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Entecavir for Hepatitis B NDA 21-797 NDA 21-798 ANTIVIRAL DRUGS ADVISORY COMMITTEE

Entecavir for Hepatitis B NDA 21-797 NDA 21-798 ANTIVIRAL DRUGS ADVISORY COMMITTEE March 11, 2005. Geographic Distribution of Chronic HBV Infection. HBsAg Prevalence. ³ 8% - High. 2-7% - Intermediate. <2% - Low. Hepatitis B by Year, United States, 1966 - 2000.

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Entecavir for Hepatitis B NDA 21-797 NDA 21-798 ANTIVIRAL DRUGS ADVISORY COMMITTEE

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  1. Entecavir for Hepatitis B NDA 21-797 NDA 21-798 ANTIVIRAL DRUGS ADVISORY COMMITTEE March 11, 2005

  2. Geographic Distribution of Chronic HBV Infection HBsAg Prevalence ³8% - High 2-7% - Intermediate <2% - Low

  3. Hepatitis B by Year, United States, 1966 - 2000 Infant immunization recommended HBsAg screening of pregnant women recommended Vaccine licensed OSHA rule enacted Adolescent Immunization recommended Decline among MSM & HCWs Decline among injecting drug users Source: NNDSS

  4. Hepatitis B • Affects ~ 400 million subjects worldwide • 1.25 million subjects in the U.S. • Most common cause of cirrhosis and HCC • Limited treatment options • Interferon • Lamivudine • Adefovir dipivoxil

  5. Hepatitis B:Treatment Options • Interferon • for compensated patients • side effect profile • Lamivudine • well-tolerated • development of resistance • Adefovir dipivoxil • active against lamivudine-resistant virus • nephrotoxicity

  6. Entecavir • Guanosine nucleoside analogue • Activity against HBV polymerase • Inhibits lamivudine-resistant virus in cell culture • Antiviral activity demonstrated in animal models • 4/6 WHV-infected woodchucks treated with ETV survived 3 years and 2/6 died of HCC, compared to a 4% survival rate in infected historic controls

  7. Entecavir • Non-clinical pharmacology/toxicology • Increased incidence of tumors in rodent studies • Lung tumors observed at low multiples of ETV exposure • Other tumors occurred at higher multiples of ETV exposure relative to humans • Animal data needs to be interpreted in context of clinical data

  8. Entecavir • Clinical studies • Conducted in eAg +, eAg- and LVD-resistant populations • Multicenter, multinational • Used endpoints similar to other approved therapies • Histologic improvement @ week 48 • 2o endpoints included virologic, biochemical and serologic

  9. Hepatitis B Advisory Committee Issues • Discuss clinical trial data in context of animal carcinogenicity test results and implications for human use • Proposed pharmacovigilance study • Pediatric usage • Labeling implications • Post-marketing studies

  10. Advisory Committee Agenda • 8:00 a.m. Call to Order and Welcoming Remarks • 8:15 a.m.BMS Presentation/Clarifying questions • 9:45 a.m.Break • 10:00 a.m.FDA Presentation/Clarifying questions • 11:00 a.m.Discussion • 12:00 p.m.Lunch • 1:00 p.m.Open Public Hearing • 2:00 p.m.Continue Discussion and Questions to the Committee • 5:00 p.m.Adjourn

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