Adefovir Dipivoxil 10 mg for the Treatment of Chronic Hepatitis B NDA 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 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
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
1 Lok AS, Gastroenterology 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
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
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
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
In Vitro Activity of Adefovir Wild-type and Lamivudine-resistant HBV Xiong et al. Hepatology, 1998, 28:
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
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
Adefovir Dipivoxil in Chronic Hepatitis B Dose Selection Doses of mg evaluated in chronic hepatitis B — 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
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
Clinical Efficacy and Safety Carol Brosgart, MD Vice President, Clinical Research Gilead Sciences
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)
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
Studies 437 and 438 Baseline Characteristics (ITT)
Studies 437 and 438 Baseline HBV Characteristics (ITT)
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 –
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
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)
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
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
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
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–
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 PLB ADV 10 Weeks log 10 copies/mL
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
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
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
Study 437 and 438 Efficacy Beyond 48 Weeks
Study 437 and 438 All ADV 10 mg (n=492) Efficacy Beyond 48 weeks a K-M estimates
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
Studies 437 and 438 Safety of Adefovir Dipivoxil 10 mg
Studies 437 and Weeks Adverse Events and Discontinuations
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
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
Studies 437 and 438 Integrated 0-48 Weeks Grade 1-4 Renal Laboratory Parameters
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) Serum phosphorus <1.5 mg/dL a 0% 0% Median change (mg/dL) a Confirmed (two consecutive laboratory abnormalities)
Studies 437 and Weeks Renal Laboratory Abnormalities a Confirmed (two consecutive laboratory abnormalities)
Studies 437 and 438 Integrated ADV 10 mg Renal Laboratory Abnormalities 0-96 Weeks a Confirmed (two consecutive laboratory abnormalities)
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
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
Studies 437 and 438 Integrated ADV 10 mg ALT Elevations > 10 x ULN 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
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
Adefovir Dipivoxil 30 mg Efficacy and Safety
Study 437 (ITT) Efficacy Results 48 Weeks
Study 437 Renal Laboratory Abnormalities 48 Weeks a Confirmed (two consecutive laboratory abnormalities)
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
Resistance Surveillance
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
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
Supportive Studies
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, Leung MWY et al. J Hepatology, Guan et al. APDW, 2002
Study 435 Compassionate Access Adefovir Dipivoxil 10 mg for the Treatment of Patients Pre- and Post-Liver Transplantation with Lamivudine-Resistant HBV
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., Perillo et al. Hepatology 2001
Study 435 Baseline Characteristics a Median
Study 435 Baseline HBV Disease Characteristics
Study 435 Median Change from Baseline in HBV DNA 169 Post- transplant Pre- transplant Pre-transplantPost-transplant log 10 copies/mL
Study 435 Week 48 Secondary Efficacy Endpoints Through NDA Safety Update
Post- transplant Week Pre- transplant Study 435 Survival Post-transplant Pre-transplant
Study 435 Patient Disposition Through NDA Safety Update
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 Median change (mg/dL) Serum phosphorus <1.5 mg/dL a 1 0 Median change (mg/dL) a Confirmed (two consecutive laboratory abnormalities) b Week 72
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
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
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
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
Lamivudine-Resistant HBV Other Supportive Studies
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 log 10 copies/mL
Study 461 ALT Normalization Week 48 ADV + LAMADVLAM Patients (%) (n=19)
Further Studies
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
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
Proposed Indication Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active liver disease