Positive five-year data showing effect of Viread(R) on liver fibrosis and cirrhosis caused by Chronic Hepatitis B

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-naïve 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 Hôpital 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-naïve.

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.

Important Information About Viread for Chronic Hepatitis B

Viread (tenofovir disoproxil fumarate) is indicated for the treatment of chronic hepatitis B in adults. The following points should be considered when initiating therapy with Viread for the treatment of HBV infection: This indication is based primarily on data from the treatment of nucleoside-treatment-naïve patients, and a smaller number of patients who had previously received lamivudine or adefovir. Patients were adults with HBeAg-positive and HBeAg-negative chronic hepatitis B with compensated liver disease. Viread was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease. The number of patients in clinical trials who had lamivudine- or adefovir-associated substitutions at baseline was too small to reach conclusions of efficacy.

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleos(t)ide analogs, including Viread, in combination with other antiretrovirals.

Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including Viread. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue anti-hepatitis B therapy, including Viread. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

New onset or worsening of renal impairment including cases of acute renal failure and Fanconi syndrome has been reported with the use of Viread. It is recommended to assess creatinine clearance (CrCl) before initiating treatment with Viread and monitor CrCl and serum phosphorus in patients at risk, including those who have previously experienced renal events while receiving Hepsera. Administering Viread with concurrent or recent use of nephrotoxic drugs should be avoided.

Viread should not be used with other tenofovir-containing products (e.g., Atripla(R), Complera(R), Truvada(R)). Viread should not be administered in combination with Hepsera.

Due to the risk of development of HIV-1 resistance, Viread should only be used as part of an appropriate antiretroviral combination regimen in HIV-infected patients with or without HBV coinfection. HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with Viread.

Decreases in bone mineral density (BMD) have been observed in HIV-infected patients. It is recommended that BMD monitoring be considered for patients with a history of pathologic fracture or who are at risk for osteopenia. The bone effects of Viread have not been studied in patients with chronic HBV infection. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of Viread.

In controlled clinical trials in patients with chronic hepatitis B with compensated liver disease, the most common adverse reaction (all grades) was nausea, observed in 9 percent of patients taking Viread at week 48. Other adverse reactions observed at week 48 in greater than 5 percent of patients treated with Viread include abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain and skin rash.

In HBV-infected patients with decompensated liver disease, the most common adverse reactions (all grades) reported in greater-than or equal to 10 percent of patients treated with Viread were abdominal pain (22 percent), nausea (20 percent), insomnia (18 percent), pruritus (16 percent), vomiting (13 percent), dizziness (13 percent), and pyrexia (11 percent).

Coadministration of Viread with didanosine increases didanosine concentrations. Use with caution and monitor for evidence of didanosine toxicity (eg, pancreatitis, neuropathy). Didanosine should be discontinued in patients who develop didanosine-associated adverse reactions. In adults weighing >60 kg, the didanosine dose should be reduced to 250 mg when it is coadministered with Viread. Data are not available to recommend a dose adjustment of didanosine for patients weighing <60 kg. Coadministration of Viread with atazanavir decreases atazanavir concentrations and increases tenofovir concentrations. Use atazanavir with Viread only with additional ritonavir; monitor for evidence of tenofovir toxicity. Coadministration of Viread with lopinavir/ritonavir increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity.

The recommended dose for the treatment of chronic hepatitis B is 300 mg once daily taken orally without regard to food. The dosing interval of Viread should be adjusted and renal function closely monitored in patients with moderate and severe renal impairment.

The parent compound of Viread was discovered through a collaborative research effort between Dr. Antonin Holy, Institute for Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic (IOCB) in Prague and Dr. Erik DeClercq, Rega Institute for Medical Research, Katholic University in Leuven, Belgium.

Please see full Prescribing Information for Viread, Complera, Truvada and Hepsera (including BOXED WARNINGS).