April 18, 2002
Gilead Announces Presentation of Data From Phase III Study of Adefovir Dipivoxil in Patients With Precore Mutant Chronic Hepatitis B
Additional Long-Term Anti-HBV and Resistance Data Presented At 37th Meeting of European Association for the Study of the Liver
These data were outlined in an oral presentation (#648) given by Stephanos Hadziyannis, MD, Department of Internal Medicine, Hipprokration General Hospital, Athens, Greece at the 37th Annual Meeting of the European Association for the Study of the Liver (EASL) in Madrid, Spain. This presentation is among the more than 20 abstracts at EASL describing the anti-HBV, safety and resistance profile of adefovir dipivoxil in a variety of chronic hepatitis B patient populations. Preliminary data from Study 438 previously were announced in September 2001.
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 the virus in the body. Gilead recently filed a New Drug Application (NDA) for adefovir dipivoxil with the U.S. Food and Drug Administration (FDA) and a Marketing Authorisation Application (MAA) with the European Medicines Evaluation Agency (EMEA). Gilead has requested a priority, or six month, review in the United States, and anticipates receiving an opinion from the Committee for Propriety Medicinal Products (CPMP) in Europe in the first half of 2003.
"The results presented today demonstrate that treatment with adefovir dipivoxil may potentially alter the course of chronic hepatitis B infections by positively impacting several important clinical markers -- liver histology, serum HBV DNA and ALT levels," said Dr. Hadziyannis. "Patients infected with precore mutant chronic hepatitis B often experience poor clinical outcomes and may exhibit more advanced liver disease. Based on its activity, safety and resistance profile, adefovir dipivoxil offers new hope for potential successful treatment of patients with chronic hepatitis B who are infected with the precore mutant form of the virus."
About Study 438
Liver biopsies were obtained from 178 patients. Sixty-four percent of patients treated with adefovir dipivoxil exhibited significant improvement in liver histology, compared with 33 percent of patients who received placebo (p=0.0002). Improvement was defined as a greater than or equal to two point reduction in the Knodell HAI score (measuring necro-inflammation -- an inflammatory process in the liver including or leading to death of liver cells) with no concurrent worsening of fibrosis (scarring of liver tissue). Treatment with adefovir dipivoxil also resulted in a median reduction in serum HBV DNA from baseline of 3.91 log10 copies/mL, compared with a median reduction of 1.35 log10 copies/mL (p less than 0.0001) in patients receiving placebo. Serum HBV DNA levels were below the limit of quantification of the assay (less than 400 copies/mL) in 51 percent of the adefovir dipivoxil-treated group, versus zero percent in the placebo group.
Adefovir dipivoxil-treated patients demonstrated a greater median reduction in levels of alanine transaminase (ALT, a measure of liver damage) than placebo patients (55 IU/L vs. 38 IU/L, p=0.01). In addition, ALT levels normalized in 72 percent of adefovir dipivoxil patients, compared with 29 percent of placebo patients (p less than 0.0001). Over the first 48 weeks of the study, the incidence of adverse events was similar in both the adefovir dipivoxil and placebo groups, and the discontinuation rate was two percent in both groups. The most common adverse events reported were headache, pharyngitis and abdominal pain.
Resistance Surveillance in Studies 437 and 438
"Adefovir possesses specific molecular characteristics intended to raise high genetic barriers to the development of viral resistance," said John C. Martin, PhD, President and CEO, Gilead. "The long-term success of therapy for chronic hepatitis B depends upon the ability of a therapeutic to effectively suppress HBV replication, to do so safely and for a long period of time without giving rise to resistant viral stains. The clinical data presented at this conference suggest that Gilead may have achieved these goals with the development of adefovir dipivoxil."
Activity of Adefovir Dipivoxil Against Different HBV Genotypes
Activity of Adefovir Dipivoxil Against cccDNA
Long-term Data from Phase II Studies
In patients treated with adefovir dipivoxil 10 mg beyond 48 weeks, adefovir dipivoxil was associated with a significant median reduction in serum HBV DNA of 3.40 log10 copies/mL (p less than 0.0001) that remained durable through up to nearly two years (3.36 log10 copies/mL at 100 1weeks, p less than 0.0001). Furthermore, by week 100, HBV DNA was undetectable (less than 400 copies/mL) in 70 percent of patients. Median reductions in ALT levels improved from week 48 to week 100 (36 IU/L to 48 IU/L), at which time these levels normalized in 63 percent of patients. In addition, over the course of the study, 21 percent of patients achieved seroconversion, in which the hepatitis B "e" antigen (used to denote HBV replication) disappears and antibodies specific for this antigen appear. Finally, genotypic and phenotypic analyses revealed no adefovir-associated resistance mutations in patients who received 72 to 136 weeks of treatment with adefovir dipivoxil.
"In patients with chronic hepatitis B and evidence of liver inflammation, the long-term suppression of the hepatitis B virus is essential to prevent liver damage and help maintain health," commented Dr. Heathcote. "These data are an important indicator of the potential durability of response to adefovir dipivoxil."
Chronic Hepatitis B
Early Access Program Initiated
For more information regarding the adefovir dipivoxil early access program, or to request program registration materials, physicians may call 1-800-GILEAD-5 or 1-650-574-3000.
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 further data from ongoing and future clinical trials may not be as favorable as current data and other risks related to regulatory review and approval of adefovir dipivoxil in the United States and Europe. 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, 2001 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.
Note to Editors: 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 or 1-650-574-3000.
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