Torcetrapib Torpedoed: Increased Risk of Mortality, Cardiovascular Events Ends Development

Michael O'Riordan

December 04, 2006

December 4, 2004 (New York, NY) – Dramatic new data from a major morbidity and mortality trial have ended all hopes for Pfizer's torcetrapib, a novel cholesteryl-ester-transfer-protein (CETP) inhibitor. Early data have shown an increased risk of mortality and cardiovascular events with the experimental high-density lipoprotein (HDL) cholesterol–raising drug, and as a result, Pfizer has halted its entire torcetrapib development program.

The news, announced Saturday night, is a tremendous blow to the company, as well as a disappointment to clinicians who hoped the HDL cholesterol–raising drug might be used with low-density lipoprotein cholesterol–lowering agents for a one-two punch in the fight against cardiovascular disease. Pfizer was so optimistic about torcetrapib that just last week it said it would seek early Food and Drug Administration approval based on the results of intravascular ultrasound (IVUS) and carotid intima-media thickness studies to be presented in early 2007.

Dr Steven Nissen (Cleveland Clinic, OH), the lead investigator of the ILLUSTRATE study, a multicenter, randomized, 1200-person IVUS study comparing torcetrapib/atorvastatin (Lipitor, Pfizer) combination therapy with atorvastatin alone in coronary heart disease patients, said the announcement was unexpected and that he is disappointed.

"I am surprised, but there was always the possibility that the drug might not work," Nissen told heartwire . "I didn't think it would be harmful, and I didn't think we would know before the end of the trial. To know this early in a major morbidity and mortality trial is pretty surprising."

The demise of torcetrapib is the result of increased mortality and cardiovascular events in the ILLUMINATE study, a randomized, double-blind evaluation of the effect of torcetrapib/atorvastatin vs atorvastatin alone on the occurrence of major cardiovascular events in 15 000 subjects with coronary heart disease or risk equivalents. The data safety monitoring board (DSMB) recommended the trial be halted due to an "imbalance of mortality and cardiovascular events." Overall, 82 patients taking the combination of torcetrapib and atorvastatin died, compared with 51 patient deaths in the atorvastatin-alone arm.

More patients died taking torcetrapib

Torcetrapib had come under scrutiny in recent months when it was shown that it increased systolic blood pressure. Early reports showed that the drug increased blood pressure by 2 to 3 mm Hg, but more recent data from the phase 3 clinical trial showed the increase to be 3 to 4 mm Hg. At the time, as reported by heartwire , some experts believed the increase in blood pressure could be managed, while others noted that such an increase would translate, populationwise, into a 20% higher stroke mortality and a 12% higher mortality from ischemic heart disease.

"We knew that torcetrapib increased blood pressure, so at least one possible explanation is that the increase in mortality is all blood-pressure related, and that it's not the mechanism of HDL raising," said Nissen. "However, I also think there is a distinct possibility that the type of HDL that is produced when you inhibit CETP is actually proatherogenic rather than antiatherosclerotic."

Nissen said there is a difference between the HDL cholesterol produced with inhibition of CETP and apoA-1 Milano, an HDL mimetic that was shown to confer heightened protection against cardiovascular disease (CVD) in a 2003 study. Whereas apoA-1 is capable of unloading cholesterol from the vessel wall, carting it back to the liver, the HDL produced with CETP inhibition is mature, cholesterol-laden HDL, said Nissen, and may be dysfunctional.

Dr Monty Krieger (Massachusetts Institute of Technology, Cambridge) also expressed disappointment with the increased mortality and cardiovascular risk with torcetrapib, adding that it is important to learn the mechanistic reasons behind the increased risk of events.

"It will be important to determine whether or not the reported excess mortality was a direct consequence of the inhibition of CETP," Krieger told heartwire . "I hope this disappointment does not quench government, academic, and industrial enthusiasm for continuing efforts to learn more about HDL metabolism and physiology and for identification and development of new and powerful approaches to target HDL metabolism for the prevention and treatment of cardiovascular disease."

Nissen told heartwire that researchers and clinicians are not ready to abandon the concept of raising HDL cholesterol. He added that the ILLUSTRATE study has completed follow-up, although the data are still blinded, and will be presented at the American College of Cardiology 2007 Scientific Sessions in New Orleans. In addition, he stressed that Pfizer deserves credit for the way it handled the negative findings from one of its most important drugs in development.

"Pfizer invested a billion dollars on an unproven mechanism in an effort to bring this forward," said Nissen. "There was no guarantee that is was going to work, and it didn't work out, but making these kinds of investments on the part of the pharmaceutical company is what brings these new drugs to market. When the trial went the wrong way, they acted decisively, they stopped the trial and publicly announced it without any effort to conceal what they had learned. They handled it exactly as it should be handled."

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.