Press Releases

Gilead Announces Data from Studies of Adefovir Dipivoxil Demonstrating Significant Improved Liver Function and Viral Load Reduction in Patients with Chronic Hepatitis B Virus Infection

Dallas, TX -- November 12, 2001

Gilead Sciences, Inc. (Nasdaq: GILD) today announced results from a large, multinational Phase III clinical trial (Study 437) which demonstrated that its investigational agent adefovir dipivoxil 10 mg significantly improved liver function and reduced levels of virus in patients with chronic hepatitis B virus (HBV) infection. These data were presented at the 52nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Dallas, Texas. Preliminary results from this study previously were announced in a press release on June 22, 2001.

Forty-eight week data from Study 437 demonstrate that patients with chronic HBV infection who received adefovir dipivoxil 10 mg once daily as monotherapy experienced statistically significant improvements in liver histology, reductions in HBV DNA and ALT levels, and a higher rate of seroconversion compared with patients given placebo. Change in liver histology is an important marker of disease progression in patients with chronic HBV infection, while HBV DNA and ALT levels are indicators of disease severity. These data were discussed in an oral presentation given today by Patrick Marcellin, M.D., Service d'Hepatologie, Hôpital Beaujon, Clichy and Professor, Université Paris VII, Paris, France (Presentation #40585).

Additional data presented yesterday at AASLD describe results of long-term treatment with adefovir dipivoxil, including the drug’s effect on HBV DNA suppression, seroconversion and lack of resistance development to treatment with adefovir dipivoxil.

“A therapy's ability to improve liver histology is among the best clinical markers to measure activity against the hepatitis B virus, making the Phase III data from this study very significant for physicians and patients alike,” said Dr. Marcellin, a clinical investigator on the study. “These clinical trial results suggest that adefovir dipivoxil holds great potential for patients with chronic hepatitis B infection.”

Study 437 Results
Study 437 is a randomized, double-blind, placebo-controlled Phase III clinical trial evaluating the safety and efficacy of adefovir dipivoxil once daily as monotherapy compared to placebo in patients with chronic HBV infection who were hepatitis B “e” antigen positive. This study enrolled 515 patients in the United States, Canada, Europe, Australia and Southeast Asia. In this study, two doses of adefovir dipivoxil were evaluated, including the 10 mg dose for which Gilead intends to seek marketing approval and an exploratory 30 mg dose. During the first year of Study 437, 172 patients were randomized to receive adefovir dipivoxil 10 mg, 173 to receive adefovir dipivoxil 30 mg and 170 to receive placebo.

For patients with assessable baseline biopsies, improvement in liver histology was observed in 53 percent of patients treated with adefovir dipivoxil 10 mg (n=168), compared to 25 percent of placebo-treated patients (n=161), as measured by liver biopsies (p<0.001). In addition to improvement in liver histology, seroconversion was observed in 12 percent of patients treated with adefovir dipivoxil 10 mg for 48 weeks, compared to six percent of patients on placebo (p=0.049). Seroconversion is defined as both the disappearance of the hepatitis B "e" antigen (HBe-antigen negative), a marker of HBV replication, and the appearance of antibodies specific for this antigen (HBe-antibody positive).

Reductions in HBV DNA also were observed. Following 48 weeks of treatment, patients in the adefovir dipivoxil 10 mg arm had a median reduction in HBV DNA from baseline of 3.52 log10 copies/mL (n=152), compared to a reduction of 0.55 log10 copies/mL in patients receiving placebo (n=148, p<0.001). This equates to a 99.97 percent reduction in circulating virus in patients on adefovir dipivoxil 10 mg treatment. Additionally, following 48 weeks of treatment with adefovir dipivoxil 10 mg, a median reduction in ALT levels of 51 IU/L was observed, compared to a reduction of 17 IU/L in the placebo group (p<0.0001). Forty-eight percent of patients treated with adefovir dipivoxil achieved normalization of ALT levels, compared to 16 percent of patients receiving placebo (p<0.001).

After 48 weeks, the study drug discontinuation rate was similar between the treatment and placebo arms, with seven percent of patients receiving adefovir dipivoxil 10 mg and eight percent of patients receiving placebo discontinuing from study. Additionally, the incidence of grade 3 and 4 laboratory abnormalities and clinical adverse events was similar between the adefovir dipivoxil 10 mg and placebo arms of this study. No patients in either the adefovir dipivoxil 10 mg or placebo groups had increases in serum creatinine of greater than or equal to 0.5 mg/dL from baseline or a serum phosphorus level less than 1.5 mg/dL, both laboratory markers of renal function, as confirmed by two consecutive laboratory assessments.

Resistance Profile
Data from a prospective, blinded genotypic analysis performed at baseline and week 48 on samples from patients in Study 437 who had detectable levels of HBV DNA suggest no resistance mutations to adefovir dipivoxil were observed after 48 weeks of therapy (n=381). Further surveillance to monitor the potential emergence of resistance mutations in patients treated with adefovir dipivoxil beyond one year is ongoing. These data will be discussed in detail in an oral presentation (Presentation #40862) tomorrow.

Long-term Therapy with Adefovir Dipivoxil – Clinical Results An extension study of 39 patients with wild type and precore mutant HBV who had completed adefovir dipivoxil dose-ranging Phase II clinical trials (Studies 412 and 413) showed that long-term treatment with adefovir dipivoxil was associated with statistically significant and sustained reductions in HBV DNA. Patients were treated with adefovir dipivoxil for up to 136 weeks, receiving 5, 30 or 60 mg for the initial 12 weeks of these studies. Patients entered the extension phase first receiving adefovir dipivoxil 30 mg. That dose was later reduced to 10 mg.

Median serum HBV DNA reductions of greater than 3.0 log10 copies/mL from baseline were sustained throughout the study with a median reduction of 3.68 log10 copies/mL at week 24 (n=37, p<0.0001), 3.40 log10 copies/mL at week 48 (n=33, p<0.0001), 3.33 log10 copies/mL at week 76 (n=27, p<0.0001) and 3.36 log10 copies/mL at week 100 (n=23, p<0.0001). Twenty-one percent of patients seroconverted (n=28), based on all available data to date. The most common adverse events reported were pharyngitis, abdominal pain and headache. One patient receiving adefovir dipivoxil 30 mg experienced a mild increase in serum creatinine from baseline that remained within normal range and was reversible with discontinuation of study drug. These data were presented on Sunday, November 11 in a poster session (Presentation #40636) by Jenny Heathcote, M.D., Toronto Western Hospital.

Long-term Therapy with Adefovir Dipivoxil – Virology Data from this study also demonstrate that no HBV polymerase mutations associated with adefovir resistance developed following up to 136 weeks of once-daily treatment with adefovir dipivoxil. These data were presented by Shelly Xiong, Ph.D., Gilead Sciences in a poster session (Presentation #40854) also on Sunday.

“The breadth of data presented at this conference are indicative of the important role we believe adefovir dipivoxil 10 mg may play for physicians and for patients with chronic HBV infection, a disease for which there remain very limited treatment options,” said John C. Martin, Ph.D., President and CEO, Gilead Sciences. “We are working with regulatory authorities to advance this important product toward approval, and intend to file regulatory applications in the United States and Europe in the first half of 2002.”

About Adefovir Dipivoxil 10 mg
Adefovir dipivoxil belongs to a class of drugs called nucleotide analogues, which are designed to work by blocking HBV DNA polymerase, an enzyme involved in the replication of HBV in the body. The investigational drug is dosed as one 10 mg tablet taken once daily.

Gilead initiated two pivotal Phase III studies to determine the safety and efficacy of adefovir dipivoxil 10 mg. Study 437 is a 48-week Phase III clinical trial evaluating the safety and efficacy of adefovir dipivoxil once daily as monotherapy compared to placebo in HBe antigen-positive patients with chronic HBV infection.

Study 438 is an ongoing international, multicenter, double-blind, placebo-controlled Phase III clinical trial that enrolled 185 patients with precore mutant HBV, or hepatitis B “e” antigen-negative virus (HBe antibody-positive, HBV DNA-positive), and compensated liver function. This two-year study is being conducted in Australia, Canada, France, Greece, Israel, Italy and Southeast Asia. Preliminary results were released on September 19, 2001. To further evaluate the long-term safety and resistance profiles of adefovir dipivoxil 10 mg in this patient population, patients are continuing on Study 438 for an additional 48 weeks of treatment.

Data from these studies will comprise the core of the regulatory filing packages in both the United States and Europe. The company anticipates filing U.S. and European regulatory packages during the first half of 2002. Adefovir dipivoxil is an investigational compound and has not yet been determined safe or efficacious in humans for its ultimate intended use.

Chronic Hepatitis B Infection
Worldwide, there are approximately 400 million chronic carriers of HBV, of which approximately one million die each year from complications of the disease, making chronic HBV one of the 10 most common causes of death. Complications of chronic HBV include cirrhosis (scarring of the liver), liver failure and primary liver cancer (hepatocellular carcinoma). Patients infected with the precore mutant strain of HBV may be predisposed to more severe and progressive liver injury. Precore mutant HBV infects up to approximately 50 percent of the 400 million chronic HBV carriers worldwide and is most prevalent in countries of the Mediterranean and Southeast Asia, where between 30-80 percent of chronic HBV patients are estimated to be infected with this strain.

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, manufacturing or sales and marketing facilities 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 resistance, safety and efficacy profile of adefovir dipivoxil observed in these data may not be observed following longer periods of treatment, risks related to Gilead’s ability to complete regulatory filings as anticipated, the risk that the FDA and other regulatory agencies could require longer-term safety and efficacy data prior to approval, 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.

For more information on Gilead Sciences, please visit the company’s Web site at or call the Gilead Corporate Communications Department at 1-800-GILEAD-5 (1-800-445-3235).