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Study: Hepsera Reduces Serum HBV DNA Replication, Sustains ALT Normalization

BERLIN--(BUSINESS WIRE)--April 15, 2004-- Gilead Sciences (Nasdaq:GILD - News) today announced 144-week data from a clinical trial (Study 438) of its oral antiviral drug Hepsera (adefovir dipivoxil 10 mg) in patients with hepatitis B "e" antigen-negative/anti-hepatitis B "e" positive (HBeAg-negative/anti-HBe positive, or precore mutant) chronic hepatitis B virus. HBeAg-negative hepatitis B is a mutant strain of the hepatitis B virus (HBV) that lacks the ability to produce the envelope ("e") antigen. In this study, patients treated with Hepsera showed progressive reductions in serum HBV DNA replication and sustained ALT normalization through 144 weeks of treatment. The development of Hepsera-related resistance mutations was delayed and infrequent among patients treated for 144 weeks. Study results were presented today at the 39th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany.

It is estimated that more than 400 million people worldwide have chronic hepatitis B, which is caused by infection with the hepatitis B virus. One quarter to one third of these individuals develop progressive liver disease, which can lead to cirrhosis and/or liver cancer. Approximately one million people die annually from complications of chronic hepatitis B, making it one of the leading causes of death worldwide. HBeAg-negative chronic hepatitis B infects approximately 14 to 24 percent of chronic hepatitis B carriers in North America and Europe, and is most prevalent in countries of the Mediterranean and Southeast Asia, where between 30 and 80 percent of chronic hepatitis B patients are estimated to be infected with this strain.

"Long-term antiviral therapy is typically needed to control HBeAg-negative chronic hepatitis B, and high rates of viral resistance can limit other treatment options," said Professor Stephanos Hadziyannis, MD, Department of Medicine, Henry Dunant Hospital, Athens, Greece, and a lead investigator for Study 438. "The durable antiviral efficacy, good tolerability profile and low rate of resistance we continue to see in this study suggest that Hepsera is a valuable treatment option for patients with HBeAg-negative hepatitis B."

Study 438 Design
The efficacy, tolerability and safety data through 144 weeks from Study 438 were presented today by Dr. Hadziyannis (Oral Presentation #46). This 96-week randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the long-term safety and efficacy of Hepsera in patients with HBeAg-negative chronic hepatitis B and compensated liver function. Following 96 weeks, patients treated with Hepsera during the second year of the study were offered the drug for up to three additional years. This study was conducted in Australia, Canada, France, Greece, Israel, Italy and Southeast Asia. To date, it is the largest placebo-controlled clinical trial in HBeAg-negative patients.

Three-year Study Results
Among patients who received continuous Hepsera treatment over 144 weeks (n=70), 79 percent of patients achieved undetectable levels of serum HBV DNA (less than 1,000 copies/mL, Roche Amplicor Monitor(TM) PCR assay, compared with 69 percent after 96 weeks. The median reduction in serum HBV DNA levels among Hepsera-treated patients was 3.63 log10 copies/mL at week 144.

Hepsera also provided sustained improvement in liver function through 144 weeks, as measured by blood levels of the liver enzyme alanine aminotransferase (ALT). The proportion of patients with ALT levels above the upper limit of normal at baseline whose ALT levels returned to normal at 144 weeks was 88 percent (n=62).

The safety profile of Hepsera over 144 weeks was consistent with that seen over 48 weeks, which was similar to placebo. The most common adverse reactions considered at least possibly related to Hepsera treatment through the third year of the study were headache, abdominal pain and asthenia (weakness). Three patients had an increase in serum creatinine of greater than or equal to 0.5 mg/dL from baseline by week 144. All cases resolved, one while continuing Hepsera therapy and two with discontinuation of Hepsera therapy. No patients had a serum phosphorus level less than 1.5 mg/dL through 144 weeks.

Probability of Resistance at 144 Weeks
Data further characterizing the long-term resistance profile of Hepsera were also presented today at EASL by Dr. Shelly Xiong of Gilead Sciences (Oral Presentation #57). To determine the incidence of Hepsera resistance after 144 weeks of treatment, data were analyzed from five clinical studies, including two pivotal studies of the drug. This analysis included 629, 293 and 167 patients who received 48, 96 and 144 weeks of Hepsera. Two mutations (rtN236T and rtA181V) in the viral polymerase have been associated with resistance to the drug. The cumulative probability of developing resistance after 144 weeks of treatment with Hepsera across these five studies remains low (3.9 percent), based on this analysis using the life table method. Through 48 weeks of treatment no Hepsera-related resistance mutations were identified and among patients treated for 96 weeks, less than 2 percent (1.6 percent) developed resistance. Resistance surveillance will continue for up to five years in long-term clinical efficacy and safety studies.

Durability of Seroconversion after Hepsera Discontinuation
To evaluate the durability of hepatitis B "e" antigen seroconversion following treatment with Hepsera, patients with compensated liver function who had undergone seroconversion in a prior clinical study (patients were from Studies 437 and 412) were enrolled in a long-term off-treatment follow-up study (Study 481). Seroconversion was defined as both the disappearance of hepatitis B "e" antigen (HBe-antigen negative), a marker of HBV replication, and the appearance of antibodies specific for "e" antigen (HBe-antibody positive). Data from an interim analysis of 66 patients were described today in a poster presentation (Presentation #424). In this study, seroconversion was shown to be durable in 91 percent of patients following discontinuation of Hepsera. Patients were followed for a median of 55 weeks after stopping treatment with Hepsera.

About Hepsera
Hepsera, the first nucleotide analogue for the treatment of chronic hepatitis B, is administered as a once-daily 10 mg tablet and works by inhibiting HBV DNA polymerase, an enzyme involved in the replication of the virus in the body. To date, Hepsera has been studied in 35 clinical trials and has been prescribed to approximately 24,000 patients. Hepsera is now available in the United States and 13 countries in Europe. In April 2002, Gilead signed a licensing agreement with GlaxoSmithKline (GSK), granting to GSK rights to commercialize Hepsera in Asia, Latin America and other territories. Hepsera has been launched in five Asian markets to date, including Hong Kong and Singapore.

In the United States, Hepsera is indicated for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.

In the European Union, Hepsera is indicated for the treatment of chronic hepatitis B in adults with compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotranseferase levels and histological evidence of active liver inflammation and fibrosis; or decompensated liver disease.

The adverse reactions considered at least possibly related to treatment reported in 3 percent or greater of patients in the first 48 weeks in Hepsera pivotal clinical studies were asthenia, headache, abdominal pain, nausea, flatulence, diarrhea and dyspepsia. With extended treatment, mild to moderate increases in serum creatinine were observed uncommonly in patients with chronic hepatitis B and compensated liver disease treated with Hepsera for a median of 49 weeks and a maximum of 109 weeks. Changes in serum creatinine were observed very commonly in patients with pre- and post-transplantation lamivudine-resistant liver disease and multiple risk factors for changes in renal function who were treated with Hepsera for up to 129 weeks, with a median time on treatment of 19 and 56 weeks, respectively. Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of treatment with antiviral therapies for hepatitis B, including Hepsera. Special warnings and precautions for use are included in the package insert regarding monitoring of renal function, post-treatment exacerbations of hepatitis, use in patients with underlying renal impairment, patients co-infected with HIV, the occurrence of nucleoside analogue-associated lactic acidosis and severe hepatomegaly with steatosis.

Source: Gilead Sciences

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