By Lisa Seachrist

Washington Editor

GAITHERSBURG, Md. - An FDA advisory panel refused to endorse the accelerated approval of Gilead Sciences Inc.'s novel reverse transcriptase inhibitor, Preveon (adefovir dipivoxil).

The Antiviral Drugs Advisory Committee voted 13 to 1 in recommending against approval of Preveon, a once-a-day pill, as a salvage therapy for patients who have failed other reverse transcriptase inhibitors. The drug's unimpressive efficacy profile in combination with a propensity for nephrotoxicity caused the panel to refuse its endorsement.

"I think this committee has done its darndest to get drugs out to patients because we recognize we aren't where we want to be yet," said panel chair Scott Hammer, chief of the Division of Infectious Disease at Columbia Presbyterian Medical Center in New York. "I wish the facts were clearer cut, but additional data is required."

Gilead filed a new drug application for Preveon in June 1999, after the FDA had granted the product a fast-track designation and guaranteed the drug a six-month accelerated review. Preveon is a nucleotide analogue that inhibits the reverse transcriptase (RT) enzyme of HIV.

The company presented two pivotal Phase III clinical trials supporting the approval of the drug as an option when patients have strains of HIV that are resistant to AZT or 3TC. The first, referred to as Study 408, tested a once-daily dose of 120 milligrams of Preveon against placebo in 442 patients with HIV who had extensive prior nucleoside reverse transcriptase inhibitor experience and were failing therapy. Patients who received Preveon had fewer copies of HIV RNA in their bloodstream and higher CD4 cell counts than patients who received the placebo.

However, the Preveon-treated patients also experienced significant nephrotoxicity - signaled by an increase in creatine levels and a decrease of phosphate levels in the blood. Gilead presented data indicating that with aggressive monitoring, reduction in dosing or elimination of the drug, the nephrotoxicity could be managed without significant permanent damage to kidneys.

In the hopes the nephrotoxicity could be ameliorated with a lower dose while still being efficacious, Gilead pitted a 60-milligram dose of the drug against the previously tested 120-milligram dose in Study 417. The drug was tested as part of a triple-drug combination in patients who had experience with nucleoside reverse transcriptase inhibitors but with no prior exposure to protease inhibitors.

The company tested the 60-milligram dose in 109 patients and the 120-milligram dose in 105 patients in a regimen that included either a nucleoside reverse transcriptase inhibitor and a protease inhibitor or two protease inhibitors. At 20 weeks, 41 percent of the patients in the 60-mg arm had their blood level of HIV RNA drop below the detectable level. Thirty-one percent of patients in the 120-milligram arm had their blood levels of HIV RNA drop below the detectable level. The company presented data indicating the lower dose results in less nephrotoxicity. As a result, Gilead suggested 60 milligrams be the dosage on the label.

The FDA, however, took issue with the conclusions of this study, highlighting the complexity of the study design and providing evidence from a federally sponsored study of the drug that there may be a drug interaction between Preveon and the protease inhibitor saquinavir. In addition, the study had a large number of dropouts and was relatively short term in duration.

"I think, in a disease that is now chronic, we have a new scenario," said panel member John Hamilton, professor of medicine at Duke University Medical Center in Durham, N.C. "This may be bad news for industry, but the short-term clinical trials aren't stepping up to the plate."

Part of the Gilead's strategy for managing nephrotoxicity would require patients to receive monthly monitoring in order to continue to receive prescriptions. Should patients develop unacceptable nephrotoxicity, the company recommended physicians back off the dosage of the drug to 30 milligrams or eliminate it altogether until the toxicity reverses.

Raising and lowering the dosages led some members of the committee and FDA to question whether resistance would develop.

"We've not seen anything to suggest resistance will develop," said Howard Jaffe, senior vice president for drug development at Gilead. "Of course, as a part of our Phase IV studies, we will be looking to see if that occurs."

"It seems to be a bit sanguine to say resistance isn't likely to develop," said panel member Judith Feinberg, associate professor of clinical medicine at the University of Cincinnati Medical Center. "I think I would like to see reasonable data in hand that these doses don't cause significant resistance."

The panel wanted to see more data showing the efficacy of the 60-milligram dose and more information on the plan to lower the dose when nephrotoxicity develops.

The company also is developing the drug as a treatment for hepatitis B. It currently is conducting a two-year study in this indication.

Trading on Gilead's stock (NASDAQ:GILD) was halted Monday during the committee meeting, which ended after the market closed. Last week the FDA approved Gilead's flu drug, Tamiflu.