Gilead Sciences Inc., seeking its second significant product approval in a year, is going before an FDA advisory panel today that is expected to issue a recommendation on Gilead's new drug application for adefovir dipivoxil, a once-daily oral treatment for hepatitis B.
While FDA staff failed to provide a clear recommendation for the Antiviral Drugs Advisory Committee in its 31-page briefing document released Monday, an analyst with Merrill Lynch Global Securities Research in New York said the document appears positive for Foster City, Calif.-based Gilead.
"There's always been a question with respect to kidney toxicity associated with this drug," Eric Ende, senior biotech analyst and first vice president with Merrill Lynch, told BioWorld Today. "In normal patients it looks very tolerable with respect to kidney toxicity. For patients who have baseline kidney insufficiency or decompensated liver disease there appears to be some potential modest increase in kidney toxicity, but the efficacy of this product appears to outweigh those risks."
Indeed, the FDA reviewers said, based on data from Gilead's two Phase III studies - which enrolled patients with compensated liver disease with adequate renal function - it appears that the clinical benefit of adefovir 10 mg is substantial and the nephrotoxicity risk is low, but perhaps not zero.
According to the document, the panel has been asked to comment on the safety of adefovir in chronic HBV patients with decompensated liver disease and/or pre-existing renal impairment.
Representatives of Gilead declined to comment on the briefing document, saying they will be available following the panel vote. Gilead gained approval for Viread for HIV in October 2001. Among its other products are Tamiflu for influenza, first approved in 1999, and AmBisome (amphotericin B) liposome for fungal infections. Second-quarter sales of AmBisome were $47.7 million and Viread sales in the quarter were $44.7 million, the two products accounting for the bulk of Gilead revenues.
Adefovir dipivoxil, which has not been assigned a trade name, is a nucleotide analogue that works by blocking the hepatitis B virus DNA polymerase, an enzyme responsible for replicating the virus. In March, Gilead filed a six-month priority review application for adefovir dipivoxil in chronically ill HBV patients who are treatment-na ve or -experienced. (See BioWorld Today, March 25, 2002.)
Since medication choices are limited in this illness, adefovir dipivoxil is expected to perform fairly well in the market. Ende, who expects approval in September, estimates sales this year of $1.9 million. By 2003, sales are estimated at $27 million (including $15 million in the U.S.), and once approval is gained in Asia, Ende said the totals should reach $111 million.
Gilead has not named a U.S. or European partner. However, in April, London-based GlaxoSmithKline plc (GSK) agreed to pay upward of $40 million for the Asian and Latin American rights to the drug. (See BioWorld Today, April 30, 2002.)
GSK sells another HBV product called lamivudine (3TC). The company intends to develop adefovir dipivoxil for patients in China, Korea, Japan and Taiwan who are treatment-na ve as well as for those who have developed resistance to lamivudine.
Intron A (interferon alpha), another HBV product, is sold by Madison, N.J.-based Schering-Plough Corp. Gilead said Intron A commonly has difficult-to-tolerate toxicities and works in a low number of patients.
Gilead's new drug application is supported by data from Phase III studies in hepatitis B "e" antigen-positive patients, hepatitis B "e" antigen-negative patients and chronic hepatitis B patients with lamivudine-resistant HBV.
Data from a 515-patient trial (Study 437) indicated that adefovir dipivoxil in na ve, chronic HBV patients showed no resistance mutations. The trial met its endpoints of liver histology improvement and showed no kidney toxicity. Also, seroconversion was observed in 12 percent of patients treated with 10 mg for 48 weeks compared to 6 percent of patients on placebo. (See BioWorld Today, June 25, 2001.)
That two-year, randomized, double-blind, placebo-controlled study evaluated adefovir dipivoxil given once daily compared to placebo. The company evaluated two doses: a 10-mg dose, for which the company will seek approval, and an exploratory 30 mg dose for the first 48 weeks.
At one time, Gilead was studying adefovir dipivoxil for HIV but abandoned the plan after an FDA advisory panel voted against recommending the product for that indication. (See BioWorld Today, Nov. 3, 1999.)
In its briefing document Monday, the agency staff attributed the HIV failure to "the drug's unacceptable nephrotoxicity profile and overall unfavorable risk-benefit profile at the studied doses. A significant proportion of HIV-infected patients who took adefovir at 60 mg daily or 120 mg daily doses experienced serum creatinine increases and hypophosphatemia."
However, Study 437 looked at lower doses for HBV. "It became apparent during this study that the adefovir 30 mg daily dose was associated with an increased risk of nephrotoxicity compared with the adefovir 10 mg daily doses," the FDA said.
The second HBV trial (Study 438) evaluated 185 patients and determined that treatment with a 10-mg once-daily dose for 48 weeks was associated with improvements in liver histology in 64 percent of patients who received the drug compared to 33 percent of patients who received placebo (p=0.0002), according to the company. (See BioWorld Today, Sept. 20, 2001.)
Gilead said there are about 400 million chronic carriers of HBV, of which about 1 million die each year. In the U.S., the disease kills between 4,000 and 5,000 annually among the 1.25 million infected. Complications can include cirrhosis, liver failure and primary liver cancer.
Gilead's stock (NASDAQ:GILD) closed Monday at $30.86, up $1.95.