Approved March, 2005
Baraclude (entecavir) is a nucleoside analog with selective activity against hepatitis B virus (HBV). Nucleoside analogs inhibit DNA synthesis in HBV infected cells, reducing viral load and disease burden in infected patients. In animal studies, long term administration of the drug was shown to reduce viral load to undetectable levels for 3-5 years.
Baraclude is specifically indicated for the treatment of chronic HBV infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease.
Baraclude is supplied as both an oral tablet and an oral solution. The recommended dose for treatment-naïve adults and adolescents age 16 or older is 0.5 mg once daily on an empty stomach. The recommended dose is increased to 1.0 mg once daily for patients with a history of hepatitis B viremia receiving lamivudine or with known lamivudine resistance mutations. For patients with renal impairment (creatine clearance <50 mL/min), dosage adjustment may be necessary.
FDA approval of Baraclude was based on 3 phase III clinical trials, enrolling a combined total of 1633 patients 16 years of age or older with chronic HBV infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of viral replication (detectable serum HBV DNA, as measured by the bDNA hybridization or PCR assay). Patients had persistently elevated ALT levels =1.3 times the upper limit of normal (ULN) and chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. This included two studies in nucleoside-therapy-naïve patients (Study AI463022, AI463027), and one in lamivudine refractory patients (AI463026).
AI463022; Study Design
This multinational, double-blind study investigated the safety and efficacy of Baraclude, versus approved therapy with lamivudine. 709 subjects (of 715 randomized) nucleoside-naive patients with chronic HBV infection and detectable HBeAg were randomized to receive 0.5 mg once daily Baraclude or 100 mg once daily lamivudine for 52 weeks. in 709 (of 715 randomized) nucleoside-naive patients with chronic HBV infection and detectable HBeAg. At baseline, patients had a mean Knodell Necroinflammatory Score (a standard diagnostic scale) of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 9.66 log10 copies/mL, and mean serum ALT was 143 U/L.
AI463027; Study Design
This multinational, double-blind study also investigated 0.5 mg once daily Baraclude versus 100 mg once daily lamivudine for 52 weeks. 638 (of 648 randomized) nucleoside-naive patients with HBeAg-negative (HBeAb-positive) chronic HBV infection were enrolled. At baseline, patients had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 7.58 log10 copies/mL, and mean serum ALT level was 142 U/L.
In both studies Baraclude was found to be superior to lamivudine in the primary efficacy endpoint of histologic improvement, defined as a 2-point reduction or greater in Knodell Necroinflammatory Score, with no worsening in Knodell Fibrosis Score at week 48. Efficacy was also seen in secondary efficacy measures, including of reduction in viral load and ALT normalization.
AI463026: Study Design
This multinational, randomized, double-blind study enrolled 286 (of 293 randomized) patients with lamivudine-refractory chronic HBV infection, who either continued on 100 mg lamivudine, or began taking 1 mg Baraclude daily for 52 weeks. At baseline, patients had a mean Knodell Necroinflammatory Score of 6.5, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 9.36 log10 copies/mL, and mean serum ALT level was 128 U/L.
Baraclude was shown to be superior to lamivudine in producing histological improvement, with 55% of individuals achieving improvement of 2 points or greater on the Knodell scale, vs 28% for continued lamivudine (p<0.01). Superiority was also seen in Ishtak Fibrosis Score with 34% achieving improvement vs. 16% for lamivudine (p<0.01). Significance was reached in a number of laboratory efficacy measures, including proportion of patients with undetectable HBV DNA levels (<300 copies/mL: 19% vs 1%, p<0.0001), mean change in viral DNA load from baseline (log10 copies/mL: -5.11% vs. -0.48%, p<0.0001) and percentage of patients achieving ALT level normalization (61% vs. 15%, p<0.0001).
Ongoing Study Commitments
Adverse events associated with the use of Baraclude may include, but are not limited to, the following:
In addition, nucleoside analogs have been associated with lactic acidosis and severe hepatomegaly with steatosis, including fatal cases. Abrupt cessation of nucleoside therapy, including Baraclude, has been associated with severe acute exacerbations of HBV disease state. Patients are recommended to consult closely with their doctors regarding liver function both while taking Baraclude and before stopping treatment.
Baraclude is a small-molecule guanosine nucleoside analog with selective activity against hepatitis B virus (HBV) polymerase. The drug is effectively phosporylated to the active triphosphate form, which competes with the natural substrate deoxyguanosine triphosphate, functionally inhibiting reverse transription actions of HBV polymerase, including base priming, negative strand DNA reverse transcription from RNA, and synthesis of the positive strand of HBV DNA. The drug produces only weak inhibition of normal cellular DNA polymerases and mitochondrial DNA polymerase.
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