Washington Editor

BETHESDA, Md. - An FDA panel of experts unanimously recommended approval of Gilead Sciences Inc.'s once-daily tablet, adefovir dipivoxil, for chronic hepatitis B.

Approval would mean patients who have few treatment options would gain access to a drug that has produced good safety and efficacy data in clinical trials, according to information presented by Gilead and FDA officials at Tuesday's committee hearing.

The positive vote, cast by the Antiviral Drugs Advisory Committee, will be forwarded to the FDA, which makes the final decision and is not bound by the recommendation.

"It's very exciting for us, the patients and physicians, and it was gratifying to hear some panel members call the drug a lifesaver,'" said Mark Perry, executive vice president of operations at Gilead.

Perry said Gilead expects to hear back from the FDA by Sept. 21, and if all goes well it would launch the product in October. Gilead then would hope for European Union approval in 2003.

Adefovir dipivoxil has not been assigned a trade name.

"The drugs we have today for hepatitis B are less than optimal, and there could be problems with long-term use of adefovir," said Kenneth Sherman, a panel consultant and director, hepatology and liver transplant medicine section, at the University of Cincinnati College of Medicine. "But restricting a drug like this to a secondary use would not be my choice. I would say this drug belongs in primary use."

Panel members agreed that the drug appears safe at the 10-mg dose for 48 weeks, the length of the pivotal trials, in patients who started with normal renal function. However, they questioned the impact of long-term use on nephrotoxicity, saying the company had not submitted that type of data.

Referencing the length of the trials and the point that chronically affected patients likely will take the drug for an extended period, Sharilyn Stanley, panel member and associate commissioner in the disease control and prevention department of the Texas Department of Health in Austin, said she would like to see data related to resistance. "We know resistance will occur," she said.

Perry said Gilead is following 150 to 200 patients for five years to collect resistance data.

The drug is a nucleotide analogue that works by blocking the hepatitis B virus DNA polymerase, an enzyme responsible for replicating the virus. Gilead filed a six-month priority review application for CHB patients who are treatment-na ve or -experienced in March. (See BioWorld Today, March 25, 2002.)

Eric Ende, senior biotech analyst and first vice president with Merrill Lynch Global Securities Research in New York, expects approval in September. If the drug is launched late this year in the U.S., he estimated sales would reach $1.9 million. With European approval sometime next year, sales could top $27 million and by the time it is approved in Asia a year later, he expected sales to hit $111 million annually.

GlaxoSmithKline plc, of London, paid Gilead upward of $40 million for Asian and Latin American rights to adefovir dipivoxil. (See BioWorld Today, April 30, 2002.)

Other products on the market for hepatitis B are lamivudine (3TC), also sold by GlaxoSmithKline, and Interon A (interferon alpha), sold by Madison, N.J.-based Schering-Plough Corp.

For Gilead, adefovir dipivoxil joins its currently marketed products that include the once-daily HIV drug, Viread, which won FDA clearance in October. Others are AmBisome, for systemic fungal infections; Tamiflu, for influenza; DaunoXome, for HIV-associated Kaposi's sarcoma; and Vistide, for AIDS-related cytomegalovirus.

In its presentation Tuesday, Gilead said patients treated with adefovir dipivoxil in placebo-controlled trials showed significant improvements in liver histology, increased rates of hepatitis B "e" antigen seroconversion, and significant and sustained reductions in levels of circulating virus.

Adefovir dipivoxil was well tolerated and the most common adverse events were asthenia (weakness), headache, abdominal pain and flu-like symptoms.

The company discussed its data from three trials referred to as studies 437, 438 and 435.

Study participant Rochelle Yedvarb, a grandmother from Florida who contracted hepatitis B virus at age 10, tearfully spoke in favor of the drug, saying it has saved her life. "I feel stronger than I ever have before. One 10-mg drug has given me my life back and the only side effect I have is optimism," she said.

Results of Study 437, a 515-patient trial, indicated that adefovir dipivoxil in na ve CHB patients showed no resistance mutations. The trial met its endpoint 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.)

The 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 it is seeking approval, and an exploratory 30-mg dose for the first 48 weeks.

The company abandoned a plan to use adefovir dipivoxil for HIV after an advisory panel voted against the proposal in November 1999 due to an unacceptable nephrotoxicity profile and unfavorable risk-benefit profile at doses ranging from 60 mg to 500 mg daily. The failure was attributed to the higher doses. (See BioWorld Today, Nov. 3, 1999.)

Study 438 evaluated 185 patients and determined that treatment with a 10-mg 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.)

And finally, Study 435 is an ongoing open-label trial designed to evaluate adefovir dipivoxil in CHB patients who have received or are awaiting liver transplants and have lamivudine-resistant HBV. To date the study has enrolled 400 patients.

Hepatitis B attacks the liver and can cause chronic infection. CHB can lead to cirrhosis of the liver, liver cancer and even death in about 25 percent to 33 percent of patients. Worldwide, CHB is the leading cause of liver cancer, according to information provided by Gilead.

About 1 million people will die this year from complications due to CHB, making it the ninth leading cause of death worldwide. Also, approximately 10 percent to 15 percent of people diagnosed with HIV are also co-infected with CHB, resulting in a dual infection that is generally more difficult to treat, the company said.

Trading on Gilead's stock (NASDAQ:GILD) was held Tuesday.