Where has all the magic gone?

Basic medicine tells us that raising HDL-cholesterol is good. It reverses the cholesterol transport which in turn lessens cholesterol plaque (reversing the cholesterol transport, from plaque to the liver for degradation). ApoA-1 Milano filled this bill. It raised HDL-cholesterol and cleared the plaque, except that it had to be given IV.

When Pfizer produced a HDL-cholesterol raiser, in the form of a pill, it was as if we had been given a magic bullet for all the cholesterol plaques in the arteries. This drug, under development by Pfizer was called torcetrapib. When I first read about torcetrapib, I was very impressed and told all my colleagues not to fear, that soon all our arteries can be cleared with this magic pill. I taught and mentioned it in my CME talks about the future in atherosclerotic plaque reversal.

Pfizer must have spend a billion dollars, testing this drug and they have undertaken two studies (I had blogged this earlier). There was this study called "Illustrate"which enrolled 1200 patients, who were either on torcetrapib+atorvastatin, or atorvastatin alone, on the end-point of plaque reversal by IVUS (intravascular ultrasound). This study is due for release at ACC in Spring 2007 at New Orleans.

The other study is called "Illuminate", which enrolled 15,000 patients on either torcetrapib+atorvastatin or atorvastatin alone. The end-point was major adverse cardiac and cerebral events. This is very much a clinical study.

Pfizer seemed to have everything sewn up. Then everything went horribly wrong. The data and safety monitoring committee of "Illuminate" reported that there was an increase in cardiac death in the torcetrapib+atorvastatin arm (82 deaths) compared to the atorvastatin arm (51 deaths). They recommended that the study be halted. Pfizer took a day to decide (I am sure that they remembered what happened with Vioxx), and stopped the trial.

When the stock market heard the news, which was very soon, Pfizer shares fell like a stone (a big stone). I feel bad for Pfizer. They have committed so much money, and to throw all of it away. It again goes to show they developing new drugs are costly, and some will fail. Perhaps that is why good drugs, when they make it to the market, cost so much.

Now the good news (every crisis has a silver lining). We learnt that Pfizer was very responsible here. They decided quickly on a crucial decision, albeit a very painful one. They did not try to hide it (perhaps they remembered vioxx, and celebrex). We also leaarned that perhaps, they are different types of HDL-cholesterol? The good types like the one from apoA-1 Milano, which does reduce plaques and the not so good types, like the one from torcetrapib, that can cause CVS events and death? Of course, a few months ago, we learned that torcetrapib does increase blood pressure, although by only a small amount. Was it this BP raising effects thatcause the cardiac deaths in "Illuminate" or is there a pro-atherosclerotic effect of torcetrapib? Obviously more work needs to be done, to help us understand the complicated process of atherosclerosis. It was a costly lesson, Pfizer, but I take my hat off to you. You acted responsibly as a good medical corporate citizen.

Update: Pfizer's (NYSE:PFE) estimate of the cost of this failure is USD 800 Million (RM 3.2 Billion). That's only the cost of the drug. Additionally, on the back of this news, Pfizer takes a USD 21 Billion (That's 81 billion Ringgit) hit to its market value. On the back of this bad news Pfizer lost an amount which is higher than Malaysia's annual budget.