Adefovir Dipivoxil 10 mg for the Treatment of Chronic Hepatitis B NDA 21-449
Download
Report
Transcript Adefovir Dipivoxil 10 mg for the Treatment of Chronic Hepatitis B NDA 21-449
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
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
Chronic Hepatitis B
Pre-clinical
Clinical Pharmacokinetics
Clinical Efficacy & Safety
Pivotal studies
Supportive studies
Further studies
Alan Taylor, PhD
Vice President
Regulatory Affairs
Carol Brosgart, MD
Vice President
Clinical Research
Chronic Hepatitis B
A 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
1Lok
AS, Gastroenterology 2001
2Lee W, NEJM 1997
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
—
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 and
lamivudine-resistant HBV
In Vitro Activity of Adefovir
Wild-type and Lamivudine-resistant HBV
Mutation
HBV DNA Polymerase
Fold Change in Ki
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
Xiong et al. Hepatology, 1998, 28:1669-1673
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%, 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
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
Chronic Hepatitis B
Exposure to Adefovir Dipivoxil
Total
2084
ADV 10 mg
1647
Pivotal studies and
transplantation
816
Other ADV doses
437
Phase 2, Supportive Studies,
Early Access
831
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
Study 437
HBeAg+
ADV 30 mg (n=173)
Placebo
ADV 10 mg (n=171)
Placebo
ADV 10 mg
Placebo
ADV 10 mg (n=138)
Study 438
HBeAg–
Week
(n=167)
(n=142)
(n=71)
(n=85)
ADV 10 mg (n=123)
Placebo
ADV 10 mg
(n=40)
(n=79)
Placebo
ADV 10 mg
(n=60)
(n=61)
0
48
Liver Histology
Liver Histology
96
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+
HBV DNA
ALT x ULN
106 copies/mL
1.2–10
HBeAg–
105 copies/mL
1.5–15
Studies 437 and 438
Baseline Characteristics (ITT)
HBeAg+
(n=511)
HBeAg–
(n=184)
Median age (years)
Male
33
74%
46
83%
Asian
Caucasian
Black
59%
36%
3%
30%
66%
3%
Prior IFN
Prior LAM
24%
2%
41%
8%
Studies 437 and 438
Baseline HBV Characteristics (ITT)
HBeAg+
(n=511)
HBeAg–
(n=184)
Median HBV DNA
(log10 copies/mL)
8.4
7.1
Median ALT
(IU/L)
xULN
94
2.3
98
2.3
10
10
Median Knodell
Total Score
Cirrhosis
6%
11%
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
Missing/unevaluable week 48 biopsy = no improvement
70%
HBeAg+
HBeAg–
64%
53%
60%
ADV
10
50%
ADV
10
40%
30%
33%
25%
PLB
20%
PLB
10%
0%
p<0.001a
aCochran-Mantel-Haenszel
Test
p<0.001a
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%
(n =)
Gender
Male Female
(388)
(119)
Ethnicity
Caucasian Asian
(238)
(249)
Age
< 40
40
(261)
(246)
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%
IFN
No Prior Prior
n=
(358)
(149)
Knodell
HBV DNA
10
< 10
7.6
< 7.6
(177)
(230)
(282)
(225)
ALT
2xULN < 2xULN
(322)
(185)
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
HBeAg+
Improved
80%
80%
71%
60%
40%
HBeAg–
41%
ADV
10
PLB
ADV
10
42%
PLB
20%
0%
13%
20%
40%
Worsened
3%
34%
60%
p<0.001a
aCochran-Mantel-Haenszel
Test
51%
p<0.001a
Studies 437 and 438 (ITT) 48 Weeks
Fibrosis – Ranked Assessment
HBeAg+
Improved
HBeAg–
48%
50%
41%
40%
30%
24%
20%
PLB
ADV
10
ADV
10
25%
PLB
10%
0%
4%
10%
14%
20%
30%
Worsened
26%
40%
p<0.001a
aCochran-Mantel-Haenszel
Test
38%
p<0.001a
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
ADV 10
-3
ADV 10
-4
-4
Weeks 0 4 8 12 16 20 24 28 32 36 40 44 48
p<0.001a
aWilcoxon
Rank-Sum Test
0 4 8 12 16 20 24 28 32 36 40 44 48
p<0.001a
Studies 437 and 438 (ITT) 48 Weeks
Serum HBV DNA < 400 copies/mL
Missing = Failure
60%
HBeAg+
HBeAg–
51%
50%
ADV
10
40%
Patients
(%) 30%
21%
20%
10%
0%
ADV
10
0%
0%
PLB
PLB
p<0.001a
aCochran-Mantel-Haenszel
Test
p<0.001a
Studies 437 and 438 (ITT) 48 Weeks
ALT Normalization
Missing = Failure
80%
HBeAg+
HBeAg–
72%
70%
ADV
10
60%
48%
50%
Patients
40%
(%)
ADV
10
29%
30%
20%
16%
10%
PLB
PLB
0%
p<0.001a
aCochran-Mantel-Haenszel
Test
p<0.001a
Study 437 (ITT) 48 Weeks
HBeAg Loss and Seroconversion
Missing = Failure
30%
25%
24%
20%
ADV
10
Patients
(%) 15%
10%
12%
11%
PLB
5%
6%
ADV
10
PLB
0%
HBeAg Loss
p=0.001a
aCochran-Mantel-Haenszel
Test
HBeAg Seroconversion
p<0.05a
Study 437 and 438
Efficacy Beyond 48 Weeks
Study 437 and 438 All ADV 10 mg (n=492)
Efficacy Beyond 48 weeks
HBeAg+
(n=309)
Week Week
72
48
HBeAg(n=183)
Week Week
72
48
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
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 438 0-48 Weeks
Adverse Events and Discontinuations
HBeAg+
HBeAg–
PLB
ADV 10
(n=167) (n=171)
PLB
(n=61)
ADV 10
(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%
<1%
2%
0%
<1%
Discontinuations
due to AEs
Studies 437 and 438 Integrated 0-48 Weeks
Grade 1-4 Treatment-Related Adverse Eventsa
PLB
(n=228)
ADV 10
(n=294)
Asthenia
14%
13%
Abdominal pain
Headache
Nausea
Flatulence
Diarrhea
Dyspepsia
11%
10%
8%
4%
4%
2%
9%
9%
5%
4%
3%
3%
aObserved
in 3% of ADV treated patients
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
Studies 437 and 438 Integrated 0-48 Weeks
Grade 1-4 Renal Laboratory Parameters
Hematuria
Proteinuria
Serum phosphorus decrease
Glycosuria
Serum bicarbonate decrease
Serum creatinine increase
BUN increase
PLB
(n=228)
ADV 10
(n=294)
31%
16%
8%
7%
<1%
0%
<1%
30%
19%
7%
3%
2%
1%
<1%
Studies 437 and 438 Integrated 0-48 Weeks
Renal Laboratory Abnormalities
PLB
(n=228)
ADV 10
(n=294)
Serum creatinine
Increase 0.5 mg/dLa
0%
0%
Median change (mg/dL)
0.0
0.0
<1.5 mg/dLa
0%
0%
Median change (mg/dL)
0.1
0.1
Serum phosphorus
aConfirmed
(two consecutive laboratory abnormalities)
Studies 437 and 438 0-48 Weeks
Renal Laboratory Abnormalities
HBeAg+
HBeAgPLB ADV 10 PLB ADV 10
(n=167) (n=171) (n=61) (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)
Studies 437 and 438 Integrated ADV 10 mg
Renal Laboratory Abnormalities 0-96 Weeks
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
aConfirmed
(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)
Stable on
drug
n=8
Resolved on
drug
n=20
Resolved on
discontinuation
n=1
Studies 437 and 438 Integrated 0-48 Weeks
ALT Elevations > 10 x ULN
PLB
(n=228)
ADV 10
(n=294)
17%
6%
Bilirubin 2.5 mg/dL and
1mg/dL above baseline
2%
0%
Albumin < 3 g/dL
1%
0%
ALT > 10 x ULN
ALT > 10 x ULN with:
PT prolonged 1.5 sec <1%
above ULN
0%
Studies 437 and 438 Integrated ADV 10 mg
ALT Elevations > 10 x ULN 48-96 Weeks
ADVADV
(n=164)
ALT > 10 x ULN
ADVPLB
(n=111)
6%
25%
<1%
3%
0%
0%
ALT > 10 x ULN with:
Bilirubin 2.5 mg/dL and
1 mg/dL above baseline
Albumin < 3 g/dL
PT prolonged 1.5 sec 0%
above ULN
0%
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
PLB
(n=167)
ADV 10
(n=171)
ADV 30
(n=173)
Histological improvement
25%
53%
59%
Median change HBV DNA
-0.55
-3.52
-4.76
-17
-51
-54
ALT normalization
16%
48%
55%
HBeAg loss
11%
24%
27%
6%
12%
14%
(log10 copies/mL)
Median change ALT
(IU/L)
HBeAg seroconversion
Study 437
Renal Laboratory Abnormalities 48 Weeks
PLB
(n=167)
ADV 10
(n=171)
ADV 30
(n=173)
Serum creatinine
Increase 0.5 mg/dLa
Median change (mg/dL)
0%
0
0%
0
7%
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
aConfirmed
(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 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
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, 2000
2 Leung MWY et al. J Hepatology, 1999
3 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.,1984
2 Perillo et al. Hepatology 2001
Study 435
Baseline Characteristics
Posttransplant
(n=196)
Pretransplant
(n=128)
54 (12–75)
51 (18–72)
Weeks on lamivudine post
loss of treatment responsea
56
69
Serum creatinine 1.5 mg/dL
28%
Weeks post-transplantationa
200
NA
Cyclosporine or tacrolimus
95%
NA
Age years (range)a
aMedian
8%
Study 435
Baseline HBV Disease Characteristics
Posttransplant
(n=196)
Pretransplant
(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%
Study 435
Median Change from Baseline in HBV DNA
log10 copies/mL
0.0
-1.0
-2.0
-3.0
Pre-transplant
-4.0
Post-transplant
-5.0
0 4 8 12
Post- 169 161 156 149
transplant
Pre103 98 91 84
transplant
24
36
48
60
72
84
96
116
88
57
43
27
24
15
52
28
13
2
2
2
0
Study 435 Week 48
Secondary Efficacy Endpoints
Posttransplant
(n=196)
Pretransplant
(n=128)
34%
81%
ALT
49%
76%
Albumin
76%
81%
Bilirubin
75%
50%
Prothrombin time
20%
83%
96%
92%
HBV DNA < 400 copies/mL
Normalization
CPT stable or improved
Through NDA Safety Update
Study 435
Survival
Post-transplant
1.0
0.8
Pre-transplant
0.6
0.4
0.2
0.0
0
8
16
24
32
40
48
56
64
72
80
88
96
69
55
42
28
Week
Post- 185
transplant
Pre96
transplant
170
155
135
127
117
109
94
84
69
50
37
24
11
5
3
2
Study 435
Patient Disposition
Posttransplant
(n=196)
Pretransplant
(n=128)
56 (129)
19 (72)
9%
10%
Adverse events
2%
2%
Patient request
0%
1%
Death
7%
5%
Lost to follow-up
0%
1%
Other
0%
1%
Median weeks follow-up (max)
Patients terminating study
Through NDA Safety Update
Study 435
Renal Laboratory Abnormalities by Week 96
Posttransplant
(n=196)
Pretransplantb
(n=128)
Serum creatinine
Increase 0.5 mg/dLa
Median change (mg/dL)
26
0.1
15
0.2
Serum phosphorus
<1.5 mg/dLa
Median change (mg/dL)
1
0.0
0
0.3
aConfirmed
b Week
72
(two consecutive laboratory abnormalities)
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 (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
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
Adefovir Dipivoxil 10 mg
Dosing Recommendations in Patients with
or at risk of Renal Impairment
Establish creatinine clearance at baseline to
select appropriate initial dose interval
Monitor throughout therapy and adjust dose
interval if required
Calculated Creatinine Clearance (mL/min)
50
20-49
10-19
<10
Requiring
Hemodialysis
10 mg
every 24
hours
10 mg
every 48
hours
10 mg
every 72
hours
10 mg
every 7
days
10 mg every 7
days posthemodialysis
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
Study n
Population
Design
460i
35
HIV Co-infection
465B
40
Decompensated
465A
95
Compensated
LAM
ADV+LAM
461
59
Compensated
LAM
ADV+LAM
ADV
Open-label
ADV+LAM
Study 461
Median Change from Baseline in HBV DNAa
log10 copies/mL
1
0
LAM (n=19)
-1
p<0.001 compared
to LAM
-2
-3
ADV+LAM
(n=19)
-4
ADV (n= 19)
-5
0
8
16
24
32
40
Weeks
aData
through primary endpoint Week 16 reported in NDA
48
Study 461
ALT Normalization Week 48
60%
53%
47%
50%
40%
Patients
30%
(%)
20%
10%
5%
0%
ADV + LAM
(n=19)
ADV
(n=19)
LAM
(n=19)
Further Studies
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 HBeAgcompensated liver disease
Efficacy and safety in patients with lamivudineresistant 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