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Fallout from failure of drug

The Baltimore Sun

A decision by Pfizer Inc. to halt tests of an experimental cholesterol drug because of increased death rates was a setback likely to provoke closer scrutiny - but not an end to efforts to bring similar medications to market.

Pfizer announced plans Saturday to end a large clinical trial of the drug torcetrapib after independent researchers monitoring the tests told company officials of the problem.

Torcetrapib was designed to raise levels of HDL, commonly called "good cholesterol." It was supposed to complement statins now on the market that lower LDL or "bad" cholesterol.

Pfizer began testing the drug on small numbers of volunteers in 1999 and more recently launched a clinical trial involving 15,000 patients at hospitals around the country. They included nearly 600 subjects at two Baltimore-area medical centers, the St. Joseph Medical Center and the University of Maryland Medical Center.

But in the second year of the five-year study, Pfizer found that 82 patients who took torcetrapib with the statin Lipitor had died, compared with 51 who had been taking Lipitor alone.

"We're frantically calling all the patients to let them know they should stop taking the medication," said Dr. Michael Miller, director of preventive cardiology at the UM Medical Center and a principal investigator.

At St. Joseph's yesterday, nurses were busy notifying hundreds of patients to stop taking the experimental drug. In all, the hospital assigned 550 volunteers to take either a combination pill or Lipitor.

"If they're not already calling us, we're calling them," said Dr. Stephen Pollock, head of cardiology there. Though disappointed in the study's outcome, Pollock said, "the system worked" because Pfizer acted swiftly when problems emerged.

Increasing scrutiny of cholesterol drugs is now more likely, FDA officials say. "We and the sponsors of these trials need to approach their development with a bit more caution," said Dr. Robert Meyer, who oversees cholesterol medications for the FDA's office of drug evaluation.

"It could be an issue that's peculiar or idiosyncratic to this particular drug, or it could be something that affects this whole class of drugs," Meyer said.

Heart disease remains the leading killer in the United States, accounting for more than 900,000 deaths in 2003, according to the American Heart Association.

But the introduction of statins in the 1980s ushered in a period of steadily declining heart-related deaths. Statins lower bloodstream concentrations of bad cholesterol that causes dangerous plaques inside the arteries.

With its experimental drug, Pfizer hoped to offer a second weapon, one that raised levels of good cholesterol that protect the heart by inhibiting production of cholesterol.

The medication was one of a new class of drugs: CETP inhibitors. The company had invested at least $800 million in the drug, according to news reports.

Pfizer was hoping for a financial bonanza to offset the loss of profits when its industry-leading statin, Lipitor, loses its patent protection by the end of the decade.

The signs looked good, said Dr. Roger Blumenthal, who heads the preventive cardiology program at the Johns Hopkins School of Medicine. The school was not part of the study.

While it raised good cholesterol, the drug also repaired lesions in the walls of blood vessels. Such capabilities had raised hopes about torcetrapib's promise of combating cardiovascular disease.

But it also raised blood pressure in some patients, which experts said might have led to the excess deaths. "It's a setback for all of us," Miller said.

Experts say there's no way of knowing if the CETP inhibitors being developed by other pharmaceutical firms will pose similar risks.

"It's too early to tell," said Dr. David A. Meyerson, a cardiologist at Johns Hopkins Bayview Medical Center and a spokesman for the American heart Association. "Small changes in the molecular structure of a compound can affect its safety and its efficacy."

Several pharmaceutical firms are hoping for FDA approval of other CETP inhibitors. Pfizer has two other candidates, and Roche is in an early-phase clinical trial of a drug that has shown none of the problems with elevated blood pressure, said Al Wasilewski, a Roche spokesman.

He said the company is continuing to work toward FDA approval.

"We're in Phase II development, we're moving forward and we're looking at filing [for FDA approval] sometime after 2009," he said.

But the higher death rate will mean closer scrutiny for any of the new class of drugs seeking federal approval. "It's going to have enormous implications on how the FDA is going to look at new drugs," Blumenthal said.

For one thing, he said, the agency will probably place less faith in studies showing improvements in "surrogate markers," laboratory evidence, such as a rise in good cholesterol or a lessening of plaques, that might translate into clinical improvement.

Pfizer was hoping for FDA approval of its drug next year after what it hoped would be positive results on ultrasound tests measuring plaques in the vessels of people taking the drug.

But Blumenthal said the FDA is likely to insist on evidence that patients taking a drug are living longer and not experiencing serious side effects.

"It goes to show that just because you improve the numbers doesn't necessarily mean that you're going to lower heart attacks and strokes," he said.

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