February 18, 2005

Federal panel examining COX-2 drugs

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Alastair J.J. Wood, M.D.

Federal panel examining COX-2 drugs

The future of a “blockbuster” class of arthritis drugs may well depend on this week's deliberations of a blue-ribbon panel chaired by Alastair J.J. Wood, M.D., professor of Pharmacology and Medicine at Vanderbilt University Medical Center.

The three-day joint hearing of two Food and Drug Administration advisory committees was to conclude today in Gaithersburg, Md. At press time, it was unclear what recommendations the panel would make regarding COX-2 inhibitors, a class of drugs that includes Celebrex and Bextra.

A third drug, Vioxx, was voluntarily withdrawn from the market in September 2004, after a study sponsored by the manufacturer, Merck & Co., indicated that long-term use of the drug doubled the risk of heart attacks and strokes.

Since then several studies, four of which were released this week, have found that use of COX-2 inhibitors, including Celebrex and Bextra, significantly increases the risk of heart problems and strokes.

Last month, Kaiser Permanente, the nation's largest not-for-profit managed-care provider, told its doctors to stop prescribing Bextra, and last week Australia's version of the FDA required boxed warning labels to alert patients about the cardiovascular risk associated with the drugs.

Wood, a former candidate for FDA commissioner who also is associate dean for External Affairs at Vanderbilt University School of Medicine, said during Wednesday's hearing that the panel's primary responsibility was to assess — and weigh — the risks and benefits associated with the use of COX-2 inhibitors.

Among the questions the FDA has asked the panel to answer are these:

Do the risk-benefit ratios for Celebrex, Bextra — and Vioxx, as well — support marketing the drugs? If so, in which patient populations do the benefits outweigh the risks, and what actions should the FDA take to ensure safe use of the drugs?

During Wednesday's hearing, Garret A. FitzGerald, M.D., a well-known expert on COX-2 inhibitors at the University of Pennsylvania, described evidence that the drugs may have a “class effect” on the heart.

They inhibit the cyclooxygenase-2 enzyme, which is associated with pain and inflammation, while sparing the COX-1 enzyme, which protects stomach lining.

The drugs were developed to reduce the risk of gastrointestinal bleeding associated with drugs like aspirin and ibuprofen, which block both COX enzymes.

However, COX-2 also is the main source of a chemical that protects the heart, whereas COX-1 produces another chemical that in mice can accelerate atherosclerosis. Selectively blocking COX-2 while leaving COX-1 unopposed thus may increase the risk of heart problems, said FitzGerald, a former Vanderbilt faculty member.

That doesn't mean the risks can't be managed. The “challenge to the future of these drugs” is to move toward personalized medicine, where patients at risk for side effects are identified early, he said.

“Indeed, the terrible beauty of this unfolding drama is how faithfully emerging clinical information has fitted the predictable science,” FitzGerald said. “And that should reassure us in terms of the likelihood that the science can predict a way to conserve the value of these drugs while managing the risk.”