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Press Release from Gilead Sciences 4/9/03
Hepsera Shows Sustained Liver Improvements in More Than 70 Percent of HBeAg-negative Chronic HBV Patients
  96-week study results show the oral antiviral drug Hepsera (adefovir dipivoxil 10 mg) improves liver function and reduces liver damage in patients with hepatitis B "e" antigen-negative (HBeAg-negative, or precore mutant) chronic hepatitis B virus (HBV).
HBeAg-negative hepatitis B is a strain of HBV with a mutation in the viral genome that eliminates the ability of the virus to produce the envelope ("e") antigen. In this study, more than 70 percent of patients treated with Hepsera showed persistent suppression of HBV DNA viral replication, continued histological improvements and sustained improvements in liver function through 96 weeks of treatment.
The study results were presented at the 11th International Symposium on Viral Hepatitis and Liver Disease (ISVHLD) in Sydney, Australia. This presentation is one of seven Hepsera abstracts to be featured at the conference. More than 400 million people worldwide have chronic hepatitis B, which is caused by infection with the hepatitis B virus, and between one quarter and one third of these individuals develop progressive liver disease, which can lead to cirrhosis and 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 up to approximately 50 percent of chronic hepatitis B carriers worldwide, 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.
"Patients with HBeAg-negative chronic hepatitis B often need years of treatment to protect them against disease progression to cirrhosis and liver cancer, but high rates of viral resistance can undermine the long-term viability of other treatment options," said Professor Stephanos Hadziyannis, MD, Department of Medicine, Henry Dunant Hospital, Athens, Greece. "The lasting efficacy and tolerability and low risk of resistance we observed in this study suggest that Hepsera may offer new hope to patients with this form of hepatitis B."
Study 438 Design
Ninety-six-week efficacy and tolerability results from Study 438 were presented today by Dr. Hadziyannis (Presentation Number 1065). To evaluate the long-term safety and efficacy of Hepsera, patients in this study will continue to receive Hepsera for an additional three years. Study 438 is a randomized, double-blind, placebo-controlled clinical trial of 184 patients with HBeAg-negative chronic hepatitis B and compensated liver function. This study is being conducted in Australia, Canada, France, Greece, Israel, Italy and Southeast Asia. To date, this is the largest placebo-controlled clinical trial in HBeAg-negative patients.
At study entry, patients were randomized (2:1) to receive Hepsera once daily (n=123) or placebo (n=61) for 48 weeks. Results from the first 48 weeks of the study were presented at the European Association for the Study of the Liver in April 2002. The 48-week results demonstrated that therapy with Hepsera was associated with significant histological, virological and biochemical improvements compared to placebo.
Following the first 48 weeks of treatment, patients who had received Hepsera for the first year of the study were re-randomized (2:1) to receive either Hepsera or placebo for a second year. Patients who received placebo for the initial 48 weeks of the study received Hepsera for the second 48 weeks of the study.
Two-year Efficacy and Tolerability
Among patients who received continuous Hepsera treatment over 96 weeks, 71 percent of patients achieved undetectable levels of serum HBV DNA (less than 1000 copies/mL, as assayed by PCR, n=70). The median reduction in serum HBV DNA levels among Hepsera-treated patients was 3.47 log10 copies/mL at week 96, corresponding to approximately a 99.97 percent decrease in viral load from a median baseline level of 7.07 log10 copies/mL. These data indicate that Hepsera provided sustained suppression of HBV viral replication - the main cause of disease progression - throughout the two year study.
Hepsera also provided sustained improvement in liver function through 96 weeks, as measured by blood levels of the liver enzyme alanine aminotransferase (ALT). The proportion of patients with abnormal baseline ALT levels whose ALT levels returned to normal at 96 weeks was 73 percent (n=64). Additionally, among patients who received an optional liver biopsy after 96 weeks of continuous Hepsera treatment (n=19), 79 percent showed improvement in liver histology.
Two-year Data Show Resistance Is Slow to Develop
Data further characterizing the resistance profile of Hepsera also were presented today at ISVHLD by Stephen Locarnini, MD, Divisional Head of Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia (Presentation Number 779).
Through 48 weeks of treatment in previous clinical studies, including two pivotal studies of the drug, no Hepsera-related resistance mutations were identified (n=629). To assess the incidence of resistance with extended treatment, investigators monitored for viral resistance in 124 patients who completed 96 weeks of treatment in various studies (including Study 438, n=79).
At 96 weeks, a novel resistance mutation (rtN236T) in the HBV polymerase was detected in two of the 124 patients (1.6 percent). The mutation reduced susceptibility to adefovir by 5- to 23-fold in vitro, but did not confer cross-resistance to lamivudine, the other oral antiviral currently approved for the treatment of chronic hepatitis B. Surveillance is ongoing for up to five years in long-term clinical efficacy and safety studies.
Safety Profile
The most common adverse reactions considered at least possibly related to Hepsera treatment through the second year of the study were headache, pharyngitis, abdominal pain and asthenia (weakness). Two patients had an increase in serum creatinine of greater than or equal to 0.5 mg/dL from baseline by week 96. Both cases resolved, one with continuation of Hepsera therapy and one with discontinuation of Hepsera therapy. No patients had a serum phosphorus level less than 1.5 mg/dL through 96 weeks.
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 and post-treatment exacerbations of hepatitis, use in patients with underlying renal impairment or patients co-infected with HIV, and occurrence of nucleoside analogue-associated lactic acidosis and severe hepatomegaly with steatosis.
About Hepsera
Hepsera, the first nucleotide analogue for chronic hepatitis B, is administered as a once-daily 10 mg tablet and works by blocking HBV DNA polymerase, an enzyme involved in the replication of the virus in the body. In clinical trials and expanded access programs, approximately 2,500 patients have been treated with Hepsera for periods of up to three years.
Hepsera was approved in the United States in September 2002 and in the European Union in March 2003. Regulatory filings for the drug also have been completed in Australia, Switzerland, Turkey and Canada, and additional regulatory filings are planned in other countries in the coming months. 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, the most significant of which are China, South Korea, Japan and Taiwan.
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. Hepsera is indicated in Europe for the treatment of chronic hepatitis B in adults with compensated liver disease with evidence of active viral replication, persistently elevated serum alanine aminotranseferase (ALT) levels and histological evidence of active liver inflammation and fibrosis; or decompensated liver disease.
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