Hepsera (adefovir dipivoxil) was approved by the FDA in September 2002 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, available as an oral 10 mg tablet, is the first nucleotide analog to be approved for this indication.
Clinical trials data suggested that treatment with adefovir dipivoxil was associated with suppression of hepatitis B virus (HBV) DNA to undetectable levels in 80% of subjects who received 12 to 15 months of treatment. These results complement previous data characterizing adefovir dipivoxil as a compound that remains active against all clinically relevant strains of HBV tested to date. The open-label study involved 23 subjects with chronic HBV infection who had failed treatment with the antiviral agent lamivudine (3TC).
In June 2001, interim phase III data evaluating adefovir dipivoxil showed that the trial met its primary endpoint of improvement in liver histology at week 48 compared to baseline. The two-year, randomized, double-blind, placebo-controlled trial enrolled 515 subjects with chronic HBV infection. Two doses of adefovir dipivoxil were evaluated, including the 10 mg dose that was approved and an exploratory 30 mg dose. Improvement in liver histology was observed in 53% of subjects treated with adefovir dipivoxil 10 mg, compared to 25% of placebo-treated subjects, as measured by liver biopsies. Similar efficacy results were obtained for adefovir dipivoxil 10 and 30 mg in terms of liver histology, seroconversion and reduction in HBV DNA.
In September 2001, preliminary phase III trial results indicated that treatment with adefovir dipivoxil 10 mg once daily for 48 weeks was associated with improvements in liver histology in 64% of drug-treated subjects compared to 33% of subjects who received placebo. The ongoing, multicenter, double-blind, placebo-controlled trial (Study 438) included 185 subjects with precore mutant chronic hepatitis B virus and compensated liver function. In addition to the primary endpoint, the trial met secondary efficacy endpoints including change in HBV viral load.
The most common adverse events reported during clinical studies were:
In addition, adverse events reported in pre- and post-liver transplant patients included, but were not limited to:
Warnings by the FDA:
1. Severe acute exacerbations of hepatitis have been reported in patients who have discontinued anti-hepatitis B therapy, including therapy with Hepsera.
2. In patients at risk of or having underlying renal dysfunction, chronic administration of Hepsera may result in nephrotoxicity.
3. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals.
Adefovir dipivoxil is a diester prodrug of adefovir, which is an acyclic nucleotide analog of adenosine monophosphate. Adefovir is phosphorylated to the active metabolite, adefovir diphosphate, by cellular kinases. Adefovir diphosphate inhibits HBV DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. (From FDA prescription label)
For further information about Hepsera, visit the product web site at www.hepsera.com.