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ORLANDO, Nov. 5 -- The star-crossed investigational HDL-boosting drug, torcetrapib, may have had a target that was fatally off center.

Yet the HDL produced by inhibiting the cholesteryl ester transfer protein (CETP) with investigational torcetrapib is apparently neither dysfunctional nor pro-atherogenic, investigators reported during the American Heart Association meeting here today.

So it was strongly suggested by a web spun from a series of studies, all of which pointed to off-target toxicity as a likely explanation for the excess mortality that shut down development of the once promising drug. These studies generated renewed enthusiasm, albeit cautious, for HDL-boosting agents.

Analysis of data from the 15,000-patient phase III trial called ILLUMINATE confirmed that compared with atorvastatin (Lipitor) the drug was associated with a 25% increase in cardiovascular events (P=0.001) and a 58% increase in cardiovascular mortality (P=0.006), said Philip J. Barter, M.D., Ph.D., of the Heart Research Institute in Sydney, Australia.

The results of the ILLUMINATE findings were simultaneously published online by the New England Journal of Medicine.

But a post-hoc analysis of those data revealed that the HDL produced by torcetrapib appeared to act in the same way as naturally occurring HDL in reducing cardiac events. Patients in the highest quintile of HDL, more than 93 mg/dL, had a 57% reduction in risk of cardiovascular events.

"This lower event rate with higher HDL is inconsistent with a dysfunctional HDL and suggests that if off-target pharmacology could have been avoided, the results with torcetrapib could have been very different," said Dr. Barter. "It leaves the way open for further exploration [of inhibition of CETP], but it neither validates nor invalidates the hypothesis that inhibiting CETP is bad."

The ILLUMINATE trial recruited 15,067 high-risk cardiovascular patients and randomized them to atorvastatin plus torcetrapib or atorvastatin plus placebo. The trial was stopped after 12 months, but during that time patients in the torcetrapib arm increased HDL by an average of 72% and reduced LDL by 25% (P

When the trial was summarily halted, researchers said they had observed a slight increase in blood pressure among patients taking torcetrapib. Originally the increase was believed to be only 2 to 3 mm Hg, but as the data were analyzed it became apparent that the increase was sometimes as great as 10 mm Hg. This observation prompted Dr. Barter and other researchers to look more carefully at mechanisms affecting blood pressure.

As they drilled into the data, they found an electrolyte imbalance -- potassium was decreased, but sodium and aldosterone were increased. The changes, Dr. Barter said, were small, but changes in sodium, potassium, and aldosterone add up to activation of the renin-angiotensin-aldosterone system, one of the major drivers of hypertension.

Dr. Barter and colleagues contacted investigators with ILLUSTRATE, an IVUS study of torcetrapib, and RADIANT, an imaging study of the drug, to find out whether there were similar electrolyte changes in patients enrolled in the trials. The answer was yes.

Stephen J. Nicholls, M.B.B.S., Ph.D., of the Cleveland Clinic, said that when he and his colleagues re-analyzed data from the 910 patients enrolled in ILLUSTRATE, they identified the same off-target toxicity. Moreover, when they cross-referenced the decreased potassium and HDL increases, they found that "in patients with the greatest decreases in potassium, the beneficial effect of HDL was no longer apparent," Dr. Nicholls said.

Moreover, although the original IVUS findings suggested that torcetrapib was not associated with a regression of atherosclerosis, "there was an inverse relationship between change in HDL-C and both percent atheroma volume and total atheroma volume (P

Steven E. Nissen, M.D., director of cardiovascular medicine at the Cleveland Clinic, said that taken together the findings suggest that the CETP inhibition should not be abandoned as a strategy for increasing HDL. He said the findings might provide impetus for pharmaceutical companies to move ahead with other CETP inhibitors that have been stalled in the development pipeline since Pfizer shut down the torcetrapib development program.

But Michael DePasquale, M.D., senior principal scientist at Pfizer, said it is unlikely that aldosterone activation of the renin-angiotensin-aldosterone system was the cause of the presser effect seen with torcetrapib.

He and his colleagues tested torcetrapib and a look-alike compound that was also developed by Pfizer in rabbits and discovered an immediate spike in blood pressure. This increase was too fast to be explained by aldosterone.

Nonetheless, Sidney Smith, M.D., of the University of North Carolina in Chapel Hill, a spokesperson for the AHA, was also enthusiastic about the possibility that CETP inhibition might finally pay off. After scanning the abstracts from Drs. DePasquale and Nicholls, as well as the ILLUMINATE report in NEJM, he said "so it may not be a class effect, it may be like the calcium channel blocker story all over again."

Calcium channel blockers are just one example of "a bad drug" in an otherwise useful class. Short-acting nifedipine was linked to increased risk of myocardial infarction.

A similar example occurred with cerivastatin (Baycol), which was withdrawn from the market after it was linked to an increased risk of fatal rhabdomyolysis, while statins as a class remain among the most commonly prescribed medications.

But the off-target toxicity was not the only thing revealed in the ILLUMINATE data. There were also more cancer deaths and more deaths from infection among the 7,533 patients randomized to torcetrapib versus the 7,534 randomized to atorvastatin. There were 24 cancer deaths in the torcetrapib arm versus 14 in atrovastatin and there were nine sepsis deaths in the atorvastatin arm versus none in the control group, Dr. Barter said.

He said he had no explanation for the difference in cancer deaths, but added that there was no difference in the total number of neoplasms diagnosed in atorvastatin patients versus torcetrapib. Moreover, there was no discernable pattern in the types of cancer diagnosed.

He said there has been some suggestion that torcetrapib affects release of cortisol, which "may have an effect on the immune system," Dr. Barter said, but he added that was "pure speculation."

In an NEJM editorial published with ILLUMINATE, Daniel J. Rader, M.D., of the University of Pennsylvania, agreed the trial results were "illuminating," but did not shed enough light to rekindle enthusiasm for HDL-targeted therapies. The study was, he wrote, "a watershed event" that may ultimately be "seen as the study that brought about rejection of the 'HDL hypothesis.' At a minimum, it will be have been responsible for shifting the focus from HDL concentration to HDL function and raising the bar for approval of new HDL-targeted therapies."

ILLUMINATE, ILLUSTRATE, and Dr. DePasquale's study were all funded by Pfizer, which developed torcetrapib. Dr. DePasquale is a Pfizer employee. Dr. Rader said he received funding from Pfizer, Roche, and Merck. Dr. Barter receives support from Abbott, Astra-Zeneca, CSL, GenFit, LifeCycle Pharma, Merck, Pfizer, Sanofi-Aventis, and Resverlogix. Dr. Nicholls and Dr. Nissen reported no disclosures.

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