Wednesday, November 21, 2007

Torcetrapib Torpedoed: When the hypothesis is immune to the data

I have watched the torcetrapib saga with interest for some time now. This drug is a powerful non-HMG-CoA-reductase inhibitor raiser of HDL (up to a 100% increase) and effects modest decreases in LDL also (20%) as reported with great fanfare in the NEJM in 2004:

Such was the enthusiasm for this drug that one editorialist in the same journal cried foul play in reference to Pfizer's intent to study the drug only with Lipitor, suggesting that such a move was intended to soften the blow to this blockbuster (read multibillion dollar) drug when it soon loses patent protection:
The tone is one of serious concern - as this drug was expected to truly be spectacular at BOTH raising HDL and preventing cardiovascular morbidity and mortality - an assumption based on the well-established use of cholesterol lowering as a surrogate endpoint in trials of cardiovascular medications.

(I'm sure the Avandia analogy is banging like a clapper in your skull right now.)

But a perspicacious consumer of the literature on torcetrapib would have noted that there were precious few and conflicting data about its efficacy as an antiatherogenic agent - preclinical data from animal studies were neither consistent nor overwhelming regarding its effects on the vasculature (in spite of the use of VERY high doses of the drug yielding high degrees of CETP inhibition) and studies of patients with CETP mutations also were inconsistent regarding its influence on the development of cardiovascular disease. Certainly, one would expect a drug with such remarkable HDL raising abilities to do something substantial and consistent to sensitive measures of atherogenesis in preclinical studies or to have some consistent and perhaps dramatic effect in patients with mutations leading to high HDL levels. (For a good review of pre-clinical studies, see: and
But alas, there was not consistent and robust evidence for anything but changes in surrogate markers. Of course this is all hindsight and it's easy for me to pontificate now that the horse was let out of the barn; first by Nissen et al:
and then today:
(In fact, I would say that the horse is galloping about the barnyard trammeling Lipitor's hopes of life after generic death.)

But what interests me now is not that the drug failed, and not that I have a new archetypal drug for failure of surrogate endpoints, but rather how difficult it is for the believers to let go. True believers die hard. How do the editors let a conclusion like this make it to print:

"In conclusion, our study neither validates nor invalidates the hypothesis that raising levels of HDL cholesterol by the inhibition of CETP may be cardioprotective. Thus, the possibility that the inhibition of CETP may be beneficial will remain hypothetical until it is put to the test in a trial with a CETP inhibitor that does not share the off-target pharmacologic effects of torcetrapib. "


Had the study been positive, would that have been the conclusion? No, the authors would have concluded that the hypothesis was validated.

So if the study is positive, the hypothesis is confirmed; but if it is negative (or shows harm), the hypothesis is immune to the data. The authors should not be allowed to have their cake and eat it too.

The above conclusion is tantamount to saying “our data do not bear on the hypothesis” which is tantamount to saying “our study was badly designed.”

Sure, another agent without that little BP problem may have more salutary effects on mortality, but I'd hate to be the guy trying to get that one through the IRB. Here we have a drug in a class that killed people in the last study. We'd better have more robust pre-clinical data the next time around. The other thing that fascinates me is the grasping for explanations. Here is a drug with ROBUST effects on HDL, and it causes an overall statistically significant increase in mortality. That's one helluva a hurdle for the next drug to jump even without the BP problem. Moreover, I refer the reader to the HOT trial:
A 5 mmHg lowering of BP over a 3.8 year period reduced mortality by a mere 0.9% (p=0.32 - not significant). That's a small increase and it's not statistically significant. But lowering LDL with simvastatin (the 4S trial: Lancet. 1994 Nov 19;344(8934):1383-9.) for 3.3 years on average led 1.7% ARR in mortality (RR 0.70 (95% CI 0.58-0.85, p = 0.0003). So it would appear that on average, you get more bang for your buck in lowering cholesterol than you do in lowering BP. With an agent that is such a potent raiser of HDL, we would certainly expect at worst a null effect if the BP effect militated against the HDL/LDL effect. I have not done a meta-analysis of trials of BP lowering or cholesterol lowering, but I would be interested in the comparison. For now, I'm substantially convinced that the BP argument is abjectly insufficient to explain the failure of this agent to improve meaningful outcomes.

So the search will go on for a molecular variation of this agent which doesn't increase BP, with the hopes that another blockbuster cholesterol agent will be discovered. But in all likelihood, this mechanism of altering cholesterol metabolism is fatally flawed and I wouldn't volunteer any of my patients for the next trial. I'd give them 80mg of generic simvastatin or atorvastatin.

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