Baraclude (entecavir)Company: Bristol-Myers Squibb
Approval Status: Approved March, 2005
Treatment for: Hepatitis B
Areas: Immune System
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-na?ve 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-na?ve 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
- Deferred pediatric study/substudy under PREA for the treatment of chronic HBV with evidence of active liver inflammation in pediatric subjects ages from birth to 16 years of age. This study will determine the entecavir exposure (pharmacokinetics profile) for pediatric subjects ages from birth through 16 years of age to support dose-selection for the efficacy and safety assessment.
Protocol submission due: December, 2005
Final report submissions due: July, 2007
- Deferred pediatric study under PREA for the treatment of chronic HBV with evidence of active liver inflammation in pediatric subjects ages from birth to 16 years of age. Using doses selected based on study/substudy in postmarketing commitment 1, conduct a pediatric safety and efficacy study of entecavir with efficacy based on the results of a variety of virologic, biochemical, serologic, and composite endpoints over at least 48 weeks of dosing and safety monitored over 48 weeks.
Protocol submission due: July, 2007
Final report submissions due: December, 2009
- Conduct and submit a final study report for a large simple safety study to assess the major clinical outcomes of death, progression of liver disease, and cancer in a broad population of HBV-infected patients using entecavir compared to standard of care over a period of 5 to 10 years of follow-up. The study should be randomized, stratified according to prior treatment, and of sufficient size to detect a difference in cancer outcomes between the two groups. Monitoring by an independent Safety Monitoring Board is recommended. Given the anticipated length of the study, it is recommended that the protocol include plans to assess the adequacy of enrollment and submit interim reports of results at yearly intervals.
Protocol submission: July, 2005
Final report submission: July, 2016
- Complete and submit the final study report for ongoing Study 048 comparing the efficacy and safety of entecavir to adefovir in patients with chronic HBV and decompensated liver disease.
Final report submission: October, 2008
- Conduct and submit a final study report for a larger study of efficacy and safety of entecavir in patients who are post-liver transplant. This study should enroll 50 to 100 patients and include analysis of virologic, biochemical, and serologic endpoints, evaluation of safety, and evaluation of HBV resistance.
Protocol submission: December, 2005
Final report submission: by December, 2008
- Complete and submit the final study report for ongoing Study 038 evaluating the safety, efficacy, and resistance profile of entecavir in patients with HIV/HBV co-infection.
Final report submission: July, 2006
- Complete and submit the final study reports for ongoing Studies 022, 027, and 026 and evaluate the safety and efficacy of entecavir compared to lamivudine during the second year of continued blinded study drug dosing.
Final report submissions: October, 2006
- Complete and submit the final study reports for ongoing Studies 901 and 049 to obtain long-term dosing (> five-years for some subjects) and follow-up data (> five-years for some subjects) on entecavir use in subjects rolled-over from the Phase-2 and Phase-3 clinical trials to address the following issues: maintenance of virologic suppression; durability of HBeAg seroconversion and the rate of new events; risk of drug-related adverse events including malignancy; and risk for development of resistance to entecavir.
Final report submission: July, 2011
- Continue to perform genotypic and phenotypic analyses of HBV DNA from patients receiving long-term entecavir therapy in ongoing clinical trials 022, 026, 027, 038, 048, and 901. Provide 96-, 144-, and 240-week data on the genotypic and phenotypic analyses of isolates from entecavir-treated patients with chronic HBV who experienced virologic rebound in serum HBV DNA levels in both the nucleoside-na?ve and the lamivudine resistant studies.
Report submissions: March 29, 2006 and annually, thereafter, summary reports of overall consecutive resistance analyses.
- Conduct and submit a final study report for a study to evaluate the safety, efficacy, and resistance profile of entecavir used in combination with another oral anti-HBV therapy in treatment-na?ve and treatment-experienced patients with chronic HBV to determine if there is any added benefit of combination therapy.
Protocol submission: December, 2005
Final report submission: December, 2009
- Determine the in vitro susceptibility to entecavir and adefovir of substitutions at rtI169 alone and in the context of lamivudine- and entecavir-associated resistance mutations. Also, determine the in vitro susceptibility to entecavir of tenofovir-associated resistance substitutions at rtA194 in a lamivudine-resistant background.
Final report submission: July, 2006
- Conduct and submit a final study report to evaluate the use of entecavir in treatment of chronic HBV infection in minority racial/ethnic groups that were under-represented in the pivotal clinical trials (Blacks/African Americans, Hispanics).
Protocol submission: December, 2005
Final report submission December, 2008
Adverse events associated with the use of Baraclude may include, but are not limited to, the following:
- Liver enzyme elevation
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.
Mechanism of Action
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.
Arosemena LR, Cortes RA, Servin L, Schiff ER. Current and future treatment of chronic hepatitis B. Minerva Gastroenterologica e Dietologica. 2005 Mar;51(1):77-93.
Tenney DJ, Levine SM, Rose RE, Walsh AW, Weinheimer SP, Discotto L, Plym M, Pokornowski K, Yu CF, Angus P, Ayres A, Bartholomeusz A, Sievert W, Thompson G, Warner N, Locarnini S, Colonno RJ.Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine. Antimicrobial Agents and Chemotherapy. 2004 Sep;48(9):3498-507
Julander JG, Colonno RJ, Sidwell RW, Morrey JD. Characterization of antiviral activity of entecavir in transgenic mice expressing hepatitis B virus. Antiviral Research. 2003 Aug;59(3):155-61
Baraclude Drug Information
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