FDA Review Perspective – Entecavir for Hepatitis B

1. FDA Review Perspective – Entecavir for Hepatitis B Linda L. Lewis, M.D. Medical Officer Division of Antiviral Drug Products

2. Outline of Presentation • Overview • Efficacy • Safety • Virology/Resistance • Risk-benefit assessment • Pharmacovigilance plan • Questions for the committee

3. Overview

4. Overview • Current treatment for chronic HBV • Interferon (IFN) • Approved 1992 • Requires parenteral administration, significant side effect profile • Lamivudine (LVD) • First effective oral therapy, approved 1998 • Emergence of resistance limits effectiveness • Adefovir (ADV) • Approved 2002 • Known renal toxicity may limit use in some populations

5. Overview • Entecavir (ETV) development program included diverse population • Multi-national sites in North and South America, Europe, and Asia (U.S. subjects about 10%) • 25% women, mix of Asian/non-Asian (Black/African Americans under-represented - 2%) • Different stages of disease and treatment (insufficient data to review in patients with decompensated liver disease)

6. Overview • Key studies – all compare ETV to LVD • 022 - Nucleoside-naïve, e antigen positive, 0.5 mg • 027 - Nucleoside-naïve, e antigen negative, 0.5 mg • 026 - Persistent viremia despite LVD treatment (LVD-refractory), e antigen positive, 1 mg • 014 - LVD-refractory, dose-finding Phase 2 study • Studies 022, 027, and 026 – primary endpoint histologic improvement in liver biopsy after 48 weeks of treatment

7. Overview • Supportive studies in special populations • 015 – Post-liver transplant pilot study • 038 – HIV/HBV co-infected patients • 048 – Patients with decompensated liver disease, compares ETV to ADV, still enrolling • No histologic endpoints; used virologic, serologic, and biochemical endpoints

8. Efficacy Review

9. Efficacy Review • FDA statistical review confirmed BMS’ primary efficacy analysis • Secondary endpoint analyses were in agreement with BMS’ conclusions • Multiple sensitivity analyses and subgroup analyses were performed that supported the primary analysis

10. Histologic Endpoints in Phase 3 ETV Studies – Primary Efficacy Endpoint Primary analysis: Only patients with evaluable baseline biopsy included, missing/inadequate Week 48 biopsy counted as failures

11. Sensitivity Analysis of Primary Endpoint C: Missing/inadequate baseline or Week 48 biopsy excluded D: Includes all treated patients, missing/inadequate Week 48 biopsy counted as failures

12. Selected Secondary Efficacy Endpoints

13. Efficacy – Subgroup Analysis • The treatment effect measured by the primary endpoint was comparable across the following strata: • Gender • Race • Age (by quartiles) • Geographic region • HBV subtype • Baseline ALT (by quartiles) • Baseline bDNA or PCR (by quartiles) • Prior LVD or IFN

14. Efficacy – Subgroup Analysis • The treatment effect measured as proportion of patients with ALT normalization or HBV DNA by PCR < 400 copies/mL at Weeks 24 or 48 was similar according to: • Gender • Race • Age (quartiles)

15. Subgroup Analyses – Primary endpoint by baseline covariates Favors ETV Favors LVD

16. Safety Review

17. Safety Review • FDA clinical review confirmed general safety assessment of ETV • No significant differences in rates or pattern of common AEs or laboratory abnormalities compared to LVD • Rates of SAEs (8% both treatment groups), discontinuations due to AEs (1% ETV, 4% LVD), and deaths (< 1% both groups) were low • ALT flares, CNS adverse events, and malignancies reviewed in detail

18. Safety Review – ALT Flares • In nucleoside-naïve subjects, mean ALT values decreased from baseline to Week 48 in both treatment groups • On-treatment ALT flares uncommon - 15/679 (2%) ETV, 27/668 (4%) LVD • Study design allowed only patients who met Response criteria to discontinue treatment and be followed off therapy; more subjects met the criteria in Study 027; analysis of off-treatment flares represents selected subjects • Off-treatment ALT flares slightly more common both groups - 15/414 (4%) ETV, 30/377 (8%) LVD

19. Safety Review – ALT Flares • In LVD-refractory subjects, on-treatment flares in 4/183 (2%) ETV subjects and 19/190 (10%) LVD subjects • Smaller proportion of LVD-refractory subjects met the Response criteria, discontinued therapy, and were followed off-treatment; selected subgroup • Off-treatment flares occurred in 3/56 (5%) ETV subjects and 0/31 LVD subjects

20. Safety Review – Nervous System Adverse Events in Study 005 • Incidence of grouped CNS events increased with increasing doses, trend toward more frequent AEs of dizziness and insomnia with 0.5 mg

21. Safety Review – On-Treatment Nervous System Adverse Events in Pivotal Studies

22. Safety Review – Malignancies Reported in Clinical Trials • Malignancies were tracked in all clinical trials • 37 subjects reported malignancies in ETV development program • 19/1497 (1.3%) ETV subjects • 9/899 (1%) LVD subjects • From special population studies • 3/83 receiving ETV alone • 2/28 receiving ADV alone • 4/849 receiving ETV + LVD

23. Safety Review – Malignancies Reported in Clinical Trials • Malignancies reported in more than one subject in either treatment group included in the NDA safety database (1497 ETV, 899 LVD): • HCC (7 ETV subjects, 4 LVD subjects) • Basal cell carcinoma (2 ETV subjects, 1 LVD subject) • Breast cancer (1 ETV subject, 2 LVD subjects including one with carcinoma in situ) • Prostate cancer (3 ETV subjects) • Six subjects reported to have malignancies were known to have had previous malignancies

24. Virology/Resistance Review

25. ETV Resistance Profile – Nucleoside-Naïve Subjects (N=434) • No genotypic or phenotypic evidence of ETV-resistance detected among 434 nucleoside-naive subjects analyzed at 48 weeks of ETV treatment (Studies 022 and 027) • 2 subjects in Study 022 experienced confirmed virologic rebound but no resistance mutations identified • Follow-up needed after 48 weeks to determine the ETV resistance pathway in naïve subjects

26. ETV Response in LVD-refractory Subjects (N=189) • LVD-refractory subjects less likely than naïve subjects to achieve HBV DNA < 400 copies/mL (21% vs 83% when data pooled) • > 2 log reductions in viral load and suppression HBV DNA < 400 copies/mL can occur in subjects with LVD-resistant HBV at baseline when treated with 1 mg ETV • LVD-resistance substitutions L80V, L180M, M204V or I can emerge in the HBV of subjects on 1 mg ETV by week 48. • These substitutions often arise in the context of mixtures at these sites and other LVD-resistant mutations at baseline.

27. ETV Resistance Profile – LVD-refractory Subjects • ETV-associated resistance substitutions in HBV polymerase: I169, T184, S202, and/or M250 • Emerged only when LVD-resistant mutations at L180 and/or M204 were present at baseline • 14/189 (7.4%) of evaluated LVD-refractory subjects treated with ETV developed resistance mutations at 48 weeks • Mutations can be associated with virologic rebound during prolonged therapy (3/14 at Week 48)

28. Cross-Resistance • LVD-resistant HBV clinical isolates showed 3- to 52-fold reduced susceptibility to ETV by in vitro assays • HBV developing ETV-associated resistance substitutions in the clinical trials were susceptible to ADV in vitro but remained resistant to LVD • ADV-resistant HBV was susceptible to ETV in vitro

29. ETV Resistance – Summary • No ETV resistance has been detected in nucleoside-naïve subjects treated with ETV through 48 weeks; longer term data are needed • ETV resistant mutations can emerge on ETV treatment when LVD mutations are present; emerge at a rate of <10% at 48 weeks • These ETV resistance mutations are associated with virologic rebound • ETV is cross-resistant with LVD but not ADV by in vitro assays

30. Risk-benefit Assessment and Pharmacovigilance Plan

31. Risk-benefit assessment • Patients with chronic HBV have increased risk of HCC and probably other malignancies • Accumulating evidence that treatment of chronic HBV may decrease the progression of disease • Efficacy of ETV as measured by liver histology, HBV DNA, or other endpoints better or equivalent to that of LVD over 48 weeks of treatment • General safety and tolerability profile of ETV similar to that of LVD

32. Risk-benefit assessment • Positive carcinogenicity findings in animal studies are not rare and are described in approved product labels • Animal carcinogenicity studies identify hazard signal not level of risk • Quantifying the human cancer risk is difficult • Mechanism of carcinogenicity is likely to be different for different drugs • Risk-benefit assessment has been made on a case-by-case basis

33. Pharmacovigilance plan • Increased monitoring and analysis of post-marketing safety reports and reporting to FDA • Continued tracking of subjects in clinical trials (through ongoing rollover and observational studies) • Proposed large simple safety study to evaluate occurrence of major events in broader clinical use

34. Pharmacovigilance plan – Proposed post-marketing study • Strengths of proposed study • Study design with randomization, active control, stratification by prior treatment, pertinent endpoints and planned analyses • Will evaluate international population, “real-life” use, allow enrollment of patients with concomitant HCV and HIV and spectrum of HBV disease • Size of study (12,500), enrollment through many local physicians each following relatively small number of patients

35. Pharmacovigilance plan – Proposed post-marketing study • Potential limitations of proposed study • Length of study may not be adequate to identify malignancies with long latency • Subjects may switch from original assigned treatment to comparator group • Number lost to follow-up may be higher than anticipated • No specific tumor type can be targeted • No way to stratify for all possible co-factors for malignancy in population

36. Pharmacovigilance plan – Proposed post-marketing study • Study would be similar in size and scope to some others that have been requested by FDA or that have identified other risk factors • Study might identify changes in 5-8 year risk of HCC or other tumors in patients receiving treatment for HBV • Negative findings at the end of the study may not equate to a conclusion of “no risk”

37. Pharmacovigilance plan – Animal carcinogenicity findings in context • Antiviral drugs with positive animal carcinogenicity findings; risk-benefit decisions • Zidovudine – Consequences of untreated HIV, uninfected infants exposed perinatally followed in long-term outcome study (PACTG 076/219) • Ritonavir – Consequences of untreated HIV • Ganciclovir – Consequences of untreated CMV, boxed warning in label • Cidofovir – Consequences of untreated CMV, boxed warning in label • Famciclovir – Treatment for HSV, weak hazard signal based on animal data

38. Pharmacovigilance plan – Animal carcinogenicity findings in context • Drugs with positive animal carcinogenicity findings approved for other indications • Lipid-lowering drugs • Anticonvulsants • Osteoporosis • ADHD • Gastroesophageal reflux

39. Pharmacovigilance plan • The FDA has requested post-marketing studies to assess the risk of human cancer for some approved drugs • Long-term prospective observational study of a drug compared to an appropriate control group • Registry of patients using the drug long term • Post-marketing surveillance program • Retrospective cohort study to measure the incidence of a specific tumor and the contribution of a drug

40. FDA Summary • In well-conducted clinical trials ETV was shown to provide superior efficacy compared to LVD in multiple analyses of histologic, virologic, biochemical, and composite endpoints • Treatment benefit of ETV over LVD greatest in LVD-refractory subjects • General safety and tolerability of ETV was similar to LVD in all populations studied • Safety and tolerability profile of ETV similar in nucleoside-naïve and LVD-refractory subjects

41. FDA Summary • Pre-clinical studies identified ETV as carcinogenic in mice and rats • Clinical relevance of animal carcinogenicity data is unknown • To date, no increase in human malignancies has been identified in the clinical trials • BMS has proposed a large simple safety study designed to identify increased cancer risk in patients receiving ETV as part of their pharmacovigilance program

42. Questions for the Committee

43. Question 1 How would you assess the risk-benefit of ETV in the context of the available clinical safety, efficacy, resistance, and non-clinical carcinogenicity data?

44. Question 2 • Does the risk-benefit assessment for entecavir support the approval of entecavir for the treatment of chronic HBV in adult patients? • If the answer to #2A is no, what information would be needed to support a resubmission?

45. Question 3 • If the answer to #2A is yes, discuss whether the results of the rodent carcinogenicity studies should impact the Indication and Usage section of the product labeling. • Based on the available data, discuss the potential role of entecavir in the HBV treatment armamentarium.

46. Question 4 • Assess the potential risks and benefits of proceeding with development of entecavir for the treatment of chronic HBV in pediatric patients. • What, if any, additional information is needed in order to proceed?

47. Question 5 Discuss the applicant’s proposed pharmacovigilance plan to address human cancer risk, including comments on the design of the proposed large simple study.

48. Question 6 Are there other issues that you would like to see addressed through post-marketing commitments?