FDAs Antiviral Drugs Advisory Committee Meeting

1
FDAs Antiviral DrugsAdvisory Committee Meeting
BARACLUDETM(entecavir / BMS 200475)
11 March 2005
2
Introduction

• Elliott Sigal, MD, PhD

3
Global Impact of Hepatitis B
1540 develop cirrhosis, liver failureor
hepatocellular carcinoma
2 billion with past / present HBV infection
350400 million with chronic hepatitis B
World Population 6 billion
Worldwide 1 million / year die from
HBV-associated liver disease United States
Chronically infected 1.25 million 5000 /
year die
4
Background

• Richard Colonno, PhD

5
Proposed Indication

• Entecavir is indicated for the treatment of
  chronic hepatitis B infection in adults with
  evidence of active liver inflammation
• Usual dose0.5 mg tablet once daily
• Lamivudine-refractory1.0 mg tablet once daily

6
BMS Presentation

• Introduction Elliott Sigal, MD, PhD
• Chief Scientific Officer President, Pharmace
  utical Research Institute
• Background Richard Colonno, PhD Vice
  President, Infectious Diseases Drug Discovery
• Nonclinical Safety Lois Lehman-McKeeman, PhD
• Distinguished Research Fellow, Discovery
  Toxicology
• Clinical Efficacy / Evren Atillasoy, MD
• Clinical Safety Director, US Medical Affairs
• Viral Resistance Richard Colonno, PhD Vice
  President, Infectious Diseases Drug Discovery
• Pharmacovigilance Donna Morgan Murray, PhDand
  Summary Executive Director, Global Regulatory
  Sciences

7
Consultants Available to the Committee

• Adrian Di Bisceglie, MD
• Saint Louis University School of Medicine
• Samuel A. Bozzette, MD, PhD
• University of California, San Diego
• Jules L. Dienstag, MD
• Massachusetts General Hospital
• James Swenberg, DVM, PhD
• University of North Carolina
• LJ Wei, PhD
• Harvard University
• Gary M. Williams, MD, DABT
• New York Medical College

Hepatology Health Policy Hepatology Toxicology/
Pathology Biostatistics Toxicology/ Pathology
8
Impact of Viral Replication on Disease
Progression Taiwan Cohort Study Results

• The incidence of hepatocellular carcinoma (HCC)
  and liver cirrhosis is correlated with level of
  viral replication
• Persistent elevation of viral load over time has
  the greatest impact on HCC risk
• Viral load predicts risk of future HCC
  independent of HBeAg status and serum ALT level
• This risk increases with increasing viral load

EASL April 2005
9
Pathophysiologic Cascade of Chronic Hepatitis B
Infection Significance of HBV Replication
HBV Replication (Measured by Serum HBV DNA)
Liver Inflammation
ALT Elevation
DiseaseProgression Liver Failure Liver
Cancer Transplant Death
Worsening histology Necroinflammation Fibrosis Cir
rhosis
10
Liaw et al LVD Treatment PreventsDisease
Progression vs Placebo

Liaw et al. N Engl J Med 20043511521-31.
11
Liaw et al Incidence of Disease Progression by
LVDR Substitutions
Number ()
Lamivudine Wild Type (N 221) LVDR (YMDD) (N
209) Placebo (N 214)
11 (5) 23 (11) 38 (18)
Adapted from Liaw et al. N Engl J Med
20043511521-31.
12
Chronic HBV Improved Oral Antiviral Therapy

• Effective
• Safe and well tolerated
• Potent
• Has low rates of resistance
• Maintain future treatment options
• Does not select for LVD or ADV resistance

13
Entecavir

• Cyclopentyl guanosine analog
• Potent Selective inhibitorof HBV replication
• No significant activity against HIV
• Poor substrate for humanpolymerases
• No inhibition of humanmitochondrial (gamma)
  polymerase
• Inhibits all 3 HBV polymerase functionsPriming,
  DNA-dependent synthesis, Reverse transcription
• Phosporylation Intracellular ETV-TP T ½ 15 hrs

14
Comparative EC50 for HBV In Cell Culture

• WT ETV EC50 4 nM (gt 300-fold more potent)

15
Woodchuck Model

• Predictive model of HBV antivirals in humans
• Efficacy
• Toxicity
• Progression to HCC
• ETV is a potent inhibitor of WHBV polymerase
• Long-term treatment (ETV 0.5 mg/kg) 14 or 36
  months
• Sustained virologic suppression up to 8 logsfor
  1 to 3 years

WHBV Woodchuck Hepatitis B Virus
16
Woodchuck Studies Survival
N 56
N 50
N 5
N 6


Animals Survivingto Age 4 ()


ControlUninfected
ControlInfected
ETV36 mo.
ETV14 mo.
Treatment
Combined p 0.0002
Historical control. Tennant, et al. Viral
Hepatitis and Liver Disease 1988 462-464 R.
Colonno, et al. Journal of Infectious Diseases,
20011841236-45
17
Nonclinical Safety
Lois Lehman-McKeeman, PhD
18
Rodent Carcinogenicity Studies Overview

• Lifetime studies in rats and mice to identify
  hazard
• Study Design
• 50-60 animals / sex / group
• Dose up to maximum-tolerated dose (MTD)
• Safety margin over human exposure
• Tumor Evaluation
• Standard histopathologic assessment
• Spontaneous tumors observed

19
Rodent Carcinogenicity StudiesStatistical
Evaluation

• Compare tumor incidences in treated vs control
  animals
• Peto-Pike trend test
• Adjusts for time and cause of death
• Statistical significance based on incidence
• lt 0.005 for a common tumor
• lt 0.025 for a rare tumor
• Determine dose level that results in no
  significant trend

FDA Guidance, 2001
20
Rodent Carcinogenicity Results for ETV

• Tumors concluded to be relevant for the
  evaluation of human safety after review with FDA
  CAC
• Tissues showing preneoplastic changes
• Mice lung adenomas and carcinomas
• Tissues not showing preneoplastic changes
• Male Mice liver carcinomas
• Female Mice Vascular tumors
• Male rats Gliomas
• Female rats Gliomas, liver adenomas,skin
  fibromas

21
Key Carcinogenicity Findings Mouse Lung
Dosage, mg/kg 0 0.004 0.04 0.4 4 Exposure 0.5 mg
(M, F) 0 2, 2 5, 2 24, 19 75, 70 Exposure 1 mg
(M, F) 0 1,1 3, 3 14, 11 42, 40 MALES Tumor
Incidence Lung Adenoma 7 13 19 28 33 Lung
Carcinoma 5 7 7 12 25 FEMALES Lung Adenoma
13 8 7 27 25 Lung Carcinoma 7 5 3 8 27
p lt 0.005

22
Lung Tumors in Mice

• Preneoplastic effects observed in mouse lung
• Increased macrophages
• Proliferation of Type II pneumocytes
• Sustained proliferation of Type II pneumocytesis
  causally-related to tumor development
• Macrophages required
• ETV is chemotactic
• No preneoplastic changes observed in rats, dogs,
  monkeys
• Entecavir is not chemotactic for human monocytes

23
Key Carcinogenicity Findings in Mice
Dosage, mg/kg 0 0.004 0.04 0.4 4 Exposure 0.5 mg
(M, F) 0 2, 2 5, 2 24, 19 75, 70 Exposure 1 mg
(M, F) 0 1,1 3, 3 14, 11 42, 40 MALES Tumor
Incidence Liver Carcinoma 1 2 5 3 13 FEMALES H
emangiomas 19 22 20 18 43
p lt 0.005
24
High Dose Rodent TumorsPossible Mode of Action

• ETV-induces dNTP pool perturbations
• Imbalance alters fidelity of DNA replication and
  repair
• Increased tumor development

25
Key Carcinogenicity Findings in Rats
Dosage, Males 0 0.003 0.02 0.2 1.4 Dosage,
Females 0 0.01 0.06 0.4 2.6 Exposure 0.5 mg (M,
F) 0 lt1, lt1 lt1, 1 8, 8 62, 43 Exposure 1 mg
(M, F) 0 lt1, lt1 lt1, lt1 5, 4 35, 24 MALES
Tumor Incidence Brain Glioma 0 2 2 3 7 FEMALES B
rain Glioma 0 0 2 0 5 Liver Adenoma 1
3 5 2 13 Skin Fibroma 0 0 2 3 5
p lt 0.005 p lt 0.025
26
Human Risk Assessment

• Lifetime studies in rats and mice identify
  carcinogenic hazard
• Human cancer risk assessment
• Other relevant data
• Dose-response relationships
• Exposure multiples
• Assessment for ETV
• Mouse lung tumors may be species specific
• ETV-induced changes in dNTP pools may contribute
  to non-linear dose response

27
Clinical Efficacy

• Evren Atillasoy, MD

28
Entecavir Clinical Program

• Broad experience
• Patterns of HBV disease
• Global
• NDA 1500 ETV-treated patients
• Comparison versus active control (LVD)

29
Clinical Experience
Special Populations N 139
Phase 3 N 1633
Phase 2 N 757
901 Rollover ETV LVD ETV
049 5 YearPost-Treatment Observation
Safety Update
30
Dose Response Mean Reduction in HBV DNA, log10
c/mL
LVD-Refractory Patients
Nucleoside-Naive Patients
Weeks
ETV 0.1(N 34)
ETV 0.01(N 52)
ETV 0.5(N 47)
ETV 0.1(N 47)
ETV 0.5(N 43)
LVD 100(N 40)
ETV 1.0(N 42)
LVD 100(N 45)
Studies 005 and 014
31
Clinical Efficacy

• Naïve eAg (022)
• Naïve eAg- (027)
• LVD-refractory eAg (026)

32
Phase III Study Design
ETV 0.5 mg (N 354)
Responders
LVD 100 mg (N 355)
Partial Responders
ETV 0.5 mg (N 325)
LVD 100 mg (N 313)
ETV 1.0 mg (N 141)
Non-Responders
LVD 100 mg (N 145)
Baseline (Liver Biopsy)
Week 48 (Liver Biopsy)
Week 52 (Patient Management Decision)
33
Key Inclusion Criteria

• Liver biopsy
• Documented HBsAg for 24 weeks
• Compensated liver diseae
• ALT 1.3 - 10 x ULN
• HBV DNA by bDNA
• eAg 3 MEq/mL (3 x 106 c/mL)
• eAg- 0.7 MEq/mL (7 x 105 c/mL)
• HIV, HCV and HDV seronegative
• Creatinine 1.5 mg/dL

Studies 022, 027 and 026
34
Baseline Patient Demographics
Naïve eAg- N 638
LVD-Ref eAg N 286
Naïve eAg N 709
Age, mean (years)
44
39
35
76
76
75
Male
62
58
40
White
37
39
57
Asian
Region
SA South AmericaNA North America
Studies 022, 027 and 026
35
Baseline HBV Characteristics
Naïve eAg- N 638
LVD-Ref eAg N 286
Naïve eAg N 709
7.6
9.4
9.7
HBV DNA by PCR, mean (log10 copies/mL)
142
128
143
ALT, mean (U/L)
HBV subtype
Studies 022, 027 and 026
36
Baseline Histology Scores
Studies 022, 027 and 026
37
Patient Disposition
Number of Patients
(96)
(90)
(96)
(95)
(94)
(87)
a Percent based on treated patients
Studies 022, 027 and 026
38
Liver Biopsy Assessment

• Single pathologist
  (Zachary Goodman, MD - AFIP)
• Blinded to treatment assignment
• Blinded to temporal sequenceof biopsy pairs

Studies 022, 027 and 026
39
Primary Endpoint at Week 48

• Histologic Improvement at Week 48,relative to
  baseline
• 2-point reduction in Knodell necroinflammatorys
  core with no worsening in Knodell fibrosis
• Evaluable Baseline Histology Cohort
• Baseline Knodell necroinflammatory score 2
• 89 of treated patients
• Missing / inadequate Week 48 biopsy no
  improvement

Studies 022, 027 and 026
40
Primary Endpoint in Naïve Patients
Histologic Improvement
at Week 48
Naïve eAg-
Naïve eAg
Difference Estimate (95 CI)p-value
Studies 022 and 027
41
Co-Primary Endpoints at Week 48in LVD-Refractory
Patients
Histologic Improvement
HBV DNA by bDNA (lt 0.7 MEq/mL) and ALT (lt 1.25 x
ULN)
Percent
Diff. Est. (97.5 CI) 27.3 (13.6, 40.9)
50.5 (40.4, 60.6)
p lt 0.0001
p lt 0.0001
Study 026
42
Secondary Histology EndpointIshak Fibrosis
Improvement at Week 48
Naïve eAg
Naïve eAg-
LVD-Ref eAg
Improved
Percent
No change
44
42
34
41
40
46
Worsened
Improvement p 0.41 p
0.65 p lt 0.01
Studies 022, 027 and 026
43
Non-Histology Secondary Endpoints at Week 48

• Virologic
• Mean HBV DNA reduction from baseline by PCR
• HBV DNA lt 400 copies/mL by PCR
• Biochemical
• Normalization of ALT ( 1 x ULN)
• Serologic
• HBe Seroconversion (eAg patients)

Studies 022, 027 and 026
44
HBV DNA lt 400 copies/mL Through Week 48 Naïve
Studies
Naïve eAg
Naïve eAg-
ETV (N 354) LVD (N 355)
ETV (N 325) LVD (N 313)
91
73
69
Percent
38
p lt 0.0001
p lt 0.0001
Weeks
Studies 022 and 027
45
HBV DNA lt 400 copies/mL Through Week 48
LVD-Refractory Study
ETV (N 141) LVD (N 145)
21
Percent
p lt 0.0001
1
Weeks
Study 026
46
HBV DNA Mean Reduction at Week 48
Naïve eAg
Naïve eAg-
LVD-Ref eAg
log10 copies/mL
p lt 0.0001 p lt 0.0001
p lt 0.0001
Studies 022, 027 and 026
47
ALT 1 x ULN at Week 48
Naïve eAg
Naïve eAg-
LVD-Ref eAg
Percent
p 0.02 p lt 0.05
p lt 0.0001
Studies 022, 027 and 026
48
HBe Seroconversion at Week 48
Naïve eAg
LVD-Ref eAg
Percent
p 0.33 p
0.06
Studies 022 and 026
49
Summary of Week 48 Efficacy
Naïve eAg Naïve eAg- LVD-Ref eAg
Histologic Improvement
HBV DNA lt 400 copies/mL
ALT 1 x ULN
HBe Seroconversion
LVD Better
ETV Better
ETV - LVD Difference Estimate and CI
Studies 022, 027 and 026
50
Clinical Safety
51
Populations in Safety Analysis
ETV 1.0 mg LVD
52
Observation Time Weeks
Nucleoside-naïve
LVD-refractory
Safety Cohort
Safety Cohort therapy may be blinded or
open-label follow-up may include time on
alternate HBV therapies
Studies 022, 027, 014, 026 Safety Update
53
Clinical Safety

• General
• Hepatic
• Malignant Neoplasms

54
Overall Safety
Number of Patients ()
Studies 022, 027, 014, 026 Safety Update
55
Adverse Events 10 On Treatment
Any adverse event 81 82 85 82 Headache 20 19
19 18 Upper respiratory tract infection 18
16 16 12 Nasopharyngitis 12 12 9 10
Cough 11 10 11 9 Abdominal Pain Upper 10
9 8 13 Fatigue 10 9 14 12 ALT
Increase 3 7 3 11
Studies 022, 027, 014 and 026 Safety Update
56
Clinical Safety

• General
• Hepatic
• Malignant Neoplasms

57
ALT Flares On- and Off-Treatment
Studies 022, 027, 014, 026 Safety Update
58
Hepatic Events in Pivotal Studies
Number of Patients
Studies 022, 027, 014 and 026 Safety Update
59
Clinical Safety

• General
• Hepatic
• Malignant Neoplasms

60
Rates of Malignant Neoplasms
Comparable rates observed in ETV and LVD
Rate/1000 PY
Safety Cohort Safety Update
61
Malignancy Diagnosis Excluding Skin Distribution
Over Time
Percent of Patients with Events
3 1497
2 899
6 1376
4 869
4 1179
2 801
1 945
0 454
N w/events
N at risk
Safety Cohort Safety Update
62
Comparison of Rates of Malignant Neoplasmsin ETV
Clinical Studies vs. Other HBV Cohorts
Rates per 1000 Patient Years
ObservationalCohort Studies
Safety Cohort
Liver Cancer, including non-HCC
63
Overall Clinical Safety Summary

• ETV and LVD have comparable safety profiles
• ETV safety profile does not vary by
• Dose 0.5 mg versus 1.0 mg
• Patient population naïve and refractory
• ETV and LVD have comparable incidencesof
  malignancy

64
Viral Resistance

• Richard Colonno, PhD

65
Early Markers of ETV Resistance

• In Vitro Studies
• LVDR (L180M M204V/I) virus displays 8 to 31
  fold decreased susceptibility to ETV
• ETV potency vs. LVDR HBV 50x gt ADV
• ADVR (A181V or N236T) viruses retain
  susceptibility to ETV

• Phase II Studies
• Two patients with LVDR HBV exhibited rebound due
  to resistance emergence following (gt76 wk) ETV
  therapy
• Key resistance substitutions emerging on ETV
  treatment
• Patient A (L180M M204V) ? I169T M250V
• Patient B (L180M M204V) ? T184G S202I ?
  I169T
• Both isolates growth impaired and susceptible to
  ADV

66
ETV Phenotypes
67
Phase III Resistance Evaluation

• Genotype Nucleoside Naïve Patients Entry and Wk
  48
• eAg pos (022) All ETV (n 339) patients
• eAg neg (027) Random ETV (n 211) patients
• Genotype LVD Refractory Patients Entry and Wk
  48
• eAg pos (026) All ETV (n 134) and LVD (n
  126) patients
• Study 014 All ETV (1 mg) (n 37) and LVD (n
  24) patients
• Phenotype all emerging substitutions identified
  during ETV therapy using recombinant clones
• Genotype and population phenotype all subjects
  experiencing virologic rebounds ( 1 log
  increase from nadir by PCR), regardless of study
  or therapy arm

68
Resistance Profile Nucleoside Naïve Patients
Percent of Patients

• Potent HBV DNA suppression(88 below 103
  copies/mL)
• Viral genotyping (n 541)identified 76 emerging
  changes, none appearing in gt0.6
• Emerging amino acid changes did not decrease ETV
  susceptibility
• 11 virologic rebounds on ETVvs. 88 on LVD

HBV DNA (Copies/mL)
81
57
Wk 0 48 0 48
ETV
LVD
n 676 655 665 621
Studies 022 and 027
69
Virologic Rebounds Nucleoside Naïve Patients

• Rebounds on ETV therapy
• All patients experienced at least 3 log
  reductions in HBV DNA levels, 7 ? 5 log
• Fully susceptible at time of rebound - population
  EC50 lt10 nM
• No emerging genotypic changes impacting ETV
  susceptibility

LVD 180 and/or 204 changes, ETV any
substitution impacting ETV susceptibility
Studies 022 and 027
70
Summary of Viral Resistance Data (Week 48)
0
0
No rebounds due to resistance
No emerging ETVR or LVDR substitutions
Nucleoside Naïve (n 541)
71
Resistance Profile LVD-Refractory Patients
Percent of Subjects

• Effective suppression ofHBV DNA levels
• All ETV (n 183) and LVD(n 190) patient
  samples genotyped at study entryand Week 48
• Five virologic rebounds in ETV treated patients
  by Week 48

11
10
10
10
9
10
8
10
7
10
HBV DNA (Copies/mL)
6
10
5
10
4
10
3
10
300-999
lt300
6
22
lt1
2
Wk 0 24 48 0 24 48
ETV
LVD
n 183 176 171 190 179 157
Studies 014 026
72
Virologic Rebounds LVD Refractory Patients
Study 026 - ETV
1011
1010
109
1
108
2
107
HBV DNA (Copies/ml)
106
105
104
103
102
Treatment (Weeks)

• Two (1) ETV treated patients experienced
  virologic rebound due to resistance by Week 48

73
Genotypic Analysis LVD Refractory Patients

• ETVR changes (I169, T184, S202 M250) detected
  in 12 ETV treated patients by Week 48
• Only detected when LVDR changes were present
• Emerging substitutions at 14 other residues
  identified
• None present in gt3 patients (1.6) or correlated
  with decreased ETV susceptibility (EC50 2.4 45
  nM)

74
ETVR Substitutions Can Be SelectedDuring LVD
Treatment

• I169T and T184S emerged on LVD therapy(study
  026)
• ETVR changes detected in 22 (6) of LVD
  refractory patients at baseline
• Nine randomized to ETV arm, leading to2
  virologic rebounds and only 2 patients
  experiencing HBV DNA reductions lt103 copies/ml

LVD can select for a number of secondary
substitutions that can significantly reduce ETV
susceptibility and clinical efficacy
75
Summary of Viral Resistance Data (Week 48)
0
0
No rebounds due to resistance
No emerging ETVR or LVDR substitutions
Nucleoside Naïve (n 541)
76
Resistance Summary

• Potent and sustained suppression of viral
  replication directly related to absence of
  resistance emergence
• Extensive analysis of nucleoside naïve patients
  showed no evidence of resistance at Week 48
• Treatment of LVD-refractory patients with ETV
  leads to 1 virologic failures due to resistance
  by Week 48
• Substitutions correlating with ETVR identified at
  residues 169, 184, 202 and 250
• LVDR substitutions are a prerequisite for
  emergence of high level ETVR
• LVD treatment can pre-select for ETVR
  substitutions identified by Week 48

77
Pharmacovigilance and Summary

• Donna Morgan Murray, PhD

78
Proposed Pharmacovigilance Plan

• Monitor events of special interest malignancies
  and hepatic events
• Targeted questionnaires to physicians
• Periodic, cumulative assessments
• Ongoing long-term safety studies
• Large safety study

79
Treatment and Long-term Safety Studies
Rollover StudiesETV Treatment
Randomized Studies
Observational Study
Responders
No ETV treatment
Phase II/III N 1945(eligible treated)
Study 901 N 940
Study 049 N 444
Responders
China Program N 876(eligible treated)
Study 050 N 255
5 Years
2nd Year
1st Year
As of Dec 2004
80
Large Safety Study Objectives

• Rigorous analysis of events of interest
• Mortality
• Neoplasms
• Progression of liver disease

81
Large Safety Study Design

• Patients will be
• Randomized 11
• ETV
• Another standard of care nucleosideor nucleotide
• Stratified as naïve or previously treated
• Followed for at least 5 years
• External, independent DSMB

82
Large Safety Study Methods

• Location multinational
• Recruitment through patients physicians
• Sample size 12,500 (6,250 in each group)
• Reporting annually on all cause mortality,
  malignancy and progression of liver disease

83
Large Safety Study Challenges

• Patients will switch therapies
• Latency of events
• Rates of malignancy
• Follow-up

84
Pathophysiologic Cascade of Chronic Hepatitis B
Infection Benefits of Entecavir
HBV Replication (Measured by Serum HBV DNA)
DiseaseProgression Liver Failure Liver
Cancer Transplant Death
85
Pathophysiologic Cascade of Chronic Hepatitis B
Infection Benefits of Entecavir
HBV Replication (Measured by Serum HBV DNA)
Liver Inflammation
ALT Elevation
DiseaseProgression Liver Failure Liver
Cancer Transplant Death
Worsening histology Necroinflammation Fibrosis Cir
rhosis
Resistance
86
Pathophysiologic Cascade of Chronic Hepatitis B
Infection Benefits of Entecavir
HBV Replication (Measured by Serum HBV DNA)
Liver Inflammation
ALT Elevation
DiseaseProgression Liver Failure Liver
Cancer Transplant Death
Worsening histology Necroinflammation Fibrosis Cir
rhosis
Resistance
87
Pathophysiologic Cascade of Chronic Hepatitis B
Infection Benefits of Entecavir
HBV Replication (Measured by Serum HBV DNA)
Liver Inflammation
ALT Elevation
DiseaseProgression Liver Failure Liver
Cancer Transplant Death
Worsening histology Necroinflammation Fibrosis Cir
rhosis
Resistance
88
Pathophysiologic Cascade of Chronic Hepatitis B
Infection Benefits of Entecavir