends on if you consider being overweight and sedentary a lifestyle

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4. anchor on December 21, 2012 12:31 PM writes...


Knowing what we know, does it make sense to Merck to go forward with clinical trial for CETP inhibitors? Discussion appreciated. Thanks

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5. Kismet on December 21, 2012 1:09 PM writes...

Sorry, I don't get it: so is the n=25k study ONGOING or did it ALSO report adverse effects?

Or is the EMA referring to the n~2k study that stopped early?

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6. Anonymous on December 21, 2012 9:42 PM writes...

Let the layoffs begin!

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7. FormerMRLer on December 21, 2012 10:41 PM writes...

@4: The HDL saga continues with yet another x in the Lose column. The parallels with the prostaglandins are striking. I was at Merck when it was announced that Merck would be stopping any work on prostaglandins due to the unfavorable regulatory environment for molecules targeting this pathway. I wonder how long until Merck and others halt their HDL-raising programs.... There may be a magic somethingcetrapib out there, but it may never see the light of day as a result of these forerunners.

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8. anonymous on December 22, 2012 8:52 AM writes...

@6....correction - Let the layoffs continue!!!!

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9. dearieme on December 22, 2012 8:55 AM writes...

Is any of the companies working on the question of why statins are useful for males who have already had a heart attack? The sceptics about the "lipid hypothesis" accept that statins can do good for this category of patient, they just don't believe the canonical account of the mechanism.

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10. NoDrugsNoJobs on December 24, 2012 10:11 AM writes...

The niacin results shouldn't be a surprise, I believe Abbott recently completed a study of niaspan with a similar result. When one looks at the effect of statins in patients having different alleles related to HDl processing, one might predict this type of result. In particular, patients with alleles resulting in increased hepatic lipase activity and therefore reduced HDl respond better to statins. It looks to be the coupleing that is important. If HDl is being broken down quickly by lipase or reuptake than LDL reuptake must be adjusted upward to compensate for an overall positive lipid effect. I sometimes wonder if increased HDL breakdown (and therefore decreased HDl through reduction in particle size of HDl) through a lipase type upregulation coupled with a statin where both are drug induced could provide an additional benefit beyond the statin alone - in other words, kind of the opposite of what we are trying now.

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11. pharmite on December 25, 2012 8:31 AM writes...

The HDL hypothesis should be about reverse-cholesterol transport and not about levels of (large or small) HDL particles. Anacetrapib has been shown in relevant pre-clinical models to promote RCT and is the only CETP inhibitor to demonstrate this effect, so far as I'm aware. Whether or not it will promote RCT in human and, if so, what impact this will have on disease is the multi-billion dollar question.

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12. Healthy on December 29, 2012 5:24 PM writes...

As European I have to say it is worrisome. It is not the first nor the second time that some drug without proved effect is held back by the FDA but is approved in Europe. It smells funny.
Moreover, when it comes to fatty acids assimilation or processing it seems that any side effect is minor. I must admit that fat is an issue, but hampering health from other angles, like reducing vitamins assimilation is not very ideal (especially when it goes unadverted).

For funding, research and peer finding please refer to the non-profit Aging Portfolio.

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13. History on January 7, 2013 12:52 PM writes...

Hearing these results made me wonder how long niacin had been used to treat hyperlipidemia. It turned out, it's been used for a long-time, but its benefits were always questionable.

A 1980 pharmacology book noted that a long-term (8-yr) study of >1000 patients by the "National Heart and Lung Institute" found niacin provided "no worthwhile benefit." (at that time, 1000 people was a large study)

Niacin did not decrease overall mortality or the death rate from heart disease. It increased the incidence of arrhythmias. (yet, it was still used???) The studies by Abbott & Merck appear to prove this prior study to be correct.

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