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Adefovir Dipivoxil 10 mg for the Treatment of Chronic Hepatitis B

Adefovir Dipivoxil 10 mg for the Treatment of Chronic Hepatitis B. NDA 21-449 August 6, 2002 Gilead Sciences, Inc. Proposed Indication. Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active liver disease. Consultants.

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Adefovir Dipivoxil 10 mg for the Treatment of Chronic Hepatitis B

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  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, MDProfessor of Medicine, Harvard Medical SchoolMassachusetts General Hospital (Gastrointestinal Unit) • Zachary D Goodman, MD, PhDChief, Division of Hepatic PathologyArmed Forces Institute of Pathology • Paul Klotman, MDChief, Division of Nephrology and Chairman, Department of Medicine Mt. Sinai School of Medicine • Eugene Schiff, MDProfessor of Medicine and Chief, Division of HepatologyDirector,Center For Liver Diseases University of Miami School of Medicine • Teresa Wright, MDProfessor 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. Chronic Hepatitis BA Global Healthcare Issue • 400 million with chronic hepatitis B worldwide1 • HBeAg+ • HBeAg– • 25-33% develop progressive disease • Cirrhosis or hepatocellular carcinoma • 1 million deaths per year • 1.25 million with chronic hepatitis B in US2 • 17,000 hospitalizations and 5,000 deaths per year • 6th leading indication for adult liver transplantation • 400 million with chronic hepatitis B worldwide1 • HBeAg+ • HBeAg– • 25-33% develop progressive disease • Cirrhosis or hepatocellular carcinoma • 1 million deaths per year • 1.25 million with chronic hepatitis B in US2 • 17,000 hospitalizations and 5,000 deaths per year • 6th leading indication for adult liver transplantation 1Lok AS, Gastroenterology 2001 2Lee W, NEJM 1997

  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 • Ki = 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 andlamivudine-resistant HBV

  9. In Vitro Activity of AdefovirWild-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 mgClinical Pharmacokinetics • Oral bioavailability 59%, T1/2  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 CLcr < 50 mL/min • No dose alteration for hepatic impairment

  12. Adefovir Dipivoxil in Chronic Hepatitis BDose Selection • Doses of 5-125 mg evaluated inchronic hepatitis B • 3-4 log10 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 BExposure to Adefovir Dipivoxil Total 2084 Other ADV doses 437 ADV 10 mg 1647 Pivotal studies and transplantation 816 Phase 2, Supportive Studies, Early Access 831  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 ADV 30 mg (n=173) Placebo (n=142) Study 437 HBeAg+ ADV 10 mg (n=171) Placebo (n=71) ADV 10 mg (n=85) Placebo (n=167) ADV 10 mg (n=138) ADV 10 mg (n=123) Placebo (n=40) Study 438 HBeAg– ADV 10 mg (n=79) Placebo (n=61) ADV 10 mg (n=60) Week 0 48 96 Liver Histology Liver Histology

  16. Documented HBsAg positive for  6 months Compensated liver disease Adequate renal function HIV, HCV, and HDV seronegative Liver biopsy Studies 437 and 438Key Inclusion Criteria HBeAg–  105 copies/mL  1.5–15 HBeAg+  106 copies/mL  1.2–10 HBV DNA ALT x ULN

  17. Studies 437 and 438Baseline Characteristics (ITT)

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

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

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

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

  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 WeeksNecroinflammation – Ranked Assessment HBeAg+ HBeAg– 80% Improved 80% 71% ADV 10 ADV 10 60% 41% 42% 40% PLB PLB Patients (%) 20% 0% 3% 13% 20% 40% 34% Worsened 51% 60% p<0.001a p<0.001a aCochran-Mantel-Haenszel Test

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

  26. Studies 437 and 438 Median Change from Baseline in HBV DNA log10 copies/mL HBeAg+ HBeAg- 0 0 PLB -1 -1 PLB -2 -2 -3 -3 ADV 10 ADV 10 -4 -4 Weeks 0 4 8 12 16 20 24 28 32 36 40 44 48 0 4 8 12 16 20 24 28 32 36 40 44 48 p<0.001a p<0.001a aWilcoxon Rank-Sum Test

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

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

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

  30. Study 437 and 438Efficacy Beyond 48 Weeks

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

  32. Studies 437 and 438 ADV 10 mgEfficacy 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 438Safety of Adefovir Dipivoxil 10 mg

  34. Studies 437 and 438 0-48 WeeksAdverse Events and Discontinuations

  35. Studies 437 and 438 Integrated 0-48 WeeksGrade 1-4 Treatment-Related Adverse Eventsa PLB ADV 10 (n=228) (n=294) Asthenia 14% 13% Abdominal pain 11% 9% Headache 10% 9% Nausea 8% 5% Flatulence 4% 4% Diarrhea 4% 3% Dyspepsia 2% 3% aObserved in  3% of ADV treated patients

  36. Studies 437 and 438 Integrated 0-48 WeeksGrade 3-4 Laboratory Abnormalitiesa 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% aObserved in  1% of ADV treated patients

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

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

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

  40. Studies 437 and 438Integrated ADV 10 mgRenal Laboratory Abnormalities 0-96 Weeks aConfirmed (two consecutive laboratory abnormalities)

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

  42. Studies 437 and 438 Integrated 0-48 WeeksALT 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 and2% 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 mgALT 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 WeeksAdefovir 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 mgEfficacy and Safety

  46. Study 437 (ITT)Efficacy Results 48 Weeks

  47. Study 437Renal Laboratory Abnormalities 48 Weeks aConfirmed (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 438Resistance 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

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