By Kim Coghill
Gilead Sciences Inc. released interim data from a Phase III study of adefovir dipivoxil in naove chronic hepatitis B patients that showed no resistance mutations.
Adefovir dipivoxil, an antiviral reverse transcriptase inhibitor, also met its endpoints of liver histology improvement and showed no kidney toxicity. In 1999, Gilead abandoned studies of adefovir dipivoxil in HIV patients. (See BioWorld Today, Nov. 3, 1999, and Dec. 2, 1999.)
Eric Ende, an analyst with Banc of America in New York, said the drug, which has not been named, should peak at about $425 million annually in worldwide sales. Gilead will not seek a marketing partner for the drug, said Amy Flood, a company spokeswoman.
Data released Friday came from one of two Phase III studies. In the second study, which is testing patients with the procore mutant strain (hepatitis B ¿e¿ antigen negative), patients have reached the 48-week mark and Gilead expects to announce results in the fourth quarter.
Gilead, of Foster City, Calif., expects to file for regulatory approval in the first half of 2002. Ende said he expects the drug to be on the market by the end of 2002 or sometime in early 2003.
Caroline Copithorne, senior biotech analyst with Morgan Stanley in San Francisco, said Friday¿s results are particularly important because patients who are resistant to current therapies are not resistant to adefovir dipivoxil, according to the study. ¿So even patients who fail the earlier therapies such as lamivudine [3TC] can still get efficacy with adefovir dipivoxil, and [Gilead] showed that in the clinical study. It is particularly important that the patients did not develop resistance mutations.¿
Copithorne and Ende agreed that sales of lamivudine have suffered, dropping to about $130 million worldwide, because patients rapidly develop resistance.
Results released Friday were from the trial known as Study 437, a two-year, randomized, double-blind, placebo-controlled study that 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.
The study enrolled 515 patients in the U.S., Canada, Europe, Australia and Southeast Asia. In the first year, 172 patients were randomized to adefovir dipivoxil 10 mg, 173 to adefovir dipivoxil 30 mg and the remaining 170 to placebo.
Not only was there improvement in liver histology, but seroconversion also was observed in 12 percent of patients treated with 10 mg for 48 weeks compared to 6 percent of patients on placebo (p=0.049). Seroconversion is the disappearance of hepatitis B ¿e¿ antigen (HBe-antigen negative), a mark of HBV replication, and the appearance of antibodies specific for the antigen (HBe-antibody positive).
¿The histology results from this Phase III clinical trial of adefovir dipivoxil 10 mg confirm the antiviral activity observed in our earlier studies and suggest that this compound may offer a meaningful clinical benefit to patients with chronic HBV infection,¿ John Martin, Gilead¿s president and CEO, said in a prepared statement.
The second Phase III trial, Study 438, is a randomized, double-blind, placebo-controlled study being conducted in Australia, Canada, France, Greece, Italy and Southeast Asia. Enrollment was completed a year ago with 185 patients.
The 30-mg exploratory arm of Study 437 indicated similar efficacy results in terms of liver histology, seroconversion and reduction in HBV DNA.
Worldwide there about 400 million chronic carriers of HBV, of which about 1 million die each year, Gilead said. 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 approved products are AmBisome, for systemic fungal infections; Tamiflu, for the flu; DaunoXome, for HIV-associated Kaposi¿s sarcoma; and Vistide, for AIDS-related cytomegalovirus. The company¿s revenues were about $58 million in the first quarter.
Gilead in May submitted a new drug application to the FDA for tenofovir disoproxil fumarate (tenofovir DF), for the treatment of HIV infection.
Gilead¿s stock (NASDAQ:GILD) closed Friday at $61.13, up $3.53.