Gilead Sciences Announces Data from Studies of Adefovir Dipivoxil, Investigational Agent for the Treatment of Chronic Hepatitis B Infection

- Data Presented at 36th Annual Meeting of the European Association for the Study of the Liver

Prague, The Czech Republic -- April 23, 2001

Gilead Sciences, Inc. (Nasdaq: GILD) today announced data from four studies of adefovir dipivoxil, the company's investigational antiviral agent for the treatment of chronic hepatitis B virus (HBV) infection, at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL) in Prague, The Czech Republic.

Data from four studies presented at the EASL conference characterize the emerging efficacy, safety and resistance profile of adefovir dipivoxil, including:

  • Virologic response (-4.01 log10 copies/mL reduction in HBV DNA after 48 weeks of treatment) to the 10 mg dose in patients with lamivudine-resistant HBV and HIV co-infection
  • No significant changes in serum electrolytes or renal function in patients with lamivudine-resistant HBV and HIV infection following 48 weeks of treatment
  • No resistance mutations were identified in nucleoside treatment-naive HBV patients following up to 60 weeks of treatment
  • A mean reduction in HBV DNA of -3.92 log10 copies/mL at 24 weeks of treatment in lamivudine-resistant HBV-infected liver transplant patients
  • Similar virologic response in "precore mutant" (hepatitis B "e" antigen negative) HBV-infected patients and in patients with hepatitis B "e" antigen positive virus

Gilead is evaluating adefovir dipivoxil 10 mg (one pill taken once daily) as a monotherapy treatment for chronic HBV infection in two multinational pivotal Phase III clinical trials. Gilead expects to release data from these Phase III trials later this year. Based on data from these and other studies, Gilead intends to file for regulatory approval of adefovir dipivoxil 10 mg in the United States and Europe in the first half of 2002.

"We are pleased to announce these data at the EASL conference in Prague, home to Dr. Antonin Holy of the Institute of Organic Chemistry and Biochemistry, a co-discoverer of adefovir," said John C. Martin, Ph.D., President and Chief Executive Officer, Gilead Sciences. "Chronic hepatitis B infection affects approximately 400 million individuals worldwide, and we believe that adefovir dipivoxil 10 mg holds great potential to address this unmet medical need. The results presented at this conference demonstrate the potential safety and antiviral activity of adefovir dipivoxil, as well as the favorable resistance profile of the drug beyond one year of therapy."

Co-Infection Study Design and Results
Interim data from a single center, open-label, ongoing 96-week pilot study of adefovir dipivoxil 10 mg in lamivudine-resistant patients co-infected with HIV and HBV were presented by Dr. Yves Benhamou, Service d'Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France (Presentation #1253).

The study enrolled 35 patients with controlled HIV infection (HIV RNA serum levels less than 2.60 log10 or 400 copies/mL). At baseline, patients had a mean HBV DNA serum level of 8.64 log10 copies/mL and documented lamivudine-associated resistance mutations. Patients had received lamivudine 150 mg twice daily as part of their antiretroviral treatment regimen for a median of 42 months prior to study entry. HBV resistance to lamivudine was detected in these patients a median of two years prior to the initiation of treatment with adefovir dipivoxil 10 mg for chronic HBV infection.

Adefovir dipivoxil 10 mg once daily was added to patients' antiretroviral regimen. Twenty-nine patients reached week 48 in this study, at which time the mean reduction in HBV DNA from baseline was -4.01 log10 copies/mL (p<0.0001). For these patients, adefovir dipivoxil 10 mg once daily was not associated with significant changes in serum electrolytes or renal function at 48 weeks. Some patients experienced transient ALT elevations that resolved with continued use of adefovir dipivoxil.

"The antiviral response observed in this study, tolerability and ease of administration for adefovir dipivoxil suggest that the compound may be an important new treatment option for patients with lamivudine-resistant HBV and HIV infection," commented Dr. Benhamou. "These results are important given the high incidence of resistance to lamivudine in patients treated for HBV, and in particular patients co-infected with HIV and HBV."

Approximately 10 percent of HIV-infected patients also are carriers of HBV, and co-infection with HIV and HBV is associated with a higher prevalence of cirrhosis than is observed in chronic HBV patients who are not HIV positive.

Resistance Data Presentations
Data further characterizing the resistance profile of adefovir dipivoxil for chronic HBV infection also were presented at the EASL conference by Shelly Xiong, Ph.D., Gilead Sciences.

In one study, genotypic analyses of HBV samples from 23 chronic hepatitis B patients were conducted (Presentation #1309). These patients participated in the extension phase of two Phase II studies (412 and 413). Following treatment with adefovir dipivoxil for 48 to 60 weeks, no resistance mutations were identified in these patients.

Dr. Xiong also described data from a virology sub-study of Study 435, which is evaluating whether lamivudine-associated mutations affect the response to adefovir dipivoxil (Presentation #1310). Study 435, an open-label clinical trial of adefovir dipivoxil 10 mg once daily, is being conducted in liver transplant and pre-transplant hepatitis B patients who failed lamivudine therapy. Genotypic analyses at baseline were conducted for 124 of the patients enrolled in this study, and HBV from 96 percent of these patients displayed YMDD mutations associated with lamivudine resistance. Adefovir dipivoxil in patients demonstrated anti-HBV activity regardless of the different patterns of lamivudine-resistant HBV mutations observed at baseline. This finding was consistent with data indicating that viruses with these resistance mutations remained sensitive to adefovir in vitro. For patients with evaluable HBV DNA at 24 weeks of treatment with adefovir dipivoxil, a mean reduction in viral load of -3.92 log10 copies/mL (n=74) was observed.

Treatment of "Precore Mutant" HBV
In a fourth presentation, clinical investigator Jenny Heathcote, M.D., Professor of Medicine at the University of Toronto, described the effect of adefovir dipivoxil on viral dynamics in patients with precore mutant hepatitis B virus (Poster #1191). In this study, 10 patients with precore mutant HBV, or hepatitis B "e" (HBe) antigen negative virus (HBe antibody positive, HBV DNA positive), were treated for 12 weeks with either adefovir dipivoxil 30 mg (n=8) or placebo (n=2). The viral replication dynamics of the HBe antigen negative patients were compared to those of a cohort of HBe antigen positive patients previously treated with adefovir dipivoxil 30 mg. The response to treatment with adefovir dipivoxil was similar in this patient population to the response observed in patients with HBe antigen positive virus, with a mean reduction in viral load at week 12 from baseline of -3.61 log10 copies/mL. This comparative analysis suggests that precore mutations do not affect the clearance or the replication efficiency of HBV.

Adefovir Dipivoxil Phase III Program
Two pivotal Phase III trials currently are underway to evaluate adefovir dipivoxil 10 mg monotherapy as a potential treatment for chronic HBV infection. Study 437, initiated in March 1999 and being conducted in Australia, Europe, North America and Southeast Asia, is a randomized, double-blind, placebo-controlled trial of adefovir dipivoxil 10 and 30 mg. Enrollment in this trial was completed in March 2000 with 515 patients. Study 438, initiated in January 2000, is evaluating adefovir dipivoxil 10 mg for the treatment of patients with precore mutant HBV infection, a strain of the virus that has evolved without the hallmark "e" antigen. This trial is being conducted in Australia, Canada, France, Greece, Israel, Italy and Southeast Asia. Enrollment was completed in June 2000 with 185 patients.

Gilead anticipates the release or presentation of data from the one-year endpoint of these studies during the second half of 2001 and potential U.S. and European regulatory filings during the first half of 2002.

Patients and physicians who would like more information about adefovir dipivoxil may contact Gilead Sciences Medical Information at 1-800-GILEAD-5 (1-800-445-3235) or 1-650-574-3000 from outside the United States.

Gilead Sciences
Gilead Sciences, Inc., headquartered in Foster City, CA, is an independent biopharmaceutical company that seeks to provide accelerated solutions for patients and the people who care for them. Gilead discovers, develops, manufactures and commercializes proprietary therapeutics for challenging infectious diseases (viral, fungal and bacterial infections) and cancer. Gilead maintains research, development or manufacturing facilities in Foster City, CA; Boulder, CO; San Dimas, CA; Cambridge, UK and Dublin, Ireland and sales and marketing organizations in the United States, Europe and Australia.

This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors that could cause actual results to differ materially from those referred to in the forward-looking statements. Such risks and uncertainties include the risk that the safety, efficacy and resistance data observed in Gilead's earlier clinical trials and preclinical testing may not be observed in Gilead's more reliable Phase III clinical trials, and the risk that adefovir dipivoxil is an investigational compound and has not yet been determined safe or efficacious in humans for its ultimate intended use, and other risks related to regulatory approval of adefovir dipivoxil. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in the Gilead Annual Report on Form 10-K for the year ended December 31, 2000 and in Gilead's Quarterly Reports on Form 10-Q, all of which are on file with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead and Gilead assumes no obligation to update any such forward-looking statements.