ppt
TRANSCRIPT
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Adefovir Dipivoxil 10 mg for the
Treatment of Chronic Hepatitis B
NDA 21-449
August 6, 2002
Gilead Sciences, Inc.
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Proposed Indication
Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active liver disease
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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
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Agenda
Introduction Alan Taylor, PhDChronic Hepatitis B Vice President
Pre-clinical Regulatory Affairs
Clinical Pharmacokinetics
Clinical Efficacy & Safety Carol Brosgart, MDPivotal studies Vice President
Supportive studies Clinical Research
Further studies
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1Lok AS, Gastroenterology 20012Lee W, NEJM 1997
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
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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
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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
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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 µM
• 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
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HBV DNA PolymeraseFold Change in Ki
Mutation Adefovir DP Lamivudine TP
Wild-type 1.0 1.0
M552I 1.3 8.0
M552V 2.2 19.6
L528M+M552V 0.8 25.2
In Vitro Activity of AdefovirWild-type and Lamivudine-resistant HBV
Xiong et al. Hepatology, 1998, 28:1669-1673
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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
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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
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Adefovir Dipivoxil in Chronic Hepatitis B Dose Selection
• Doses of 5-125 mg evaluated in chronic 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
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Chronic Hepatitis BExposure to Adefovir Dipivoxil
Total 2084
ADV 10 mg1647
Other ADV doses437
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
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Clinical Efficacy and Safety
Carol Brosgart, MD
Vice President, Clinical Research
Gilead Sciences
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Adefovir Dipivoxil Pivotal Studies
9648
Liver Histology
Study 438HBeAg–
Week 0
Liver Histology
ADV 10 mg (n=171)Study 437HBeAg+
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)
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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–
≥ 105 copies/mL
≥ 1.5–15
HBeAg+
≥ 106 copies/mL
≥ 1.2–10
HBV DNA
ALT x ULN
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Studies 437 and 438Baseline Characteristics (ITT)
HBeAg+(n=511)
HBeAg–(n=184)
Median age (years) 33 46
Male 74% 83%
AsianCaucasianBlack
59%36%
3%
30%66%
3%
Prior IFNPrior LAM
24% 2%
41% 8%
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Studies 437 and 438Baseline HBV Characteristics (ITT)
HBeAg+(n=511)
HBeAg–(n=184)
Median HBV DNA(log10 copies/mL) 8.4 7.1
Median ALT (IU/L) xULN
942.3
982.3
Median KnodellTotal Score
10 10
Cirrhosis 6% 11%
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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–
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33%
64%
25%
53%
0%
10%
20%
30%
40%
50%
60%
70%
Studies 437 and 438 (ITT) 48 WeeksPrimary Endpoint: Improvement in Liver Histology
p<0.001a
Patients(%)
PLB
ADV 10
PLB
ADV10
HBeAg+ HBeAg–
p<0.001a
Missing/unevaluable week 48 biopsy = no improvement
aCochran-Mantel-Haenszel Test
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Studies 437 and 438 Integrated 48 Weeks (ITT)Histological Improvement by Demographic Characteristics
0%
10%
20%
30%
40%
50%
60%
70%PlaceboADV 10
Gender Ethnicity Age
Patients(%)
Male
Female Caucasian Asian ≥ 40 < 40(n =) (388) (119) (238) (249) (261) (246)
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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)
PlaceboADV 10
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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
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Studies 437 and 438 (ITT) 48 WeeksNecroinflammation – Ranked Assessment
p<0.001a p<0.001a
HBeAg+ HBeAg–
Improved
Worsened
Patients(%)
42%
80%
51%
3%
ADV10
PLB PLB
ADV10
41%
71%
34%
13%
40%
20%
0%
20%
40%
60%
80%
60%
aCochran-Mantel-Haenszel Test
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p<0.001a p<0.001a
Studies 437 and 438 (ITT) 48 WeeksFibrosis – Ranked Assessment
24%
41%
26%
14%
30%
20%
10%
0%
10%
20%
30%
40%
50%
PLB
ADV10
Improved
Worsened
25%
48%
38%
4%
PLB
ADV10
Patients(%)
40%
aCochran-Mantel-Haenszel Test
HBeAg+ HBeAg–
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Studies 437 and 438 Median Change from Baseline in HBV DNA
aWilcoxon Rank-Sum Test
p<0.001a
HBeAg-
p<0.001a
HBeAg+
PLB
ADV 10-4
-3
-2
-1
0
PLB
ADV 10
Weeks 0 4 8 12 16 20 24 28 32 36 40 44 48
-4
-3
-2
-1
0
0 4 8 12 16 20 24 28 32 36 40 44 48
log10 copies/mL
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Studies 437 and 438 (ITT) 48 WeeksSerum HBV DNA < 400 copies/mL
p<0.001a p<0.001a
0% 0%
21%
51%
0%
10%
20%
30%
40%
50%
60%
PLB
ADV10
PLB
ADV10
HBeAg+ HBeAg–
Patients(%)
aCochran-Mantel-Haenszel Test
Missing = Failure
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Studies 437 and 438 (ITT) 48 Weeks ALT Normalization
29%
16%
72%
48%
0%
10%
20%
30%
40%
50%
60%
70%
80%
PLB
ADV10
PLB
ADV10
HBeAg+ HBeAg–
p<0.001a p<0.001a
Patients(%)
aCochran-Mantel-Haenszel Test
Missing = Failure
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Study 437 (ITT) 48 WeeksHBeAg Loss and Seroconversion
11%
6%
24%
12%
0%
5%
10%
15%
20%
25%
30%
HBeAg Loss HBeAg Seroconversion
PLB
ADV10
PLB
ADV10
p=0.001a p<0.05a
Patients(%)
aCochran-Mantel-Haenszel Test
Missing = Failure
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Study 437 and 438 Efficacy Beyond 48 Weeks
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Study 437 and 438 All ADV 10 mg (n=492)Efficacy Beyond 48 weeks
HBeAg+(n=309)
HBeAg-(n=183)
Week48
Week72
Week48
Week72
HBV DNA < 400 copies/mLa 26% 46% 66% 80%
ALT normalizationa 67% 78% 76% 81%
HBeAg lossa 23% 44% NA NA
HBeAg seroconversiona 14% 23% NA NA
aK-M estimates
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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
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Studies 437 and 438 Safety of Adefovir Dipivoxil 10 mg
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Studies 437 and 438 0-48 WeeksAdverse Events and Discontinuations
HBeAg+ HBeAg–
PLB ADV 10 PLB ADV 10 (n=167) (n=171) (n=61) (n=123)
Adverse events (AEs) 89% 87% 74% 76%
Treatment-related AEs 56% 53% 36% 33%
Serious AEs 5% 5% 7% 3%
Deaths 0 0 0 0
Discontinuation rate 8% 7% 2% 2%
Discontinuations due to AEs
<1% 2% 0% <1%
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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
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Studies 437 and 438 Integrated 0-48 Weeks Grade 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
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Studies 437 and 438 Integrated 0-48 Weeks Grade 1-4 Renal Laboratory Parameters
PLB(n=228)
ADV 10(n=294)
Hematuria 31% 30%
Proteinuria 16% 19%
Serum phosphorus decrease 8% 7%
Glycosuria 7% 3%
Serum bicarbonate decrease <1% 2%
Serum creatinine increase 0% 1%
BUN increase <1% <1%
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Studies 437 and 438 Integrated 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)
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Studies 437 and 438 0-48 Weeks Renal Laboratory Abnormalities
HBeAg+ HBeAg-
PLB (n=167)
ADV 10 (n=171)
PLB (n=61)
ADV 10 (n=123)
Serum creatinine Increase ≥ 0.3 mg/dLa
1%
5%
5%
2%
Serum phosphorus < 2.0 mg/dLa
1%
0%
0%
0%
aConfirmed (two consecutive laboratory abnormalities)
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Studies 437 and 438 Integrated ADV 10 mgRenal Laboratory Abnormalities 0-96 Weeks
aConfirmed (two consecutive laboratory abnormalities)
All ADV 10 (n=492)
Serum creatinine Increase ≥ 0.3 mg/dLa ≥ 0.5 mg/dLa Median change (mg/dL)
29 (6%)
2 (<1%) 0.1
Serum phosphorus < 2.0 mg/dLa Median change (mg/dL)
0
0.0
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Study 437 and 438 All ADV 10 mgResolution of ≥ 0.3 mg/dL Increases in Serum Creatinine 0-96 Weeks (n=29)
Resolved ondrugn=20
Stable ondrugn=8
Resolved on discontinuation
n=1
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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 and 2% 0% ≥ 1mg/dL above baseline
Albumin < 3 g/dL 1% 0%
PT prolonged ≥ 1.5 sec <1% 0% above ULN
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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
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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
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Adefovir Dipivoxil 30 mgEfficacy and Safety
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Study 437 (ITT)Efficacy Results 48 Weeks
PLB ADV 10 ADV 30 (n=167) (n=171) (n=173)
Histological improvement 25% 53% 59%
Median change HBV DNA (log10 copies/mL)
-0.55 -3.52 -4.76
Median change ALT (IU/L)
-17 -51 -54
ALT normalization 16% 48% 55%
HBeAg loss 11% 24% 27%
HBeAg seroconversion 6% 12% 14%
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Study 437Renal Laboratory Abnormalities 48 Weeks
aConfirmed (two consecutive laboratory abnormalities)
PLB ADV 10 ADV 30(n=167) (n=171) (n=173)
Serum creatinineIncrease ≥ 0.5 mg/dLa
Median change (mg/dL)0%
00%
07%0.2
Serum phosphorus< 1.5 mg/dLa
< 2.0 mg/dLa
Median change (mg/dL)
0%1%0.1
0%0%0.1
0% 5% -0.1
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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
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Resistance Surveillance
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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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Studies 437 and 438Resistance 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 log10 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
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Supportive Studies
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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, 20002 Leung MWY et al. J Hepatology, 19993 Guan et al. APDW, 2002
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Study 435 Compassionate Access
Adefovir Dipivoxil 10 mg for the Treatment of Patients Pre- and Post-Liver Transplantation
with Lamivudine-Resistant HBV
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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
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Study 435Baseline Characteristics
Post-transplant(n=196)
Pre-transplant(n=128)
Age years (range)a 54 (12–75) 51 (18–72)
Weeks on lamivudine postloss of treatment responsea 56 69
Serum creatinine ≥ 1.5 mg/dL 28% 8%
Weeks post-transplantationa 200 NA
Cyclosporine or tacrolimus 95% NA
aMedian
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Study 435Baseline HBV Disease Characteristics
Post-transplant (n=196)
Pre- transplant (n=128)
Median HBV DNA (log10 copies/mL)
8.2 7.4
Median ALT x ULN 2.1 1.8
CPT Score ≥ 7 23% 63%
Serum bilirubin > ULN 30% 66%
Serum albumin < LLN 22% 59%
Prothrombin Time > ULN 16% 53%
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Study 435Median Change from Baseline in HBV DNA
169Post-transplant
161 156 149 116 88 57 43 27 24 15
103Pre-transplant
98 91 84 52 28 13 2 2 2 0
-5.0
-4.0
-3.0
-2.0
-1.0
0.0
0 4 8 12 24 36 48 60 72 84 964 8 12 24 36 48 60 72 84 96
Pre-transplant Post-transplant
log10 copies/mL
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Post-transplant
(n=196)
Pre-transplant
(n=128)
HBV DNA < 400 copies/mL 34% 81%
Normalization
ALT 49% 76%
Albumin 76% 81%
Bilirubin 75% 50%
Prothrombin time 20% 83%
CPT stable or improved 96% 92%
Study 435 Week 48Secondary Efficacy Endpoints
Through NDA Safety Update
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Post-transplant
185 170 155 135 127 117
0.0
0.2
0.4
0.6
0.8
1.0
0 8 16 24 32 40 48 56 64 72 80 88 96
Week
109 94 84 69 55 42 28
Pre-transplant
96 69 50 37 24 11 5 3 2
Study 435Survival
Post-transplant
Pre-transplant
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Post-transplant
(n=196)
Pre-transplant
(n=128)
Median weeks follow-up (max) 56 (129) 19 (72)
Patients terminating study 9% 10%
Adverse events 2% 2%
Patient request 0% 1%
Death 7% 5%
Lost to follow-up 0% 1%
Other 0% 1%
Study 435Patient Disposition
Through NDA Safety Update
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Study 435Renal Laboratory Abnormalities by Week 96
Post- Pre- transplant transplantb
(n=196) (n=128) Serum creatinine
Increase ≥ 0.5 mg/dLa 26 15 Median change (mg/dL) 0.1 0.2
Serum phosphorus<1.5 mg/dLa 1 0 Median change (mg/dL) 0.0 0.3
aConfirmed (two consecutive laboratory abnormalities)b Week 72
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Study 435Post-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 (CLcr< 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
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Study 435Pre-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
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• 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
Calculated Creatinine Clearance (mL/min)
≥ 50 20-49 10-19 <10
RequiringHemodialysis
10 mgevery 24
hours
10 mgevery 48
hours
10 mgevery 72
hours
10 mgevery 7
days
10 mg every 7days post-
hemodialysis
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Study 435Summary
• 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
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Lamivudine-Resistant HBVOther Supportive Studies
Study n Population Design
460i 35 HIV Co-infection
465B 40 Decompensated Open-label ADV+LAM
465A 95 Compensated
LAM ADV+LAM
461 59 Compensated LAM ADV+LAM ADV
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-5
-4
-3
-2
-1
0
1
aData through primary endpoint Week 16 reported in NDA
p<0.001 comparedto LAM
ADV+LAM(n=19)
ADV (n= 19)
LAM (n=19)
Study 461 Median Change from Baseline in HBV DNAa
Weeks
0 8 16 24 32 40 48
log10 copies/mL
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Study 461ALT Normalization Week 48
53%
47%
5%
0%
10%
20%
30%
40%
50%
60%
ADV + LAM ADV LAM
Patients(%)
(n=19) (n=19) (n=19)
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Further Studies
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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
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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
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Proposed Indication
Adefovir dipivoxil is indicated for the treatment of chronic hepatitis B in adults with evidence of active liver disease