Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV) Switch Data in HBeAg-Negative Patients with Chronic Hepatitis B (Study 102)

Patrick Marcellin 1 , Maria Buti 2 , Zahary Krastev 3 , Selim Gurel 4 , Rozalina Balabanska 5 , Geoff Dusheiko 6 , Robert Myers 7 , E Jenny Heathcote 8 , Jeff Sorbel 9 , Jane Anderson 9 , Elsa Mondou 9 and Franck Rousseau 9 1 Hopital Beaujon, Clichy, France; 2 Hospital Valle Hebron, Barcelona, Spain; 3 University Hospital “St Ivan Rilsky”, Sofia, Bulgaria; 4 University of Uludag, Bursa, Turkey; 5 Tokuda Hospital, Sofia, Bulgaria; 6 Royal Free Hospital, London U.K.; 7 University of Calgary, Calgary Alberta, Canada; 8 Toronto Western Hospital, University of Toronto, Toronto Ontario, Canada; 9 Gilead Sciences, Durham NC

59 th Annual Meeting of the American Association for the Study of Liver Disease October 31-November 4, 2008 San Francisco, CA Oral Presentation # 146

Australia & New Zealand

W.Cheng

D. Crawford P. Desmond E. Gane J. George P. Gow I.Kronborg

C. Moyes M. Ngu S. Roberts J. Sasadeusz W. Sievert N.Stace

S. Strasser F. Weilert

US & Canada

N. Afdahl F. Anderson M. Bennett N. Bzowej S. Chan A. DiBisceglie P. Gaglio N. Gitlin S. Gordon J. Heathcote

US & Canada

K. Hu I.Jacobson

L. Jeffers K. Kaita A. Lok P. Martin T. Min R. Myers T. Nguyen P. Pockros N.Ravendhran

R. Rubin V.Rustgi

M. Sherman M. Shiffman M. Tong H. Trinh N. Tsai C. Wang Z. Younossi

Acknowledgements Participating Centers

Bulgaria, Czech Republic & Poland

R. Balabanska M. Beniowski R. Flisiak A.Gladysz

W. Halota A. Horban P. Husa I. Kotzev Z.Krastev

W. Kryczka T. Mach J. Sperl K. Tchernev P. Urbanek M. Volfova

Spain, Germany & France

K. Barange Y. Benhamou T. Berg J. Bronowicki W. Boecher P. Buggisch M. Buti J. Calleja

Spain, Germany & France

T. Casanovas J. Enriquez G. Gerken F. Habersetzer T. Heintges C. Hezode H. Hinrichsen D. Huppe S. Kaiser M. Manns P. Mathurin S. Mauss B. Moller J. Peterson M. Prieto G. Teuber C. Trepo R. Zachoval J. Zarski S. Zeuzem

UK & Netherlands

R. DeMan G. Dusheiko D. Mutimer R. Williams

Greece, Turkey & Italy

U. Akarka P. Andreone G. Dalekos G. Germanidis S. Gurel S. Hadziyannis G. Kitis O. Kurdas S. Ozenirler M. Rizzetto H. Senturk O. Ozdogan

Gilead Sciences

J. Dinsdale A. Foster E. Montgomery

ICON Quintiles

Patrick Marcellin, MD Hospital Beaujon, University of Paris

I have financial relationships within the last 12 months relevant to my presentation with: Hoffman La Roche, Schering Plough, Gilead Sciences, Bristol Myers Squibb and Idenix-Novartis,Vertex, Human Genome Sciences, Cytheris, Intermune, Pharmasset and Tibotec .

AND My presentation does include discussion of off-label use of emtricitabine for the treatment of chronic hepatitis B

Background

• Tenofovir DF (TDF) is a nucleotide analog and obligate chain terminator • Approved for HIV-1 in 2001: ~ 2 million patient-years of experience • Approved for chronic hepatitis B (CHB) in 2008 • Week 48 Phase 3 data showed TDF superior to ADV: – 93% of HBeAg-negative TDF-treated patients had HBV DNA <400 copies/mL

Aim

To evaluate the safety and efficacy of: • 2 years of TDF therapy • Switch from ADV to TDF

HBeAg Negative Study 102 Design

Year 8

Double Blind

Year 1

Open-label

Year 2 Tenofovir 300 mg Tenofovir 300 mg Adefovir 10 mg Tenofovir 300 mg Pre-treatment Liver Biopsy Week 48 Liver Biopsy Week 72 * Week 96 Patients (on study drug) TDF TDF-TDF: N= 250 235 225 TDF FTC/TDF: N= (2) * ADV ADV-TDF: N= 125 112 110 Week 384 * Week 72 HBV DNA ≥ 400 copies/mL option to add emtricitabine (FTC) to TDF in a fixed dose tablet

Key Eligibility Criteria

• HBeAg- patients • Age 18-69 years • Compensated liver disease • Lamivudine experienced or naive • HBV DNA > 10 5 copies/mL • ALT > ULN and <10 x ULN • Knodell necroinflammatory score ≥ 3 • HIV-1, HDV, HCV seronegative

Methods

Assessments During Year 2 (after week 48 through week 96) • HBV DNA and laboratory analyses every 8 weeks • HBsAg every 16 weeks • Resistance surveillance: patients with HBV DNA ≥ 400 copies/mL (69 IU/mL)

Baseline Disease and Demographic Characteristics

CHARACTERISTIC Mean Age (years) Race Caucasian Asian Male Prior lamivudine experience Mean HBV DNA (log 10 copies/mL) Mean ALT (U/L) Mean Knodell necroinflammatory score Mean Knodell fibrosis score Knodell fibrosis score = 4 (cirrhosis) Viral Genotype A B C D TDF (N=250) 44 64% 25% 77% 17% 6.86

128 7.8

2.3

19% 12% 9% 12% 64% ADV (N=125) 43 65% 24% 78% 18% 6.98

164 7.8

2.4

20% 11% 14% 10% 63%

% Patients with HBV DNA <400 copies/mL (95% CI) (ITT)

100 90 80 70 60 50 40 30 20 10 0 0 8 Randomized Double Blind 16 24 32 40 48 Weeks on Study 56 64 Open Label 72 80 88 96 TDF-TDF ADV-TDF N= N=

91% 89% P=0.672

18% LAM Exp: 93% 96%

% Patients with HBV DNA <400 copies/mL (95% CI) (On-Treatment Analysis)

100 90 30 20 10 0 80 70 60 50 40 0 8 Open Label 16 24 32 40 48 56 Weeks on Study 64 72 80 88 96 TDF-TDF N= ADV-TDF N=

99% 100% P=0.166

18% LAM Exp: 97% 100%

~ 89% Retention

Mean HBV DNA (log

10

copies/mL) (95% CI)

TDF-TDF ADV-TDF 8 7 6 5 1 0 4 3 2 LLOQ 0 8 Randomized Double Blind 16 24 32 P<0.001

40 48 Weeks on Study 56 Open Label P=0.181

64 72 80 88 96

ADV Switch Patients

HBV DNA response (below 400 copies/mL) at Week 96 for ADV patients who switched to TDF at Week 48: • Viral suppression on ADV is maintained after switching to TDF – 100% of patients (76/76) were responders at Week 96 • Viral suppression of viremic patients on ADV is rapidly obtained with TDF – At week 64: 94% – At week 96: 100%

Mean ALT (U/L) (95% CI)

TDF-TDF ADV-TDF 200 175 150 125 100 75 50 25 0 0 Randomized Double Blind Open Label 8 16 24 32 40 48 56 Weeks on Study 64 72 80 88 96 35 U/L 34 U/L

P=0.827

ULN for females=34 U/L ULN for males=43 U/L

Patients with Virologic Breakthrough During Year 2

Definition of Virologic Breakthrough: • confirmed ≥400 copies/mL after being <400 copies/mL OR • confirmed 1 log increase from nadir

Patients with Virologic Breakthrough

Pt 7957 5 4 7 6 11 10 9 8 3 LLOQ 2 1 0 FTC+TDF 8 TDF TDF 16 24 32 40 48 56 64 72 80 88 96 Weeks on Study Non-adherent (TDF levels BQL) Pt 6852 5 4 7 6 11 10 9 8 3 LLOQ 2 1 0 TDF TDF 8 16 24 32 40 48 56 64 72 80 88 96 Weeks on Study non-adherent (TDF levels BQL)

Patients with Virologic Breakthrough

Pt 1674 11 10 9 5 4 8 7 6 3 LLOQ 2 1 0 8 16 24 32 40 48 56 64 72 80 88 96 Weeks on Study Patient off drug between weeks 80 and 96 Pt 1669 7 6 5 4 11 10 9 8 3 LLOQ 2 1 0 TDF TDF 8 16 24 32 40 48 56 64 72 80 88 96 Weeks on Study Patient off drug between weeks 80 and 96

Resistance Surveillance

Genotyping (HBV pol / RT)

All patients : – at baseline – yearly if ≥ 400 copies/mL (≥ 69 IU/mL – at discontinuation of TDF mono-therapy if ≥ 400 copies/mL

Phenotyping (HBV pol / RT)

Any patient post-baseline with: – conserved site changes in pol/RT – virologic breakthrough – polymorphic site changes (> 1 patient)

Resistance Surveillance Results

No resistance up to 2 years of TDF mono-therapy • No HBV pol/RT amino acid substitutions associated with TDF resistance were detected through 96 weeks of TDF monotherapy Week 96 TDF Resistance Surveillance; A Snow-Lampart et al. Poster # 977

Summary of Safety Data during Open Label TDF Week 96

Study Drug-Related SAE Deaths Metastatic liver carcinoma G3 or G4 Laboratory Discontinue due to an AE hepatic neoplasm dizziness, fatigue, lack of concentration Confirmed ↓ phosphorus < 2mg/dL Confirmed 0.5 mg/dL  in creatinine Confirmed creatinine clearance <50 mL/min

TDF-TDF (N=250)

1 (<1%) 1 (<1%) 23 (10%) 2 (1%) 1 1 2 (<1%) 0 0

ADV-TDF (N=125)

0 0 11 (10%) 0 0 0 1 (<1%) 0 0

Conclusions Week 96

• TDF demonstrated durable, potent antiviral activity through Week 96: – 99% of patients on therapy had HBV DNA <400 copies/mL • No resistance to TDF monotherapy detected up to 2 years • Patients can safely and effectively switch from ADV to TDF treatment: – 100% of patients had HBV DNA <400 copies/mL • TDF was well tolerated through Week 96

Patient Disposition

N= 250 Tenofovir DF (TDF) N= 375 Randomized and Treated Discontinued Treatment Prior to Week 48 TDF = 6 ADV = 4 N = 125 Adefovir Dipivoxil (ADV) Entered Open-Label TDF Period TDF  TDF = 235 ADV  TDF = 112 TDF  TDF n = 225 Completed Week 96 Discontinued Treatment Between Weeks 48 and 96 TDF  TDF n = 10 ADV  TDF n = 2 Permanently Initiated FTC/TDF prior to Week 96 TDF  TDF n = 2 ADV  TDF n = 0 ADV  TDF n = 110 Completed Week 96

Patient Disposition

N= 250 Tenofovir DF (TDF) N= 375 Randomized and Treated Discontinued Treatment Prior to Week 48 TDF N = 6 ADV N = 4 N = 125 Adefovir Dipivoxil (ADV) TDF  TDF N = 225 TDF-TDF – FTC/TDF* N= 2 (of 225) Completed Week 96 Marcellin P, et al., AASLD 2008; Oral #146 Entered Open-Label TDF Period TDF  TDF = 235 ADV  TDF = 112 Discontinued Treatment Between Weeks 48 and 96 TDF  TDF N = 10 ADV  TDF N = 2 ADV  TDF N = 110 ADV-TDF – FTC/TDF* N= 0 (of 110) Completed Week 96

~ 89% Retention

*Permanently Initiated FTC/TDF Combination therapy  Week 72 TDF  TDF N = 2 ADV  TDF N = 0