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Pfizer's Astonishing Torcetrapib Data


Data shows torcetrapib increased death and cardiovascular events from the start in clinical trials.


Torcetrapib was supposed to be the drug that saved Pfizer's (PFE) cardiovascular empire, currently based upon Lipitor and its ever-diminishing patent life. Instead, torcetrapib left a $800 mln hole in Pfizer's balance sheet (the cost of the development program) when Pfizer terminated the program on December 2, 2006.

It's pretty obvious why they did. From the very beginning of the study, torcetrapib had a higher rate of deaths and cardiovascular events (CVEs). In fact, there was a highly statistically-significant chance of death or CVE in patients who were randomized to torcetrapib. This is quite amazing, calling into question why the trial was not halted sooner. I strongly expect once these data filter into the plaintiff lawyer community, that question will be asked and answered in courtrooms. Fortunately, the risk of death or CVE seems to disappear once people stopped taking the drug.

With the exception of any potential legal liability, this stuff is already baked into Pfizer's stock price. What people are looking at is whether the entire class of drugs (CETP-inhibitors) are doomed. Both Takeda and Merck (MRK) are developing CETP inhibitors.

From the very beginning of my time here at Minyanville, I've been saying CETP inhibition doesn't work. The idea of this class of drugs is to increase HDL (good) cholesterol in the bloodstream. HDL is akin to a garbageman, strolling around the bloodstream picking up LDL (bad) cholesterol.

On the face, CETP inhibition sounds really good as it dramatically increases HDL. However, it does so by preventing HDL from offloading its bad LDL garbage. This means you have more HDL garbage trucks, but they are all full. There is some short-term benefit as the number of garbage trucks increase, but that benefit goes away over time.

I've suggested blood pressure increases seen with torcetrapib could have been the result of these fuller garbage trucks. The data today could call this into question, though the aldosterone increase tagged as the culprit could be getting feedback from the immune system. Much work will need to be done here to figure out this relationship.

Separate data presented earlier today tried to delink the blood pressure decrease from CETP inhibition. Pfizer-generated data shows the entire torcetrapib molecular class increases blood pressure. Merck's drug is not the same molecular class of CETP-inhibitors and it did not, in fact, increase blood pressure in Pfizer's models. (I don't have my Takeda files with me and don't remember offhand its molecular class.)

The investigator presenting the torcetrapib data showed a slide ranking HDL decreases by quartile and relating those quartiles to deaths and cardiac events. These data appear to show the higher the HDL increases, the lower the death and CVEs. He interpreted this as proof positive CETP does not create inferior HDL. The problem is the data are barely statistically significant, which in a 15,000 patient trial is important. Additionally, there are so many competing mortality and morbidity pathways in this trial I don't think these data are reliable proof positive for CETP inhibition. The doctor charged with commenting on the torcetrapib presentation agrees.

Frankly, I do not believe CETP inhibitors will demonstrate a benefit in reduced CVEs and less death. I've always freely admitted I was very much in the minority on this point. A generation of post-docs will be dissecting these data and I expect we'll see more on this point. Until Merck's drug is through pivotal trials, however, I don't think the issue will be put to rest.

To sum up, the effects on Pfizer (and its stock price) from today's data:

1) The fact torcetrapib failed is old news and built in.

2) The fact it wasn't close and the increase in death and CVD was seen from the beginning is new, but will only be a factor if we see lawsuits on behalf of patients in the trial.

3) The fate of other CETP-inhibitors from Merck and Takeda is no different, in my view. Some who are already inclined to be cheering for those drugs will have ammunition to bolster their case, but only in regards to the blood pressure connection.

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