Merck ( MRK) has gone up over the last week on the news of a positive phase II trial of a new cholesterol drug- a CETP inhibitor. They found improvement in HDL and no impact on blood pressure.
This class of drugs is specifically designed to raise HDL cholesterol (good cholesterol). The first drug in this class was a miserable failure. Pfizer spent hundreds of millions doing very extensive long term trials of the drug, before concluding that while it did increase HDL dramatically, it didn’t cause regression of coronary plaques and increased dramatically the likelihood of heart attacks, unstable angina ( episodes of chest pain) and death. This was the most expensive failed drug project in the history of pharma. The drug increased blood pressure by a few points, and some have attributed these adverse finding to this side effect. To me, and to most, this seems like wishful thinking. The small degree of blood pressure effects were very unlikely to result in such bad outcomes. One would at least have expect improvement in the coronary plaque- followed by ultrasounding the coronary from the inside out (IVUS) if this class of drug were to have potential. Clearly there is much we don’t understand about lipids and it seems very likely that blocking CETP results in a build up of other atherogenic particles.
With this background in mind, I was very surprised by Merck’s recent press release. I am short Merck’s stock- and this gave me additional reason to be confident in this stance. I assumed that Merck had given up on this project. To get this drug to market, they would certainly need very extensive trials- much like those that Pfizer did- costing hundreds of millions and lasting many years. This is particularly true in light of the troubling findings with Pfizer’s drug and the heightened level of concern in general at the FDA. These would be very much unlike the short term trials they were able to do to get Zetia and Vytorin on the market- I personally feel that those drugs should have been required to show some actual outcomes data as well.
The risk/reward on this new drug seems to fall very much on the side of risk. Lots of expensive drawn out trials for a compound which seems destined to failure.
Comments
Carey Richardson
October 12, 2007
You may be a good doctor, but your investment record is mixed. I suggest that you go take the pole out from your behind and cover your Merck already.
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MD, MD
October 12, 2007
Pfizer has not shown the complete data from their failed trial with their CETP inhibitor. It would be of interest to learn whether the individuals that died or had an MI also had increased BP in response to treatment. Also what is the compositon of the lipid particles after CETPi treatment?
In response to Zetia/Vytorin outcomes, please remember that Lipitor/Pfizer initially came to market without any outcomes data and rode the results of the simvastatin and pravastatin outcomes data. Currently Crestor has no outcomes data. Lastly, Vytorin has simvastatin in it and thus has at least its known benefits. The question to be answered is the incremental benefit in clinical outcomes when adding Zetia to a statin.
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CETP inhibitor does not increase "good" HDL
October 13, 2007
Supposedly the "good" HDL is the HDL that carries cholesterol and oxidized lipid back into liver. The "good" HDL in action is moving in the direction of liver. However, CETP inhibiton blocked this movement. In fact, it increases accumulation of "oxidized" lipid and causes plaque instability by promoting foam cell formation.
A parallel: when you count the number of the trucks in a highway travelling at speed of 65 mile/hour, the higher number is an indication how much goods being transported. But when you block a high way artery and then count the number of trucks, it does not mean anything but blocked traffic.
HDLs anti-inflammatory effects were not demonstrated by PFE trial.
The HDL dogma may be wrong if used this way. It should be a marker in well functioning RCT (reverse cholesterol transport). If RCT is blocked, it does not mean much more than trouble. Foam cells, unstable plaques, infiltration of inflammatory cells into plaques together with oxidized lipid should be considered. Otherwise, we are wasting investor's money and driving R&D cost way up.
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pharmaking
October 14, 2007
@MD,MD.
I agree that lipitor had no outcomes data for several years, and that Crestor also doesn't have any now.
There are a few problems with that argument
1: Lipitor and Crestor could at least use the class effect argument, where as ezetimide is a new class with no evidence of benefit (The was a small study in Circ last year suggesting that ezetimide had none of the benefits of statins with respect to flow mediated vasoreactivity.)
2: Crestor at least has IVUS data, and apparently will have mortality data released at AHA. As far as I can tell, Merck is no where near ready with this kind of data.
3: It is true that simva has a lot of good data, but if I want to use simva- which I do- why wouldn't I just write for it- It is generic and quite cheap.
Regarding the CETP, no doubt the wreckage of this trial will be picked over for a while. My question to you is "Do you know of any drugs that decrease BP by 3 or 4 points and decrease your risk of MI by 50%?" I beleive the answer is no, and if not, how can we attribute such a large increase in events to such a small change in BP?
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