November 13, 2001
Gilead Announces Data from Studies of Adefovir Dipivoxil in Patients with Lamivudine-Resistant Chronic Hepatitis B Virus Infection
Data Presented at 52nd AASLD Meeting
Dallas, TX -- November 13, 2001
Gilead Sciences, Inc. (Nasdaq: GILD) today announced data from a clinical study (Study 435) of adefovir dipivoxil 10 mg once daily in post-liver transplant patients with lamivudine-resistant chronic hepatitis B virus (HBV) infection. In this study, treatment with adefovir dipivoxil 10 mg once daily for 48 weeks resulted in a statistically significant decrease in HBV DNA of 4.6 log10 copies/mL (n=28). Data were presented at the 52nd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Dallas, Texas.
Additional data presented today further characterize the resistance profile of adefovir dipivoxil as well as its profile in lamivudine-resistant chronic HBV patients who have developed the YMDD mutation associated with lamivudine resistance and in patients co-infected with chronic HBV and HIV.
Antiviral Activity in Post-Transplant Patients
Results from Study 435 were described in an oral presentation by Eugene Schiff, M.D., Center for Liver Disease, University of Miami, Florida (Presentation #40619). Study 435 is an open-label multicenter clinical study enrolling patients with lamivudine-resistant chronic HBV infection who have received or are wait-listed for a liver transplant. The data presented are from a cohort of post-transplant patients (n=131) with clinical evidence of lamivudine failure. These patients received adefovir dipivoxil 10 mg once daily in addition to their existing HBV therapy (lamivudine, hepatitis B immunoglobulin, famciclovir or ganciclovir). The dose of adefovir dipivoxil was adjusted in patients with renal impairment at baseline.
At baseline, patients had a median serum HBV DNA of 8.2 log10 copies/mL. Following 24 weeks of treatment with adefovir dipivoxil, the median reduction in HBV DNA was 3.7 log10 copies/mL (n=53, p<0.0001), and at week 48 the median reduction was 4.6 log10 copies/mL (n=28, p<0.0001). Statistically significant improvements in ALT, bilirubin and albumin levels, clinical markers of liver function, also were observed at weeks 24 and 48, compared to baseline. The most common adverse events reported were asthenia (weakness), headache, pharyngitis and abdominal pain. Drug discontinuation due to adverse events was uncommon.
"The emergence of resistance is a significant problem with prolonged lamivudine treatment for chronic HBV infection. This is even more problematic for transplant patients who are in great immediate need of alternative therapies to combat lamivudine-resistant virus and to protect the second chance that they’ve been given with liver transplantation," commented Dr. Schiff, a clinical investigator on the study. "The clinical improvements and safety profile observed to date in these post-transplant patients suggest that adefovir dipivoxil may be an important new treatment option."
Susceptibility of Lamivudine-resistant HBV to Adefovir Dipivoxil
A separate presentation given by Shelly Xiong, Ph.D., Gilead Sciences reviewed resistance data from Study 435 evaluating the antiviral activity of adefovir in vitro and in patients with different patterns of HBV mutations associated with lamivudine resistance (Presentation #40118). Genotypic analysis was performed for all available baseline samples of patients enrolled in Study 435. Ninety-six percent of the 207 baseline samples had YMDD mutations associated with resistance to lamivudine. Patients had received lamivudine for an average of 2.5 years prior to study entry.
The study found that the administration of adefovir dipivoxil 10 mg once daily demonstrated sustained viral load reductions in lamivudine-resistant HBV in patients for up to 72 weeks, with a median reduction in HBV DNA of 4.7 log10 copies/mL (n=14). In addition, an analysis showed that the virus remained sensitive to adefovir in vitro regardless of the patterns and numbers of genetic mutations associated with lamivudine resistance.
Treatment of Decompensated Lamivudine-Experienced Patients with YMDD Mutant HBV
Interim data from an ongoing study conducted in collaboration with GlaxoSmithKline were described yesterday in an oral presentation given by Robert Perrillo, M.D., Oschner Clinic, New Orleans (Presentation #40161). These data are from an open label arm of a clinical study evaluating adefovir dipivoxil 10 mg and lamivudine 100 mg in patients with decompensated chronic hepatitis B, YMDD mutant HBV and evidence of reduced response to lamivudine (n=39). The interim results demonstrated that the addition of once-daily adefovir dipivoxil 10 mg to an ongoing course of lamivudine 100 mg daily therapy resulted in a median reduction in HBV DNA from baseline of 3.9 log10 copies/mL at 24 weeks of treatment (p<0.001). In addition, laboratory markers of liver disease indicated improvements in liver function from baseline to week 24. The number of patients with abnormal albumin decreased from 51 percent to 26 percent, the number with abnormal bilirubin decreased from 38 percent to 18 percent and the number of patients with abnormal ALT decreased from 95 percent to 49 percent. Four serious adverse events were reported, but none were considered related to treatment. The study is ongoing.
The administration of lamivudine results in the development of resistance (YMDD) mutations in approximately 15 to 32 percent of patients after one year of therapy with lamivudine and approximately 67 percent of patients at four years.
Adefovir Dipivoxil Treatment for Lamivudine Resistant HBV in HIV-Infected Patients
Interim data also were presented on Sunday, November 11 from an ongoing two-year, open-label, single-center study of 35 patients co-infected with lamivudine-resistant chronic HBV and HIV. Based on published data, lamivudine resistance occurs in 50 percent of HIV/HBV co-infected patients after two years of lamivudine therapy and in 90 percent of patients treated up to four years. Adefovir dipivoxil 10 mg once daily was added to patients’ existing lamivudine treatment and resulted in a statistically significant mean reduction from baseline of 4.74 log10 copies/mL serum HBV DNA at 72 weeks (n=28; p<0.0001). In addition, adefovir dipivoxil therapy reduced necroinflammatory activity in the liver for eight of 15 patients with available biopsies at baseline and one year. No patients with available biopsies exhibited an increase in necroinflammatory activity. Nine percent of patients seroconverted by week 72 (n=33). 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). Additionally, 25 percent of patients achieved ALT normalization at week 72.
No significant adefovir dipivoxil treatment-related changes in serum electrolytes or renal function were observed. No patient developed adefovir-associated HIV reverse transcriptase or HBV polymerase mutations in genotypic evaluations performed at baseline and week 48. These data were presented in a poster session (Presentation #40774) by Yves Benhamou, M.D., Service d’Hépato-Gastroentérologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
"There is now a significant body of data suggesting that adefovir dipivoxil 10 mg may play a prominent role in the treatment of chronic HBV infection for a range of patients, many of whom currently have few treatment options," said John C. Martin, Ph.D., President and CEO of Gilead Sciences. "We believe these data from studies of adefovir dipivoxil are particularly significant for physicians and their patients combating lamivudine-resistant HBV infection."
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. Results were described in a presentation yesterday at AASLD.
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, 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 www.gilead.com or call the Gilead Corporate Communications Department at 1-800-GILEAD-5 (1-800-445-3235).