Let's talk about torcetrapib. Like Madonna, Dunkirk and other things that are known by one name, torcetrapib has taken on more than just the name of a failed drug. As I wrote in my last blog, this class of drugs (the CETP inhibitors) followed from the observation of a human genetic abnormality, which led to very high levels of HDL. It is urban legend in cardiology that for every 1% rise in HDL, a 3% reduction in mortality occurs. This data, however, was in the era before statins and was primarily the result of using niacin by itself. See my past blog post, Aim high and Fail, for the debacle of adding niacin to a statin. As I have stated in the past, statins reduce cardiovascular death by about one-third in those that take the class of drugs. What about the other 66%? If we could just find a drug to raise HDL, then all would be right with the world. The development of the drug torcetrapib began in 1990 and was first given to humans in 1999. According to Pfizer's press release, they began full-scale production of the drug in 2005. Large scale studies began in 2004. I and my research group participated in one of them. The large-scale clinical trial that the FDA required was named ILLUMINATE or Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events. In this trial, and the others in the program, the combination of atorvastatin and torcetrapib lead to a decrease of 20% in LDL and an increase of 61% in HDL compared to the group that took atorvastatin alone. I need to point out that this study is not a placebo study. Further, an increase in HDL of 60% was unheard of. The excitement that this compound generated was epic. The hope was that this combination would lead to an impressive reduction in cardiovascular mortality. Nothing of the sort happened. In fact, on December 2, 2006, it was revealed that the combination of atorvastatin and torcetrapib resulted in a 60% increase in cardiovascular deaths, and the study was halted. In fact, every study of the drug was halted, and the compound was done. Pfizer was also done. After spending close to $1 billion on the drug and betting the "farm"on it, Pfizer withdrew from cardiovascular disease management entirely. How did this happen? No one knows for sure, but two pieces of information were brought forward. The first was that there was an increase in the mean blood pressure of the study group of 4.6 mm Hg. I for one don't understand the implication of this, but a big deal was made of it. Patients with cardiovascular disease are often hypertensive and are on medication. Couldn't a small increase in meds have avoided this? The second piece of information was published in The NEJM on March 29, 2007 (N Engl J Med 2007; 356:1304-1316). This article was concerning a study known as ILLUSTRATE or the Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation. Briefly, the two groups (one on atorvastatin and one on atorvastatin and torcetrapib) underwent intravascular ultrasound at baseline and two years later. The expectation would be that the study group would have a reduction in their atheroma burden. At the end of the study, there was no appreciable difference. If anything is learned, it is that it is better to prevent this illness than try to "Drano" it out. I for one believed that this was the end of this class of drugs. Three other companies had agents in the same class, and after review of the data, each believed that their compound would succeed where torcetrapib failed. Strike one...
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