Zetia and Vytorin – Where’s the beef? 

 

What do you do if you run a trial which shows that your drug adds nothing to the standard of care? When you are making billions of dollars a year from the sales of this drug, you stall, change the trial design or ideally try to bury the trial completely. At least that seems to be what you do if you are Merck and Schering Plough. Several years ago Merck and Schering joined forces to launch Zetia- a drug which inhibits cholesterol absorption from the intestines- and the Vytorin – which is a combination of zetia and simvastatin(which is a statin like Lipitor, Crestor etc.). These drugs have exceeded the sales estimates of most- selling about 5 billion/year and still growing. There is to date no evidence that lowering cholesterol with zetia is as good for you as lowering it with a statin (for which the evidence abounds). Many doctors have accepted the LDL lowering as the ultimate goal, but there is some reason to wonder whether we should. The recent trials of Pfizer’s experimental CETP drugs showed a marked decrease in LDL and an increase in heart attacks and cardiac death. (Many have attributed this to a deleterious blood pressure effect of the drug- the cause remains uncertain, but clearly these results show the danger of using LDL as your goal without looking at hard endpoints.) In order to prove that their drugs are truly beneficial, Merck and Schering designed a series of endpoint trials. The first of these trials – Enhance- completed followup more than a year ago. This trial was a comparison of vytorin- the combination of zetia and simvastatin- and simvastatin( which, by the way, is now generic and very cheap). The primary endpoints are intimal thickening of the arteries of the neck and thigh. These are a way of measuring cholesterol in the arteries. Still not a very hard endpoint- like death or heart attack, but a major step towards showing benefit of adding zetia to standard therapy. This data was eagerly awaited by the cardiology community and we expected to see the results at the American College of Cardiology last year. It wasn’t presented then, or at the American Heart Association meeting a month ago. Companies usually try to rush positive data to the meetings. In this case, on the other hand, they have been “analyzing” this data for about a year now.

There has been increasing concern regarding an attempt to sweep this data under the rug. The official line from Merck and Schering is that they are having trouble analyzing the data. They convened an expert panel which announced a week ago that the primary endpoint of the trial was being changed. They will no longer look at the femoral- thigh- artery at all and they will now be looking primarily at the carotid- neck- artery in one location instead of the three locations they had previously planned. Changing the primary endpoint of a trial a year after the trial was completed is highly unorthodox.

The principal investigation was quoted as saying: "These are very important data for the company. The drug has huge sales, and this study will be the first real indication as to whether it is working. Everybody is understandably nervous. My opinion was that everything was fine the way it was and we should just continue, but they wanted some additional reassurance from outside experts and they got it. I didn't like it very much, but it was necessary to settle their minds." An article in the NYTimes quotes Dr. Bruce Patsy (University of Washington, Seattle) questioning the change in end point. "This sounds highly unusual to me. You need to live with your primary end point."

It is sad that the big pharmaceutical companies can strongarm the principal investigators in trials such as this. They change endpoints and drag out the analysis as long as possible- trying to eek out as much money from the drugs, before they are shown to be ineffective- as it appears they will be.  When this type of thing happens we all lose- patients receive inappropriate therapy and a lot of money is wasted on useless drugs. We all pay the price of these meds- in higher medical insurance rates and tax rates.

I intend to make some of that money back by shorting MRK and SGP about a month before the ACC meeting. This seems like a no lose gamble. If this trial is not on the docket for the late breaking trials this time around there will be hell to pay. If the trial is negative, these stocks will be badly hurt. Even if the trial is positive (I guess you never know), the changed endpoint will be still raise suspicions and prevent MRK and SGP from getting much PR benefit from the trial.

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