An experimental heart drug abandoned by Pfizer because of safety problems failed to reduce the plaque that clogs arteries even though it raised so-called good cholesterol, new studies released yesterday show.
The studies cast additional doubt on the effectiveness of an approach to fighting heart disease that was once perceived to hold great promise and is still pursued by other pharmaceutical companies.
Researchers said it was too soon to discount the approach entirely.
“We may yet be able to salvage the class, but we face an extremely difficult uphill battle,” Dr. Steven E. Nissen of the Cleveland Clinic, senior author of a new study, said in an interview.
Dr. Nissen’s study and two others, all of which used ultrasound to measure clogging in arteries, were presented yesterday at the American College of Cardiology meeting in New Orleans. Two of the studies were also published online by The New England Journal of Medicine.
The Pfizer drug, torcetrapib, was hailed by the company and many outside experts as the forerunner of a new class of drugs that would prevent heart attacks by significantly raising the levels of high-density lipoprotein cholesterol, or HDL, often called good cholesterol.
Existing drugs known as statins, like Lipitor, also made by Pfizer, work by reducing low-density lipoprotein, or LDL, also called bad cholesterol.
In December, Pfizer abruptly abandoned torcetrapib after learning that it increased the risk of death in a late-stage clinical trial involving 15,000 patients.
Since then, a huge question has swirled through the scientific and pharmaceutical communities. Are the torcetrapib problems specific to the drug, which raised blood pressure significantly, or do they mean the entire approach used by the drug was flawed?
If that is the case, it is also likely to doom similar drugs under development by Merck, Roche and Pfizer itself.
The new studies will not answer the question definitively. That will require more analysis, including of Pfizer’s failed trial.
The three new imaging studies, all of which had been completed before Pfizer dropped work on torcetrapib, showed that the drug did indeed raise good cholesterol sharply, by up to 61 percent in one study. The drug also lowered bad cholesterol below the level achieved by Lipitor alone.
Despite that, the studies showed virtually no difference in the amount of plaque in the arteries of patients who had taken torcetrapib and those who had not.
“Something very strange is actually going on with this drug where none of these fantastic changes translate into any benefit for the arterial wall,” Dr. John J. P. Kastelein of the University of Amsterdam said at a news conference at the medical meeting.
Dr. Kastelein was the lead investigator in two studies that looked at the effect of torcetrapib on the walls of the carotid artery in the neck. The third study, led by Dr. Nissen, looked at arteries in the heart.
Torcetrapib inhibits a protein called cholesteryl ester transfer protein that has a role in removing cholesterol from the bloodstream.
One hypothesis is that this approach is flawed, in essence, because it increases HDL quantity but not quality. In other words, the HDL particles it produces are not good at the job HDL is supposed to perform, removing cholesterol from the arterial walls and carrying it to the liver for disposal.
Dr. Alan R. Tall, a professor of medicine at Columbia University, said in an interview that the new studies, by showing that torcetrapib did not worsen atherosclerosis, provided “a glimmer of hope” that the problems were not a class effect.
Dr. Tall wrote an editorial about the studies in The New England Journal of Medicine and is a consultant to Pfizer and other drug companies.
There is yet a third possibility, that raising HDL by any means might not be beneficial. But most scientists discount that, saying there is too much evidence from other studies supporting increasing HDL.
Some possible new evidence came from another study reported at the cardiology meeting yesterday and published online by The Journal of the American Medical Association. In that study, HDL derived in part from donated human blood plasma was given to patients by infusion.
After four infusions, the volume of plaque was significantly reduced compared with the volume before the treatments. The difference in reduction between treated patients and those given placebos was not statistically significant, however, though some researchers said that could have been because the 180-participant trial was too small.
Dr. Jean-Claude Tardif of the Montreal Heart Institute, the lead investigator, said that the results were “yet another piece of evidence that shows that the HDL world is not dead because of torcetrapib.”
Dr. Tardif is a consultant to Pfizer, and one of his co-authors is an employee of CSL Ltd., which sponsored the study.
Dr. Antonio M. Gotto Jr., dean of the Weill Cornell Medical College, said the studies, with which he was not involved, suggested that “it matters how you raise HDL.”
