Two Year Tenofovir Disoproxil Fumarate (TDF) Treatment and Adefovir Dipivoxil (ADV)

Switch Data in HBeAg-Negative Patients with Chronic Hepatitis B (Study 102)

1Hopital Beaujon, Clichy, France; 2Hospital Valle Hebron, Barcelona, Spain; 3University Hospital “St Ivan Rilsky”, Sofia, Bulgaria; 4University of Uludag, Bursa, Turkey; 5Tokuda Hospital, Sofia, Bulgaria; 6Royal

Free Hospital, London U.K.; 7University of Calgary, Calgary Alberta, Canada; 8Toronto Western Hospital, University of Toronto, Toronto Ontario, Canada; 9Gilead Sciences, Durham NC

Patrick Marcellin1, Maria Buti2, Zahary Krastev3, Selim Gurel4, Rozalina Balabanska5, Geoff Dusheiko6, Robert Myers7, E Jenny Heathcote8, Jeff Sorbel9, Jane Anderson9, Elsa Mondou9 and Franck Rousseau9

59th Annual Meeting of the American Association for the Study of Liver DiseaseOctober 31-November 4, 2008

San Francisco, CAOral Presentation # 146

Acknowledgements Participating Centers

Australia &New Zealand

W.ChengD. CrawfordP. DesmondE. GaneJ. GeorgeP. GowI.KronborgC. MoyesM. NguS. RobertsJ. SasadeuszW. SievertN.StaceS. StrasserF. Weilert

US & CanadaN. AfdahlF. AndersonM. BennettN. BzowejS. ChanA. DiBisceglieP. GaglioN. GitlinS. GordonJ. Heathcote

US & CanadaK. HuI.JacobsonL. JeffersK. KaitaA. LokP. Martin T. MinR. MyersT. NguyenP. PockrosN.RavendhranR. RubinV.RustgiM. ShermanM. ShiffmanM. TongH. TrinhN. TsaiC. WangZ. Younossi

Bulgaria, Czech Republic & PolandR. BalabanskaM. Beniowski R. FlisiakA.GladyszW. HalotaA. HorbanP. HusaI. KotzevZ.KrastevW. KryczkaT. MachJ. SperlK. TchernevP. UrbanekM. Volfova

Spain, Germany & FranceK. BarangeY. BenhamouT. BergJ. BronowickiW. BoecherP. BuggischM. ButiJ. Calleja

Spain, Germany & France T. CasanovasJ. EnriquezG. GerkenF. HabersetzerT. HeintgesC. HezodeH. HinrichsenD. HuppeS. KaiserM. MannsP. MathurinS. MaussB. MollerJ. PetersonM. PrietoG. TeuberC. TrepoR. ZachovalJ. ZarskiS. Zeuzem

UK & NetherlandsR. DeManG. DusheikoD. MutimerR. Williams

Greece, Turkey & ItalyU. AkarkaP. AndreoneG. DalekosG. GermanidisS. GurelS. HadziyannisG. KitisO. KurdasS. OzenirlerM. RizzettoH. SenturkO. Ozdogan

Gilead SciencesJ. DinsdaleA. FosterE. Montgomery

ICONQuintiles

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

RA

ND

OM

IZA

TIO

N

2:1

Tenofovir 300 mg

Adefovir 10 mg

Open-label

Week 48

Liver BiopsyPre-treatment Liver Biopsy

Double Blind

Week 96

Tenofovir 300 mg

Tenofovir 300 mg

HBeAg Negative Study 102 Design

*Week 72 HBV DNA ≥ 400 copies/mL option to add emtricitabine (FTC) to TDF in a fixed dose tablet

Year 2Year 1

Week 72*

TDF TDF-TDF: N= 250 235 225 TDF FTC/TDF: N= (2)* ADV ADV-TDF: N= 125 112 110

Patients (on study drug)

Week 384

Year 8

• HBeAg- patients• Age 18-69 years • Compensated liver disease• Lamivudine experienced or naive• HBV DNA > 105 copies/mL • ALT > ULN and <10 x ULN• Knodell necroinflammatory score ≥ 3• HIV-1, HDV, HCV seronegative

Key Eligibility Criteria

Methods

• HBV DNA and laboratory analyses every 8 weeks

• HBsAg every 16 weeks

• Resistance surveillance: patients with HBV DNA ≥ 400 copies/mL (69 IU/mL)

Assessments During Year 2 (after week 48 through week 96)

Baseline Disease andDemographic Characteristics

 CHARACTERISTICTDF

(N=250)ADV

(N=125)

Mean Age (years) 44 43

Race Caucasian Asian

64%25%

65%24%

Male 77% 78%

Prior lamivudine experience 17% 18%

Mean HBV DNA (log10 copies/mL) 6.86 6.98

Mean ALT (U/L) 128 164

Mean Knodell necroinflammatory score Mean Knodell fibrosis score

7.82.3

7.82.4

Knodell fibrosis score = 4 (cirrhosis) 19% 20%

Viral Genotype A B C D

12%9%

12%64%

11%14%10%63%

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

Pe

rce

nta

ge

(%

)

0

10

20

30

40

50

60

70

80

90

100

Weeks on Study

0 8 16 24 32 40 48 56 64 72 80 88 96

89%

91% P=0.672

Randomized Double Blind Open Label

18% LAM Exp: 93%

96%

250TDF-TDF N= 250250 245245245 243243243 248248248 247247247 242242242 243243243 234234234

125ADV-TDF N= 125125 125125125 124124124 120120120 123123123 123123123 122122122 122122122

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

Pe

rce

nta

ge

(%

)

0

10

20

30

40

50

60

70

80

90

100

Weeks on Study

0 8 16 24 32 40 48 56 64 72 80 88 96

250TDF-TDF N= 250250 242242242 239239239 242242242 241241241 226226226 224224224 214214214125ADV-TDF N= 125125 123123123 121121121 117117117 117117117 110110110 109109109 109109109

99%100%

P=0.166

~ 89% Retention

Randomized Double Blind Open LabelRandomized Double Blind

18% LAM Exp: 97% 100%

Mean HBV DNA (log10copies/mL) (95% CI)

P=0.181

Randomized Double Blind Open Label

P<0.001

Mea

n (9

5% C

I) H

BV

DN

A (

Log 1

0 C

opie

s/m

L)

0

1

2

3

4

5

6

7

8

Weeks on Study

0 8 16 24 32 40 48 56 64 72 80 88 96

250TDF-TDF N=250250 242242242 239239239 242242242 241241241 226226226 224224224 214214214125ADV-TDF N=125125 123123123 121121121 117117117 117117117 110110110 109109109 109109109

LLOQ

ADV Switch Patients

• 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%

HBV DNA response (below 400 copies/mL) at Week 96 for ADV patients who switched to TDF at Week 48:

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

ean

(95%

CI)

ALT

(U

/L)

0

25

50

75

100

125

150

175

200

Weeks on Study

0 8 16 24 32 40 48 56 64 72 80 88 96

250TDF-TDF N= 250250 244244244 238238238 242242242 240240240 223223223 223223223 215215215125ADV-TDF N= 125 123123 122122 118118 117117 107107 108108 108108

P=0.82735 U/L34 U/L

Randomized Double Blind Open Label

ULN for females=34 U/LULN 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

HB

V D

NA

(Log

10 C

opie

s/m

L)

1

2

3

4

5

6

7

8

9

10

11

Weeks on Study

0 8 16 24 32 40 48 56 64 72 80 88 96

LLOQ

TDF TDF

FTC+TDF

Non-adherent (TDF levels BQL)

HB

V D

NA

(Lo

g 10

Cop

ies/

mL)

1

2

3

4

5

6

7

8

9

10

11

Weeks on Study

0 8 16 24 32 40 48 56 64 72 80 88 96

LLOQ

TDFTDF

non-adherent (TDF levels BQL)

Pt 6852

Patients with Virologic Breakthrough

Pt 1674

HBV

DN

A (L

og10

Cop

ies/

mL)

1

2

3

4

5

6

7

8

9

10

11

Weeks on Study

0 8 16 24 32 40 48 56 64 72 80 88 96

LLOQ

Pt 1669

Patient off drug between weeks 80 and 96 Patient off drug between weeks 80 and 96

TDF TDF TDF TDF

HB

V D

NA

(Lo

g10

Cop

ies/

mL)

1

2

3

4

5

6

7

8

9

10

11

Weeks on Study

0 8 16 24 32 40 48 56 64 72 80 88 96

LLOQ

TDF TDF

Resistance Surveillance

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

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

Genotyping(HBV pol / RT)

Phenotyping(HBV pol / RT)

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

  TDF-TDF (N=250)

ADV-TDF (N=125)

Study Drug-Related SAE 1 (<1%) 0

Deaths Metastatic liver carcinoma 1 (<1%) 0

G3 or G4 Laboratory 23 (10%) 11 (10%)

Discontinue due to an AE hepatic neoplasm dizziness, fatigue, lack of concentration

2 (1%)11

000

Confirmed ↓ phosphorus < 2mg/dL 2 (<1%) 1 (<1%)

Confirmed 0.5 mg/dL in creatinine 0 0

Confirmed creatinine clearance <50 mL/min 0 0

ConclusionsWeek 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= 375Randomized and Treated

TDFTDFn = 225

Completed Week 96

N = 125Adefovir Dipivoxil (ADV)

Entered Open-Label TDF Period TDFTDF = 235 ADVTDF = 112

Discontinued Treatment Prior to Week 48

TDF = 6ADV = 4

N= 250Tenofovir DF (TDF)

ADVTDFn = 110

Completed Week 96

Discontinued Treatment Between Weeks 48 and 96 TDFTDF n = 10ADVTDF n = 2

Permanently Initiated FTC/TDF prior to Week 96TDFTDF n = 2ADVTDF n = 0

Patient Disposition

N= 375Randomized and Treated

TDFTDFN = 225

TDF-TDF – FTC/TDF*N= 2 (of 225)

Completed Week 96

N = 125Adefovir Dipivoxil (ADV)

Entered Open-Label TDF Period TDFTDF = 235 ADVTDF = 112

Discontinued Treatment Prior to Week 48

TDF N = 6ADV N = 4

N= 250Tenofovir DF (TDF)

ADVTDFN = 110

ADV-TDF – FTC/TDF*N= 0 (of 110)

Completed Week 96

Discontinued Treatment Between Weeks 48 and 96

TDFTDF N = 10ADVTDF N = 2

Marcellin P, et al., AASLD 2008; Oral #146

~ 89% Retention

*Permanently Initiated FTC/TDF Combination

therapy Week 72TDFTDF N = 2ADVTDF N = 0