FDA’s Antiviral Drugs Advisory Committee Meeting

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

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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

7

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

8

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

9

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

)

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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

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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

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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

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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


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)


Other

D

C B

A

OtherA

B

CD

Other

D

CB

A

142 128143ALT, mean (U/L)

Naïve eAg-Naïve eAg-N = 638N = 638



36

Baseline Histology ScoresBaseline Histology Scores



Naïve eAg-Naïve eAg-N = 638N = 638


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


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


40

Primary Endpoint in Naïve Patients: Primary Endpoint in Naïve Patients: Histologic Improvement at Week 48 Histologic Improvement at Week 48


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


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


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


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



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


68

78

6160

71

15

0

10

20

30

40

50

60

70

80

90

100

Perc

ent

Perc

ent

LVDETV


p = 0.02 p < 0.05 p < 0.0001

48

HBe Seroconversion at Week 48HBe Seroconversion at Week 48


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+


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)


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



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 ––


58

Hepatic Events in Pivotal StudiesHepatic Events in Pivotal Studies

EventsEventsOn- and Off-TreatmentOn- and Off-Treatment



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


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


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


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


Liver Inflammation

ALT Elevation

Resistance


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



Serum HBV DNA)

Liver Inflammation

ALT Elevation DiseaseProgressionLiver FailureLiver CancerTransplantDeathResistance


Entecavir results in superior normalization of ALT in both nucleoside-naïve and LVD-refractory patients

86


Serum HBV DNA)

Liver Inflammation



ETV provides superior improvement in histology in both nucleoside-naïve and LVD-refractory patients


87



Serum HBV DNA)

Liver Inflammation

ALT Elevation DiseaseProgressionLiver FailureLiver CancerTransplantDeath


ETV has favorable resistance profile compared to LVD

• No resistance in nucleoside-naïve patients• Resistance uncommon in LVD-refractory patients

Resistance

88



Serum HBV DNA)

Liver Inflammation



FDA’s Antiviral Drugs Advisory Committee Meeting

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