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  1. FDA’s Antiviral DrugsAdvisory Committee Meeting BARACLUDETM(entecavir / BMS 200475) 11 March 2005

  2. Introduction Elliott Sigal, MD, PhD

  3. Global Impact of Hepatitis B 15–40% develop cirrhosis, liver failureor hepatocellular carcinoma 2 billion with past / present HBV infection 350–400 million with chronic hepatitis B World Population 6 billion Worldwide: ~1 million / year die from HBV-associated liver disease United States: Chronically infected ~1.25 million; ~5000 / year die

  4. Background Richard Colonno, PhD

  5. Proposed Indication • Entecavir is indicated for the treatment of chronic hepatitis B infection in adults with evidence of active liver inflammation • Usual dose:0.5 mg tablet once daily • Lamivudine-refractory:1.0 mg tablet once daily

  6. BMS Presentation • Introduction Elliott Sigal, MD, PhD • Chief Scientific Officer & President, Pharmaceutical Research Institute • Background Richard Colonno, PhDVice President, Infectious Diseases Drug Discovery • Nonclinical Safety Lois Lehman-McKeeman, PhD • Distinguished Research Fellow, Discovery Toxicology • Clinical Efficacy / Evren Atillasoy, MD • Clinical SafetyDirector, US Medical Affairs • Viral Resistance Richard Colonno, PhDVice President, Infectious Diseases Drug Discovery • Pharmacovigilance Donna Morgan Murray, PhDand SummaryExecutive Director, Global Regulatory Sciences

  7. Consultants Available to the Committee • Hepatology • Health Policy • Hepatology • Toxicology/ • Pathology • Biostatistics • Toxicology/ • Pathology • Adrian Di Bisceglie, MD • Saint Louis University School of Medicine • Samuel A. Bozzette, MD, PhD • University of California, San Diego • Jules L. Dienstag, MD • Massachusetts General Hospital • James Swenberg, DVM, PhD • University of North Carolina • LJ Wei, PhD • Harvard University • Gary M. Williams, MD, DABT • New York Medical College

  8. Impact of Viral Replication on Disease Progression: Taiwan Cohort Study Results • The incidence of hepatocellular carcinoma (HCC) and liver cirrhosis is correlated with level of viral replication • Persistent elevation of viral load over time has the greatest impact on HCC risk • Viral load predicts risk of future HCC independent of HBeAg status and serum ALT level • This risk increases with increasing viral load EASL April 2005

  9. Pathophysiologic Cascade of Chronic Hepatitis B Infection: Significance of HBV Replication HBV Replication (Measured by Serum HBV DNA) Liver Inflammation ALT Elevation DiseaseProgression Liver Failure Liver Cancer Transplant Death Worsening histology Necroinflammation Fibrosis Cirrhosis

  10. Placebo (n = 215) ITT population Lamivudine (n = 436) Placebo 18% Percentage withDisease Progression p = 0.001 Lamivudine 8% Time to Disease Progression (months) Liaw et al: LVD Treatment PreventsDisease Progression vs Placebo Liaw et al.N Engl J Med 2004;351:1521-31.

  11. Liaw et al: Incidence of Disease Progression by LVDR Substitutions Number (%) Lamivudine Wild Type (N = 221) LVDR(YMDD) (N = 209) Placebo (N = 214) 11 (5) 23 (11) 38 (18) Adapted from Liaw et al.N Engl J Med 2004;351:1521-31.

  12. Chronic HBV: Improved Oral Antiviral Therapy • Effective • Safe and well tolerated • Potent • Has low rates of resistance • Maintain future treatment options • Does not select for LVD or ADV resistance

  13. O N NH NH2 CH2 N N OH OH Entecavir • Cyclopentyl guanosine analog • Potent Selective inhibitorof HBV replication • No significant activity against HIV • Poor substrate for humanpolymerases • No inhibition of humanmitochondrial (gamma) polymerase • Inhibits all 3 HBV polymerase functions:Priming, DNA-dependent synthesis, Reverse transcription • Phosporylation: Intracellular ETV-TP T ½ ~ 15 hrs

  14. Comparative EC50 for HBV In Cell Culture WT: ETV EC50 = 4 nM (> 300-fold more potent)

  15. Woodchuck Model • Predictive model of HBV antivirals in humans • Efficacy • Toxicity • Progression to HCC • ETV is a potent inhibitor of WHBV polymerase • Long-term treatment (ETV 0.5 mg/kg): 14 or 36 months • Sustained virologic suppression up to 8 logsfor 1 to 3 years WHBV – Woodchuck Hepatitis B Virus

  16. Woodchuck Studies: Survival N = 56 N =50 N =6 N =5 * ‡ Animals Survivingto Age 4 (%) * ‡ ControlUninfected ControlInfected ETV14 mo. ETV36 mo. Treatment * Combined p = 0.0002 ‡ Historical control. Tennant, et al. Viral Hepatitis and Liver Disease 1988: 462-464 R. Colonno, et al. Journal of Infectious Diseases, 2001;184:1236-45

  17. Nonclinical Safety Lois Lehman-McKeeman, PhD

  18. Rodent Carcinogenicity Studies: Overview • Lifetime studies in rats and mice to identify hazard • Study Design • 50-60 animals / sex / group • Dose up to maximum-tolerated dose (MTD) • Safety margin over human exposure • Tumor Evaluation • Standard histopathologic assessment • Spontaneous tumors observed

  19. Rodent Carcinogenicity Studies:Statistical Evaluation • Compare tumor incidences in treated vs control animals • Peto-Pike trend test • Adjusts for time and cause of death • Statistical significance based on incidence < 0.005 for a common tumor < 0.025 for a rare tumor • Determine dose level that results in no significant trend FDA Guidance, 2001

  20. Rodent Carcinogenicity: Results for ETV • Tumors concluded to be relevant for the evaluation of human safety after review with FDA CAC • Tissues showing preneoplastic changes • Mice: lung adenomas and carcinomas • Tissues not showing preneoplastic changes • Male Mice: liver carcinomas • Female Mice: Vascular tumors • Male rats: Gliomas • Female rats: Gliomas, liver adenomas,skin fibromas

  21. Key Carcinogenicity Findings: Mouse Lung • Dosage, mg/kg 0 0.004 0.04 0.4 4 • Exposure: 0.5 mg (M, F) 0 2, 2 5, 2 24, 19 75, 70 • Exposure: 1 mg (M, F) 0 1,1 3, 3 14, 11 42, 40 • MALES % Tumor Incidence • Lung Adenoma 7 13 19* 28* 33* • Lung Carcinoma5 7 7 12 25* • FEMALES • Lung Adenoma 13 8 7 27 25* • Lung Carcinoma 7 5 3 8 27* * p < 0.005

  22. Lung Tumors in Mice • Preneoplastic effects observed in mouse lung: • Increased macrophages • Proliferation of Type II pneumocytes • Sustained proliferation of Type II pneumocytesis causally-related to tumor development • Macrophages required • ETV is chemotactic • No preneoplastic changes observed in rats, dogs, monkeys • Entecavir is not chemotactic for human monocytes

  23. Key Carcinogenicity Findings in Mice • Dosage, mg/kg 0 0.004 0.04 0.4 4 • Exposure: 0.5 mg (M, F) 0 2, 2 5, 2 24, 19 75, 70 • Exposure: 1 mg (M, F) 0 1,1 3, 3 14, 11 42, 40 • MALES % Tumor Incidence • Liver Carcinoma 1 2 5 3 13* • FEMALES • Hemangiomas19 22 20 18 43* * p < 0.005

  24. phosphorylation ETV ETV-TP GDP dGTP dGDP High Dose Rodent Tumors:Possible Mode of Action • ETV-induces dNTP pool perturbations: • Imbalance alters fidelity of DNA replication and repair • Increased tumor development

  25. Key Carcinogenicity Findings in Rats Dosage, Males 0 0.003 0.02 0.2 1.4 Dosage, Females 0 0.01 0.06 0.4 2.6 Exposure: 0.5 mg (M, F) 0 <1, <1 <1, 1 8, 8 62, 43 Exposure: 1 mg (M, F) 0 <1, <1 <1, <1 5, 4 35, 24 MALES % Tumor Incidence Brain Glioma 0 2 2 3 7** FEMALES Brain Glioma 0 0 2 0 5** Liver Adenoma 1 3 5 2 13* Skin Fibroma 0 0 2 3**5** * p < 0.005; ** p < 0.025

  26. Human Risk Assessment Lifetime studies in rats and mice identify carcinogenic hazard • Human cancer risk assessment • Other relevant data • Dose-response relationships • Exposure multiples • Assessment for ETV • Mouse lung tumors may be species specific • ETV-induced changes in dNTP pools may contribute to non-linear dose response

  27. Clinical Efficacy Evren Atillasoy, MD

  28. Entecavir Clinical Program • Broad experience: • Patterns of HBV disease • Global • NDA: ~ 1500 ETV-treated patients • Comparison versus active control (LVD)

  29. Clinical Experience Special Populations N = 139 Phase 2 N = 757 Phase 3 N = 1633 901 Rollover ETV + LVD ETV 049 5 YearPost-Treatment Observation Safety Update

  30. Dose Response –Mean Reduction in HBV DNA, log10 c/mL Nucleoside-Naive Patients LVD-Refractory Patients Weeks ETV 0.01(N = 52) ETV 0.1(N = 34) ETV 0.1(N = 47) ETV 0.5(N = 47) ETV 0.5(N = 43) LVD 100(N = 40) ETV 1.0(N = 42) LVD 100(N = 45) Studies 005 and 014

  31. ClinicalEfficacy • Naïve eAg+ (022) • Naïve eAg- (027) • LVD-refractory eAg+ (026)

  32. Phase III Study Design • ETV 0.5 mg (N = 354) Responders • LVD 100 mg (N = 355) Partial Responders • ETV 0.5 mg (N = 325) • LVD 100 mg (N = 313) • ETV 1.0 mg (N = 141) Non-Responders • LVD 100 mg (N = 145) Baseline (Liver Biopsy) Week 48 (Liver Biopsy) Week 52 (Patient Management Decision)

  33. Key Inclusion Criteria • Liver biopsy • Documented HBsAg+ for ≥24 weeks • Compensated liver diseae • ALT 1.3 − 10 x ULN • HBV DNA by bDNA eAg+: ≥ 3 MEq/mL (3 x 106 c/mL) eAg- : ≥ 0.7 MEq/mL (7 x 105 c/mL) • HIV, HCV and HDV seronegative • Creatinine ≤ 1.5 mg/dL Studies 022, 027 and 026

  34. Baseline Patient Demographics • Naïve eAg+ • N = 709 • Naïve eAg- • N = 638 • LVD-Ref eAg+ • N = 286 • Age, mean (years) • 35 • 44 • 39 • Male • 75% • 76% • 76% • White • 40% • 58% • 62% • Asian • 57% • 39% • 37% • Region SA – South AmericaNA – North America Studies 022, 027 and 026

  35. Baseline HBV Characteristics • Naïve eAg+ • N = 709 • Naïve eAg- • N = 638 • LVD-Ref eAg+ • N = 286 • 9.7 • 7.6 • 9.4 • HBV DNA by PCR, • mean (log10 copies/mL) • ALT, mean (U/L) • 143 • 142 • 128 • HBV subtype Studies 022, 027 and 026

  36. Baseline Histology Scores Studies 022, 027 and 026

  37. Patient Disposition Number of Patients (96%) (90%) (96%) (95%) (94%) (87%) a Percent based on treated patients Studies 022, 027 and 026

  38. Liver Biopsy Assessment • Single pathologist (Zachary Goodman, MD - AFIP) • Blinded to treatment assignment • Blinded to temporal sequenceof biopsy pairs Studies 022, 027 and 026

  39. Primary Endpoint at Week 48 • Histologic Improvement at Week 48,relative to baseline • ≥ 2-point reduction in Knodell necroinflammatoryscore with no worsening in Knodell fibrosis • Evaluable Baseline Histology Cohort • Baseline Knodell necroinflammatory score ≥ 2 • 89% of treated patients • Missing / inadequate Week 48 biopsy =no improvement Studies 022, 027 and 026

  40. Primary Endpoint in Naïve Patients: Histologic Improvement at Week 48 • Naïve eAg+ • Naïve eAg- Difference Estimate (95% CI)p-value Studies 022 and 027

  41. ETV LVD Co-Primary Endpoints at Week 48in LVD-Refractory Patients Histologic Improvement HBV DNA by bDNA (< 0.7 MEq/mL) and ALT (< 1.25 x ULN) Percent Diff. Est. (97.5% CI): 27.3 (13.6, 40.9) 50.5 (40.4, 60.6) p < 0.0001 p < 0.0001 Study 026

  42. ETV LVD Secondary Histology Endpoint:Ishak Fibrosis – Improvement at Week 48 Naïve eAg+ Naïve eAg- LVD-Ref eAg+ Improved Percent No change 46 40 41 34 44 42 Worsened Improvement: p = 0.41 p = 0.65 p < 0.01 Studies 022, 027 and 026

  43. Non-Histology Secondary Endpoints at Week 48 • Virologic: • Mean HBV DNA reduction from baseline by PCR • HBV DNA < 400 copies/mL by PCR • Biochemical: • Normalization of ALT (≤ 1 x ULN) • Serologic: • HBe Seroconversion (eAg+ patients) Studies 022, 027 and 026

  44. HBV DNA < 400 copies/mL Through Week 48 –Naïve Studies Naïve eAg+ Naïve eAg- ETV (N = 354) LVD (N = 355) ETV (N = 325) LVD (N = 313) 91 73 69 Percent 38 p < 0.0001 p < 0.0001 Weeks Studies 022 and 027

  45. HBV DNA < 400 copies/mL Through Week 48 – LVD-Refractory Study ETV (N = 141) LVD (N = 145) 21 Percent p < 0.0001 1 Weeks Study 026

  46. ETV LVD HBV DNA Mean Reduction at Week 48 Naïve eAg+ Naïve eAg- LVD-Ref eAg+ log10 copies/mL p < 0.0001 p < 0.0001 p < 0.0001 Studies 022, 027 and 026

  47. ETV LVD ALT ≤ 1 x ULN at Week 48 Naïve eAg+ Naïve eAg- LVD-Ref eAg+ Percent p = 0.02 p < 0.05 p < 0.0001 Studies 022, 027 and 026

  48. ETV LVD HBe Seroconversion at Week 48 Naïve eAg+ LVD-Ref eAg+ Percent p = 0.33 p = 0.06 Studies 022 and 026

  49. Summary of Week 48 Efficacy Naïve eAg+ Naïve eAg- LVD-Ref eAg+ Histologic Improvement HBV DNA < 400 copies/mL ALT ≤ 1 x ULN HBe Seroconversion LVD Better ETV Better ETV - LVD: Difference Estimate and CI Studies 022, 027 and 026

  50. Clinical Safety