Gilead Sciences, Inc. (Nasdaq:GILD) today announced new five-year data from the open-label phase of two pivotal Phase 3 clinical trials (Studies 102 and 103) evaluating the efficacy of Viread(R) (tenofovir disoproxil fumarate) for the treatment of chronic hepatitis B virus (HBV) infection among primarily treatment-naÃ¯ve patients. Results show that Viread maintains long-term viral suppression of HBV and is associated with a reduction in liver fibrosis and a reversal of cirrhosis. Among patients in both studies, the majority (88 percent) experienced an improvement in overall liver histology. Together, these two studies represent one of the largest datasets evaluating the impact of an oral antiviral therapy on histologic changes and showing a reduction in liver fibrosis. These findings are being presented Monday, November 7 at the 62nd annual meeting of the American Association for the Study of Liver Diseases (The Liver Meeting 2011) in San Francisco.
"We have long theorized that long-term antiviral therapy can not only help chronic hepatitis B patients achieve and maintain virologic suppression, but also help to improve clinical outcomes, including a reduction in the risk of fibrosis or cirrhosis," said Patrick Marcellin, MD, of HÃ´pital Beaujon in Clichy, France, INSERM CRB3 and University of Paris Denis Diderot, and the principal investigator of Study 102. "These results represent an important advance in HBV therapy because they elucidate Viread's potential to reduce or reverse signs of liver damage in patients with chronic hepatitis B."
Studies 102 and 103 were designed to compare Viread to Hepsera(R) (adefovir dipivoxil) in a blinded manner over 48 weeks, among both HBeAg-negative (Study 102) and HBeAg-positive (Study 103) patients with compensated liver disease. Patients originally randomized to Hepsera in both studies were switched to open-label Viread at 48 weeks and patients randomized to Viread continued on open-label Viread.
The data show that the majority of patients who received Viread continuously for 240 weeks experienced sustained suppression of HBV DNA (viral load) levels in the blood below 400 copies/mL (83 percent and 64 percent for Studies 102 and 103, respectively). Patients who were randomized to Hepsera and rolled over to Viread at week 48 and received Viread for a subsequent 192 weeks also maintained viral suppression (84 percent and 66 percent for Studies 102 and 103, respectively).
Notably, among the 331 patients who had paired biopsies at both baseline and week 240, 292 (88 percent) experienced an improvement in overall liver histology, as measured by an improvement of at least two points in Knodell necroinflammatory score without worsening in Knodell fibrosis score. Of the 94 patients who had cirrhosis (Ishak fibrosis score greater-than or equal to 5) at the start of therapy, 69 (73 percent) experienced regression of cirrhosis and 68 (72 percent) had at least a two-point reduction in Ishak fibrosis score.
Among HBeAg-positive patients receiving Viread through 240 weeks (Study 103), the cumulative probability (estimated by Two-State Markov model) of "s" antigen loss and seroconversion was 9 percent and 7 percent, respectively. Additionally, no resistance to Viread emerged over 240 weeks of treatment.
"Viral resistance is a significant challenge for physicians treating patients with chronic hepatitis B," said Jenny Heathcote, MD, of the University of Toronto, Canada, and the principal investigator for Study 103. "These five-year results are important in that they demonstrate Viread's high genetic barrier to resistance, which is essential for the long-term success of HBV therapy."
Viread for HBV was approved by the U.S. Food and Drug Administration (FDA) in 2008 and has since become the most-prescribed medicine for chronic HBV in the United States. These five-year data have been submitted to the FDA and to the European Medicines Agency for review and potential inclusion in the Viread label.
About Studies 102 and 103
Studies 102 and 103 were both multi-center, randomized, double-blind Phase 3 clinical trials comparing Viread to Hepseraamong HBeAg-negative (Study 102; n=375) and HBeAg-positive (Study 103; n=266) chronic hepatitis B patients with compensated liver disease. Patients had HBV DNA above 100,000 copies/mL and elevated levels of alanine aminotransferase (ALT, an enzyme that serves as a measure of liver inflammation) upon study initiation. The majority of patients were treatment-naÃ¯ve.
Patients originally randomized to Hepsera in both studies rolled over to open-label Viread treatment (n=196) at week 48, while patients originally randomized to Viread continued open-label Viread (n=389). All patients were asked to undergo liver biopsy at 48 weeks of treatment and again at five years of treatment, and a total of 331 patients were evaluated in the histology analysis.
Seventy-two percent of patients in Study 102 and 50 percent of patients in Study 103 achieved normalized ALT at week 240. Viread was well-tolerated in both studies. The most commonly observed adverse events were abdominal pain, nasopharyngitis, headache, influenza, back pain and hypertension. Across both studies, 2.1 percent of patients who received Viread for five years discontinued treatment due to an adverse event and 0.9 percent of patients experienced a confirmed increase in serum creatinine of at least 0.5 mg/dL or calculated creatinine clearance less than 50 mL/min.
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