1. Adefovir Dipivoxil 10 mg for the Treatment of Chronic Hepatitis B NDA 21-449 August 6, 2002 Gilead Sciences, Inc.

2. Proposed Indication Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active liver disease

3. Consultants  Jules L. Dienstag, MD Professor of Medicine, Harvard Medical School Massachusetts General Hospital (Gastrointestinal Unit)  Zachary D Goodman, MD, PhD Chief, Division of Hepatic Pathology Armed Forces Institute of Pathology  Paul Klotman, MD Chief, Division of Nephrology and Chairman, Department of Medicine Mt. Sinai School of Medicine  Eugene Schiff, MD Professor of Medicine and Chief, Division of Hepatology Director,Center For Liver Diseases University of Miami School of Medicine  Teresa Wright, MD Professor of Medicine University of California, San Francisco

4. Agenda Introduction Alan Taylor, PhD Chronic Hepatitis B Vice President Pre-clinical Regulatory Affairs Clinical Pharmacokinetics Clinical Efficacy & Safety Carol Brosgart, MD Pivotal studies Vice President Supportive studies Clinical Research Further studies

5. 1 Lok AS, Gastroenterology 2001 2 Lee W, NEJM 1997 Chronic Hepatitis B A Global Healthcare Issue  400 million with chronic hepatitis B worldwide 1 — HBeAg+ — HBeAg–  25-33% develop progressive disease — Cirrhosis or hepatocellular carcinoma — 1 million deaths per year  1.25 million with chronic hepatitis B in US 2 — 17,000 hospitalizations and 5,000 deaths per year — 6th leading indication for adult liver transplantation  400 million with chronic hepatitis B worldwide 1 — HBeAg+ — HBeAg–  25-33% develop progressive disease — Cirrhosis or hepatocellular carcinoma — 1 million deaths per year  1.25 million with chronic hepatitis B in US 2 — 17,000 hospitalizations and 5,000 deaths per year — 6th leading indication for adult liver transplantation

6. Current Therapies for Chronic Hepatitis B  Limited treatment options — Interferon alpha  Cytokine immunomodulator  Parentally administered  Safety and tolerability issues  Contraindicated for decompensated liver disease — Lamivudine  Nucleoside analog  Orally administered  Resistance

7. Goals for New Antiviral Therapies for Chronic Hepatitis B  Safe and well-tolerated for long term use  Effective in all patient populations — HBeAg+ and HBeAg– — HBV genotypes (A-G) — Compensated and decompensated liver disease — Post-liver transplantation — Drug resistant virus  High threshold for the development of resistance

8. Adefovir Dipivoxil  Oral prodrug of adefovir  Nucleotide analog of adenosine monophosphate  Potent in vitro activity against hepadnaviruses, retroviruses, and herpes viruses  Competitive inhibitor of HBV DNA polymerase — K i = 0.1  M  Long intracellular half-life (12-36 hours)  Adefovir-associated resistance mutation sites identified in HIV RT not present in HBV DNA polymerase  In vitro activity against wild-type and lamivudine-resistant HBV

9. In Vitro Activity of Adefovir Wild-type and Lamivudine-resistant HBV Xiong et al. Hepatology, 1998, 28:1669-1673

10. Preclinical Pharmacology and Toxicology  Antiviral activity and safety in DHBV, WHV, and transgenic mice expressing HBV — Reduced serum viremia in all models — In DHBV model, reduced cccDNA in liver and DHBV DNA/viral antigen in bile duct epithelial cells — No adverse effects in woodchucks  Dose proportional PK of adefovir following oral administration of adefovir dipivoxil  Eliminated as unchanged adefovir in urine  Kidney principal target organ

11. Adefovir Dipivoxil 10 mg Clinical Pharmacokinetics  Oral bioavailability 59%, T 1/2  7 hours  Pharmacokinetics not affected by food, chronic hepatitis B disease, demographic characteristics  No clinically relevant drug-drug interactions — Not substrate or inhibitor of CYP450 — Lamivudine, acetaminophen, ibuprofen, trimethoprim/sulfamethoxazole  Change in dosing interval required in patients with moderate to severe renal impairment — Increased exposure with CL cr < 50 mL/min  No dose alteration for hepatic impairment

12. Adefovir Dipivoxil in Chronic Hepatitis B Dose Selection  Doses of 5-125 mg evaluated in chronic hepatitis B — 3 - 4 log 10 copies/mL reduction in HBV DNA at all doses > 5 mg at 4-12 weeks  Adefovir dipivoxil 60 and 120 mg in HIV  10 and 30 mg selected for evaluation in HBV  Sustained HBV DNA reduction and increased ALT normalization up to 136 weeks — No adefovir-associated resistance mutations identified (n=27) — Renal laboratory abnormalities at 30 mg  10 mg target dose for registration

13. Chronic Hepatitis B Exposure to Adefovir Dipivoxil Total 2084 ADV 10 mg 1647 Other ADV doses 437 Phase 2, Supportive Studies, Early Access 831 Pivotal studies and transplantation 816  48 Weeks 578  72 Weeks 420  96 Weeks 256 As of NDA Safety update

14. Clinical Efficacy and Safety Carol Brosgart, MD Vice President, Clinical Research Gilead Sciences

15. Adefovir Dipivoxil Pivotal Studies 9648 Liver Histology Study 438 HBeAg– Week 0 Liver Histology ADV 10 mg (n=171) Study 437 HBeAg+ ADV 30 mg (n=173) Placebo (n=167) Placebo (n=142) ADV 10 mg (n=138) ADV 10 mg (n=123) ADV 10 mg (n=79) Placebo (n=40) Placebo (n=71) ADV 10 mg (n=85) Placebo (n=61)ADV 10 mg (n=60)

16. Studies 437 and 438 Key Inclusion Criteria  Documented HBsAg positive for  6 months  Compensated liver disease  Adequate renal function  HIV, HCV, and HDV seronegative  Liver biopsy HBeAg–  10 5 copies/mL  1.5–15 HBeAg+  10 6 copies/mL  1.2–10 HBV DNA ALT x ULN

17. Studies 437 and 438 Baseline Characteristics (ITT)

18. Studies 437 and 438 Baseline HBV Characteristics (ITT)

19. Studies 437 and 438 Primary Endpoint  Improvement in liver histology at week 48, relative to baseline (ADV 10 mg vs. placebo) — Defined as  2 point reduction in the Knodell necroinflammatory score with no worsening in fibrosis — Missing/unevaluable week 48 biopsy = no improvement  Histology assessed — One histopathologist blinded to treatment assignment and sequence (baseline or week 48) — Knodell and Ishak scoring systems  Evaluable paired biopsies — 86% HBeAg+ — 91% HBeAg –

20. Studies 437 and 438 (ITT) 48 Weeks Primary Endpoint: Improvement in Liver Histology p<0.001 a Patients (%) PLB ADV 10 PLB ADV 10 HBeAg+HBeAg– p<0.001 a Missing/unevaluable week 48 biopsy = no improvement a Cochran-Mantel-Haenszel Test

21. Studies 437 and 438 Integrated 48 Weeks (ITT) Histological Improvement by Demographic Characteristics 0% 10% 20% 30% 40% 50% 60% 70% Placebo ADV 10 GenderEthnicityAge Patients (%) Male FemaleCaucasianAsian  40 < 40 (n =)(388)(119)(238)(249)(261)(246)

22. Studies 437 and 438 Integrated 48 Weeks (ITT) Histological Improvement by Baseline HBV Characteristics  2xULN < 2xULN< 7.6  7.6 No Prior Prior  10 < 10 0% 10% 20% 30% 40% 50% 60% 70% 80% Patients (%) IFN Knodell HBV DNA ALT n =(358)(149)(177)(230)(282)(225)(322)(185) Placebo ADV 10

23. Studies 437 and 438 Secondary Endpoints  Ranked assessment of liver histology  Change in serum HBV DNA — Roche Amplicor  PCR, LLQ = 400 copies/mL  Change in ALT  HBeAg loss and seroconversion (Study 437)  Resistance

24. Studies 437 and 438 (ITT) 48 Weeks Necroinflammation – Ranked Assessment p<0.001 a HBeAg+ HBeAg– Improved Worsened Patients (%) 42% 80% 51% 3% ADV 10 PLB ADV 10 41% 71% 34% 13% 40% 20% 0% 20% 40% 60% 80% 60% a Cochran-Mantel-Haenszel Test

25. p<0.001 a Studies 437 and 438 (ITT) 48 Weeks Fibrosis – Ranked Assessment 24% 41% 26% 14% 30% 20% 10% 0% 10% 20% 30% 40% 50% PLB ADV 10 Improved Worsened 25% 48% 38% 4% PLB ADV 10 Patients (%) 40% a Cochran-Mantel-Haenszel Test HBeAg+ HBeAg–

26. Studies 437 and 438 Median Change from Baseline in HBV DNA a Wilcoxon Rank-Sum Test p<0.001 a HBeAg- p<0.001 a HBeAg+ PLB ADV 10 -4 -3 -2 0 PLB ADV 10 Weeks 0 4 8 12 16 20 24 28 32 36 40 44 48 -4 -3 -2 0 0 4 8 12 16 20 24 28 32 36 40 44 48 log 10 copies/mL

27. Studies 437 and 438 (ITT) 48 Weeks Serum HBV DNA < 400 copies/mL p<0.001 a PLB ADV 10 PLB ADV 10 HBeAg+HBeAg– Patients (%) a Cochran-Mantel-Haenszel Test Missing = Failure

28. Studies 437 and 438 (ITT) 48 Weeks ALT Normalization PLB ADV 10 PLB ADV 10 HBeAg+HBeAg– p<0.001 a Patients (%) a Cochran-Mantel-Haenszel Test Missing = Failure

29. Study 437 (ITT) 48 Weeks HBeAg Loss and Seroconversion PLB ADV 10 PLB ADV 10 p=0.001 a p<0.05 a Patients (%) a Cochran-Mantel-Haenszel Test Missing = Failure

30. Study 437 and 438 Efficacy Beyond 48 Weeks

31. Study 437 and 438 All ADV 10 mg (n=492) Efficacy Beyond 48 weeks a K-M estimates

32. Studies 437 and 438 ADV 10 mg Efficacy Summary  Statistically significant improvement in — Liver histology — HBV DNA — ALT — HBeAg loss and seroconversion (Study 437)  Histological improvement appears similar across all baseline demographics and disease characteristics  Continued improvement in efficacy beyond 48 weeks

33. Studies 437 and 438 Safety of Adefovir Dipivoxil 10 mg

34. Studies 437 and 438 0-48 Weeks Adverse Events and Discontinuations

35. Studies 437 and 438 Integrated 0-48 Weeks Grade 1-4 Treatment-Related Adverse Events a PLB ADV 10 (n=228) (n=294) Asthenia14%13% Abdominal pain 11% 9% Headache 10% 9% Nausea 8% 5% Flatulence 4% 4% Diarrhea 4% 3% Dyspepsia 2% 3% a Observed in  3% of ADV treated patients

36. Studies 437 and 438 Integrated 0-48 Weeks Grade 3-4 Laboratory Abnormalities a PLB ADV 10 (n=228) (n=294) ALT (> 5 x ULN) 41%20% AST (> 5 x ULN) 23% 8% Hematuria (  3+) 10% 11% CK (> 4 x ULN) 7% 7% Amylase (> 2 x ULN) 4% 4% Glycosuria (  3+) 3% 1% a Observed in  1% of ADV treated patients

37. Studies 437 and 438 Integrated 0-48 Weeks Grade 1-4 Renal Laboratory Parameters

38. Studies 437 and 438 Integrated 0-48 Weeks Renal Laboratory Abnormalities PLB ADV 10 (n=228) (n=294) Serum creatinine Increase  0.5 mg/dL a 0% 0% Median change (mg/dL) 0.0 0.0 Serum phosphorus <1.5 mg/dL a 0% 0% Median change (mg/dL) 0.1 0.1 a Confirmed (two consecutive laboratory abnormalities)

39. Studies 437 and 438 0-48 Weeks Renal Laboratory Abnormalities a Confirmed (two consecutive laboratory abnormalities)

40. Studies 437 and 438 Integrated ADV 10 mg Renal Laboratory Abnormalities 0-96 Weeks a Confirmed (two consecutive laboratory abnormalities)

41. Study 437 and 438 All ADV 10 mg Resolution of  0.3 mg/dL Increases in Serum Creatinine 0-96 Weeks (n=29) Resolved on drug n=20 Stable on drug n=8 Resolved on discontinuation n=1

42. Studies 437 and 438 Integrated 0-48 Weeks ALT Elevations > 10 x ULN PLB ADV 10 (n=228) (n=294) ALT > 10 x ULN 17% 6% ALT > 10 x ULN with: Bilirubin  2.5 mg/dL and 2% 0%  1mg/dL above baseline Albumin < 3 g/dL 1% 0% PT prolonged  1.5 sec <1% 0% above ULN

43. Studies 437 and 438 Integrated ADV 10 mg ALT Elevations > 10 x ULN 48-96 Weeks ADV  ADV ADV  PLB (n=164) (n=111) ALT > 10 x ULN 6% 25% ALT > 10 x ULN with: Bilirubin  2.5 mg/dL and <1% 3%  1 mg/dL above baseline Albumin < 3 g/dL 0% 0% PT prolonged  1.5 sec 0% 0% above ULN

44. Studies 437 and 438 Integrated 0-96 Weeks Adefovir Dipivoxil 10 mg Safety Summary  Safety and tolerability of ADV 10 mg similar to placebo through 48 weeks — Increases in ALT and AST more frequent on placebo  Safety appears similar with extended dosing  Incidence of increases in serum creatinine is low — One patient discontinued  No hypophosphatemia  Increases in serum ALT after stopping treatment — Liver function should be closely monitored for at least 12 weeks after discontinuation of therapy

45. Adefovir Dipivoxil 30 mg Efficacy and Safety

46. Study 437 (ITT) Efficacy Results 48 Weeks

47. Study 437 Renal Laboratory Abnormalities 48 Weeks a Confirmed (two consecutive laboratory abnormalities)

48. Study 437 Assessment of Adefovir Dipivoxil 30 mg  Efficacy demonstrated with ADV 10 and 30 mg  Renal laboratory abnormalities with ADV 30 mg  Safety profile of ADV 10 mg similar to placebo and favorable for long-term dosing

49. Resistance Surveillance

50. Studies 437 and 438 Resistance Surveillance  Prospective, blinded analysis  Methods — Sequenced RT domain of HBV DNA polymerase (344 amino acids) — Compared baseline and week 48 — Assessed phenotypic resistance in vitro for all emerging substitutions at conserved sites  498 of 695 patients with paired samples had detectable HBV DNA > 400 copies/mL at baseline and week 48

51. Studies 437 and 438 Resistance Surveillance Results  10 patients with substitutions at conserved sites — 6 in placebo — 4 in ADV  2 ADV 10 mg, 2 ADV 30 mg  S467A, H481L, V562A, H582Q  All had ~4 log 10 copies/mL HBV DNA reductions at week 48 and no rebound viremia  All susceptible to adefovir in vitro  No adefovir-associated resistance mutations identified up to 48 weeks

52. Supportive Studies

53. Lamivudine Resistance  Incidence of mutations (YMDD) 1-3 — 24% at 1 year — 69% at 5 years  Resistance associated with — Loss of HBV DNA suppression — Increased ALT — Loss of histological and clinical benefit 1 Lai et al. Gastroenterol Hepatol, 2000 2 Leung MWY et al. J Hepatology, 1999 3 Guan et al. APDW, 2002

54. Study 435 Compassionate Access Adefovir Dipivoxil 10 mg for the Treatment of Patients Pre- and Post-Liver Transplantation with Lamivudine-Resistant HBV

55. Study 435 Mortality Rates in Advanced Liver Disease  One year survival rates prior to the availability of therapies for chronic hepatitis B — Post-liver transplantation: 73% 1 — Decompensated cirrhosis: 65% 2  Survival improved with therapies for hepatitis B  Lamivudine resistance is associated with significant morbidity and mortality in high-risk patients 1 Weissberg et al. Ann Intern Med.,1984 2 Perillo et al. Hepatology 2001

56. Study 435 Baseline Characteristics a Median

57. Study 435 Baseline HBV Disease Characteristics

58. Study 435 Median Change from Baseline in HBV DNA 169 Post- transplant 161156 149116 88 57 43 27 24 15 103 Pre- transplant 98 91 84 52 28 13 2 2 2 0 -5.0 -4.0 -3.0 -2.0 0.0 0481224364860728496481224364860728496 Pre-transplantPost-transplant log 10 copies/mL

59. Study 435 Week 48 Secondary Efficacy Endpoints Through NDA Safety Update

60. Post- transplant 185170155135127117 0.0 0.2 0.4 0.6 0.8 1.0 081624324048566472808896 Week 109 94 84 69 55 42 28 Pre- transplant 96 69 50 37 24 11 5 3 2 Study 435 Survival Post-transplant Pre-transplant

61. Study 435 Patient Disposition Through NDA Safety Update

62. Study 435 Renal Laboratory Abnormalities by Week 96 Post- Pre- transplant transplant b (n=196) (n=128) Serum creatinine Increase  0.5 mg/dL a 26 15 Median change (mg/dL) 0.1 0.2 Serum phosphorus <1.5 mg/dL a 1 0 Median change (mg/dL) 0.0 0.3 a Confirmed (two consecutive laboratory abnormalities) b Week 72

63. Study 435 Post-Transplantation Patients with Confirmed Increases in Serum Creatinine  0.5 mg/dL from Baseline (n=26)  Concomitant cyclosporine or tacrolimus (n=26)  Pre-existing medical condition placing patient at risk for renal dysfunction (n=11)  Pre-existing renal impairment (CL cr < 50 mL/min) (n=8)  Decompensated cirrhosis at baseline (n=4) or disease progression during treatment (n=6)  Acute intercurrent medical event prior to onset of serum creatinine increase (n=13)  Other concomitant nephrotoxic agents administered just prior to event (n=2) Through NDA Safety Update

64. Study 435 Pre-Transplantation Patients with Confirmed Increases in Serum Creatinine  0.5 mg/dL from Baseline (n=15)  Serum creatinine increase post liver transplantation (n=11)  Decompensated cirrhosis (n=3) — Disease progression or addition of gentamicin  Non-treatment emergent (n=1) — 3 months following last dose of ADV Through NDA Safety Update

65.  Establish creatinine clearance at baseline to select appropriate initial dose interval  Monitor throughout therapy and adjust dose interval if required Adefovir Dipivoxil 10 mg Dosing Recommendations in Patients with or at risk of Renal Impairment

66. Study 435 Summary  Efficacy — Change in HBV DNA and ALT similar to pivotal studies — Normalization of albumin, bilirubin, and prothrombin time — Stabilization or improvement in CPT Score — No adefovir-associated resistance mutations identified through 48 weeks (n=55)  Safety — Safety profile consistent with advanced liver disease and co-morbidities — Renal function should be monitored closely before and during therapy

67. Lamivudine-Resistant HBV Other Supportive Studies

68. a Data through primary endpoint Week 16 reported in NDA p<0.001 compared to LAM ADV+LAM (n=19) ADV (n= 19) LAM (n=19) Study 461 Median Change from Baseline in HBV DNA a Weeks 081624324048 log 10 copies/mL

69. Study 461 ALT Normalization Week 48 ADV + LAMADVLAM Patients (%) (n=19)

70. Further Studies

71.  Long term safety and efficacy up to 5 years  Durability of seroconversion up to 5 years  ADV dosing guidelines in chronic hepatitis B patients with renal impairment  Safety and efficacy in pediatrics, pregnancy, and other populations  Drug-drug interaction studies  Co-infection (Studies ACTG 5127, 5149)  Combination therapy in treatment-naïve patients  Resistance surveillance

72. Adefovir Dipivoxil for the Treatment of Chronic Hepatitis B  Efficacy and safety in HBeAg+ and HBeAg- compensated liver disease  Efficacy and safety in patients with lamivudine- resistant HBV  No adefovir-associated resistance mutations identified up to 48 weeks

73. Proposed Indication Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active liver disease