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
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,
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.
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.
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.