By Jim Shrine
Gilead Sciences Inc. continued its recent run of stock-driving news with the initiation of a Phase III trial of adefovir dipivoxil for treating chronic hepatitis B virus (HBV).
The trial is the first of two pivotal studies that together are designed to support international registrations of the product, a nucleoside analogue that in higher doses also has shown efficacy against HIV (it is called Preveon for HIV).
The Phase III HBV trial, called Study 437, will run two years but data for the regulatory package will be taken from the first year of treatment, said Alison Murray, director of clinical development for Foster City, Calif.-based Gilead. Second-year results will be used to gauge long-term safety and resistance issues.
The trial will enroll 500 patients at 97 sites in North America, Europe, Australia and Southeast Asia, including the areas of Hong Kong, Thailand, Taiwan, the Philippines and Malaysia. It will test daily oral administration of 10 mg and 30 mg of drug against placebo in a randomized, double-blind trial.
The filing time line will depend on how quickly Gilead can get the second study up and running, Murray said, adding that regulatory approval could be sought as early as sometime in 2001.
Endpoints in the first study include liver histology, changes in viral load and rates of seroconversion, which is defined as both the disappearance of hepatitis B "e" antigen and the appearance of antibodies specific for that antigen. Most of the patients will be treatment naove.
The difference in the second pivotal study is that it will be among HBV patients who are "e" antigen negative, Murray said.
"The two studies together will cover a large proportion of the hepatitis B patients who require treatment," Murray said.
Current treatments for hepatitis B include alpha interferon and lamivudine, a Glaxo Wellcome plc/BioChem Pharma Inc. drug from the same class as adefovir dipivoxil that was approved in the U.S. in December. That product is approved or pending approval in more than 30 countries, including the largest HBV market, China. Alpha interferon is ineffective in some patient populations and also comes with a higher price and more side effects. (See BioWorld Today, Dec. 10, 1998, p. 1; and Jan. 10, 1999, p. 1.)
"One of the problems with lamivudine is you get resistance developing in a reasonable proportion of patients after one year of therapy," Murray said. "Fourteen to 30 percent of patients have some rebound in viral load. Ideally, we would like a drug that offers longer-term suppression of hepatitis B. We think that's what's potentially special about adefovir."
Separately, Gilead is close to starting a compassionate use program that will provide adefovir dipivoxil to liver transplant patients who have developed resistance to lamivudine, she said.
Murray said there should be no problems with quick enrollment for the Phase III study.
"We've been bowled over by the enthusiasm of investigators," she said. "They are beating down our door to participate. It's really nice to be in a situation like that."
Gilead's Phase II trial in 67 HBV patients showed median reduction of HBV DNA of more than 99.99 percent.
Gilead spokeswoman Sheryl Meredith said Gilead is pursuing a partnership for adefovir dipivoxil for HBV on terms that are to be determined.
The company plans to market Preveon on its own, and significantly supplemented its sales capabilities with the $550 million stock purchase two weeks ago of NeXstar Pharmaceuticals Inc., of Boulder, Colo. Another late-stage product - an oral influenza drug called GS4104 - is partnered with F. Hoffmann-La Roche Ltd., of Basel, Switzerland.
Meredith said Roche is expecting to file a new drug application (NDA) in GS4104 in April, and the filing of an NDA on Preveon is expected in the second quarter.
Gilead's stock (NASDAQ:GILD) gained $0.938 per share Wednesday to close at $51.125, up 1.9 percent on the day but about 185 percent more than the $18 range it was trading at about seven months ago.
The stock has run up strongly even since acquisition of NeXstar on March 1, when it opened at $41.25. If the stock keeps its recent momentum, that will change the terms of that acquisition.
The deal called for NeXstar shareholders to receive 0.425 of a share of Gilead if Gilead's stock closed between $36.47 and $45.88 on average for 20 trading days leading up to NeXstar's stockholder meeting, which likely will be in a few months. If the stock price averages $51.50 over that time, however, the exchange rate would fix at 0.376. (See BioWorld Today, March 2, 1999, p. 1.)