fda’s antiviral drugs advisory committee meeting
DESCRIPTION
FDA’s Antiviral Drugs Advisory Committee Meeting. BARACLUDE TM (entecavir / BMS 200475). 11 March 2005. Introduction. Elliott Sigal, MD, PhD. Global Impact of Hepatitis B. 15–40% develop cirrhosis, liver failure or hepatocellular carcinoma. 2 billion with past / present HBV infection. - PowerPoint PPT PresentationTRANSCRIPT
1
BARACLUDEBARACLUDETMTM
(entecavir / BMS 200475)(entecavir / BMS 200475)
FDA’s Antiviral DrugsFDA’s Antiviral DrugsAdvisory Committee MeetingAdvisory Committee Meeting
11 March 200511 March 2005
2
IntroductionIntroductionElliott Sigal, MD, PhDElliott Sigal, MD, PhD
3
Global Impact of Hepatitis BGlobal Impact of Hepatitis B
World PopulationWorld Population6 billion6 billion
2 billion with past / present 2 billion with past / present HBV infectionHBV infection
350–400 million with 350–400 million with chronic hepatitis Bchronic hepatitis B
15–40% develop 15–40% develop cirrhosis, liver failurecirrhosis, liver failure
or hepatocellular or hepatocellular carcinomacarcinoma
Worldwide: Worldwide: ~1 million / year die from HBV-associated liver disease ~1 million / year die from HBV-associated liver diseaseUnited States: United States: Chronically infected ~1.25 million; ~5000 / year dieChronically infected ~1.25 million; ~5000 / year die
4
BackgroundBackgroundRichard Colonno, PhDRichard Colonno, PhD
5
Proposed IndicationProposed Indication
Entecavir is indicated for the treatment of Entecavir is indicated for the treatment of chronic hepatitis B infection in adults with chronic hepatitis B infection in adults with evidence of active liver inflammationevidence of active liver inflammation
Usual dose:Usual dose:0.5 mg tablet once daily0.5 mg tablet once daily
Lamivudine-refractory:Lamivudine-refractory:1.0 mg tablet once daily1.0 mg tablet once daily
6
BMS PresentationBMS PresentationIntroductionIntroduction Elliott Sigal, MD, PhDElliott Sigal, MD, PhD
Chief Scientific Officer & President,Chief Scientific Officer & President,Pharmaceutical Research InstitutePharmaceutical Research Institute
BackgroundBackground Richard Colonno, PhD Richard Colonno, PhDVice President, Infectious DiseasesVice President, Infectious DiseasesDrug DiscoveryDrug Discovery
Nonclinical SafetyNonclinical Safety Lois Lehman-McKeeman, PhDLois Lehman-McKeeman, PhDDistinguished Research Fellow,Distinguished Research Fellow,Discovery ToxicologyDiscovery Toxicology
Clinical Efficacy /Clinical Efficacy / Evren Atillasoy, MDEvren Atillasoy, MDClinical SafetyClinical Safety Director, US Medical AffairsDirector, US Medical Affairs
Viral ResistanceViral Resistance Richard Colonno, PhDRichard Colonno, PhDVice President, Infectious DiseasesVice President, Infectious DiseasesDrug DiscoveryDrug Discovery
Pharmacovigilance Pharmacovigilance Donna Morgan Murray, PhDDonna Morgan Murray, PhDand Summaryand Summary Executive Director,Executive Director,
Global Regulatory SciencesGlobal Regulatory Sciences
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Consultants Available to the CommitteeConsultants Available to the CommitteeAdrian Di Bisceglie, MDAdrian Di Bisceglie, MD Saint Louis University School of MedicineSaint Louis University School of Medicine
Samuel A. Bozzette, MD, PhDSamuel A. Bozzette, MD, PhD University of California, San DiegoUniversity of California, San Diego
Jules L. Dienstag, MD Jules L. Dienstag, MD Massachusetts General HospitalMassachusetts General Hospital
James Swenberg, DVM, PhDJames Swenberg, DVM, PhDUniversity of North CarolinaUniversity of North Carolina
LJ Wei, PhDLJ Wei, PhD Harvard UniversityHarvard University
Gary M. Williams, MD, DABTGary M. Williams, MD, DABT New York Medical CollegeNew York Medical College
Hepatology
Health PolicyHealth Policy
Hepatology
Toxicology/Toxicology/Pathology
BiostatisticsBiostatistics
Toxicology/Toxicology/Pathology
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Impact of Viral Replication on Disease Impact of Viral Replication on Disease Progression: Taiwan Cohort Study ResultsProgression: Taiwan Cohort Study Results
The incidence of hepatocellular carcinoma The incidence of hepatocellular carcinoma (HCC) and liver cirrhosis is correlated with (HCC) and liver cirrhosis is correlated with level of viral replicationlevel of viral replication
Persistent elevation of viral load over time Persistent elevation of viral load over time has the greatest impact on HCC riskhas the greatest impact on HCC risk
Viral load predicts risk of future HCC Viral load predicts risk of future HCC independent of HBeAg status and serum independent of HBeAg status and serum ALT levelALT level
– This risk increases with increasing This risk increases with increasing viral loadviral load
EASL April 2005
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Pathophysiologic Cascade of Chronic Hepatitis B Pathophysiologic Cascade of Chronic Hepatitis B Infection: Significance of HBV ReplicationInfection: Significance of HBV Replication
Worsening histologyNecroinflammationFibrosisCirrhosis
HBV Replication (Measured by
Serum HBV DNA)
Liver Inflammation
ALT Elevation DiseaseProgressionLiver FailureLiver CancerTransplantDeath
10
Liaw et al: LVD Treatment PreventsLiaw et al: LVD Treatment PreventsDisease Progression vs PlaceboDisease Progression vs Placebo
Liaw et al.Liaw et al. N Engl J Med 2004;351:1521-31.
0
5
10
15
20
25
0 6 12 18 24 30 36
Perc
enta
ge w
ithPe
rcen
tage
with
Dis
ease
Pro
gres
sion
Dis
ease
Pro
gres
sion
Time to Disease Progression (months)Time to Disease Progression (months)
p = 0.001p = 0.001
18%18%
8%8%
Placebo (n = 215) ITT populationLamivudine (n = 436)
Placebo
Lamivudine
11
Liaw et al: Incidence of Disease Progression Liaw et al: Incidence of Disease Progression by LVDby LVDRR Substitutions Substitutions
Number (%)Number (%)
Adapted from Liaw et al.Adapted from Liaw et al. N Engl J Med 2004;351:1521-31.
LamivudineLamivudineWild Type (N = 221)Wild Type (N = 221)
LVDLVDRR (YMDD)(YMDD) (N = 209) (N = 209)
Placebo (N = 214)Placebo (N = 214)
11 (5)11 (5)
23 (11)23 (11)
38 (18)38 (18)
12
Chronic HBV: Improved Oral Antiviral TherapyChronic HBV: Improved Oral Antiviral Therapy
EffectiveEffective
Safe and well toleratedSafe and well tolerated
PotentPotent
Has low rates of resistanceHas low rates of resistance
Maintain future treatment optionsMaintain future treatment options– Does not select for LVD or ADV Does not select for LVD or ADV
resistanceresistance
13
EntecavirEntecavir Cyclopentyl guanosine analog Cyclopentyl guanosine analog
Potent Selective inhibitorPotent Selective inhibitorof HBV replication of HBV replication
No significant activity against HIVNo significant activity against HIV
Poor substrate for humanPoor substrate for humanpolymerasespolymerases
No inhibition of humanNo inhibition of humanmitochondrial (gamma) polymerasemitochondrial (gamma) polymerase
Inhibits all 3 HBV polymerase functions:Inhibits all 3 HBV polymerase functions:Priming, DNA-dependent synthesis, Reverse transcriptionPriming, DNA-dependent synthesis, Reverse transcription
Phosporylation: Intracellular ETV-TP T ½ ~ 15 hrsPhosporylation: Intracellular ETV-TP T ½ ~ 15 hrs
N
NHNN
NNOHOH
OHOH
O
CHCH22 NH2
14
Comparative ECComparative EC5050 for HBV In Cell Culture for HBV In Cell Culture
WT: ETV ECWT: ETV EC5050 = 4 = 4 nMnM (> 300-fold more potent) (> 300-fold more potent)
1
10
100
1000
10000
100000
ETV LVD ADV LdT TFV
EC50
(nM
)
15
Woodchuck ModelWoodchuck Model
WHBV – Woodchuck Hepatitis B VirusWHBV – Woodchuck Hepatitis B Virus
Predictive model of HBV antivirals in humansPredictive model of HBV antivirals in humans– EfficacyEfficacy– ToxicityToxicity– Progression to HCCProgression to HCC
ETV is a potent inhibitor of WHBV polymeraseETV is a potent inhibitor of WHBV polymerase Long-term treatment (ETV 0.5 mg/kg): Long-term treatment (ETV 0.5 mg/kg):
14 or 36 months14 or 36 months Sustained virologic suppression up to 8 logsSustained virologic suppression up to 8 logs
for 1 to 3 yearsfor 1 to 3 years
16
Woodchuck Studies: SurvivalWoodchuck Studies: Survival
0
20
40
60
80
100
Ani
mal
s Su
rviv
ing
Ani
mal
s Su
rviv
ing
to A
ge 4
(%)
to A
ge 4
(%)
* Combined p = 0.0002* Combined p = 0.0002‡ Historical control. Tennant, et al. Historical control. Tennant, et al. Viral Hepatitis and Liver DiseaseViral Hepatitis and Liver Disease 1988: 462-464 1988: 462-464R. Colonno, et al. R. Colonno, et al. Journal of Infectious Diseases,Journal of Infectious Diseases, 2001;184:1236-45 2001;184:1236-45
*‡
‡
ControlControlUninfectedUninfected
ControlControlInfectedInfected
ETVETV36 mo.36 mo.
TreatmentTreatment
N = 56 N = 50 N = 5N = 6
ETVETV14 mo.14 mo.
*
17
Nonclinical SafetyNonclinical Safety
Lois Lehman-McKeeman, PhDLois Lehman-McKeeman, PhD
18
Rodent Carcinogenicity Studies: OverviewRodent Carcinogenicity Studies: Overview
Lifetime studies in rats and mice to identify hazardLifetime studies in rats and mice to identify hazard Study DesignStudy Design
– 50-60 animals / sex / group50-60 animals / sex / group– Dose up to maximum-tolerated dose (MTD)Dose up to maximum-tolerated dose (MTD)– Safety margin over human exposureSafety margin over human exposure
Tumor EvaluationTumor Evaluation– Standard histopathologic assessmentStandard histopathologic assessment– Spontaneous tumors observedSpontaneous tumors observed
19
Rodent Carcinogenicity Studies:Rodent Carcinogenicity Studies:Statistical Evaluation Statistical Evaluation
Compare tumor incidences in treated vs control Compare tumor incidences in treated vs control animalsanimals
Peto-Pike trend testPeto-Pike trend test– Adjusts for time and cause of deathAdjusts for time and cause of death– Statistical significance based on incidenceStatistical significance based on incidence
< 0.005 for a common tumor< 0.005 for a common tumor< 0.025 for a rare tumor< 0.025 for a rare tumor
Determine dose level that results in no significant Determine dose level that results in no significant trendtrend
FDA Guidance, 2001
20
Rodent Carcinogenicity: Results for ETVRodent Carcinogenicity: Results for ETVTumors concluded to be relevant for the evaluation Tumors concluded to be relevant for the evaluation of human safety after review with FDA CACof human safety after review with FDA CAC
Tissues showing preneoplastic changesTissues showing preneoplastic changes– Mice: lung adenomas and carcinomasMice: lung adenomas and carcinomas
Tissues not showing preneoplastic changesTissues not showing preneoplastic changes– Male Mice: liver carcinomasMale Mice: liver carcinomas– Female Mice: Vascular tumorsFemale Mice: Vascular tumors– Male rats: GliomasMale rats: Gliomas– Female rats: Gliomas, liver adenomas,Female rats: Gliomas, liver adenomas,
skin fibromas skin fibromas
21
Key Carcinogenicity Findings: Mouse LungKey Carcinogenicity Findings: Mouse Lung
Dosage, mg/kgDosage, mg/kg 00 0.0040.004 0.040.04 0.40.4 44Exposure: 0.5 mg (M, F)Exposure: 0.5 mg (M, F) 00 2, 22, 2 5, 25, 2 24, 1924, 19 75, 7075, 70Exposure: 1 mg (M, F)Exposure: 1 mg (M, F) 00 1,11,1 3, 33, 3 14, 1114, 11 42, 4042, 40
MALESMALES % Tumor Incidence% Tumor IncidenceLung Adenoma Lung Adenoma 77 1313 19*19* 28* 28* 33*33*Lung CarcinomaLung Carcinoma 5 5 77 77 1212 25*25*
FEMALESFEMALESLung Adenoma Lung Adenoma 1313 88 77 2727 25*25*Lung Carcinoma Lung Carcinoma 7 7 55 33 88 27*27*
* p < 0.005
22
Lung Tumors in MiceLung Tumors in Mice Preneoplastic effects observed in mouse lung:Preneoplastic effects observed in mouse lung:
– Increased macrophagesIncreased macrophages– Proliferation of Type II pneumocytes Proliferation of Type II pneumocytes
Sustained proliferation of Type II pneumocytesSustained proliferation of Type II pneumocytesis causally-related to tumor developmentis causally-related to tumor development
– Macrophages requiredMacrophages required– ETV is chemotacticETV is chemotactic
No preneoplastic changes observed in rats, dogs, No preneoplastic changes observed in rats, dogs, monkeysmonkeys
Entecavir is not chemotactic for human monocytesEntecavir is not chemotactic for human monocytes
23
Key Carcinogenicity Findings in MiceKey Carcinogenicity Findings in Mice
Dosage, mg/kgDosage, mg/kg 00 0.0040.004 0.040.04 0.40.4 44
Exposure: 0.5 mg (M, F)Exposure: 0.5 mg (M, F) 00 2, 22, 2 5, 25, 2 24, 1924, 19 75, 7075, 70
Exposure: 1 mg (M, F)Exposure: 1 mg (M, F) 00 1,11,1 3, 33, 3 14, 1114, 11 42, 4042, 40
MALESMALES % Tumor Incidence% Tumor Incidence
Liver Carcinoma Liver Carcinoma 1 1 22 55 33 13*13*
FEMALESFEMALES
HemangiomasHemangiomas 19 19 2222 2020 1818 43*43*
* p < 0.005
24
ETV-TPETV-TPETVETV
GDPGDP dGDPdGDP dGTPdGTP
phosphorylationphosphorylation
High Dose Rodent Tumors:High Dose Rodent Tumors:Possible Mode of ActionPossible Mode of Action
ETV-induces dNTP pool perturbations:ETV-induces dNTP pool perturbations:
Imbalance alters fidelity of DNA Imbalance alters fidelity of DNA replication and repairreplication and repair
Increased tumor developmentIncreased tumor development
25
Key Carcinogenicity Findings in RatsKey Carcinogenicity Findings in RatsDosage, MalesDosage, Males 00 0.0030.003 0.020.02 0.2 0.2 1.41.4Dosage, FemalesDosage, Females 00 0.010.01 0.060.06 0.40.4 2.62.6Exposure: 0.5 mg (M, F)Exposure: 0.5 mg (M, F) 00 <1, <1<1, <1 <1, 1 <1, 1 8, 88, 8 62, 4362, 43Exposure: 1 mg (M, F)Exposure: 1 mg (M, F) 00 <1, <1<1, <1 <1, <1 <1, <1 5, 4 5, 4 35, 2435, 24
MALESMALES % Tumor Incidence% Tumor IncidenceBrain GliomaBrain Glioma 00 22 22 33 7**7**
FEMALESFEMALESBrain GliomaBrain Glioma 00 00 22 00 5**5**Liver Adenoma Liver Adenoma 1 1 33 55 22 13*13*Skin FibromaSkin Fibroma 00 00 22 3**3** 5**5*** p < 0.005; ** p < 0.025
26
Lifetime studies in rats and mice identify Lifetime studies in rats and mice identify carcinogenic hazardcarcinogenic hazard
Human cancer risk assessmentHuman cancer risk assessment– Other relevant dataOther relevant data– Dose-response relationshipsDose-response relationships– Exposure multiplesExposure multiples
Assessment for ETVAssessment for ETV– Mouse lung tumors may be species specificMouse lung tumors may be species specific– ETV-induced changes in dNTP pools may ETV-induced changes in dNTP pools may
contribute to non-linear dose responsecontribute to non-linear dose response
Human Risk AssessmentHuman Risk Assessment
27
Clinical EfficacyClinical Efficacy
Evren Atillasoy, MDEvren Atillasoy, MD
28
Entecavir Clinical ProgramEntecavir Clinical Program
Broad experience:Broad experience:
– Patterns of HBV diseasePatterns of HBV disease
– GlobalGlobal
– NDA: ~ 1500 ETV-treated patientsNDA: ~ 1500 ETV-treated patients
Comparison versus active control (LVD)Comparison versus active control (LVD)
29
Clinical ExperienceClinical Experience
Special Special PopulationsPopulations
N = 139N = 139
Safety UpdateSafety Update
Phase 3Phase 3N = 1633N = 1633
Phase 2Phase 2N = 757N = 757
901 Rollover901 RolloverETV + LVD ETVETV + LVD ETV
0490495 Year5 Year
Post-Treatment Post-Treatment ObservationObservation
30
-6
-5
-4
-3
-2
-1
0
B/L 24 48
Dose Response –Dose Response –Mean Reduction in HBV DNA, logMean Reduction in HBV DNA, log1010 c/mL c/mL
-6
-5
-4
-3
-2
-1
0
B/L 4 12 22WeeksETV 0.1
(N = 34)
ETV 0.5(N = 43)
ETV 0.01(N = 52)
LVD 100(N = 40)
Studies 005 and 014Studies 005 and 014
ETV 0.5(N = 47)
ETV 1.0(N = 42)
ETV 0.1(N = 47)
LVD 100(N = 45)
LVD-Refractory PatientsLVD-Refractory PatientsNucleoside-Naive PatientsNucleoside-Naive Patients
31
ClinicalClinical EfficacyEfficacy Naïve eAg+ (022)Naïve eAg+ (022)
Naïve eAg- (027)Naïve eAg- (027)
LVD-refractory eAg+ (026)LVD-refractory eAg+ (026)
32
Naïve eAg+ (022)Naïve eAg+ (022)
Naïve eAg- (027)Naïve eAg- (027)
LVD-Ref eAg+ (026)LVD-Ref eAg+ (026)
Phase III Study DesignPhase III Study Design
Baseline(Liver Biopsy)
Week 48(Liver Biopsy)
Week 52(Patient Management Decision)
Responders
Partial Responders
Non-Responders
ETV 0.5 mg (N = 354)
LVD 100 mg (N = 145)ETV 1.0 mg (N = 141)
LVD 100 mg (N = 313)ETV 0.5 mg (N = 325)
LVD 100 mg (N = 355)
33
Key Inclusion CriteriaKey Inclusion Criteria Liver biopsyLiver biopsy Documented HBsAg+ for Documented HBsAg+ for ≥≥ 24 weeks 24 weeks Compensated liver diseaeCompensated liver diseae ALT 1.3 ALT 1.3 −− 10 x ULN 10 x ULN HBV DNA by bDNAHBV DNA by bDNA
eAg+: ≥ 3 MEq/mL (3 x 10eAg+: ≥ 3 MEq/mL (3 x 1066 c/mL) c/mL)eAg- : ≥ 0.7 MEq/mL (7 x 10eAg- : ≥ 0.7 MEq/mL (7 x 1055 c/mL) c/mL)
HIV, HCV and HDV seronegativeHIV, HCV and HDV seronegative Creatinine Creatinine ≤ 1.5 mg/dL≤ 1.5 mg/dL
Studies 022, 027 and 026Studies 022, 027 and 026
34
Baseline Patient DemographicsBaseline Patient DemographicsNaïve eAg-Naïve eAg-
N = 638N = 638
Region
62%58%40%White
37%39%57%Asian
76%
44 3935Age, mean (years)
76%75%Male
LVD-Ref eAg+LVD-Ref eAg+N = 286N = 286
Naïve eAg+Naïve eAg+N = 709N = 709
Europe
Asia
NASA
Studies 022, 027 and 026Studies 022, 027 and 026
Europe
Asia
NA
SA SA
NA
Asia
Europe
SA – South AmericaNA – North America
35
Baseline HBV CharacteristicsBaseline HBV Characteristics
HBV subtype
7.6 9.49.7HBV DNA by PCR,mean (log10 copies/mL)
Studies 022, 027 and 026Studies 022, 027 and 026
Other
D
C B
A
OtherA
B
CD
Other
D
CB
A
142 128143ALT, mean (U/L)
Naïve eAg-Naïve eAg-N = 638N = 638
LVD-Ref eAg+LVD-Ref eAg+N = 286N = 286
Naïve eAg+Naïve eAg+N = 709N = 709
36
Baseline Histology ScoresBaseline Histology Scores
Studies 022, 027 and 026Studies 022, 027 and 026
Naïve eAg+Naïve eAg+N = 709N = 709
Naïve eAg-Naïve eAg-N = 638N = 638
LVD-Ref eAg+LVD-Ref eAg+N = 286N = 286
KnodellKnodellNecroinflammatory, meanNecroinflammatory, mean 7.87.8 7.87.8 6.56.5Fibrosis, meanFibrosis, mean 1.71.7 1.91.9 1.81.8
Ishak fibrosisIshak fibrosisMeanMean 2.32.3 2.52.5 2.32.3
CirrhosisCirrhosisKnodell 4Knodell 4 7%7% 7%7% 8%8%
37
Naïve eAg+Naïve eAg+ Naïve eAg-Naïve eAg- LVD-Ref eAg+LVD-Ref eAg+ETVETV LVD LVD ETVETV LVDLVD ETV ETV LVDLVD
Patient DispositionPatient Disposition
RandomizedRandomized 357357 358358 331331 317317 147147 146146
TreatedTreated 354354 355355 325325 313313 141141 145145
Completed 1 yrCompleted 1 yraa 340340 321321 311311 296296 133133 126126
DC during yr 1DC during yr 1 1414 3434 1414 1717 88 1919
DC w/ AEDC w/ AE DeathDeath Other Other
1100
1313
9922
2323
662266
990088
110077
8811
1010
Studies 022, 027 and 026 Studies 022, 027 and 026
Number of PatientsNumber of Patients
a Percent based on treated patients
(96%)(96%) (90%)(90%) (96%)(96%) (95%)(95%) (94%)(94%) (87%)(87%)
38
Liver Biopsy AssessmentLiver Biopsy Assessment
Single pathologist Single pathologist (Zachary Goodman, MD - AFIP) (Zachary Goodman, MD - AFIP)
– Blinded to treatment assignmentBlinded to treatment assignment
– Blinded to temporal sequenceBlinded to temporal sequenceof biopsy pairsof biopsy pairs
Studies 022, 027 and 026Studies 022, 027 and 026
39
Primary Endpoint at Week 48Primary Endpoint at Week 48
Histologic Improvement at Week 48,Histologic Improvement at Week 48,relative to baseline relative to baseline
– ≥ ≥ 2-point reduction in Knodell necroinflammatory2-point reduction in Knodell necroinflammatoryscore with no worsening in Knodell fibrosisscore with no worsening in Knodell fibrosis
Evaluable Baseline Histology CohortEvaluable Baseline Histology Cohort– Baseline Knodell necroinflammatory score Baseline Knodell necroinflammatory score ≥ 2≥ 2– 89% of treated patients89% of treated patients
Missing / inadequate Week 48 biopsy =Missing / inadequate Week 48 biopsy =no improvementno improvement
Studies 022, 027 and 026Studies 022, 027 and 026
40
Primary Endpoint in Naïve Patients: Primary Endpoint in Naïve Patients: Histologic Improvement at Week 48 Histologic Improvement at Week 48
Studies 022 and 027Studies 022 and 027
ETVETV0.5 mg0.5 mgN = 314N = 314
LVDLVD100 mg100 mgN = 314N = 314
ETVETV0.5 mg0.5 mgN = 296N = 296
LVDLVD100 mg100 mgN = 287N = 287
226 (72%)226 (72%) 195 (62%)195 (62%) 208 (70%)208 (70%) 174 (61%)174 (61%)
9.9 (2.6, 17.2) 9.9 (2.6, 17.2) p = 0.0085p = 0.0085
9.6 (2.0, 17.3)9.6 (2.0, 17.3)p = 0.0143p = 0.0143
Naïve eAg-Naïve eAg-Naïve eAg+Naïve eAg+
Difference Estimate (95% CI)p-value
41
Co-Primary Endpoints at Week 48Co-Primary Endpoints at Week 48in LVD-Refractory Patients in LVD-Refractory Patients
Histologic Histologic ImprovementImprovement
HBV DNA by bDNA (< 0.7 MEq/mL) HBV DNA by bDNA (< 0.7 MEq/mL) and ALT (< 1.25 x ULN)and ALT (< 1.25 x ULN)
Diff. Est. (97.5% CI): Diff. Est. (97.5% CI): 27.3 (13.6, 40.9) 50.5 (40.4, 60.6) 27.3 (13.6, 40.9) 50.5 (40.4, 60.6) p < 0.0001 p < 0.0001 p < 0.0001 p < 0.0001 Study 026Study 026
LVDETV
Perc
ent
Perc
ent
42
Worsened
Secondary Histology Endpoint:Secondary Histology Endpoint:Ishak Fibrosis – Improvement at Week 48Ishak Fibrosis – Improvement at Week 48
Studies 022, 027 and 026Studies 022, 027 and 026
Naïve eAg+Naïve eAg+ Naïve eAg-Naïve eAg- LVD-Ref eAg+LVD-Ref eAg+
Perc
ent
Perc
ent Improved
No change
Improvement:Improvement: p = 0.41 p = 0.65 p < 0.01 p = 0.41 p = 0.65 p < 0.01
44 4234414046
LVDETV
43
Non-Histology Secondary Endpoints at Week 48Non-Histology Secondary Endpoints at Week 48
Studies 022, 027 and 026Studies 022, 027 and 026
Virologic:Virologic: Mean HBV DNA reduction from baseline by PCRMean HBV DNA reduction from baseline by PCR HBV DNA < 400 copies/mL by PCRHBV DNA < 400 copies/mL by PCR
Biochemical:Biochemical: Normalization of ALT (Normalization of ALT (≤ ≤ 1 x ULN)1 x ULN)
Serologic:Serologic: HBe Seroconversion (eAg+ patients)HBe Seroconversion (eAg+ patients)
44
0
20
40
60
80
100
B/L 12 24 36 480
20
40
60
80
100
B/L 12 24 36 48
HBV DNA < 400 copies/mL Through Week 48 –HBV DNA < 400 copies/mL Through Week 48 –Naïve StudiesNaïve Studies
Studies 022 and 027Studies 022 and 027
Perc
ent
Perc
ent
Naïve eAg+ Naïve eAg+ Naïve eAg-Naïve eAg-
ETV (N = 354) LVD (N = 355)
ETV (N = 325) LVD (N = 313)
Weeks
69
38
91
73
p < 0.0001 p < 0.0001
45
0
10
20
30
40
B/L 12 24 36 48
HBV DNA < 400 copies/mL Through Week 48 – HBV DNA < 400 copies/mL Through Week 48 – LVD-Refractory StudyLVD-Refractory Study
Study 026Study 026
ETV (N = 141) LVD (N = 145)
Weeks
Perc
ent
Perc
ent
p < 0.0001
21
1
46
HBV DNA Mean Reduction at Week 48HBV DNA Mean Reduction at Week 48
Studies 022, 027 and 026Studies 022, 027 and 026
Naïve eAg+Naïve eAg+ Naïve eAg-Naïve eAg- LVD-Ref eAg+LVD-Ref eAg+
log
log 10
10
copi
es/m
Lco
pies
/mL
p < 0.0001 p < 0.0001 p < 0.0001
LVDETV
47
ALT ≤ 1 x ULN at Week 48ALT ≤ 1 x ULN at Week 48
Studies 022, 027 and 026Studies 022, 027 and 026
68
78
6160
71
15
0
10
20
30
40
50
60
70
80
90
100
Perc
ent
Perc
ent
LVDETV
Naïve eAg+Naïve eAg+ Naïve eAg-Naïve eAg- LVD-Ref eAg+LVD-Ref eAg+
p = 0.02 p < 0.05 p < 0.0001
48
HBe Seroconversion at Week 48HBe Seroconversion at Week 48
Studies 022 and 026Studies 022 and 026
Naïve eAg+Naïve eAg+ LVD-Ref eAg+LVD-Ref eAg+
p = 0.33 p = 0.06
LVDETV
Perc
ent
Perc
ent
49
-20 -10 0 10 20 30 40 50 60
Summary of Week 48 EfficacySummary of Week 48 Efficacy
HBe SeroconversionHBe Seroconversion
ALT ALT ≤ 1 x ULN≤ 1 x ULN
HBV DNA < 400 copies/mLHBV DNA < 400 copies/mL
Histologic ImprovementHistologic Improvement
ETV - LVD: Difference Estimate and CI ETV - LVD: Difference Estimate and CI
Naïve eAg+Naïve eAg-LVD-Ref eAg+
Studies 022, 027 and 026Studies 022, 027 and 026
LVD Better ETV Better
50
Clinical SafetyClinical Safety
51
Populations in Safety AnalysisPopulations in Safety AnalysisNucleoside-naïveNucleoside-naïvePh 3 eAg+ and eAg-Ph 3 eAg+ and eAg- N = 1347N = 1347
ETVETV679679
LVDLVD668668
LVD-refractoryLVD-refractoryPh 3 and Selected Ph 2Ph 3 and Selected Ph 2 N = 373N = 373‡‡
ETVETV183183
LVDLVD190190
Safety CohortSafety Cohort10 Phase 2/3 Studies10 Phase 2/3 Studies N = 2396N = 2396
ETVETV14971497
LVDLVD899899
‡‡ ETV 1.0 mg & LVDETV 1.0 mg & LVD
52
Observation Time – Weeks Observation Time – Weeks
ETVETV0.5 mg0.5 mg
LVDLVD100 mg100 mg
ETVETV1.0 mg1.0 mg
LVDLVD100 mg100 mg ETVETV LVDLVD
On Blinded On Blinded TherapyTherapy Patients (N) Patients (N) 679679 668668 183183 190190 14971497 899899 Mean (weeks)Mean (weeks) 6666 6161 6868 5151 5656‡‡ 5858‡‡
Off-treatmentOff-treatmentFollow-upFollow-up Patients (N) Patients (N) 431431 392392 5656 3131 923923 471471 Mean (weeks)Mean (weeks) 2222 1919 1515 1313 2424‡‡ 2020‡‡
Studies 022, 027, 014, 026 – Safety UpdateStudies 022, 027, 014, 026 – Safety Update
Nucleoside-naNucleoside-naïveve LVD-refractoryLVD-refractory Safety Cohort Safety Cohort ‡‡
‡ ‡ Safety Cohort: therapy may be blinded or open-label; follow-up may include time Safety Cohort: therapy may be blinded or open-label; follow-up may include time on alternate HBV therapieson alternate HBV therapies
53
Clinical SafetyClinical Safety GeneralGeneral HepaticHepatic
Malignant NeoplasmsMalignant Neoplasms
54
Overall SafetyOverall Safety
Nucleoside-naNucleoside-naïveve LVD-refractoryLVD-refractory
ETVETV0.5 mg0.5 mgN = 679N = 679
LVDLVD100 mg100 mgN = 668N = 668
ETVETV1.0 mg1.0 mgN = 183N = 183
LVDLVD100 mg100 mgN = 190N = 190
DiscontinuationDiscontinuationdue to AEdue to AE
7 (1)7 (1) 18 (3)18 (3) 4 (2)4 (2) 14 (7)14 (7)
SeriousSeriousadverse eventsadverse eventson treatmenton treatmentDeathsDeaths
48 (7)48 (7)
2 (0.3)2 (0.3)
54 (8)54 (8)
4 (0.6)4 (0.6)
19 (10)19 (10)
1 (0.5)1 (0.5)
14 (7)14 (7)
2 (1.1)2 (1.1)
Studies 022, 027, 014, 026 – Safety UpdateStudies 022, 027, 014, 026 – Safety Update
Number of Patients (%)Number of Patients (%)
55
Adverse Events ≥ 10% – On TreatmentAdverse Events ≥ 10% – On Treatment
Any adverse event 81 82 85 82Headache 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
PercentPercentNucleoside-naïveNucleoside-naïve LVD-refractoryLVD-refractory
ETVETVN = 679N = 679
LVDLVDN = 668N = 668
ETVETVN = 183N = 183
LVDLVDN = 190N = 190
Studies 022, 027, 014 and 026 – Safety UpdateStudies 022, 027, 014 and 026 – Safety Update
56
Clinical SafetyClinical Safety GeneralGeneral
HepaticHepatic Malignant NeoplasmsMalignant Neoplasms
57
ALT Flares: On- and Off-TreatmentALT Flares: On- and Off-Treatment
Nucleoside-naNucleoside-naïveve LVD-refractoryLVD-refractory
ETVETV0.5 mg0.5 mg
LVDLVD100 mg100 mg
ETVETV1.0 mg1.0 mg
LVDLVD100 mg100 mg
On-TreatmentOn-TreatmentNN 679679 668668 183183 190190FlaresFlares 15 (2%)15 (2%) 28 (4%)28 (4%) 4 (2%)4 (2%) 21 (11%)21 (11%)
Off-Treatment Off-Treatment NN 431431 392392 5656 3131FlaresFlares 25 (6%)25 (6%) 38 (10%)38 (10%) 3 (5%)3 (5%) 00Median Weeks toMedian Weeks toOff-Treatment FlareOff-Treatment Flare 2424 1010 1818 ––
Studies 022, 027, 014, 026 – Safety UpdateStudies 022, 027, 014, 026 – Safety Update
58
Hepatic Events in Pivotal StudiesHepatic Events in Pivotal Studies
EventsEventsOn- and Off-TreatmentOn- and Off-Treatment
ETVETVN = 862N = 862
LVDLVDN = 858N = 858
ALT FlareALT Flarew/ Hepatic Lab Abnormalityw/ Hepatic Lab Abnormality 22 88
ALT FlareALT Flarew/ Hepatic Clinical Eventw/ Hepatic Clinical Event 11 33
Non-HCC Hepatic SAENon-HCC Hepatic SAEw/o Flarew/o Flare 22 66
Number of PatientsNumber of Patients
Studies 022, 027, 014 and 026 – Safety UpdateStudies 022, 027, 014 and 026 – Safety Update
59
Clinical SafetyClinical Safety GeneralGeneral
HepaticHepatic
Malignant NeoplasmsMalignant Neoplasms
60
Rates of Malignant NeoplasmsRates of Malignant Neoplasms
ETVETVN = 1497N = 1497
LVDLVDN = 899N = 899
AllAll 8.48.4 7.67.6
All / excluding skinAll / excluding skin 6.96.9 6.86.8
HCCHCC 3.53.5 3.43.4
Non-HCC/Non-HCC/excluding skinexcluding skin
3.53.5 3.43.4
Safety Cohort – Safety UpdateSafety Cohort – Safety Update
Comparable rates observed in ETV and LVDComparable rates observed in ETV and LVD
Rate/1000 PY Rate/1000 PY
61
Malignancy Diagnosis Excluding Skin: Malignancy Diagnosis Excluding Skin: Distribution Over Time Distribution Over Time
Safety Cohort – Safety UpdateSafety Cohort – Safety Update
0.2
0.440.34
0.11
0.22
0.46
0.25
00.0
0.2
0.4
0.6
0.8
1.0
0 - 24 Weeks 24 - 48 Weeks 48 - 72 Weeks > 72 Weeks
Perc
ent o
f Pat
ient
s w
ith E
vent
sPe
rcen
t of P
atie
nts
with
Eve
nts
N at riskN at risk3
14972
8996
13764
8694
11792
8011
9450
454N w/events
LVDETV
62
Comparison of Rates of Malignant NeoplasmsComparison of Rates of Malignant Neoplasmsin ETV Clinical Studies vs. Other HBV Cohortsin ETV Clinical Studies vs. Other HBV Cohorts
NeoplasmNeoplasmETVETV
N = 1497N = 1497LVDLVD
N = 899N = 899
USUSCohortCohort
N = 4190N = 4190
Taiwan Taiwan CohortCohort
N = 4155N = 4155
HCCHCC 3.53.5 3.43.4 4.64.6 3.63.6‡‡
AllAll 8.48.4 7.67.6 –– ––
All / excluding skinAll / excluding skin 6.96.9 6.86.8 9.79.7 6.56.5
Non-HCC/Non-HCC/excluding skinexcluding skin
3.53.5 3.43.4 4.74.7 3.13.1
‡‡ Liver Cancer, including non-HCC
Safety CohortSafety Cohort
Rates per 1000 Patient YearsRates per 1000 Patient Years
ObservationalObservationalCohort StudiesCohort Studies
63
Overall Clinical Safety SummaryOverall Clinical Safety Summary
ETV and LVD have comparable safety profilesETV and LVD have comparable safety profiles
ETV safety profile does not vary byETV safety profile does not vary by– Dose – 0.5 mg versus 1.0 mg Dose – 0.5 mg versus 1.0 mg – Patient population – naïve and refractoryPatient population – naïve and refractory
ETV and LVD have comparable incidencesETV and LVD have comparable incidencesof malignancy of malignancy
64
Viral ResistanceViral Resistance
Richard Colonno, PhDRichard Colonno, PhD
65
Early Markers of ETV ResistanceEarly Markers of ETV ResistanceIn VitroIn Vitro Studies Studies
LVDLVDRR (L180M + M204V/I) virus displays 8 to 31 fold decreased (L180M + M204V/I) virus displays 8 to 31 fold decreased susceptibility to ETVsusceptibility to ETV
ETV potency vs. LVDETV potency vs. LVDRR HBV 50x > ADV HBV 50x > ADV ADVADVR R (A181V or N236T) viruses retain susceptibility to ETV(A181V or N236T) viruses retain susceptibility to ETV
Phase II StudiesPhase II Studies Two patients with LVDTwo patients with LVDRR HBV exhibited rebound due to resistance HBV exhibited rebound due to resistance
emergence following (>76 wk) ETV therapyemergence following (>76 wk) ETV therapy Key resistance substitutions emerging on ETV treatment Key resistance substitutions emerging on ETV treatment
Patient A (L180M & M204V) Patient A (L180M & M204V) + I169T & M250V + I169T & M250V
Patient B (L180M & M204V) Patient B (L180M & M204V) + T184G & S202I + T184G & S202I + I169T + I169T Both isolates growth impaired and susceptible to ADVBoth isolates growth impaired and susceptible to ADV
66
ETV PhenotypesETV Phenotypes
SubstitutionsSubstitutions Fold Reduction in SusceptibilityFold Reduction in Susceptibility WT (ayw genotype D)WT (ayw genotype D) –– WTWT + I169T+ I169T 0.60.6 WTWT + T184 to A, F, G, I, L or S+ T184 to A, F, G, I, L or S 2.42.4 WTWT + S202 to G or I+ S202 to G or I 0.70.7 WTWT + M250V+ M250V 8.78.7 LVDLVDR R (L180M + M204V)(L180M + M204V) 7.67.6
LVDLVDR R + I169T+ I169T 7.07.0 LVDLVDR R + T184 to A, F, G, I, L or S+ T184 to A, F, G, I, L or S 16 - 7016 - 70 LVDLVDR R + S202 to C, G or V+ S202 to C, G or V 11 - 10011 - 100 LVDLVDR R + M250 to L or V+ M250 to L or V 113 - 242113 - 242 LVDLVDR R ++ M250V + I169TM250V + I169T > 741> 741 LVDLVDR R ++ T184G + S202IT184G + S202I > 741> 741
67
Phase III Resistance Evaluation Phase III Resistance Evaluation Genotype Nucleoside Naïve Patients – Entry and Wk 48Genotype Nucleoside Naïve Patients – Entry and Wk 48
– eAg pos (022): All ETV (n = 339) patientseAg pos (022): All ETV (n = 339) patients– eAg neg (027): Random ETV (n = 211) patientseAg neg (027): Random ETV (n = 211) patients
Genotype LVD Refractory Patients – Entry and Wk 48Genotype LVD Refractory Patients – Entry and Wk 48– eAg pos (026): All ETV (n = 134) and LVD (n = 126) patientseAg pos (026): All ETV (n = 134) and LVD (n = 126) patients– Study 014: All ETV (1 mg) (n = 37) and LVD (n = 24) patientsStudy 014: All ETV (1 mg) (n = 37) and LVD (n = 24) patients
Phenotype all emerging substitutions identified during ETV Phenotype all emerging substitutions identified during ETV therapy using recombinant clonestherapy using recombinant clones
Genotype and population phenotype all subjects experiencing Genotype and population phenotype all subjects experiencing virologic rebounds ( ≥ 1 log increase from nadir by PCR), virologic rebounds ( ≥ 1 log increase from nadir by PCR), regardless of study or therapy armregardless of study or therapy arm
68
≥≥10101111
1010 99
1010 88
1010 77
1010 66
1010 55
1010 44
1010 33
300-999300-999<300<300
1010 1010
ETVETV LVDLVDn = n = 676 655676 655 665 621665 621
HB
V D
NA
(Cop
ies/
mL)
HB
V D
NA
(Cop
ies/
mL)
Percent of PatientsPercent of Patients
Wk Wk 00 4848 0 480 48
Resistance Profile: Nucleoside Naïve PatientsResistance Profile: Nucleoside Naïve Patients
Studies 022 and 027Studies 022 and 027
Potent HBV DNA suppressionPotent HBV DNA suppression(88% below 10(88% below 1033 copies/mL) copies/mL)
Viral genotyping (n =541)Viral genotyping (n =541)identified 76 emerging changes, identified 76 emerging changes, none appearing in >0.6%none appearing in >0.6%
Emerging amino acid changes did Emerging amino acid changes did not decrease ETV susceptibilitynot decrease ETV susceptibility
11 virologic rebounds on ETV11 virologic rebounds on ETVvs. 88 on LVD vs. 88 on LVD
81% 57%
69
Virologic Rebounds: Nucleoside Naïve PatientsVirologic Rebounds: Nucleoside Naïve Patients
StudyStudy022 022
eAg poseAg pos027027
eAg negeAg neg022 022
eAg poseAg pos027027
eAg negeAg neg
TreatmentTreatment ETV (354)ETV (354) ETV (325)ETV (325) LVD (355)LVD (355) LVD (313)LVD (313)
ReboundsRebounds 6 (2%)6 (2%) 5 (2%)5 (2%) 63 (18%)63 (18%) 25 (8%)25 (8%)
Genotypic Genotypic Resistance*Resistance* 0 of 60 of 6 0 of 50 of 5 61 of 6261 of 62 23 of 2523 of 25
*LVD = 180 and/or 204 changes, ETV = any substitution impacting ETV susceptibility
Studies 022 and 027Studies 022 and 027
Rebounds on ETV therapyRebounds on ETV therapy All patients experienced at least 3 log reductions in HBV DNA All patients experienced at least 3 log reductions in HBV DNA
levels, 7 levels, 7 5 log 5 log Fully susceptible at time of rebound - population ECFully susceptible at time of rebound - population EC5050 <10 nM <10 nM No emerging genotypic changes impacting ETV susceptibilityNo emerging genotypic changes impacting ETV susceptibility
70
Summary of Viral Resistance Data (Week 48)Summary of Viral Resistance Data (Week 48)
NucleosideNucleosideNaïveNaïve
(n = 541)(n = 541)
No emerging No emerging ETVETVR R or LVDor LVDR R
substitutionssubstitutions
0%0%No rebounds due No rebounds due
to resistanceto resistance
0%0%
71
Resistance Profile: LVD-Refractory PatientsResistance Profile: LVD-Refractory Patients
Studies 014 & 026Studies 014 & 026
Effective suppression ofEffective suppression ofHBV DNA levels HBV DNA levels
All ETV (n = 183) and LVDAll ETV (n = 183) and LVD(n = 190) patient samples (n = 190) patient samples genotyped at study entrygenotyped at study entryand Week 48and Week 48
Five virologic rebounds in ETV Five virologic rebounds in ETV treated patients by Week 48treated patients by Week 48
≥≥10101111
1010 99
1010 88
1010 77
1010 66
1010 55
1010 44
1010 33
300-999300-999<300<300
1010 1010
HB
V D
NA
(Cop
ies/
mL)
HB
V D
NA
(Cop
ies/
mL)
ETVETV LVDLVDn = n = 183 176 171183 176 171 190 179 157190 179 157
Percent of SubjectsPercent of Subjects
Wk Wk 0 24 480 24 48 0 24 480 24 486%6% 22%22% <1%<1% 2%2%
72
Virologic Rebounds: LVD Refractory PatientsVirologic Rebounds: LVD Refractory PatientsStudy 026 - ETVStudy 026 - ETV
Two (1%) ETV treated patients experienced virologic rebound Two (1%) ETV treated patients experienced virologic rebound due to resistance by Week 48due to resistance by Week 48
HB
V D
NA
(Cop
ies/
ml)
HB
V D
NA
(Cop
ies/
ml)
Treatment (Weeks)Treatment (Weeks)
101022
101033
101044
101055
101066
101077
101088
101099
10101010
2020 4040 6060 808000
10101111
1122
GenotypicGenotypicChangesChanges
Phenotype (ECPhenotype (EC50 50 nM)nM)
BaselineBaseline Wk 48 (FC)Wk 48 (FC)
11 T184S/AT184S/A 4.54.5 87 (19)87 (19)
22 T184T/AT184T/AS202S/GS202S/G 6464 986 (15)986 (15)
33 NoneNone 8.18.1 23 (3)23 (3)
44 A200A/VA200A/V 8.98.9 33 (4)33 (4)
55 NoneNone 4.84.8 6.8 (<2)6.8 (<2)Off Treatment
3344
55
73
Genotypic Analysis: LVD Refractory PatientsGenotypic Analysis: LVD Refractory Patients
ETVR changes (I169, T184, S202 & M250) detected in 12 ETV treated patients by Week 48
− Only detected when LVDOnly detected when LVDRR changes were changes were presentpresent
Emerging substitutions at 14 other residues Emerging substitutions at 14 other residues identifiedidentified
– None present in >3 patients (1.6%) or None present in >3 patients (1.6%) or correlated with decreased ETV susceptibility correlated with decreased ETV susceptibility (EC(EC5050 2.4 – 45 nM) 2.4 – 45 nM)
74
ETVETVRR Substitutions Can Be Selected Substitutions Can Be SelectedDuring LVD TreatmentDuring LVD Treatment
I169T and T184S emerged on I169T and T184S emerged on LVD therapy(study 026)
ETVETVRR changes detected in 22 (6%) of LVD changes detected in 22 (6%) of LVD refractory patients at baseline refractory patients at baseline
Nine randomized to ETV arm, leading toNine randomized to ETV arm, leading to2 virologic rebounds and only 2 patients 2 virologic rebounds and only 2 patients experiencing HBV DNA reductions <10experiencing HBV DNA reductions <1033 copies/ml 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)Summary of Viral Resistance Data (Week 48)
NucleosideNucleosideNaïveNaïve
(n = 541)(n = 541)
No emerging No emerging ETVETVR R or LVDor LVDR R
substitutionssubstitutions
0%0%No rebounds due No rebounds due
to resistanceto resistance
0%0%
Virologic rebound Virologic rebound due to resistancedue to resistance
LVDLVDRefractoryRefractory(n = 183)(n = 183)
12 (7%)12 (7%)180M180M++
204I/V204I/V
180M180M++
204I/V204I/V
+169L/M,184X, +169L/M,184X, 202G or 250V/L202G or 250V/L
2 (1%)2 (1%)
76
Resistance SummaryResistance Summary Potent and sustained suppression of viral replication Potent and sustained suppression of viral replication
directly related to absence of resistance emergencedirectly related to absence of resistance emergence Extensive analysis of nucleoside naïve patients Extensive analysis of nucleoside naïve patients
showed no evidence of resistance at Week 48showed no evidence of resistance at Week 48 Treatment of LVD-refractory patients with ETV leads Treatment of LVD-refractory patients with ETV leads
to 1% virologic failures due to resistance by Week 48to 1% virologic failures due to resistance by Week 48 Substitutions correlating with ETVSubstitutions correlating with ETVRR identified at identified at
residues 169, 184, 202 and 250residues 169, 184, 202 and 250 LVDLVDRR substitutions are a prerequisite for emergence substitutions are a prerequisite for emergence
of high level ETVof high level ETVRR LVD treatment can pre-select for ETVLVD treatment can pre-select for ETVRR substitutions substitutions
identified by Week 48identified by Week 48
77
Pharmacovigilance Pharmacovigilance and Summaryand SummaryDonna Morgan Murray, PhDDonna Morgan Murray, PhD
78
Proposed Pharmacovigilance PlanProposed Pharmacovigilance Plan
Monitor events of special interest – Monitor events of special interest – malignancies and hepatic eventsmalignancies and hepatic events
– Targeted questionnaires to physiciansTargeted questionnaires to physicians– Periodic, cumulative assessmentsPeriodic, cumulative assessments
Ongoing long-term safety studiesOngoing long-term safety studies
Large safety studyLarge safety study
79
Treatment and Long-term Safety StudiesTreatment and Long-term Safety Studies
Phase II/IIIPhase II/IIIN = 1945N = 1945
(eligible treated)(eligible treated)
22ndnd Year Year11stst Year Year
Randomized StudiesRandomized StudiesRollover Studies:Rollover Studies:
ETV TreatmentETV Treatment
Study 901Study 901N = 940N = 940
Observational StudyObservational Study
Study 049Study 049N = 444N = 444
China ProgramChina ProgramN = 876N = 876
(eligible treated)(eligible treated)Study 050Study 050
N = 255N = 255
5 Years5 Years
As of Dec 2004As of Dec 2004
RespondersResponders
RespondersResponders
No ETV treatmentNo ETV treatment
80
Large Safety Study – ObjectivesLarge Safety Study – Objectives
Rigorous analysis of events of interest:Rigorous analysis of events of interest:
Mortality Mortality
NeoplasmsNeoplasms
ProgressionProgression of liver disease of liver disease
81
Large Safety Study – DesignLarge Safety Study – Design
Patients will be:Patients will be:
– Randomized 1:1Randomized 1:1• ETVETV• Another standard of care nucleosideAnother standard of care nucleoside
or nucleotideor nucleotide
– Stratified as naïve or previously treatedStratified as naïve or previously treated
– Followed for at least 5 yearsFollowed for at least 5 years
External, independent DSMBExternal, independent DSMB
82
Large Safety Study – MethodsLarge Safety Study – Methods
Location:Location: multinationalmultinational
Recruitment:Recruitment: through patients’ through patients’ physiciansphysicians
Sample size:Sample size: 12,50012,500(6,250 in each group)(6,250 in each group)
Reporting:Reporting: annually on all causeannually on all causemortality, malignancy andmortality, malignancy andprogression of liver progression of liver
diseasedisease
83
Large Safety Study – ChallengesLarge Safety Study – Challenges
Patients will switch therapiesPatients will switch therapies
Latency of eventsLatency of events
Rates of malignancyRates of malignancy
Follow-upFollow-up
84
Worsening histologyNecroinflammationFibrosisCirrhosis
Liver Inflammation
ALT Elevation
Resistance
HBV Replication (Measured by
Serum HBV DNA)
DiseaseProgressionLiver FailureLiver CancerTransplantDeath
Pathophysiologic Cascade of Chronic Hepatitis B Pathophysiologic Cascade of Chronic Hepatitis B Infection: Benefits of EntecavirInfection: Benefits of Entecavir
ETV provides superior viral suppression in both nucleoside-naïve and LVD-refractory patients
85
Worsening histologyNecroinflammationFibrosisCirrhosis
HBV Replication (Measured by
Serum HBV DNA)
Liver Inflammation
ALT Elevation DiseaseProgressionLiver FailureLiver CancerTransplantDeathResistance
Pathophysiologic Cascade of Chronic Hepatitis B Pathophysiologic Cascade of Chronic Hepatitis B Infection: Benefits of EntecavirInfection: Benefits of Entecavir
Entecavir results in superior normalization of ALT in both nucleoside-naïve and LVD-refractory patients
86
HBV Replication (Measured by
Serum HBV DNA)
Liver Inflammation
ALT Elevation DiseaseProgressionLiver FailureLiver CancerTransplantDeathResistance
Pathophysiologic Cascade of Chronic Hepatitis B Pathophysiologic Cascade of Chronic Hepatitis B Infection: Benefits of EntecavirInfection: Benefits of Entecavir
ETV provides superior improvement in histology in both nucleoside-naïve and LVD-refractory patients
Worsening histologyNecroinflammationFibrosisCirrhosis
87
Worsening histologyNecroinflammationFibrosisCirrhosis
HBV Replication (Measured by
Serum HBV DNA)
Liver Inflammation
ALT Elevation DiseaseProgressionLiver FailureLiver CancerTransplantDeath
Pathophysiologic Cascade of Chronic Hepatitis B Pathophysiologic Cascade of Chronic Hepatitis B Infection: Benefits of EntecavirInfection: Benefits of Entecavir
ETV has favorable resistance profile compared to LVD
• No resistance in nucleoside-naïve patients• Resistance uncommon in LVD-refractory patients
Resistance
88
Worsening histologyNecroinflammationFibrosisCirrhosis
HBV Replication (Measured by
Serum HBV DNA)
Liver Inflammation
ALT Elevation DiseaseProgressionLiver FailureLiver CancerTransplantDeathResistance
Pathophysiologic Cascade of Chronic Hepatitis B Pathophysiologic Cascade of Chronic Hepatitis B Infection: Benefits of EntecavirInfection: Benefits of Entecavir