Cholesterol Drug's Failure Is a Blow to Researchers

By Rob Stein
Washington Post Staff Writer
Monday, December 4, 2006

The discovery that an experimental cholesterol drug is dangerous is a major setback for what has been considered one of the most promising new approaches to fighting the nation's leading killer, experts said yesterday.

Pfizer Inc. abruptly announced late Saturday that it was terminating all work on the drug torcetrapib after an outside panel determined that patients taking the compound in a large international experiment appeared to have an increased risk of dying.

The decision was a major blow for the world's biggest drug company, which had already been struggling. The company had invested at least $800 million in the drug, which was expected to be a blockbuster if approved, as hoped, as early as next year.

But perhaps of greater importance, the development was a disappointment for what many experts consider one of the most important avenues of medical research -- lowering the risk for heart attacks and strokes by boosting levels of high-density lipoprotein, so-called good cholesterol.

"It's a major blow -- a huge setback for the field," said Steven Nissen, the president of the American College of Cardiology. "Everyone agreed this was an extremely promising approach. This sets back the field by years."

While experts stressed that the overall concept remains promising, the news raises disturbing questions about the most advanced approach to boosting HDL, and will require researchers at Pfizer and elsewhere to take a much closer look at similar compounds being developed to determine whether they carry similar risks.

"We'll certainly have to approach all these programs with more caution now as this plays out," said Robert Meyer, a drug safety expert at the Food and Drug Administration.

Heart disease is the nation's leading cause of death. The number of Americans suffering heart attacks and strokes has been dropping, in part because of the development of cholesterol-lowering drugs known as statins, which have become one of the most widely used and effective tools in medicine. Those drugs work by lowering levels of low-density lipoprotein, or LDL, which is known as the "bad" cholesterol because it accumulates inside arteries. But many patients remain at risk even when their LDL has been brought to a level considered safe.

Many researchers have hoped that the next major advance in fighting heart disease would come from a new generation of drugs that boost levels of HDL, which gets the "good" distinction because it clears cholesterol from the blood.

Although a number of compounds designed to boost HDL levels are being studied, torcetrapib was by far the furthest along in development. After initial studies showed the drug was highly effective at raising HDL levels, Pfizer launched a study involving more than 15,000 patients at high risk for heart attack and stroke. Half took torcetrapib along with the statin Lipitor; the other half took Lipitor alone.

"I'm 50 steps from the cardiac care unit, which is filled with patients with advanced heart disease. We've done everything we can for them, but they are still suffering. We want to be able to do something for them. This looked like it might make it," said Nissen, who was conducting another study of the drug for Pfizer.

But an independent panel of experts that was meeting regularly to monitor the trial discovered on Friday that 82 patients getting torcetrapib had died, compared with 51 who had been taking Lipitor alone, prompting the sudden announcement.

The company said it would scour the data it had collected about the drug to try to determine what had caused the excess risk. Earlier research had indicated that the drug increased blood pressure slightly, but it remained unclear whether that was the problem.

"We now know that the drug did not work, but we do not have a clear answer about why the drug did not work until we see more of the data," said Christie Ballantyne of the Baylor College of Medicine.

Torcetrapib works by inhibiting an enzyme called cholesterol ester transfer protein. Because other compounds under development work the same way, a key question will be whether that approach is the problem.

"There's always been a lot of concerns about whether this is the right way to raise HDL," Ballantyne said. "This is clearly the end of this drug. The question is, is this the end of this class of drugs?"

Because some drugs that inhibit the enzyme do not raise blood pressure, it could turn out that those drugs are still safe, Ballantyne and other experts said.

"There's a lot of scrambling that's going to be to going on to figure out if this is a fundamentally flawed compound, or whether this approach is flawed," said Daniel Rader of the University of Pennsylvania.

Even if the approach is flawed, researchers will certainly not abandon the goal of raising HDL, he said.

"I think it is terribly important to emphasize that this development says nothing about the overall strategy," said Rader, noting that many other strategies for raising HDL by different mechanisms are being actively explored.

"Improving HDL function could be more important than actually raising its levels, and strategies for this approach are also being developed," Rader said.

Researchers are also studying variations of the drug niacin, which can boost HDL levels but has not been considered practical because of side effects.

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