Slide set 4

Baraclude (entecavir) for

®

the treatment of chronic

hepatitis B
Introduction

• At the completion of this slide set, you should be

able to:
– Describe the Baraclude preclinical and clinical trial data
– Describe Baraclude and its:
• mechanism of action
• pharmacokinetics
• indication
• dosing and administration

2
Baraclude® (entecavir)

I. Preclinical and phase I data

II. Efficacy and safety profile of Baraclude
III. Baraclude – summary of product characteristics

3
Preclinical and Phase I data

• Baraclude is characterised chiefly by:

– Activity against hepatitis B virus (HBV)
– An antiviral effect 30 times more potent than that of
lamivudine (LVD) in vitro
– Efficacy against wild-type strains of HBV and ADV-
resistant mutants
– A pharmacokinetic profile that allows once-daily
administration

Honkoop P & de Man RA. Expert Opin. Investig. Drugs 2003;12:683–688. 4

Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Preclinical and phase I data

A. Chemical and physical properties

B. Pharmacokinetic data
C. Toxicological data
D. Mechanism of action
E. Antiviral activity

5
Chemical and physical properties

• Baraclude
– Entecavir is the active substance in Baraclude
– Guanosine nucleoside analogue
– White to off-white powder slightly soluble in water
• pH of saturated solution: 7.9 at 25°C
– Molecular weight: 295.3

Baraclude® (entecavir) Summary of Product Characteristics. October 2009. 6

Baraclude® US Product Information. July 2009.
Chemical and physical properties

• Chemical structure
OH
– C12 H15 N5 O3 H2O
4S
OH
3R

• H2O
N 1S
N CH2
H2N

NH
N

7
Baraclude® US Product Information. July 2009.
Preclinical and phase I data

A. Chemical and physical properties

B. Pharmacokinetic data
C. Toxicological data
D. Mechanism of action
E. Antiviral activity

8
Pharmacokinetic data

• Absorption
– Rapid absorption in healthy volunteers, with Cmax* achieved
between 30 minutes and 1.5 hours after administration
– In dose-ranging studies† between 0.1 mg–1 mg, increase in
Cmax and AUC‡ is proportional to dose
– AUC reduced by around 20% after eating
– For LVD-refractory patients, Baraclude must be taken
outside meal times (2 hours before or after a meal)
* Cmax: peak plasma concentration achieved by a drug following administration
†
Dose-ranging: gradual increase in the test doses administered
‡
AUC (area under the curve): determination of the quantity of medicine reabsorbed after entering the blood circulation

9
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Pharmacokinetic data

• Bioavailability*
– Estimated to be at least 70% in healthy subjects, the
bioavailability of the tablets is equivalent to that of the oral
solution
– Patients may take the tablets or the oral solution as
desired (bioequivalent)

* Bioavailability: fraction or percentage of the drug reaching the systemic circulation following administration

10
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Pharmacokinetic data

• Distribution
– The pharmacokinetic profile of Baraclude following oral
administration suggests extensive distribution to tissues
– Protein binding to human plasma protein is approximately
13% in vitro

11
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Pharmacokinetic data

• Metabolism / elimination
– Baraclude is not a substrate*, an inducer† or an inhibitor‡ of
cytochrome P450
– Effective accumulation half-life of around 24 hours
– Elimination half-life of 128–149 hours
– Eliminated principally in urine, with approximately 70% in
the unchanged form

* Enzymatic substrate: molecule on which an enzyme acts

†
Enzymatic inducer: a drug able to induce synthesis of additional quantities of biotransformation enzyme involved in the metabolism of
another associated drug
‡
Enzymatic inhibitor: drug able to inhibit biotransformation enzymes for other drugs

12
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Pharmacokinetic data

• Key points…
– Race and gender: no significant effect
– AUC
  29% in elderly subjects vs. young subjects
– Dose should be adjusted according to renal function in the elderly
  20% when administered with food
• Effective accumulation half-life: 24 hours
 Once-daily administration
– Elimination: mainly in urine

13
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
 Pharmacokinetic data

• Patients with renal failure

– Dosage adjustment necessary if creatinine clearance <50 mL/min
– The table shows the increasing serum concentrations of Baraclude as renal function declines

Pharmacokinetic data for Baraclude in renally impaired patients

Creatinine clearance (mL/min)
Severe Severe
Normal Mild Moderate Severe managed with managed
Parameter
>80 >50≤80 3050 20–<30 haemodialysis with CAPD*
(N=6) (N=6) (N=6) (N=6) (N=6) (N=4)

Cmax
(ng/mL)
8.1 10.4 10.5 15.3 15.4 16.6

AUC
([Link]/mL)
27.9 51.5 69.5 145.7 233.9 221.8

* CAPD: continuous ambulatory peritoneal dialysis

14
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Pharmacokinetic data

• Patients with hepatic impairment

– No significant change in pharmacokinetic profile
– No dosage adjustment necessary
• Post-liver transplant patients
– Baraclude exposure increased (~2-fold) in patients on a
stable dose of cyclosporine A or tacrolimus
– Renal function should be evaluated before and during
treatment

15
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Pharmacokinetic data

• Key point…
– Baraclude is not a substrate, an inhibitor or an inducer of
the cytochrome P450 enzyme system

16
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Preclinical and phase I data

A. Chemical and physical properties

B. Pharmacokinetic data
C. Toxicological data
D. Mechanism of action
E. Antiviral activity

17
Toxicological data

• Carcinogenicity
– Malignancies were species specific and occurred at high
doses of Baraclude
– Malignancies observed in rats and mice at exposures ≥4 and
≥2 x that in humans at 0.5 mg and 1 mg, respectively, were:
– Hepatic carcinomas and adenomas
– Vascular tumours
– Brain gliomas
• The predictivity of the findings for humans is not known
– BMS continues to submit safety reports to regulators every 6
months

18
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Toxicological data

• Mutagenicity
– None observed
• Effects on fertility
– In rats, high doses of Baraclude for 4 weeks had no adverse affect on
fertility (males or females)
– In rodents and dogs, degeneration of the seminiferous tubules observed
following exposures ≥26 times those in humans
• Teratogenic effects
– In rats and rabbits
• No maternal or foetal toxicity following exposure ≥21 times those in humans
• At higher exposures embryo-foetal toxicity observed

19
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Preclinical and phase I data

A. Chemical and physical properties

B. Pharmacokinetic data
C. Toxicological data
D. Mechanism of action
E. Antiviral activity

20
Mechanism of action

21
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Mechanism of action
• Baraclude selectively inhibits the three functions of the HBV
DNA polymerase
First three nucleotide bases that form
1 Priming RNA nucleotide DNA bind to the RNA nucleotide,
binding eventually forming a DNA strand

HBV polymerase HBV polymerase HBV polymerase

2 Reverse
transcription
Negative strand DNA synthesis
RNA

DNA
HBV polymerase
Positive strand DNA synthesis

3 DNA-dependent
DNA synthesis

22
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Pharmacokinetic data

• Key point…
– Baraclude inhibits all three HBV DNA polymerase functions
– Baraclude has no significant antiviral activity against
influenza, CMV, HSV or VZV

23
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Preclinical and phase I data

A. Chemical and physical properties

B. Pharmacokinetic data
C. Toxicological data
D. Mechanism of action
E. Antiviral activity

24
Antiviral activity

• In human hepatic cells transfected with a wild-type HBV strain

– Baraclude inhibited HBV DNA synthesis
– EC50=0.004 µM
• For LVD-resistant HBV (rtL180M and M204V)
– Median EC50=0.026 µM (range 0.010–0.059 µM)
• ADV-resistant HBV (rtN236T or A181V) remained fully
susceptible

The in vitro antiviral activity of Baraclude was confirmed

in vivo using the duck and woodchuck models

Baraclude® (entecavir) Summary of Product Characteristics. October 2009. 25

Honkoop P & de Man RA. Expert Opin. Investig Drugs 2003; 12:683–688.
Antiviral activity

• Key point…
– In wild-type strains of HBV in vitro, Baraclude was 30 times
more potent than lamivudine

26
Honkoop P & de Man RA. Expert Opin. Investig Drugs 2003; 12:683–688.
Baraclude® (entecavir)

I. Preclinical and phase I data

II. Efficacy and safety of Baraclude
III. Baraclude – summary of product characteristics

27
Efficacy and safety of Baraclude

A. Phase II studies
B. Pivotal phase III studies
C. Long-term cohorts
D. Clinical resistance

28
Phase II studies

• Study aims
– Confirmation of the efficacy of Baraclude in patients with
chronic hepatitis B
– Determination of the minimum effective dose in different
patient subpopulations
– Obtaining initial safety profile data
• Primary efficacy evaluation criterion
– Assay of HBV DNA by bDNA and PCR

De Man R, et al. Hepatology 2001; 34:578–582.

Chang TT, et al. Gastroenterology 2005; 1198–1209. 29
Pessoa MG, et al. AIDS 2008; 22:1779–1787.
Phase II studies
Study Study design
AI463-0041 • Duration: 4 weeks
• 42 treatment-naïve patients or pre-treated with LVD or interferon (if stopped 6 months prior to study)
• Baraclude 0.05, 0.1, 0.5 and 1 mg/day versus placebo
AI463-0072 • Duration: 24 weeks
• Open, follow-on study from ETV-004, 1 mg/day of Baraclude
• 28 patients
AI463-0053 • Duration: 24 weeks
• 177 patients naïve to treatment with nucleosides
• Baraclude 0.01. 0.1 and 0.5 mg/day versus LVD 100 mg/day
AI463-0144 • Duration: up to 76 weeks of treatment plus 24 weeks of follow up
• 181 patients with viraemia on LVD
• Baraclude 0.1, 0.5 and 1 mg/day versus LVD 100 mg/day
AI463-0155 • Duration: up to 104 weeks with option for responders at 96 weeks to continue treatment
• Open-label study
• 9 liver transplant patients
• Baraclude 1 mg/day
AI463-0386 • Duration: 24 weeks plus open-label Baraclude for 24 weeks
• Randomised, comparative, double-blind study
• 68 patients coinfected with HIV-HBV
• Baraclude 1.0 mg/day versus placebo

1. De Man R, et al. Hepatology 2001; 34:578–582.

2. AI463-007 Clinical Study Report, 23/07/2003.
3. Lai CL, et al. Gastroenterology 2002; 123:1831–1838.
4. Chang TT, et al. Gastroenterology 2005; 1198–1209.
5. Shakil AO, et al. J Hepatol. 2002; 36(suppl 1):S122. 30
6. Pessoa MG, et al. AIDS 2008; 22:1779–1787.
Phase II studies

• Principal results
– Study AI463-014
– Study AI463-038

• The Phase II studies provided information on the effective

dose selection for Baraclude for the Phase III studies
• 0.5 mg/day for nucleoside-naïve patients
• 1.0 mg/day for lamivudine-refractory patients

31
Phase II studies

• Study AI463-014, LVD-refractory, HBeAg(+) or (–)

– Reduction in viral DNA significantly superior for Baraclude 0.5 mg and
1.0 mg/day vs. LVD 100 mg/day (p=0.0001)
– Supported the selection of a 1 mg dose in lamivudine-refractory
patients
0

-1
100 mg LVD
Mean change in
log10 HBV DNA

-2

-3 0.1 mg Baraclude ‡

-4
0.5 mg Baraclude *
-5 1.0 mg Baraclude *
-6
B/L 4 8 12 16 20 24 28 32 36 40 44 48 * p = 0.0001 vs. LVD
‡
p <0.005 vs. LVD
Weeks

32
Chang TT, et al. Gastroenterology 2005; 1198–1209.
Phase II studies

• Study AI463-038, HIV–HBV co-infection

– Results showed that Baraclude is effective when taken as
part of a lamivudine-containing HAART regimen

33
Pessoa MG, et al. AIDS 2008; 22:1779–1787.
Efficacy and safety profile of Baraclude

A. Phase II studies
B. Pivotal phase III studies
C. Long-term cohorts
D. Clinical resistance

34
Phase III studies

• Study overviews
Number of patients Evaluation criteria Week
Study Population randomised; 48
dose of Baraclude
• Liver histology
• HBV DNA undetectable
• Nucleoside-naïve 715
AI463-0221 • Loss of HBeAg
• HBeAg(+) Baraclude: 0.5 mg
• ALT normalisation
• HBe seroconversion
• Liver histology
• Lamivudine- • HBV DNA undetectable
AI463-026 2 refractory 293 • Loss of HBeAg
• HBeAg(+) Baraclude: 1 mg
• ALT normalisation
• HBe seroconversion
• Liver histology
• Nucleoside-naïve 648
AI463-0273 • HBV DNA undetectable
• HBeAg(-) Baraclude: 0.5 mg
• ALT normalisation

1. Chang TT, et al. N Engl J Med 2006; 354:1001–1010.

2. Sherman M, et al. Gastroenterology 2006; 130:2039–2049. 35
3. Lai CL, et al. N Engl J Med 2006; 354:1011–1020.
Phase III studies

• Study 022: Baraclude versus lamivudine in

nucleoside-naïve HBeAg(+) patients

– Study aims
• To compare the efficacy and safety profile of Baraclude
and lamivudine in nucleoside-naïve HBeAg(+) chronic
hepatitis B patients

36
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022

• Study design
– Randomised, double-blind, multicentre, international study
– 709 patients included in efficacy analysis (715 randomised)
Protocol-defined response criteria: Study 022
Response category Description
HBV DNA <0.7 MEq/mL* by bDNA and HBeAg
Complete response
undetectable
HBV DNA <0.7 MEq/mL* by bDNA but HBeAg
Virological response
detectable
Patients with detectable viral DNA
Non-response
(≥0.7 MEq/mL*) by bDNA

* 0.7 MEq/mL ~ 700,000 copies/mL ~ 1.4 x 10 5 IU/mL

37
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022
• Study design
Virological responders
Baraclude 0.5 mg Continue blinded treatment
once daily
Complete responders
or non-responders
Double-blind treatment
Off-treatment
Lamivudine 100 mg
once daily Virological responders
Continue blinded treatment

Randomisation Week 48:

Liver biopsy Week 52:
Screening Implement patient Week 96
Week 0: management decision
Liver biopsy based on Week 48 data
 Non-responders had the option of enrolling in a separate BMS rollover protocol (study 901) or Early
Access program (study 900); complete responders and non-responders who did not enrol in a rollover
study were followed for at least 24 weeks after treatment ended

38
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022

• Principal inclusion criteria

– Age 16 years
– Chronic hepatitis B [HBsAg(+) >6 months] confirmed by biopsy
– HBeAg(+)
– No prior treatment with nucleoside analogues within last 24 weeks, or
lamivudine lasting more than 12 weeks
– Viral load (HBV DNA) ≥3 MEq/mL*
(by bDNA)
– ALT: between 1.3 and 10 times the upper limit of normal (ULN)
– No signs of hepatic decompensation

* 3.0 MEq/mL ~ 3,000,000 copies/mL ~ 5.9 x 10 5 IU/mL

39
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022

• Primary endpoint – histological improvement

– Biopsy performed at Week 48:

• Histological improvement defined as reduction of 2 points or more
in the Knodell necroinflammatory score without worsening of
fibrosis score (modification of fibrosis score <1), compared with
baseline biopsy

40
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022
• Secondary endpoints
– Histological:
• Improvement in Ishak fibrosis score ≥1 point
– Virological:
• Mean reduction in viral load in log10 copies/mL (PCR)
• Viral load undetectable by PCR (<300 copies/mL)
– Serological:
• Proportion of patients with loss of HBeAg
• Proportion of patients presenting anti-HBe seroconversion
– Biochemical:
• Proportion of patients with normalised ALT levels (≤1.0 X ULN)

41
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
 Study 022

• Demographic and baseline characteristics

Characteristic Baraclude (N=354) Lamivudine (N=355)
Mean age 35 years 35 years
Gender 77% male 74% male
Race/ethnic group 58% Asian, 40% Caucasian 57% Asian, 40% Caucasian
Prior treatment with interferon (IFN) 13% 13%
Mean Knodell necroinflammatory score 7.8 7.7
Mean baseline HBV DNA 9.62 log10 copies/ml 9.69 log10 copies/ml
Mean baseline ALT 140.5 IU/l 146.3 IU/l
A 27% A 28%
B 19% B 22%
HBV genotype
C 31% C 25%
D 10% D 14%

42
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022
• 48-week results: primary endpoint
– Baraclude treatment resulted in significantly higher rates of
histological improvement compared with lamivudine treatment
100
90 p=0.009 Baraclude
80 (n=314*)
70 Lamivudine (n=314*)
Patients (%)

72%
60
62%
50
40
30
20 24%
21%
10
0
226/314 195/314 66/314 74/314
Improvement No improvement†
* Number of patients having an evaluable biopsy (satisfactory sample and Knodell score for inflammatory necrosis 2)
†
In this analysis, unsatisfactory or lost biopsies were considered as “no improvement”

43
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022
• 48-week results
– 67% of patients with undetectable viral load in the Baraclude group
(compared with 36% in the lamivudine group)

≥1011
1010 ETV 0.5 mg once daily
9 (N=354)
10
108 LVD 100 mg once daily
7
10 (N=355)
106
105
104
103
0-999
<300 67% p < 0.001 36% lower limit of quantification = 300 copies/ml

BL Week 48 BL Week 48
(n=352) (n=341) (n=354) (n=324)

44
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022
• 48-week results
– Mean change in HBV DNA (by PCR) from baseline greater with
Baraclude
Mean HBV DNA (log10 copies/ml)

10
Baraclude 0.5 mg (N=354)

Lamivudine 100 mg (N=355)

8

6 Mean HBV DNA change

at Week 48

-5.4 log10 copies/ml

4
-6.9 log10 copies/ml
lower limit of quantification = 300 copies/ml
2
p < 0.001

0
B/L 12 24 36 48
Weeks

45
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022
• 48-week results
– Proportion of patients with ALT normalisation (≤1.0 X ULN)
significantly higher in the Baraclude group
100
90
Baraclude 0.5 mg once daily (N=354)
80 p = 0.02
Lamivudine 100 mg once daily (N=355)
70 68%
60%
60
50
40
30
20
10
0
242/354 213/355
ALT ≤ 1.0 X ULN

46
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022
• 48-week results
– Similar proportions of Baraclude- and lamivudine-treated patients
achieved improvement in Ishak fibrosis score
p=0.41
50 Baraclude 0.5 mg once daily (n=314)
39% Lamivudine 100 mg once daily
40 35%
(n=314)
30
Patients (%)

20 Improved

10

0 46% 40% No change

-10 8% 10%
-20 Worsened
-30

Chang TT, et al. N Engl J Med 2006; 354:1001–1010. 47

Baraclude® US Product Information. July 2009.
Study 022
• 48-week results
– Similar proportions of Baraclude- and lamivudine-treated patients
achieved HBeAg loss and seroconversion
Baraclude 0.5 mg once daily (N=354) Lamivudine 100 mg once daily (N=355)
50 50

40 40
Patients (%)

Patients (%)
30 30
p=0.45 p=0.33

20 22% 20 21%
20%
18%
10 10

0 0
78/354 70/355 74/354 64/355
HBeAg loss HBeAg seroconversion

48
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022
• 48-week results
– More Baraclude- versus lamivudine-treated patients achieved
Response or Virological Response at Week 48
100
Baraclude 0.5 mg once daily (N=354)*
90
Lamivudine 100 mg once daily (N=355)*
80
70%
70
Patients (%)

60
50 46%
40
30 26%
21% 19%
20
10 5%
0
n= 74 67 247 165 19 95
Responder Virological Non-responder
Responder

*Missing patients: Baraclude (n=14); lamivudine (n=29)

49
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022
• 48-week results
– A higher proportion of Baraclude-treated patients sustained
complete response through the 24-week off-treatment follow-up period
100
90
82%
80 Baraclude 0.5 mg once daily (n=74)
73%
70 Lamivudine 100 mg once daily (n=67)
Patients (%)

60
50
40
30
20
10
0
Complete response
(HBV DNA <0.7 MEq/mL* and eAg loss

* 0.7 MEq/mL ~ 700,000 copies/mL ~ 1.4 x 10 5 IU/mL

50
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022
• 48-week results
– ALT flares on- and off-treatment

Period Baraclude Lamivudine

On-treatment 3% 6%

Off-treatment* 1% 7%

*
During 24-week post-treatment follow-up period

51
Chang TT, et al. N Engl J Med 2006; 354:1001–1010.
Study 022
• Results beyond 48 weeks of treatment
– Treatment was discontinued when the prespecified response
criteria were met at 48 weeks or during the second year of
therapy
• HBV DNA <0.7 MEq/mL and loss of HBeAg
– Cumulative confirmed analysis was used for treatment up to 96
weeks
• Includes any patient who achieved a confirmed endpoint during the 96-
week treatment period
• Confirmed result – response on two sequential measurements or at last
measurement

52
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
 Study 022
• Cumulative confirmed response rates for up to 96 weeks Baraclude
treatment
Baraclude 0.5 mg once daily (N=354)
100 p<0.0001
87 Lamivudine 100 mg once daily (N=355)
80 79
80
Patients (%)

60
39
40 31
26
20
5 3
0
HBV DNA ALT HBeAg HBsAg
undetectable† normalization‡ seroconversion¶§ loss¶
*Cumulative = proportion of treated patients who ever achieved a confirmed endpoint on-treatment. Confirmed = 2 sequential measurements (or
last observation) meeting the success criteria †HBV DNA <300 copies/mL; ‡ALT ≤1.0 x ULN; ¶Includes 24 weeks of post-treatment follow-up;
§
HBeAg loss plus appearance of anti-HBe

53
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Study 022
• Safety profile and adverse events (AEs)*
– Incidence of AEs comparable in the two treatment groups
(serious AEs: 8% for both)
– The most common AEs were:
• Headache
• Upper respiratory tract infection
• Nasopharyngitis
• Cough
• Pyrexia
• Upper abdominal pain
• Fatigue
• Diarrhoea
– Discontinuations due to adverse effects
• <1% in Baraclude group vs. 3% in lamivudine group
– Continued treatment with Baraclude for a median duration of 96 weeks did not reveal
any new safety signals

*Mean exposure to study therapy was 75 weeks for Baraclude & 65 weeks for LVD

Chang TT, et al. N Engl J Med 2006; 354:1001–1010. 54

Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Study 022

• Summary
– Baraclude versus LVD in nucleoside-naïve HBeAg(+) pts
– Baraclude was superior to LVD for the following endpoints:
• Histological improvement (72% vs. 62%; p=0.009)
• Mean reduction in HBV DNA from baseline
(-6.9 log10 copies/mL vs. -5.4 log10 copies/ml; p<0.001)
• Undetectable HBV DNA <300 copies/mL (67% vs. 36%; p<0.001)
• ALT normalisation (68% vs. 60%; p=0.02)
– Safety profiles were comparable for the two drugs

Chang TT, et al. N Engl J Med 2006; 354:1001–1010. 55

Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Phase III studies

• Study 027: Baraclude versus lamivudine in

nucleoside-naïve HBeAg(-) patients

– Study aims
• To compare the efficacy and safety profile of Baraclude and
lamivudine in nucleoside-naïve HBeAg(-) chronic hepatitis B
patients

56
Lai C-L, et al. N Engl J Med 2006; 354:1011–1020.
Study 027

• Study design
– International, multicentre, randomised, double-blind study
– 638 patients included in efficacy analysis (648 randomised)
Protocol-defined response criteria: Study 027
Response category Description
HBV DNA <0.7 MEq/mL* by bDNA and
Complete response
ALT <1.25 x ULN
HBV DNA <0.7 MEq/mL* by bDNA but
Virological response
ALT ≥1.25 x ULN
Patients with detectable viral DNA
Non-response
(≥0.7 MEq/mL*) by bDNA
* 0.7 MEq/mL ~ 700,000 copies/mL ~ 1.4 x 10 5 IU/mL

57
Lai C-L, et al. N Engl J Med 2006; 354:1011–1020.
Study 027
• Study design
Virological responders
Baraclude 0.5 mg Continue blinded treatment
once daily
Complete responders
or non-responders
Double-blind treatment
Off-treatment
Lamivudine 100 mg
once daily Virological responders
Continue blinded treatment

Randomisation Week 48:

Liver biopsy Week 52:
Screening Implement patient Week 96
Week 0: management decision
Liver biopsy based on Week 48 data
 Non-responders had the option of enrolling in a separate BMS rollover protocol (study 901) or Early
Access program (study 900); complete responders and non-responders who did not enrol in a rollover
study were followed for at least 24 weeks after treatment ended

58
Lai C-L, et al. N Engl J Med 2006; 354:1011–1020.
Study 027

• Primary inclusion criteria

– Age 16 years
– Chronic hepatitis B [HBsAg(+) >6 months] confirmed by biopsy
– HBeAg(-) [study 022: HBeAg(+)]
– No prior treatment with nucleoside analogues within last 24 weeks, or
lamivudine lasting more than 12 weeks
– Viral load (by bDNA) 0.7 MEq/mL*
[study 022: ≥3 MEq/mL]
– ALT: between 1.3 and 10 X ULN
– No signs of hepatic decompensation

* 0.7 MEq/mL ~ 700,000 copies/mL ~ 1.4 x 10 5 IU/mL

59
Lai C-L, et al. N Engl J Med 2006; 354:1011–1020.
Study 027

• Primary endpoint – histological improvement

– Biopsy performed at Week 48:

• Histological improvement defined as reduction of 2 points or more
in the Knodell necroinflammatory score without worsening of
fibrosis score (modification of fibrosis score <1), compared with
baseline biopsy

60
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Study 027

• Secondary endpoints
– Improvement in Ishak fibrosis score ≥1 point
– Mean reduction in viral load in log10 copies/mL (PCR)
– Viral load undetectable by PCR (<300 copies/mL)
– Proportion of patients with normalised ALT levels
(≤1.0 X ULN)

61
Lai C-L, et al. N Engl J Med 2006; 354:1011–1020.
 Study 027

• Demographic and baseline characteristics

Characteristic Baraclude (N=325) Lamivudine (N=313)
Mean age 44 years 44 years
Gender 76% male 75% male
Race/ethnic group 38% Asian, 59% Caucasian 41% Asian, 56% Caucasian
Prior treatment with interferon (IFN) 13% 12%
Mean Knodell necroinflammatory score 8.0 7.7
Mean baseline HBV DNA 7.6 log10 copies/mL 7.6 log10 copies/mL
Mean baseline ALT 141 IU/L 143 IU/L
A 10% A 11%
B 14% B 19%
HBV genotype
C 18% C 16%
D 48% D 43%

62
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Study 027
• 48-week results: primary endpoint
– Baraclude treatment resulted in significantly higher rates of
histological improvement compared with lamivudine treatment
100
90 p=0.01 Baraclude
80 (n=296*)
70 Lamivudine (n=287*)
Patients (%)

70%
60
61%
50
40
30
20 26%
19%
10
0
208/296 174/287 57/296 76/287
Improvement No improvement†
* Number of patients having an evaluable biopsy (satisfactory sample and Knodell score for inflammatory necrosis 2)
†
In this analysis, unsatisfactory or lost biopsies were considered as “no improvement”

63
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Study 027
• 48-week results
– 90% of patients with undetectable viral load in the Baraclude group
(compared with 72% in the lamivudine group)

> 1 0 11
1 0 10 ETV 0.5 mg once daily
(N=325)
109
108 LVD 100 mg once daily
7
10 (N=313)
106
105
104
103
3 0 0 -999
<30 0 90% 72% lower limit of quantification = 300 copies/ml
p < 0.001
BL Week 48 BL Week 48
(n=324) (n=314) (n=311) (n=297)

64
Lai C-L, et al. N Engl J Med 2006; 354:1011–1020.
Study 027
• 48-week results
– After 48 weeks of treatment, mean reduction in viral load significantly
higher in the Baraclude group

10 Baraclude 0.5 mg (N=325)

HBV DNA Mean Level (log10 copies/ml)

Lamivudine 100 mg (N=313)

8

6
Mean HBV DNA change
at Week 48
4
-4.5 log10 copies/ml
-5.0 log10 copies/ml
lower limit of quantification = 300 copies/ml
2
p < 0.001

0
B/L 12 24 36 48
Weeks

65
Lai C-L, et al. N Engl J Med 2006; 354:1011–1020.
Study 027
• 48-week results
– Proportion of patients with normalised ALT levels (≤1.0 X ULN)
significantly higher in the Baraclude group
100
p = 0.045
90 Baraclude 0.5 mg once daily (N=325)
80 78%
Lamivudine 100 mg once daily (N=313)
71%
70
60
50
40
30
20
10
0
253/325 222/313
ALT ≤ 1.0 X ULN

66
Lai C-L, et al. N Engl J Med 2006; 354:1011–1020.
Study 027
• 48-week results
– Similar proportions of Baraclude- and lamivudine-treated patients
achieved improvement in Ishak fibrosis score
p=0.65
50 Baraclude 0.5 mg once daily (n=296)
40 38% Lamivudine 100 mg once daily
36%
(n=287)
30
Patients (%)

20 Improved

10

0 41% 34% No change

-10
12%
-20 15%
Worsened
-30

Lai C-L, et al. N Engl J Med 2006; 354:1011–1020. 67

Baraclude® US Product Information. July 2009.
Study 027
• 48-week results
– More Baraclude- versus lamivudine-treated patients achieved
Response or Virological Response at Week 48
100
Baraclude 0.5 mg once daily (N=325)*
85%
78% Lamivudine 100 mg once daily (N=313)*
80
Patients (%)

60

40

20
10% 11% 6%
<1%
0
n= 275 245 34 34 3 18
Responder Virological Non-responder
Responder

*Missing patients: Baraclude (n=13); lamivudine (n=16)

68
Lai C-L, et al. N Engl J Med 2006; 354:1011–1020.
Study 027
• 48-week results
– More than half of the HBeAg(-) patients did not achieve a sustained
complete response through the 24-week off-treatment follow-up period
– Baraclude-treated patients were more likely to have a sustained
complete response
Baraclude 0.5 mg once daily (n=275)
80
Lamivudine 100 mg once daily
Patients (%) (n=245)
60
48%
40 35% * 0.7 MEq/mL ~ 700,000 copies/mL
~ 1.4 x 105 IU/mL
20

0
Complete response
(HBV DNA <0.7 MEq/mL* and ALT <1.25 x ULN)

69
Lai C-L, et al. N Engl J Med 2006; 354:1011–1020.
Study 027
• 48-week results
– ALT flares on- and off-treatment

Period Baraclude Lamivudine

On-treatment <1% 2%

Off-treatment* 8% 11%

*
During 24-week post-treatment follow-up period

70
Lai C-L, et al. N Engl J Med 2006; 354:1011–1020.
Study 027
• Results beyond 48 weeks of treatment
– Treatment was discontinued when the prespecified response
criteria were met at 48 weeks or during the second year of therapy
• HBV DNA <0.7 MEq/mL and ALT <1.25 X ULN

– Cumulative confirmed analysis was used for treatment up to 96

weeks
• Includes any patient who achieved a confirmed endpoint during the 96-week
treatment period
• Confirmed result – response on two sequential measurements or at last
measurement

71
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
 72

Study 027
• Cumulative confirmed response rates for up to 96 weeks Baraclude
treatment

p<0.0001 p=0.05 Baraclude 0.5 mg once daily (N=325)

100 94 Lamivudine 100 mg once daily (N=313)
89
84
80 77
Patients (%)

60

40

20
0
HBV DNA ALT
undetectable† normalization‡
*Cumulative = proportion of treated patients who ever achieved a confirmed endpoint on-treatment. Confirmed = 2 sequential measurements (or
last observation) meeting the success criteria †HBV DNA <300 copies/mL; ‡ALT ≤1.0 x ULN.

72
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Study 027
• Safety profile and AEs*
– Incidence of AEs comparable between the two groups
– Most common adverse effects were:
• Headache • Back pain
• Arthralgia • Myalgia
• Diarrhoea • Upper abdominal pain
• Insomnia • Influenza
• Cough • Nasopharyngitis
• Nausea • Dyspepsia
• Upper respiratory tract infection • Fatigue
– Discontinuations due to adverse events
• 2% in the Baraclude group vs. 3% in the LVD group
– Continued treatment with Baraclude for a median duration of 96 weeks did not reveal
any new safety signals

*Mean exposure to study therapy was 56 weeks in both treatment groups

Lai C-L, et al. N Engl J Med 2006; 354:1011–1020. 73

Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Study 027

• Summary
– Baraclude versus LVD in nucleoside-naïve HBeAg(-) pts
– Baraclude was superior to LVD for the following endpoints:
• Histological improvement (70% vs. 61%; p=0.01)
• Mean reduction in HBV DNA from baseline
(-5.0 log10 copies/ml vs. -4.5 log10 copies/ml; p<0.001)
• Undetectable HBV DNA <300 copies/ml (90% vs. 72%; p<0.001)
• ALT normalisation (78% vs. 71%; p=0.045)
– Safety profiles were comparable for the two drugs

Lai C-L, et al. N Engl J Med 2006; 354:1011–1020. 74

Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Phase III studies

• Study 026: Baraclude versus lamivudine in

lamivudine-refractory HBeAg(+) patients

– Study aims
• To compare the efficacy and safety profile of Baraclude and LVD in
HBeAg(+) patients with chronic hepatitis B resistant to LVD

75
Sherman M, et al. Gastroenterology 2006; 130:2039–2049.
Study 026

• Study design
– International, multicentre, randomised, double-blind study
– 286 patients included in the efficacy analysis (293 randomised)

Protocol-defined response criteria: Study 026

Response category Description
HBV DNA <0.7 MEq/mL* by bDNA and HBeAg
Complete response
undetectable
HBV DNA <0.7 MEq/mL* by bDNA but HBeAg
Virological response
detectable
Patients with detectable viral DNA
Non-response
(≥0.7 MEq/mL*) by bDNA
* 0.7 MEq/mL ~ 700,000 copies/mL ~ 1.4 x 10 5 IU/mL

76
Sherman M, et al. Gastroenterology 2006; 130:2039–2049.
Study 026
• Study design
Virological responders
Baraclude 1.0 mg Continue blinded treatment
once daily
Complete responders
or non-responders
Double-blind treatment
Off-treatment
Lamivudine 100 mg
once daily Virological responders
Continue blinded treatment

Randomisation Week 48:

Liver biopsy Week 52:
Screening Implement patient Week 96
Week 0: management decision
Liver biopsy based on Week 48 data
 Non-responders had the option of enrolling in a separate BMS rollover protocol (study 901) or Early
Access program (study 900); complete responders and non-responders who did not enrol in a rollover
study were followed for at least 24 weeks after treatment ended

77
Sherman M, et al. Gastroenterology 2006; 130:2039–2049.
Study 026

• Primary inclusion criteria

– Age 16 years
– Chronic hepatitis B [HBsAg(+) >6 months] confirmed by liver biopsy
– HBeAg(+)
– Resistant to LVD:
• HBV DNA detectable by bDNA after 36 weeks of treatment
• Or presenting with viral rebound under LVD, recurrence on
discontinuation of treatment or confirmed YMDD mutation
• Still on LVD at the start of the study
• Viral load HBV DNA ≥3 mEq/mL (by bDNA)*
– ALT: between 1.3 and 10 X ULN
– Compensated liver function

* 3.0 MEq/mL ~ 3,000,000 copies/mL ~ 5.9 x 10 5 IU/mL

78
Sherman M, et al. Gastroenterology 2006; 130:2039–2049.
Study 026

• Co-primary efficacy endpoints

– Improvement in Knodell necroinflammatory score with

no worsening of fibrosis score
– HBV DNA <0.7 mEq/mL* by bDNA and ALT <1.25 X ULN

* 0.7 MEq/mL ~ 700,000 copies/mL ~ 1.4 x 10 5 IU/mL

79
Sherman M, et al. Gastroenterology 2006; 130:2039–2049.
Study 026

• Secondary endpoints included

– Mean reduction in viral load by PCR

– Proportion of patients with undetectable viral load by PCR
(<300 copies/ml)
– Normalisation of ALT (≤1.0 X ULN)
– Proportion of patients with loss of HBeAg
– Proportion with anti-HBe seroconversion
– Improvement in Ishak fibrosis score 1 point

80
Sherman M, et al. Gastroenterology 2006; 130:2039–2049.
 Study 026

• Demographic and baseline characteristics

Characteristic Baraclude (N=141) Lamivudine (N=145)
Mean age 38 years 40 years
Gender 74% male 77% male
Race/ethnic group 40% Asian, 59% Caucasian 34% Asian, 64% Caucasian
Detectable YMDD mutations 84% 86%
Mean Knodell necroinflammatory score 6.5 6.5
Mean baseline HBV DNA 9.48 log10 copies/ml 9.24 log10 copies/ml
Mean baseline ALT 124 IU/l 132 IU/l
A 26% A 22%
B 16% B 12%
HBV genotype
C 19% C 19%
D 32% D 39%

81
Sherman M, et al. Gastroenterology 2006; 130:2039–2049.
Study 026
• 48-week results
– Baraclude significantly improved liver histology in lamivudine-refractory
patients compared with LVD
100
90 Baraclude
80 (n=124*)
p<0.0001 Lamivudine (n=116*)
70
Patients (%)

60
50 55% 57%
40
30 34%
20 28%
10
0
68/124 32/116 42/124 66/116
Improvement No improvement†
* Number of patients having an evaluable biopsy (satisfactory sample and Knodell score for inflammatory necrosis 2)
†
In this analysis, unsatisfactory or lost biopsies were considered as “no improvement”

82
Sherman M, et al. Gastroenterology 2006; 130:2039–2049.
Study 026
• 48-week results
– 19% of patients with undetectable viral load in the Baraclude group
(compared with 1% in the LVD group)

>1011
1010 ETV 1.0 mg once daily
(N=141)
109
108 LVD 100 mg once daily
107 (N=145)
106
105
104
103
300-999
<300 19% 1% lower limit of quantification = 300 copies/ml

BL Week 48 BL Week 48
p < 0.0001

83
AI463-026 Clinical Study Report, 26/10/2005.
Study 026
• 48-week results
– After 1 year of treatment, mean reduction in viral load significantly
better in Baraclude group
Mean HBV DNA change
Mean HBV DNA (log10 copies/mL)

10 at Week 48

-0.48 log10 copies/ml

8
Baraclude 1.0 mg (N=141)

6 Lamivudine 100 mg (N=145)

-5.1 log10 copies/ml

4
p < 0.0001

lower limit of quantification = 300 copies/ml

2

B/L 12 24 36 48
Weeks

84
Sherman M, et al. Gastroenterology 2006; 130:2039–2049.
Study 026
• 48-week results
– Proportion of patients with normalisation of ALT significantly higher in
Baraclude group
100
P<0.0001
90 Baraclude 1.0 mg once daily (N=141)
80 Lamivudine 100 mg once daily (N=145)
70
61%
60
50
40
30
20 15%
10
0
86/141 22/145
ALT ≤ 1.0 X ULN

85
Sherman M, et al. Gastroenterology 2006; 130:2039–2049.
Study 026
• 48-week results
– A greater proportion of Baraclude- than lamivudine-treated patients
achieved improvement in Ishak fibrosis score

50 p=0.0019
Baraclude 1.0 mg once daily (N=141)
40 Lamivudine 100 mg once daily (N=145)
34%
30
Patients (%)

20 16% Improved

10

0 44% 42% No change

-10
11%
-20 Worsened
-30 26%

86
Sherman M, et al. Gastroenterology 2006; 130:2039–2049.
Study 026
• 48-week results
– A greater proportion of Baraclude- than lamivudine-treated patients
achieved HBeAg loss
Baraclude 1.0 mg once daily (N=141) Lamivudine 100 mg once daily (N=145)

50 50

40 40
Patients (%)

Patients (%)
30 30
p=0.0278 p=0.06
20 20

10 10
10%
3% 8% 3%
0 0
14/141 5/145 11/141 4/145
HBeAg loss HBeAg seroconversion
87
Sherman M, et al. Gastroenterology 2006; 130:2039–2049.
Study 026
• 48-week results
– More Baraclude- versus lamivudine-treated patients achieved
Response or Virological Response at Week 48
100
Baraclude 0.5 mg once daily (N=141)*
90 83%
Lamivudine 100 mg once daily (N=145)*
80
70
Patients (%)

60 57%
50
40
30 28%
20 13%
10
<1% 5%
0
n= 13 1 80 7 40 121
Responder Virological Non-responder
Responder

*Missing patients: Baraclude (n=8); lamivudine (n=16)

88
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Study 026
• 48-week results
– ALT flares on-treatment

Period Baraclude Lamivudine

On-treatment <1% 11%

89
Sherman M, et al. Gastroenterology 2006; 130:2039–2049.
Study 026
• Results beyond 48 weeks of treatment
– Treatment was discontinued when the prespecified response
criteria were met at 48 weeks or during the second year of
therapy
• HBV DNA <0.7 MEq/mL and loss of HBeAg
– Cumulative confirmed analysis was used for treatment up to 96
weeks
• Includes any patient who achieved a confirmed endpoint during the 96-
week treatment period
• Confirmed result – response on two sequential measurements or at last
measurement

90
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Study 026
• Cumulative confirmed response rates for up to 96 weeks Baraclude
treatment
Baraclude 1.0 mg once daily (N=141)
100
85% Lamivudine 100 mg once daily (N=145)
80
Patients (%)

60
p<0.0001
40 30% 29% p=0.0011

20 17%
1% 6%
0
HBV DNA ALT HBeAg
Undetectable† Normalization‡ Seroconversion
*Cumulative = proportion of treated patients who ever achieved a confirmed endpoint on-treatment. Confirmed = 2 sequential measurements (or
last observation) meeting the success criteria †HBV DNA <300 copies/mL; ‡ALT ≤1.0 x ULN; ¶Includes 24 weeks of post-treatment follow-up;
§
HBeAg loss plus appearance of anti-HBe

Yurdaydin C, et al. 41st EASL 2006; 26-30 April 2006; Vienna, Austria. Oral 80 91
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Study 026

• Response outcomes (viral load < 300 copies/mL) through Week 96

by baseline viral load
100

Patients (%) 80 73%

60

40

20 16%

0
Baseline VL <107 ≥107
(n) n = 8/11 n = 21/130

92
Sherman M, et al. Hepatology 2008; 48:99–107.
Study 026
• Safety profile and AEs*
– Incidence of AEs was comparable between the Baraclude and LVD groups
– The most common AEs were:
• Upper respiratory tract infection • Cough
• Headache • Nausea
• Fatigue Nasopharyngitis
•
• Upper abdominal pain • Increased ALT
– Discontinuations due to adverse effects
• 1% Baraclude group vs. 7% LVD group
– Continued treatment with Baraclude for a median duration of 96 weeks did
not reveal any new safety signals

*Mean exposure to study therapy was 63 weeks for Baraclude & 52 weeks for LVD

Sherman M, et al. Gastroenterology 2006; 130:2039–2049. 93

Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Study 026

• Summary
– Baraclude versus LVD in LVD-refractory HBeAg(+) patients
– Baraclude was superior to LVD for the following endpoints:
• Histological improvement (55% vs. 28%; p<0.0001)
• Mean reduction in HBV DNA from baseline
(-5.1 log10 copies/ml vs. -0.48 log10 copies/ml; p < 0.0001)
• Undetectable HBV DNA <300 copies/ml (19% vs. 1%; p<0.0001)
• ALT normalisation (61% vs. 15%; p<0.0001)
– Safety profiles were comparable for the two drugs

94
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Efficacy and safety profile of Baraclude

A. Phase II studies
B. Pivotal phase III studies
C. Long-term cohorts
• HBeAg(+) 5-year cohort
• HBeAg(-) re-treatment cohort
• Long-term histology cohort
D. Clinical resistance

95
HBeAg(+) 5-year cohort: ETV-022/-90
• Patients from ETV-022 who enrolled in ETV-901 with a treatment
gap of <35 days comprise the HBeAg(+) 5-year cohort
• This analysis cohort was defined without regard to:
– Treatment response at end of dosing in ETV-022
– HBV DNA, ALT measurements or HBV serology at the start of
dosing in ETV-901
• Patients enrolled in ETV-901 initially received a combination of
Baraclude 1.0 mg and LVD 100 mg daily. Subsequently, patients
switched to Baraclude 1.0 mg daily.

96
Han S, et al. 59th AASLD, October 31-November 4, 2008, San Francisco, USA.. Poster 893.
 HBeAg(+) 5-year cohort: ETV-022/-901
ETV-022 (0.5 mg) ETV-901 (1.0 mg)

Week 48* Week 96 Week 240†

Treatment gap >35
11 days between 022
R=74 R=37 and 901, n=37

Baraclude 243 151

. VR=247 VR=198 183
N=354

NR=19 NR=8 5–year cohort

(missing=14)
21 n=146

*Week 52 patient management based on Week 48 data.

† Different dosing regimen for naïve patients in the 901 study.

• Responders (R) • Virologic Responders (VR)

• Non-responders (NR)
–<0.7 MEq/mL by bDNA –<0.7 MEq/mL by bDNA
– ≥0.7 MEq/mL by bDNA
and loss of HBeAg but HBeAg(+)

97
Han S, et al. 59th AASLD, October 31-November 4, 2008, San Francisco, USA.. Poster 893.
HBeAg(+) 5-year cohort: ETV-022/-901
• The majority of patients achieve HBV DNA <300 copies/mL through 5-yrs

12 HBeAg(+) Baraclude long-term cohort (ETV-022 → ETV-901)

10
(log10 copies/mL)
Mean HBV DNA

4
300 copies/mL
2

0
Baseline Year 1 Year 2 Year 3 Year 4 Year 5
n=146 146 140 131 108 94*

* Five patients who remained on treatment at the Year 5 visit had missing PCR values (NC=M).

98
Han S, et al. 59th AASLD, October 31-November 4, 2008, San Francisco, USA.. Poster 893.
HBeAg(+) 5-year cohort: ETV-022/-901

• Patient flow
– 99/146 (68%) patients completed 5 years of treatment
– A total of 47 patients discontinued treatment before the Year 5 visit

– The reasons for patient discontinuation included:

• Subject withdrew =14 (30%)
• Completed Treatment =12 (26%)
• Death = 5 (11%)
• Other = 9 (19%)

– Among patients who discontinued treatment prior to the Year 5 visit, 37

(79%) had HBV DNA <300 copies/mL at their last visit

99
Han S, et al. 59th AASLD, October 31-November 4, 2008, San Francisco, USA.. Poster 893.
 HBeAg(+) 5-year cohort ETV-022/-901
• The majority of patients achieve HBV DNA <300 copies/mL through 5-yrs
ETV-022 HBeAg(+) Baraclude Long-term Cohort (ETV-022→ETV-901)
Year 1 Year 1 Year 2 Year 3 Year 4 Year 5
100 94%
89% 91%
HBV DNA <300 copies/mL
Proportion of patients (%)

83%
80
67%

60 55%

40

20

n=
0 236/354 80/146 116/140 116/131 98/108 88/94*

* Five patients who remained on treatment at the Year 5 visit had missing PCR values (NC=M).

100
Han S, et al. 59th AASLD, October 31-November 4, 2008, San Francisco, USA.. Poster 893.
 HBeAg(+) 5-year cohort: ETV-022/-901
• The majority of patients achieve ALT normalisation through 5-yrs
ETV-022 HBeAg(+) Baraclude Long-term Cohort (ETV-022→ETV-901)
Year 1 Year 1 Year 2 Year 3 Year 4 Year 5
100
86%
Proportion of patients (%)

78% 80%
80 77%
68%
ALT ≤1 x ULN

65%
60

40

20

n= 0 242/354 95/146 109/140 103/134 96/112 78/98*

* One patient who remained on treatment at the Year 5 visit had missing ALT values (NC=M).

101
Han S, et al. 59th AASLD, October 31-November 4, 2008, San Francisco, USA.. Poster 893.
HBeAg(+) 5-year cohort: ETV-022/-901

• HBeAg seroconversion
– In ETV-022, through 120 weeks of on/off-treatment follow-up
• 31% HBe seroconversion
– Due to protocol-defined management criteria, most patients
who achieved HBeAg loss or HBe seroconversion in ETV-022 discontinued
study therapy and did not meet the entry criteria for the long-term cohort
– HBeAg(+) Baraclude long-term cohort (n=146):
• Five patients achieved HBe seroconversion during ETV-022
• Continued treatment resulted in 33 additional patients
achieving HBe seroconversion in ETV–901 long-term cohort (on-treatment and
during 6 months of post-treatment follow-up)

102
Han S, et al. 59th AASLD, October 31-November 4, 2008, San Francisco, USA.. Poster 893.
HBeAg(+) 5-year cohort: ETV-022/-901

• HBsAg loss
– In ETV-022, through 120 weeks of on/off-treatment follow-up
• 5% HBsAg loss

– Among the 146 patients in this cohort, 1 patient achieved HBsAg loss
in ETV-022

– Continuous treatment with Baraclude in ETV-901 resulted in a further

two patients achieving HBsAg loss

103
Han S, et al. 59th AASLD, October 31-November 4, 2008, San Francisco, USA.. Poster 893.
HBeAg(+) 5-year cohort: ETV-022/-901

• Cumulative safety of patients in the nucleoside-naïve

HBeAg(+) Baraclude 5- year treatment cohort
Baraclude 1.0 mg once daily n (%)
Any adverse event* 133 (91)
Grade 3–4 adverse event 24 (16)
Serious adverse event 20 (14)
Discontinuation due to adverse event 0 (0)
All deaths† 5
On-treatment ALT flare ‡ 1 (<1)
* Most common AEs, occurring in ≥10% of pts: Upper respiratory tract infection (31%); headache (21%); cough (17%); diarrhoea (16%); influenza
(17%); nasopharyngitis (16%); pyrexia (12%); and upper abdominal pain (10%).
†
Causes of death were: liver failure (1 patient); motorbike accident (1 patient); car accidents (2 patients) and unknown (1 patient). No deaths were
attributed to study therapy by the investigator. ‡
ALT flare=ALT >2 x baseline ALT and >10 x ULN.

104
Han S, et al. 59th AASLD, October 31-November 4, 2008, San Francisco, USA.. Poster 893.
HBeAg(-) Baraclude re-treatment cohort

• The nucleoside-naïve HBeAg(-) Baraclude re-treatment cohort

described here consists of 99 patients
– Initially treated with Baraclude in ETV-027
– Subsequently enrolled in ETV-901 with >60 day gap in treatment
– Patients initially treated with combination Baraclude 1.0 mg and 100 mg
LVD daily, prior to receiving Baraclude 1.0 mg daily as monotherapy*

• This analysis cohort was defined without regard to:

– Treatment response at end of dosing in ETV-027
– HBV DNA or ALT measurements at the start of dosing in ETV-901

105
Shouval D, et al. 59th AASLD Meeting, October 31-November 4, 2008, San Francisco, USA. Poster 927.
HBeAg(-) Baraclude re-treatment cohort
ETV-027 ETV-901

Entered ETV-900* 1 Not treated 2

Left the programme† 59 Treatment gap of ≤60 days 10

Treatment gap of >60 days

Rolled over into ETV-049‡ 154 = re-treatment cohort 99

Rolled over into ETV-901 Total ETV-901 111

111

Total ETV-027
325
* ETV-900: Baraclude for subjects with chronic hepatitis B infection: an early access programme.
†
Left the programme: Did not enter a rollover trial (ETV-900 or ETV-901) or enrol in 049 after completing study ETV-027.
‡
ETV-049: Long-term off-treatment assessment of treatment outcomes with Baraclude and lamivudine for chronic
hepatitis B infection in patients who have enrolled in Phase III Baraclude trials.

106
Lai CL, et al. 18th APASL Meeting, March 23-26, 2008, Seoul, Korea. Oral presentation.
HBeAg(-) Baraclude re-treatment cohort

• Patient flow
– 66/99 (66%) patients continued re-treatment for 3 years
– Thirty-two patients discontinued treatment before the Year 3 visit

– Main reasons for patient discontinuation included:

• Completed treatment=19 (59%)
• Subject withdrew=5 (16%)
• Non-compliance=2 (6%)
• Other=6 (19%)

– Among patients who discontinued treatment prior to the Year 3 visit,

24 (75%) had HBV DNA <300 copies/mL on their last PCR measurement

107
Shouval D, et al. 59th AASLD Meeting, October 31-November 4, 2008, San Francisco, USA. Poster 927.
HBeAg(-) Baraclude re-treatment cohort
• The majority of patients achieve HBV DNA <300 copies/mL through 3-years re-treatment with
Baraclude

ETV-027 ETV-901

100 94% 93% 94% 95%

Proportion of patients (%)

91%
Off-treatment >60 days

83%
80
59%
60

40

20
4%
0
EOD Baseline Wk 12 Wk 24 Wk 48 Wk 72 Wk 96 Wk 144
n= 93/99 4/99 56/95 79/95 84/90 72/77 67/74
54/57*
* 10 patients who remained on treatment at Week 144 of ETV-901 visit had missing PCR samples.
EOD: end of dosing
108
Shouval D, et al. 59th AASLD Meeting, October 31-November 4, 2008, San Francisco, USA. Poster 927.
HBeAg(-) Baraclude re-treatment cohort
• The majority of patients achieve ALT normalisation through
3-years re-treatment with Baraclude

ETV-027 ETV-901

100
Proportion of patients (%)

86%
Off-treatment >60 days

83% 80% 79%

80 78% 75%

60 57%

40

20
9%
0
EOD Baseline Wk 12 Wk 24 Wk 48 Wk 72 Wk 96 Wk 144
n= 77/99 9/97 56/99 72/96 79/95 64/80 60/76 57/66*

* One patient who remained on treatment at Week 144 of ETV-901 visit had missing ALT sample.

109
Shouval D, et al. 59th AASLD Meeting, October 31-November 4, 2008, San Francisco, USA. Poster 927.
 HBeAg(-) Baraclude re-treatment cohort

• Cumulative safety for the re-treatment cohort

HBeAg(-) ETV
All ETV-027
Re-treatment Cohort
n=325 n=99

Any Adverse Events§ 246 (76) 79 (80)

Serious Adverse Events 21 (6) 19 (19)

Discontinuation due to Adverse Events 6 (2) 2 (2)

All deaths 3† (<1) 1 (1)

On-treatment ALT flare ± 3/324 (<1) 5/99 (5)
§ Most common Adverse Events, occurring in ≥10% of pts: upper respiratory tract infection, arthralgia, nasopharyngitis, headache, ALT
increase, upper abdominal pain, back pain, and abdominal pain.
† On-treatment and during follow-up, no deaths attributed to study therapy
± on treatment flare =ALT>2 x baseline and >10 x ULN; off treatment flare=ALT>2 x Reference or >10 x ULN

110
Shouval D, et al. 59th AASLD Meeting, October 31-November 4, 2008, San Francisco, USA. Poster 927.
 Long-term histology cohort

Comprises nucleoside-naïve patients from:

ETV-022
HBeAg(+)
Subset of 901 rollover study
• Minimum of 3 years, Baraclude therapy
ETV-027 • Adequate baseline and long-term biopsies
HBeAg(-) • Baseline Knodell necroinflammatory score of ≥2

Biopsy Biopsy (optional) Biopsy

Baseline Week 48 Week 96 Week 144* Week 192† Week 240† Week 288† Week 336 †
(Year 1) (Year 2) (Year 3) (Year 4) (Year 5) (Year 6) (Year 7)

Time on Baraclude *
Week 144 (+ 24 weeks).
†
(± 24 weeks)

Liaw Y-F, et al. AASLD, October 31 - November 4, 2008, San Francisco, USA. Poster 894. Hepatology 2008;48: 706A. 111
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
 Long-term histology cohort
Baseline characteristics compared to phase III:
ETV-022 Cohort ETV-027 Cohort Long-term histology
HBeAg(+), (N=354) HBeAg(-), (N=325) Cohort
Number in cohort, n (%) 41(72%) 16 (28%) 57
Age, mean (years) 35 44 40
Male (%) 77 76 82
Race: Asian (%) 58 38 67
Non-Asian (%) 42 62 33
HBV DNA
9.62 7.60 9.40
mean (log10 copies/mL)
ALT, mean (U/L) 140 141 142
HBV genotype (%)
A 13 10 10 12 18
10 27 14 13
B
C 48 18 27
31 19 33
D
Other
112
Liaw Y-F, et al. AASLD, October 31 - November 4, 2008, San Francisco, USA. Poster 894. Hepatology 2008;48: 706A.
 Long-term histology cohort
Long-term Baraclude treatment achieves histologic improvement in the majority of patients with undetectable DNA

Histologic improvement* Improvement in Ishak fibrosis score

(≥1-point decrease)
100 96% 100
88%

Proportion of patients (%)

Proportion of patients (%)

80 73% 80

60 60

40 40 32%

20 20

41/56† 55/57 18/56† 50/57

0 0
Week 48 Long-term‡ Week 48 Long-term‡
* ≥2-point decrease in Knodell necroinflammatory score and no worsening of Knodell fibrosis score compared with BL.
†
One patient had an inadequate Week 48 biopsy.
‡
Median time of long-term biopsy: 6 years (range: 3–7 years).

Liaw Y-F, et al. AASLD, October 31 - November 4, 2008, San Francisco, USA. Poster 894. Hepatology 2008;48: 706A. 113
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
 Long-term histology cohort
Baraclude achieves regression of Knodell necroinflammatory score in most patients with undetectable DNA

60
Knodell
50 necroinflammatory
score
40
Patients (N)

10–14
7–9
30 4–6
0–3
20 Missing

10 N=57

0
Baseline Week 48 Long-term*
* Median time of long-term biopsy: 6 years (range: 3–7 years)
114
Liaw Y-F, et al. AASLD, October 31 - November 4, 2008, San Francisco, USA. Poster 894. Hepatology 2008;48: 706A.
 Long-term histology cohort
Baraclude achieves regression of Ishak fibrosis score in the majority patients with undetectable DNA

60
Ishak
50
fibrosis score
6
40
Patients (N)

5
4
30 3
2
20 1
0
10 Missing
N=57
0
Baseline Week 48 Long-term*
* Median time of long-term biopsy: 6 years (range: 3–7 years)
115
Liaw Y-F, et al. AASLD, October 31 - November 4, 2008, San Francisco, USA. Poster 894. Hepatology 2008;48: 706A.
Long-term histology cohort

• Reversal of fibrosis in patients with advanced

fibrosis/cirrhosis
– Ten patients had baseline advanced fibrosis/cirrhosis (Ishak fibrosis
score=4, 5 or 6)
• All demonstrated an improvement in Ishak fibrosis score
(≥1-point improvement)
– Four patients had a liver biopsy with cirrhosis at baseline; all
demonstrated an improvement in Ishak fibrosis score
• The median change in Ishak fibrosis score was a 3 point decrease (range:
-1 to -4)

Liaw Y-F, et al. AASLD, October 31 - November 4, 2008, San Francisco, USA. Poster 894. Hepatology 2008;48: 706A. 116
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
 Long-term histology cohort

• Cumulative safety for the long-term histology cohort

Long-term histology cohort
n=69*
Any Adverse Event§ 79 (80)
Grade 3-4 Adverse Event 79 (80)
Serious Adverse Event 19 (19)
Discontinuation due to Adverse Event 2 (2)
All deaths 1 (1)†
On-treatment ALT flare‡ 5/99 (5)
* Safety was evaluated in the full long-term histology cohort (n=69), which include the efficacy evaluable cohort (n=57).
§ Most common AEs, occurring in ≥10% of pts: upper respiratory tract infection (32%), diarrhea (23%), headache (19%), nasopharyngitis
(16%), ALT increase (14%), abdominal pain (13%), influenza (13%), back pain (12%), pyrexia (12%), arthralgia (10%), cough (10%),
hypertension (10%), insomnia (10%), pharyngolaryngeal pain (10%)
† One death occurred due to myocardial ischemia and was not attributed to study medication
‡ on treatment flare =ALT>2 x baseline and >10 x ULN; off treatment flare=ALT>2 x Reference or >10 x ULN

117
Liaw Y-F, et al. AASLD, October 31 - November 4, 2008, San Francisco, USA. Poster 894. Hepatology 2008;48: 706A.
Efficacy and safety profile of Baraclude

A. Phase II studies
B. Pivotal phase III studies
C. Clinical resistance

118
Monitoring for resistance during the Baraclude
clinical trials
• Patients*
– HBeAg(+) and HBeAg(-) patients1-4
– Nucleoside-naïve and lamivudine-refractory patients 1-4
• Treatment
– ≤35 day treatment gap between studies if entering roll-over study ETV-901
• Methodology
– HBV DNA measured by PCR1,2
– Direct sequencing and ultra-sensitive PCR method to detect single-
nucleotide polymorphisms1,2

* From clinical studies: ETV-022, ETV-027, ETV-901 (nucleos(t)ide-naïve patients) and ETV-014, ETV-015, ETV-026

& ETV-901 (lamivudine-refractory patients). Patients from all of these studies could roll-over into ETV-901.

1. Colonno R, et al. Hepatology 2006;44:1656-65. 2. Tenney D, et al. Antimicrob Agents Chemother. 2007;51:902-11. 3. EMEA
Scientific Discussion, accessed March 2008. [Link] 119
4. Chang TT, et al. Gastroenterology 2005;129:1198-209.
Monitoring for resistance during the Baraclude
clinical trials
• Selection of patients for testing:1,2
– Sequencing of reverse transcriptase in baseline samples from all patients
– Sequencing of reverse transcriptase of on-treatment samples from all
Baraclude-treated patients with HBV DNA levels >300 copies/mL
– Phenotyping of any samples with novel substitutions
– Phenotyping of all baseline and on-treatment samples from all patients
experiencing a virological breakthrough, defined as:
o ≥1.0 log10 increase in HBV DNA from nadir
• Analysis methods1-3
– Incidence at discrete time intervals and cumulative probabilities

1. Colonno R, et al. Hepatology 2006;44:1656-65. 2. Tenney D, et al. Antimicrob Agents Chemother. 2007;51:902-11. 120
3. Tenney D, et al. 18th APASL, March 23-26 2008, Seoul, South Korea. PL02. Hepatology Int. 2008;2:A88-A89.
Baraclude 6-year programme: Naïve patient flow
Years 1-2 Years 2-6
Randomized Studies ETV-901 Rollover
0.5 mg Study
1.0 mg ETV
Responders1
ETV - 022:
Naïve
HBeAg+
Virologic ETV -
Responders1
901
ETV - 027:
Naïve Non-Responders
HBeAg-
• Treatment Gap Time
≤35 days for resistance cohort 1. protocol defined response criteria
121
Tenney, DJ M, et al 44th EASL, April 22–6, 2009, Copenhagen, Denmark. Oral 20. J. Hepatol 2009;50(suppl 1), S10.
Nucleoside-naïve cohort (HBeAg(+) & HBeAg(-)):
Cumulative probability of Baraclude resistance through
6 years
ETVr = LVDr (M204V ± L180M) + T184, S202 and/or M250 substitutions
15
Cumulative Probability (%)

10

1.2 1.2 1.2 1.2

0.2 0.5
0
Years 1 2 3 4 5 6
N=663 N=278 N=149 N=120 N=108 N=99

122
Tenney, DJ M, et al 44th EASL, April 22–6, 2009, Copenhagen, Denmark. Oral 20. J. Hepatol 2009;50(suppl 1), S10.
Lamivudine-refractory: patient flow
Randomized Studies Rollover Study
1.0 mg 1.0 mg ETV
Responders1

ETV-026 Virologic
HBeAg+ Responders1

Non-Responders1
ETV-014 ETV-901
1.0 mg group Any

ETV-015
Post- Any
Transplant 1. protocol defined response criteria

123
Tenney, DJ M, et al 44th EASL, April 22–6, 2009, Copenhagen, Denmark. Oral 20. J. Hepatol 2009;50(suppl 1), S10.
Lamivudine-refractory cohort (HBeAg(+)): Cumulative
probability of Baraclude resistance through 6 years

ETVr = LVDr (M204V ± L180M) + T184, S202 and/or M250 substitutions

100
Cumulative Probability (%)

75
57
51
50 46
36

25
15
6
0
Years 1 2 3 4 5 6
N=187 N=146 N=80 N=52 N=33 N=29

124
Tenney, DJ M, et al 44th EASL, April 22–6, 2009, Copenhagen, Denmark. Oral 20. J. Hepatol 2009;50(suppl 1), S10.
 Baraclude® (entecavir)

I. Preclinical and phase I data

II. Efficacy and safety profile of Baraclude
III. Baraclude – summary of product characteristics

125
Baraclude – summary of product
characteristics
A. Presentation
B. Current indications
C. Dosage
D. Contraindications
E. Warnings and precautions for use
F. Drug interactions
G. Safety profile
H. Management of overdose
I. Summary

126
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Presentation

• Baraclude is supplied in two forms:

– Film-coated triangular tablets
• White tablet containing 0.5 mg
• Pink tablet containing 1 mg
• Excipients: lactose monohydrate, microcrystalline cellulose, crospovidone,
povidone and magnesium stearate
– Oral solution, ready to use
• Containing 0.05 mg/ml
• Clear, colourless to pale yellow solution (210 ml bottle)
– The tablets and oral solution are interchangeable
• 10 ml solution = one 0.5 mg tablet
• 20 ml solution = one 1.0 mg tablet

127
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Baraclude – summary of product
characteristics
A. Presentation
B. Current indications
C. Dosage
D. Contraindications
E. Warnings and precautions for use
F. Drug interactions
G. Safety profile
H. Management of overdose
I. Summary

128
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Current indications

• Baraclude is indicated for the treatment of chronic

hepatitis B virus infection in adults with compensated liver
disease and evidence of active viral replication,
persistently elevated serum ALT levels and histological
evidence of active inflammation and/or fibrosis

• This indication for Baraclude is based upon clinical trial data in:
– Nucleoside-naïve patients
– HBeAg(+) and (-) patients

129
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Baraclude – summary of product
characteristics
A. Presentation
B. Current indications
C. Dosage
D. Contraindications
E. Warnings and precautions for use
F. Drug interactions
G. Safety profile
H. Management of overdose
I. Summary

130
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Dosage

• Recommended dosage
– Adult nucleoside-naïve patients
• 0.5 mg/day in a single daily dose
• May be taken with or without food

– Lamivudine-refractory
(i.e. evidence of viraemia while on
lamivudine or confirmed YMDD mutation)
• 1.0 mg/day in a single daily dose
• Should be taken on an empty stomach
(more than 2 hours before or more than 2 hours after a meal)

131
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Dosage

• The optimum duration of treatment is unknown

– Treatment discontinuation may be considered as follows:
• HBeAg(+) patients: until HBeAg or HBsAg seroconversion (evident
in two consecutive serum samples at least 36 months apart) or
until loss of efficacy
• HBeAg(-) patients: until HBsAg seroconversion, or until loss of
efficacy
• No dose adjustment required for patients with
hepatic impairment

132
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Dosage

• Dose adjustment for patients with renal impairment

Baraclude dosage*
Creatinine clearance
(mL/min) Lamivudine-refractory
Nucleoside-naïve patients
patients
 50 0.5 mg/day 1.0 mg/day
30–49 0.25 mg/day 0.5 mg/day
10–29 0.15 mg/day 0.3 mg/day
<10 (haemodialysis or
continuous ambulatory 0.05 mg/day 0.1 mg/day
peritoneal dialysis)†
* for doses <0.5 mg, Baraclude oral solution is available
†
on haemodialysis days, administer Baraclude after haemodialysis

133
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Dosage

• Key points…
– Dose adjustment based on age is not required
– Dose should be adjusted according to the patient’s renal
function

134
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Baraclude – summary of product
characteristics
A. Presentation
B. Current indications
C. Dosage
D. Contraindications
E. Warnings and precautions for use
F. Drug interactions
G. Safety profile
H. Management of overdose
I. Summary

135
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Contraindications

• Contraindications
– Known hypersensitivity to Baraclude or any of the excipients

136
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Baraclude – summary of product
characteristics
A. Presentation
B. Current indications
C. Dosage
D. Contraindications
E. Warnings and precautions for use
F. Drug interactions
G. Safety profile
H. Management of overdose
I. Summary

137
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Warnings and precautions for use

• Renal impairment
– Dose adjustment is recommended
• Exacerbations of hepatitis
– On-treatment and post-treatment exacerbations have been reported
– Hepatic function should be monitored for at least 6 months after discontinuation of
hepatitis B therapy
• Patients with decompensated cirrhosis (not in indication)
– Higher rate of serious hepatic adverse events observed in these patients
– Should be monitored regularly for all parameters associated with hepatitis B, liver
and renal function and antiviral response
• Lactic acidosis
– Associated with all nucleoside analogues, risk cannot be excluded for Baraclude

138
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Warnings and precautions for use
• Resistance
– Virological response should be closely monitored in LVD-refractory patients
• Liver transplant recipients
– Renal function should be evaluated before and during use
• Co-infection with hepatitis C or D
– No data on the efficacy of Baraclude in these populations
• Co-infection with HIV
– Baraclude has not been evaluated in patients not concurrently receiving effective HIV
treatment
– Emergence of Baraclude resistance has been observed in patients not receiving
HAART
– Baraclude has not been studied as a HIV treatment and is not recommended for this
use

139
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Warnings and precautions for use

• General
– Baraclude has not been proven to reduce the risk of HBV transmission;
appropriate precautions should still be taken
• Lactose
– Baraclude contains 120.5 mg lactose in each 0.5 mg dose
– Patients with galactose intolerance, the Lapp lactose deficiency or glucose-
galactose malabsorption should not take this medicine
– A lactose-free Baraclude oral solution is available for these individuals

140
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Warnings and precautions for use

Other warnings and precautions for use of ETV

There are no adequate data from Baraclude use in pregnant women.
Studies in animals have demonstrated reproductive toxicity at high
Pregnancy doses. Baraclude should not be used in pregnancy unless clearly
necessary. There are no data on the effect of maternal transmission –
appropriate interventions should be used.
Animal studies have shown excretion in breast milk. Breastfeeding not
Breast-feeding
recommended during treatment with Baraclude.
Ability to No studies have been performed. However, dizziness, fatigue and
drive/use somnolence are common side effects which may affect the ability to drive
machinery and use machinery.
There are no available studies on the efficacy and safety profile of
Children
Baraclude in children aged under 18 years.

141
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Baraclude – summary of product
characteristics
A. Presentation
B. Current indications
C. Dosage
D. Contraindications
E. Warnings and precautions for use
F. Drug interactions
G. Safety profile
H. Management of overdose
I. Summary

142
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Drug interactions

Drugs Description
Baraclude is eliminated by the kidneys; coadministration with
Drugs eliminated by the renal medicinal products that reduce renal function or compete for
route active tubular secretion may increase serum concentrations of
either medicinal product
The pharmacokinetic parameters of Baraclude and other drugs
Other anti-HBV treatments showed no change during interaction studies with lamivudine,
adefovir and tenofovir
Baraclude is not a substrate, inducer or inhibitor of CYP450;
Drugs metabolised by the
therefore CYP450-mediated drug interactions are unlikely to
CYP450 enzyme system
occur with Baraclude

143
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Baraclude – summary of product
characteristics
A. Presentation
B. Current indications
C. Dosage
D. Contraindications
E. Warnings and precautions for use
F. Drug interactions
G. Safety profile
H. Management of overdose
I. Summary

144
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Safety profile

• Adverse reactions considered at least possibly

related to treatment with Baraclude
Nucleoside-naïve patients† Lamivudine-refractory patients‡
Adverse reactions* Baraclude 0.5 mg (N=679) Baraclude 1.0 mg (N=183)
Gastrointestinal common: vomiting, diarrhoea, common: vomiting, diarrhoea,
disorders nausea, dyspepsia nausea, dyspepsia
General disorders common: fatigue common: fatigue
Nervous system common: headache, dizziness, very common: headache
disorders somnolence common: dizziness, somnolence
Psychiatric
common: insomnia common: insomnia
disorders
* Frequency is defined as very common (≥ 1/10); common (≥ 1/100, < 1/10). Within each frequency grouping, undesirable events are presented in order
of decreasing seriousness
†
Safety profile based on treatment exposure to Baraclude 0.5 mg daily for a median of 53 weeks
‡
Safety profile based on treatment exposure to Baraclude 1 mg daily for a median of 69 weeks

145
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Safety profile

• Laboratory abnormalities

Nucleoside-naïve patients Lamivudine-refractory patients

Laboratory tests Baraclude Lamivudine Baraclude Lamivudine

0.5 mg 100 mg 1.0 mg 100 mg
(N=679) (N=668) (N=183) (N=190)
ALT >10-times ULN and
2% 4% 2% 11%
>2-times baseline
Albumin <2.5 g/dl <1% <1% 0% 2%

Platelets <50,000/mm3 <1% <1% <1% <1%

Baraclude® (entecavir) Summary of Product Characteristics. October 2009. 146

Baraclude® US Product Information. July 2009.
Safety profile

• In patients co-infected with HIV (study 038)

– Patients treated with Baraclude were on lamivudine-
containing HAART regimens
– Safety profile comparable with that seen in monoinfected
HBV patients

147
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Baraclude – summary of product
characteristics
A. Presentation
B. Current indications
C. Dosage
D. Contraindications
E. Warnings and precautions for use
F. Drug interactions
G. Safety profile
H. Management of overdose
I. Summary

148
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Management of overdose

• No case of overdose has been reported

– Healthy subjects receiving a single dose of up to 40 mg of
Baraclude or repeated doses of up to 20 mg/day for more
than 14 days had no unexpected adverse reactions
• In the event of overdose
– Patients should be monitored for evidence of toxicity and
given standard supportive treatment as necessary

149
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Baraclude – summary of product
characteristics
A. Presentation
B. Current indications
C. Dosage
D. Contraindications
E. Warnings and precautions for use
F. Drug interactions
G. Safety profile
H. Management of overdose
I. Summary

150
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.
Summary

• Baraclude
– Available as tablets and oral solution
– Indicated for the treatment of chronic hepatitis B
– 0.5 mg/day for nucleoside-naïve patients
– 1 mg/day for lamivudine-refractory patients
• must be taken outside meal times (2 hours before or 2 hours after a meal)
– Has warnings associated with exacerbations of hepatitis, lactic acidosis
and co-infected patients
– Is not a substrate, inducer or inhibitor of CYP450
– Safety profile comparable with lamivudine
– No cases of overdose reported in clinical trials to date

151
Baraclude® (entecavir) Summary of Product Characteristics. October 2009.