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New HIV Drug Rejected by FDA Advisory Panel

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Nov. 1, 1999 (Gaithersburg, Md.) -- An FDA Advisory Committee failed to recommend a new drug, ADV (adefovir dipivoxil), for treatment of HIV. Some were hoping the drug would be an important addition to the list of already available anti-HIV drugs. "Physicians and patients are scrambling," says Christopher Mathews, MD, committee consultant. Thousands of patients have already received ADV under a special experimental "expanded access" program.

A string of physicians and HIV patients, speaking on the drug's behalf, emphasized that the drug would be an important option for patients who fail with other therapies. Many of these patients and physicians were paid by the drug's manufacturer, Gilead Sciences, to attend the committee meeting.

In a lopsided 13-1 vote, the FDA's Antiviral Drugs Advisory Committee today moved not to recommend approval of ADV, which is a reverse transcriptase inhibitor similar to AZT (zidovudine). The company had sought to market the drug for patients who had failed other treatments for HIV.

Although the drug has shown promise, the firm had limited data for its proposed dosage. Moreover, the agent has shown troublesome kidney toxicity.

In one trial of more than 400 patients, ADV demonstrated a significant reduction in the HIV virus that lasted through 48 weeks of treatment. But the trial showed no effect on CD-4 cell count, a marker of severity of the disease, and several other trials failed to demonstrate positive results -- or lacked sufficient power for FDA to evaluate.

According to panel member, Wafaa Ed-Sadr, MD, "I don't think we're there yet."

Although the ADV studies that the company initially conducted focused on a 120 mg daily dose, liver toxicity concerns prompted Gilead to halve the proposed dose. One trial then compared the 60 mg and 120 mg doses, which were administered to patients as part of varying combination therapy. Results suggested similar outcomes, but the study lacked long-term measures of the lower doses' effectiveness and safety.

Members of the committee said they were concerned that the other medications that patients took in that trial were actually responsible for the observed effectiveness.

Committee chair Scott Hammer, MD, tells WebMD, "The committee would like to see clear-cut efficacy data at the 60mg dose." He says, "the issue of safety is paramount in the committee's mind but in my own opinion, that would not be the issue that would stop the committee from recommending approval."

The researchers did indeed see some liver abnormalities in patients taking ADV. Toxicity usually only developed after 24 weeks of therapy, and the firm said that liver toxicity went away for more than 95% of patients after the drug was discontinued. Gilead also said it was committed to a "risk management" program for the drug, which would require monthly liver tests and offer doctors preprinted prescription pads to help limit refills to those who take the tests.

Committee member Judith Feinbein, MD, and others said that monthly monitoring would be "inadequate" in some cases, and that further clinical trials were necessary to establish a safer dosage. She recommended that a 30 mg dose be evaluated.

However, the Treatment Action Group, an AIDS group, recommended against approval of the drug, citing equivocal efficacy and toxicity concerns. "The overwhelming preponderance of studies of the drug's activity have been disappointing, and the rate of serious [kidney] toxicity in patients treated with [ACV] is high," the group declared in the statement.

The FDA often follows the recommendations of its advisory committees but is not bound by their actions.

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