Pegylated Interferons for Chronic Hepatitis B

1
Pegylated Interferons for Chronic Hepatitis B

• Erich Flögel

2
Pegylated Interferons for Chronic Hepatitis B

• Introduction
• Pegasys marketing strategies
• Dismouting Pegasys Key messages
• Defending Hepsera Positioning against Peg IFN
• Hepsera Offense against Peg IFN
• Peg IFN Clinical Data Set

3
Introduction
4
Pegylated Interferons

• Pegylated IFN a-2a
• Pegasys
• Roche
• Approved in EU for CHC and CHB
• Pegylated IFN a-2b
• Peg Intron (Viraferon Peg)
• Schering Plough
• Approved in EU for CHC only

5
Pegylated IFN a-2a EMEA Label for Chronic
Hepatitis B
Pegasys is indicated for the treatment of
HBeAg-positive or HBeAg-negative chronic
hepatitis B in adult patients with compensated
liver disease and evidence of viral replication,
increased ALT and histologically verified liver
inflammation and/or fibrosis
6
Pegylated IFN a-2a Posology and Method of
Administration

• Recommended dose
• 180 ?g once weekly by subcutaneous administration
  in the abdomen
• Product has to stored in a refrigerator
• Duration of treatment
• 48 weeks therapy
• for both HBeAg positive and negative CHB
• Dose adjustment in patients with renal
  impairement
• 135?g once weekly

7
Pegylated IFN a-2a Dose Adjustment for Adverse
Reactions

• Any moderate to severe adverse reactions
• 135?g once weekly
• Haematological AE
• Neutrophil count lt 750/mm3 90 ?g once weekly
• Platelet count lt 50,000/mm3 90 ?g once weekly
• Liver function AE
• Treatment should not be initiated if ALT gt 10 x
  ULN

8
Pegylated IFN a-2a Contraindications

• Hypersentivity to IFN
• Autoimmune hepatitis
• Severe hepatic dysfunction or decompensated
  cirrhosis
• Neonates and young children up to 3 years old
• History of severe pre-existing cardiac disease
• Pregnancy and lactation
• HIV/HCV patients with cirrhosis and CP score gt 6

9
Pegylated IFN a-2a Special Warning Liver
function

• Peg IFN should be discontinued if
• Development of hepatic decompensation during
  treatment
• Progressive increase in ALT, despite dose
  reduction
• Increase in ALT and in direct bilirubin

Disease exacerbations during therapy ( transient
and potentially significant increases in ALT) are
not uncommon. Marked ALT flares (gt 10x ULN) in
clinical trials In 50 of cases Peg IFN dosing
was reduced or withheld until ALT elevatons
subsided
10
Peg IFN aPharmacodynamic Properties
11
PegasysMarketing Strategies
12
Pegasys Positioning Statement

• Pegasys is the only pegylated interferon with the
  approval for CHB, indicated in both forms of the
  disease, that has demonstrated superior benefits
  against the two leading medications used to treat
  today, LAM and conventional IFN and that offers
  the advantages of a finite treatment duration and
  long-lasting remission after stopping treatment.

13
Pegasys is positioned First line
Survival
yes
ALT normalisationHBV DNA suppression

• 2nd line therapy
• Maintenance therapy
• eg nucleoside/tide analogues
• Optimal Properties
• Well tolerated
• Low rates of resistance
• Favourable safety

no

• 1st line therapy
• Therapy with highest chance of sustained response
  (remission) with a defined tmt. duration
• eg peginterferon alfa-2a or IFN?
• Optimal Properties
• High rate of sustained response
• Defined duration
• Favourable safety
• Well tolerated

or IFN? contraindicated / not tolerated
14
Pegasys Top Marketing Strategies

1. Convert standard IFN prescriptions to PEG ASAP
2. Gain Market Share from the current market leader
3. Increase penetration in patient segments where
   standard IFN was weak
4. Capture pre-treated patients

15
Pegasys Key Messages

• Pegasys has a dual mode of action antiviral and
  immunomodulatory
• allowing to achieve off-treatment sustained HBeAg
  and HBsAg seroconversion
• That could explain the higher rate of sustained
  response
• Pegasys induces lasting remission in HBeAg
  positive chonic hepatitis B
• Pegasys provides long-term clinical benefit in
  HBeAg negative patients without need of
  continuous medication

16
Pegasys Key Messages

• Pegasys is superior in efficacy to conventional
  IFN
• Pegasys is superior to LAM, the most commonly
  used therapy for HBV infection
• Pegasys is effective in difficult-to-treat
  patients
• Peg IFN is able to achieve off-treatment
  sustained HBsAg seroconversion even in patients
  traditionally considered to be difficult to
  treat, such as Asian patients or HBeAg - patients
• compensated cirrhosis
• low ALT or high HBV DNA levels at baseline
• HBV genotype C
• Pegasys is effective in IFN and LAM pre-treated
  patients
• Pegasys is well-tolerated

17
Pegasys Supporting Data

• Hadziyannis et al. NEJM 2005
• Germanidis et al. AASLD 2004
• Lau et al. AASLD 2004
• Marcellin et al. EASL 2005

• Pegasys has a dual mode of action antiviral and
  immunomodulatory
• allowing to achieve off-treatment sustained HBeAg
  and HBsAg seroconversion
• That could explain the higher rate of sustained
  response
• Pegasys induces lasting remission in HBeAg
  positive chonic hepatitis B
• Pegasys provides long-term clinical benefit in
  HBeAg negative patients without need of
  continuous medication

18
Pegasys Supporting Data

• Cooksley et al. J Viral Hepatitis 2003
• Marcellin et al. NEJM 2005
• Lau et al. AASLD 2004
• Lau et al. AASLD 2004
• Marcellin et al. NEJM 2005
• Cooksley et al. EASL 2005
• Cooksley et al. EASL 2005
• Lau et al. EASL 2005

• Pegasys is superior in efficacy to conventional
  IFN
• Pegasys is superior to LAM, the most commonly
  used therapy for HBV infection
• Pegasys is effective in difficult-to-treat
  patients
• HBeAg negative disease
• compensated cirrhosis
• low ALT or high HBV DNA levels at baseline
• HBV genotype C
• Pegasys is effective in IFN and LAM pre-treated
  patients
• Pegasys is well-tolerated

19
Roche Strategies to displace Hepsera

• Modest end-of-treatment response
• Limited evidence of sustained treatment response
• In HBeAg and HBeAg-, HBV DNA levels return to
  baseline after adefovir is discontinued
• Although recent data suggest that HBeAg
  seroconversion can be maintained post-therapy,
  HBsAg seroconversion has been a very rare
  occurrence
• Dose adjustment with renal insufficiency
• Post-treatment ALT flares
• Adefovir is associated with post-treatment ALT
  flares (gt10 x ULN in 24 of patients)
• Low level viral resistance
• Drug-resistant HBV strains are not Innocent
  Bystanders

Roche slide set , EASL 2005
20
1- On-treatment Response to ADV in HBeAg- CHB
On-treatment response (48 weeks)
Placebo Adefovir 10 mg qd
72
75
64
60
51
45
Patients ()
33
29
30
15
0
0
HBV DNA lt400 cp/mL
Normal ALT
Improved histology
Hadziyannis et al. N Eng J Med 2003
Roche slide set , EASL 2005
21
1- On-therapy Response to Adefovir in HBeAg CHB
EOT response (48 weeks)
Placebo Adefovir 10 mg od
75
60
53
45
Percent of patients
25
24
30
12
11
15
6
0
HBeAg seroconversion
HBeAg loss
Improved histology
Marcellin et al. N Eng J Med 2003
Roche slide set , EASL 2005
22
2- Response with ADV after 12 Months of
Treatment and 6 Months of Follow-up in HBeAg- CHB
40
31
30
Patients with response ()
20
10
5
0
HBV DNA suppression
ALT normalisation
HBV DNA lt1000 cp/mL
Hadziyannis et al. AASLD Oral 2003
Roche slide set , EASL 2005
23
2- Responses after Discontinuation of ADV in
HBeAg-
100
ALT normalisation
Adefovir 10 mg qd
90
HBV DNA response
80
70
60
Patients ()
50
40
31
32
30
20
8
5
10
0
0
4
8
12
24
36
48
60
72
84
96
HBV DNA lt1000 copies/mL
Weeks
Hadziyannis. AASLD Oral 2003
Roche slide set , EASL 2005
24
Dismounting Pegasys Key Messages
25
1- Pegasyss dual mode of action IS NOT FULLY
ELUCIDATED

•  It is believed that IFN ameliorate viral
  infection by exerting direct antiviral effect and
  by modifying the immune response to infection 
•  The mechanism by which IFN exerts its antiviral
  effect is complex and not yet fully elucidated 

Pegasys EMEA EPAR
26
2- Lasting remission in HBeAg IS NOT DOCUMENTED
The goal of treatment for HBeAg-positive patients
is HBeAg seroconversion1
Are those patients true HBeAg seroconverters or
did they aquiere precore mutants?
One third
n271 patients in the Peg IFN monotherapy arm
Durability?
n87/271 patients
Did all the 87 patients who had HBeAg
seroconversion enter the LT study? If yes,
durability of response is 84
Baseline 2
n73/153 patients
Week 72 2
Week 96 3
patients with HBeAg seroconversion
1 Lok, McMahon. Hepatology 2004 (AASLD
Guidelines) 2 Lau et al. AASLD 2004
3 EMEA SPC
27
3- Pegasys DOES NOT provide long-term durable
response in HBeAg- patients
The goal of treatment for HBeAg-negative patients
is long-term HBV DNA suppression below
detectable in order to prevent/delay disease
progression.
Number of patients with HBV DNA lt 400 c/mL
n177 patients in the Peg IFN monotherapy arm
n112 patients with HBV DNA lt 400 c/mL
n34 patients
n17
Baseline 1
Week 96 2
Week 72 1
Week 48 1
1 Marcellin et al. N Engl J Med 2004
3511206-17 2 Marcellin et al. EASL 12005
28
4- Pegasys is NOT superior in efficacy to
conventional IFN
IFN (3-6 months) 1 n837
Peg IFN a 2b (12 months) 2 n136
100
Peg IFN a 2a (12 months) 3n271
80
60
Patients ()
37
36
34
32
40
29
20
8
7
3
0
HBeAg
HBeAg loss
HBsAg loss
1 Wong et al Ann Intern Med 1993119312-23. 2
Janssen HLA et al, Lancet 2005365123-129 3 Lau
G et al, Hepatology 2004 40 (suppl 1) 171A
seroconversion
29
5 - Pegasys is NOT superior to LAM at end of
treatment
Marcellin P, et al. N Engl J Med 2004
3511206-17
30
6- Pegasys is NOT effective in difficult-to-treat
patients High HBV DNA at BL
72 non responders
53
Patients with HBeAg seroconversion ()
28
18
37/70
39/138
11/63
gt10.26
?9.07
9.0710.26
HBV DNA (log10 cp/mL)
Cooksley et al. EASL 2005
31
6- Pegasys is NOT effective in difficult-to-treat
patients Low ALT at BL
100
80
60
Patients with HBeAg seroconversion ()
41
40
30
29
20
27/92
36/121
24/58
0
gt 5 x ULN
? 2 x ULN
2-5 x ULN
Cooksley G, et al. EASL 2005
32
Patients with Genotype B, C or D have almost NO
CHANCE to achieve HBsAg seroconversion
6- Pegasys is NOT effective in difficult-to-treat
patients genotypes B , C and D
Hadziyannis S, et al. EASL 2005
33
7- Pegasys efficacy in LAM-R patients is unknown

• Almost similar results in the LAM arm regarless
  of pre-exposure to LAM
• All patients 19
• Pre-exposure to LAM 17
• No exposure to LAM 20

This demonstrates that patients were not LAM-
resistant LAM pre-exposure does NOT mean
LAM-resistance.
Pegasys efficacy is similar regarless of LAM
pre-exposure patients but its efficacy is NOT
demonstrated in patients with proven
LAM-resistance
34
7- Peg IFN efficacy is standard IFN
non-responders is UNCLEAR
Janssen et al, Lancet 2005 HBeAg patients
Lau GK, et al. EASL 2005 HBeAg patients

• Absence of previous IFN therapy was a predictive
  factor of response (multivariate analysis, p0.04)

Response to Peg IFN seems similar in naive
patients and patients with IFN pre-exposure
Pre-exposure NON RESPONSE
35
8- Pegasys safety profile is similar to that of
standard IFN
EMEA SPC
36
8- Pegasys safety profile is similar in CHB and
in CHC
EMEA SPC
37
8- Pegasys has a poor tolerability

• Tolerability of Peg IFN is poor and limits its
  use for long- term therapy

HBeAg Study Lau et al. EASL 2005 n271 HBeAg- Study Marcellin et al. NEJM 2004 n177
Dose modification due to adverse events and/or Lab. abnormalities (Peg IFN monotherapy arm) 40 47
38
8- Pegasys mode of administration safety
profile limit treatment adherence

• HBeAg study 22 patients received lt 90 Peg
  dose
• Roche messages
• Lower drug exposure does not impact on the HBeAg
  seroconversion rate
• HBeAg responders and non-responders have the same
  drug exposure

• Cooksley JVH 2003
• 28 combined response with 180 µg vs 27 with 90
  µg at EOF
• Is 180 ?g the optimal dose for Peg IFN a-2a in
  CHB?

39
Peg IFN Clinical Summary

• Peg IFN is effective in a minority of
  HBV-infected patients
• In HBeAg patients, only 1/3 of patients respond
  to Peg IFN
• Predictors of response are the same as for
  standard IFN
• HBeAg , High ALT, low HBV DNA, genotype A
• Poor sustained response in HBeAg patients
• High incidence of side effects, leading to gt 40
  dose reduction and requiring active physician
  monitoring
• Contra-indicated in decompensated liver disease
• Inconvenient method of administration
• High cost

40
Defending Hepsera Positioning against Peg IFN
41
Roche Strategies to displace Hepsera

• Modest end-of-treatment response
• Limited evidence of sustained treatment response
• In HBeAg and HBeAg-, HBV DNA levels return to
  baseline after ADV is discontinued
• Although recent data suggest that HBeAg
  seroconversion can be maintained post-therapy,
  HBsAg seroconversion has been a very rare
  occurrence
• Dose adjustment with renal insufficiency
• Post-treatment ALT flares
• Adefovir is associated with post-treatment ALT
  flares (gt10 x ULN in 24 of patients)
• Low level viral resistance
• Drug-resistant HBV strains are not Innocent
  Bystanders

Roche slide set , EASL 2005
42
Hepsera Contra-arguments ADV has a modest end of
treatment response In HBeAg and HBeAg-, HBV
DNA levels return to baseline after ADV is
discontinuedAdefovir is associated with
post-treatment ALT flares
Peg IFN Treatment course of limited duration
ADV Long-term maintenance therapy
43
Hepsera contra-arguments Although recent data
suggest that HBeAg seroconversion can be
maintained post-therapy, HBsAg seroconversion has
been a very rare occurrence
40
30
patients
20
10
3.2
3
0
0
2
3
1
LAM
Peg IFN a-2a
Hepsera
72 weeks (24 weeks off therapy)
24 months
96 weeks
1. Hadziyannis SJ et al. Hepatology 2000 32
847-851 2. Marcellin et al. N Engl J Med 2004
3511206-17 3. Gilead Data On File
44
Hepsera contra-arguments Dose adjustment with
renal insufficiency

• Dose adjustment is recommended for any anti-HBV
  therapy in case of renal impairement LAM, ADV,
  ETV as well as Pegasys
• Pegasys EMEA SPC

• More over, dose reduction is very common with
  Pegasys with regards to side effects
• Marcellin NEJM 2004 1 patient / 2 had to have a
  dose modification of Peg IFN due to side effects

45
Hepsera Offense against Peg IFN
46
Phase III Trials Endpoints
Peg IFN a -2a Hepsera
HBeAg Primary Endpoints HBeAg seroconversion HBV DNA lt 105 c/mL (COBAS) Histological improvement
HBeAg Secondary endpoints HBeAg loss HBsAg seroconversion ALT normalization HBV DNA change from baseline HBeAg loss seroconversion ALT normalization HBV DNA reduction HBV DNA lt 400 copies/mL (PCR) Histology ranked assessment
HBeAg - Primary Endpoints ALT Normalization HBV DNA lt 2 x 104 c/mL (COBAS LLQ 200 c/mL) Histological improvement
HBeAg - Secondary endpoints Histological improvement HBsAg loss seroconversion HBV DNA lt 400 copies/mL Combined response Histology ranked assessment HBV DNA reduction HBV DNA lt 400 copies/mL ALT normalization
47
Peg IFN a vs Hepsera in HBeAg CHB 48-week
Efficacy Summary
Peg IFN (Lau et al.) (n271) Peg IFN (Lau et al.) (n271) Peg IFN (Lau et al.) (n271) Hepsera (Marcellin et al.) (n123) Hepsera (Marcellin et al.) (n123)
HBV DNA decline HBV DNA decline -4.5 log -3.52
HBV DNA lt 400 c/mL HBV DNA lt 400 c/mL 25 21
ALT normalization ALT normalization NA 48
HBeAg seroconversion HBeAg seroconversion 27 12
Amplicor PCR assay, LLQ 400 c/mL Mean HBV
DNA level at baseline 8.25 log c/mL
COBAS PCR assay, LLQ 400 c/mL Mean HBV DNA
level at baseline 9.7 log c/mL
48
Peg IFN a vs Hepsera in HBeAg CHB HBeAg
seroconversion Over Time
60
48
50
40
32
Patients ()
27
30
20
10
0
Peg IFN
Hepsera
Lau et al. AASLD 2004 Pegasys EMEA SCP
Marcellin et al. EASL 2005
Kaplan Meier estimates
49
Peg IFN a vs Hepsera in HBeAg CHB KEY MESSAGES

• Hepsera delivers increasing efficacy over time in
  HBeAg patients up to 3 years
• Increasing HBV DNA undetectability
• Increasing ALT normalization
• Increasing rate of HBeAg seroconversion
• Similar rate between 3 years of Hepsera therapy
  and 2 years Peg IFN (1year follow-up)

50
Peg IFN a vs Hepsera in HBeAg- CHB 48-week
Efficacy Summary
Peg IFN (Marcellin et al.) (n177) Peg IFN (Marcellin et al.) (n177) Peg IFN (Marcellin et al.) (n177) Hepsera (Hadziyannis et al.) (n123) Hepsera (Hadziyannis et al.) (n123)
HBV DNA decline HBV DNA decline -4.1 log -3.91
HBV DNA lt 400 c/mL HBV DNA lt 400 c/mL 63 51
ALT normalization ALT normalization 38 72
COBAS PCR assay, LLQ 400 c/mL Median HBV DNA
level at baseline 6.99 log c/mL
Amplicor PCR assay, LLQ 400 c/mL Median HBV
DNA level at baseline 7.1 log c/mL
51
Peg IFN a vs Hepsera in HBeAg- CHB 96-week
Efficacy
Peg IFN 1
Hepsera 2
HBsAg seroconversion at 96 weeks
100
83
80
71
30
59
60
Patients ()
20
40
10
17
20
3.2
2.88
4/124
5/177
0
0
Peg IFN 1
Hepsera
HBV DNA lt LLQ
ALT normalization
Peg IFN COBAS PCR assay LLQ 400
copies/mL Hepsera Amplicor PCR assay LLQ 1000
copies/mL
1. Marcellin et al. EASL 2005 2. Hadziyannis et
al. EASL 2005
52
Peg IFN a vs Hepsera in HBeAg- CHB KEY MESSAGES

• Hepsera delivers increasing efficacy over time in
  HBeAg- patients up to 4 years
• Increasing HBV DNA undetectability
• Increasing ALT normalization
• Increasing imporvement in liver fibrosis (up to 3
  years)
• Hepsera induces the same rate of HBsAg
  seroconversion after 2 years as compared with 1
  year after the end of a Peg IFN course
• Patients get the chance to cure the disease with
  2-year Hespera or with a course of Pegasys
• For a similar cost (average European yearly
  patient cost)
• 2-year Hepsera 12,680
• 1-year Pegasys 11,000

53
Peg IFN a vs Hepsera in CHB KEY MESSAGES

• Hepsera delivers consistent response across all
  patient populations and disease stages
• Hepsera is indicated for and can be safely used
  in patients with decompensated liver function
• Hepsera provides convenient dosing
• one dose, with or without food
• With increased exposure to Hepsera, Adverse
  Events beyond 48 weeks were similar in nature and
  severity to placebo.

54
Peg IFN aClinical Data Set
55
Roche Clinical Development Programme Overview
Patient Population Study arms Reference
Phase II n194 HBeAg Compensated liver disease n194 HBeAg Compensated liver disease Peg IFN 90 µg / w Peg IFN 180 µg / w Peg IFN 270 µg / w IFN a-2a 4.5 MUI tiw Cooksley G, et al. J Viral Hep 2003
Phase III n814 HBeAg Compensated liver disease n814 HBeAg Compensated liver disease Peg IFN Peg IFNLAM LAM Lau GK, et al AASLD2004
Phase III n537 HBeAg- Compensated liver disease n537 HBeAg- Compensated liver disease Peg IFN Peg IFNLAM LAM Marcellin, P et al. N Engl J Med 2004
56
Schering Plough Clinical Development Programme
Overview
Patient Population Study arms Reference
Investigator trial n307 HBeAg Compensated liver disease Peg IFN Peg IFNLAM Janssen HLA, et al Lancet 2005
Investigator trial n100 HBeAg Compensated liver disease Peg IFNLAM LAM Chan HLY, et al Ann Intern Med 2005
57
Phase II Dosing-Finding Study
58
Peg IFN a-2a in HBeAg CHBStudy Design
Cooksley G, et al. J Viral Hep 2003 10 298-305
59
Peg IFN a-2a in HBeAg CHB Efficacy Endpoints

• Serological Response
• End of follow-up HBeAg loss and HBeAg
  seroconversion
• On treatment quantitative HBeAg
• Combined response
• ALT normalization
• HBV DNA lt 500,000 copies/mL
• HBeAg loss

Cooksley G, et al. J Viral Hep 2003 10 298-305
60
Peg IFN a-2a in HBeAg CHBSerological Response
at EOF (Week 48)
patients
Cooksley G, et al. J Viral Hep 2003 10 298-305
61
Peg IFN a-2a in HBeAg CHBCombined Response at
EOF (Week 48)
Cooksley G, et al. J Viral Hep 2003 10 298-305
62
Peg IFN a-2a Dose-finding StudyAuthors
Conclusion

• Peg IFN 180 demonstrated greater efficacy in
  reduction of HBV DNA lt 500,000 c/mL, reduction in
  HBeAg and combined response
• Peg IFN is well-tolerated
• Peg IFN is associated with greater efficacy thant
  standard IFN in patients with difficult-to-treat
  disease
• Low baseline ALT
• High baseline HBV DNA

Cooksley G, et al. J Viral Hep 2003 10 298-305
63
Peg IFN a-2a Dose-finding StudyKEY MESSAGES

• Peg IFN was compared to a sub-optimal dose of
  standard IFN
• Approved IFN dose 5 to 10 MUI tiw
• EASL recommended dose is 5 MUI/day or 9 10 MUI
  tiw
• Study Endpoints are not relevant
• HBeAg response loss of HBeAg but not HBeAg
  seroconversion
• HBV DNA cut off very high 500,000 copies/mL
  about 5.7 log
• Unclear rational for selecting the 180 µg dose
• 28 combined response with 180 µg vs 27 with 90
  µg at EOF
• Choice has been made with regards to the approved
  dose in CHC.

64
Phase III Studies
65
Roche Phase III Trials Efficacy Summary (Week 72)
HBeAg (study WV16240) HBeAg (study WV16240) HBeAg (study WV16240) HBeAg- (study WV16241) HBeAg- (study WV16241) HBeAg- (study WV16241)
Response parameter Peg IFN PLB (n271) Peg IFN LAM (n271) LAM (n272) Peg IFN PLB (n177) Peg IFN LAM (n179) LAM (n181)
HBeAg seroconversion 32 27 19 NA NA NA
HBV DNA response 32 34 22 43 44 29
ALT normalization 41 39 28 59 60 44
HBsAg seroconversion 3 3 0 3 2 0
p gt 0.01 vs lamivudine
66
Peg Interferons in HBeAg patients

• Roche Marcellin, P et al. N Engl J Med 2004
• Schering Janssen HLA, et al. Lancet 2005

67
Peg IFN a-2a in HBeAg CHB Study Design

• Patients with HBeAg CHB were randomized using a
  111 ratio (n814)

EOF 72 weeks
EOT 48 weeks
Randomized
180 µg Peg IFN qw oral placebo qd (n 271)
24 week follow-up
180 µg Peg IFN qw 100 mg lamivudine qd (n 271)
100 mg lamivudine qd (n 272)
0
24
48
72
Study weeks
Lau GK, et al. AASLD 2004
68
Peg IFN a-2a in HBeAg CHBKey Inclusion

• HBsAg for ? 6 months
• HBV DNA gt 500,000 copies/mL
• (COBAS Amplicor HBV Monitor)
• Serum ALT gt1 but ? 10 x ULN at screening
• Less than 20 with serum ALT 1 2 x ULN
• Liver biopsy proven CHB

Lau GK, et al. AASLD 2004
69
Peg IFN a-2a in HBeAg CHB Study Endpoints

• Co-primary endpoints (assessed 24 weeks after
  EOT)
• HBeAg Seroconversion
• HBV DNA lt 100,000 copies/mL
• Secondary endpoints
• HBeAg loss
• HBsAg seroconversion (loss of HBsAg/presence of
  anti-HBs AB)
• ALT normalization
• HBV DNA change from baseline

Lau GK, et al. AASLD 2004
70
Peg IFN a-2a in HBeAg CHBBaseline
Characteristics
Peg IFN PLB (n271) Peg IFN LAM (n271) LAM (n272)
Male () 79 77 79
Race Caucasian () Asian () 9 87 8 87 12 85
Mean age (years) 32 32 32
Mean weight (kg) 66 66 67
Mean baseline ALT (x ULN) 3.8 3.8 3.4
Mean baseline HBV DNA (log10 cp/mL) 9.7 10.1 10.1
Bridging fibrosis/cirrhosis () 18 15 17
Pt reporting prior use of LAM () 12 9 15
Pt reporting prior use of IFN? () 11 12 12
Lau GK, et al. AASLD 2004
71
Peg IFN a-2a in HBeAg CHB HBV DNA Levels Over
Time
12
On-treatment
Follow-up
10
Peg IFN
2.0
8
2.4
LAM
2.6
Peg IFN
(log10 copies/mL)
4.5
6
LAM
5.8
4
7.2
2
0
Study week
6
12
18
24
30
36
42
48
54
60
66
72
Lau GK, et al. AASLD 2004
72
Peg IFN a-2a in HBeAg CHB HBV DNA lt 400
copies/mL
Peg IFN a-2a (n271)
Peg IFN a-2aLAM (n271)
LAM (n272)
100
80
69
Patients ()
60
40
40
25
20
0
End of Treatment 1 Week 48
End of Follow up 2 Week 72
1- Fried et al. EASL 205, abstract 488 2-
73
Peg IFN a-2a in HBeAg CHB ALT Normalization at
EOF (Week 72)
100
80
p0.002
60
p0.006
patients
40
41
39
28
20
n271
n271
n272
n271
n271
n272
0
LAM
Peg IFN
Peg IFNLAM
Lau GK, et al. AASLD 2004
74
Peg IFN a-2a in HBeAg CHB HBeAg Seroconversion
Over Time
On-treatment
Follow-up
HBeAg Seroconversion ()
32
27
plt0.001
27
p0.023
19
24
20
Study week
Lau et al. AASLD 2004
75
Peg IFN a 2a in HBeAg CHBResponse at the EOF
(72 weeks)
Lau et al., AASLD 2004
76
Peg IFN a 2a in HBeAg CHB HBV DNA reduction at
W48 and HBeAg Response at W72 with Peg IFN
Fried et al. EASL 2005, Abstract 488
77
Peg IFN a 2a in HBeAg CHB LT Study (WV 16866)

• Sustained HBeAg seroconversion in Peg IFN arm

100
80
60
48
Patients ()
32
40
20
87/271
73/153
0
24 weeks after EOT
48 weeks after EOT
Pegasys SmPC
78
Peg IFN a-2a in HBeAg CHB Effect of Baseline
Factors on HBeAg Seroconversion at W72

• ALT level
• HBV DNA level
• Genotype
• Previous treatment exposure
• Peg IFN dose exposure

79
Peg IFN a-2a in HBeAg CHB HBeAg Seroconversion
at EOF (Week 72) by Baseline ALT
Peg IFN (n271)
Peg IFN LAM (n271)
LAM (n272)
50
41
40
37
30
29
28
30
27
Percentage
20
20
20
16
10
27/92
19/93
19/96
36/121
30/111
20/129
24/58
25/67
13/47
0
? 2 x ULN
2-5 x ULN
gt 5 x ULN
Cooksley G, et al. EASL 2005, abstract 71
80
Peg IFN a-2a in HBeAg CHB HBeAg Seroconversion
at EOF (Week 72) by Baseline HBV DNA
Peg IFN
Peg IFN LAM
LAM
53
Patients with HBeAg seroconversion ()
36
31
28
27
21
18
17
10
24/78
39/138
40/147
21/123
11/63
14/68
7/71
37/70
20/56
?9.07 (1st Quartile)
9.0710.26
gt10.26 (4th Quartile)
HBV DNA (log10 cp/mL)
Cooksley et al. EASL 2005 , abstract 71
81
Peg IFN a-2a in HBeAg CHB HBeAg Seroconversion
at EOF (Week 72) by Genotype
Peg IFN
Peg IFN LAM
LAM
52
Patients with HBeAg seroconversion ()
31
30
29
28
23
22
22
20
18
18
18
12/23
4/18
3/15
23/76
24/82
17/73
50/162
43/156
29/162
2/9
2/11
3/17
Genotype
Cooksley et al. EASL 2005, abstract 71
82
Peg IFN a-2a in HBeAg CHB HBeAg Seroconversion
at EOF (Week 72) by Previous treatment
100
pretreated with LAM
all patients
without previous therapy
pretreated with IFN
80
60
HBeAg seroconversion rate
43
40
34
32
32
31
27
27
25
20
19
17
20
13
0
Peg IFN
Peg IFNLAM
LAM
Lau GK, et al. EASL 2005, abstract 31
83
Peg IFN a-2a in HBeAg CHB HBeAg seroconversion
at EOF (Week 72) by Drug Exposure

• Exposure to Peg IFN
• Total study dose 8640 ?g (180 ?g/week for 48
  wks)
• 211 (78) patients received gt90 of the total
  dose (gt7776 ?g)
• HBeAg seroconversion at Week 72

The rate of response was lower in patients who
received lt90 of the total dose (difference was
not significant)
Lau GK, et al. EASL 2005, abstract 31
84
Peg IFN a-2a in HBeAg CHB HBsAg Seroconversion
according to Genotype
Peg IFN (n271) Peg IFN LAM (n271) LAM(n272)
HBsAg seroconversion 8 (3)p0.004 8 (3)p0.004 0
Genotype AD
A 5/23 (22) 2/18 (11) -
B 0/76 (0) 1/82 (1) -
C 3/162 (2) 4/156 (3) -
D 0/9 (0) 0/11 (0) -
vs lamivudine one patient treated with
PegIFNLAM was infected with genotype G and
achieved HBsAg seroconversion

• HBsAg seroconversion occured exclusively in
  patients who achieved HBeAg seroconversion at
  week 72

Hadziyannis et al. EASL 2005, abstract 491
85
Peg IFN a-2a in HBeAg CHB HBsAg Seroconversion
according to Ethnicity
Peg IFN (n271) Peg IFN LAM (n271) LAM(n272)
HBsAg seroconversion 8 (3)p0.004 8 (3)p0.004 0
Ethnicity
Asian 3/238 (1) 5/238 (2) -
Causasian 5/24 (21) 3/23 (13) -

• The rate of HBsAg seroconversion is significantly
  higher in Caucasian than in Asian patients (p lt
  0.0001)

Hadziyannis et al. EASL 2005, abstract 491
86
Peg IFN a-2a in HBeAg CHBALT Flares on Treatment
Peg IFN a-2a (n271)
Peg IFN a 2aLAM (n271)
LAM (n272)
40
32
30
27
24
18
Percentage
20
13
11
10
0
gt5 to ?10 x ULN
gt10 x ULN
Marked ALT Elevations
Moderate ALT Elevations
Piratvisuth et al. EASL 2005, abstract 523
87
Peg IFN a-2a in HBeAg CHBRelationship between
On-therapy ALT elevations and HBeAg
seroconversion at EOF
Patients with HBeAg seroconversion at Week 72 Patients with HBeAg seroconversion at Week 72 Patients with HBeAg seroconversion at Week 72
Peg IFN (n271) Peg IFN LAM (n271) LAM (n272)
gt 10 x ULN 42 34 10
gt 5 - lt 10 x ULN 38 31 25
lt 5 x ULN 26 23 19
p 0.027 for trend(Cochran-Armitage trend test)

• Marked on-treatment ALT were more common in Peg
  IFN treated patients who achieved HBeAg
  seroconversion than who did not 6 months after
  the EOT (as for standard IFN, Liaw et al, J
  Gastroenterol Hepatol 2003 18246-52)

Piratvisuth et al. EASL 2005, abstract 523
88
Peg IFN a-2a in HBeAg CHB Emergence of
Resistance
Peg IFN Peg IFN LAM LAM
YMDD at Week 48 NA 11 34
plt0.001 for comparison with LAM
Lau GK, et al. AASLD 2004
89
Peg IFN a-2a in HBeAg CHB Common Adverse Events
Peg IFN placebo (n271) Peg IFN LAM (n271) LAM (n272)
Pt with ? 1 adverse event 240 (89) 240 (89) 152 (56)
Pyrexia 133 (49) 148 (55) 12 (4)
Fatigue 112 (41) 107 (39) 38 (14)
Headache 76 (28) 81 (30) 27 (10)
Myalgia 70 (26) 77 (28) 8 (3)
Alopecia 55 (20) 78 (29) 6 (2)
Decreased appetite 41 (15) 34 (13) 5 (2)
Injection site reaction 30 (11) 15 (6) 0
AE gt10
Lau GK, et al. AASLD 2004
90
Peg IFN a-2a in HBeAg CHB Serious Adverse
Events and Deaths
Peg IFN placebo (n271) Peg IFN LAM (n271) LAM (n272)
All body systems Total patients with at least 1 SAE Total number of SAEs Deaths 12 (4) 12 0 16 (6) 16 3 5 (2) 5 1
3 deaths in combination group were unrelated to
therapy (2 car accidents and 1 house fire septic
shock) 2 patients in lamivudine group had
complete liver failure after cessation of therapy
1 liver transplant and 1 death
Lau GK, et al. AASLD 2004
91
Peg IFN a-2a in HBeAg CHB Withdrawals from
Study Medication
Reasons for withdrawal Peg IFN PLB (n271) Peg IFN LAM (n271) LAM (n272)
Safety 8 (3) 12 (4) 2 (lt1)
Non-safety 9 (3) 6 (2) 12 (4)
Total 17 (6) 18 (7) 14 (5)
Lau GK, et al. AASLD 2004
92
Peg IFN a-2a in HBeAg CHB Dose Modification

• All patients randomized to Peg IFN alone (n271)
  started treatment with 180 ug once weekly.
• In total, 109 (40) of patients required a Peg
  IFN dose modification for adverse events and/or
  lab abnormalities.
• Lab abnormalities were main reasons
• Neutropenia 22
• ALT elevations 12
• Thrombocytopenia 9

93
Peg IFN a-2a in HBeAg CHB On-treatment ALT
elevations Safety Considerations
Peg IFN n271
Peg IFN LAM n271
ALT elevations gt 5 x ULN n 160/542
Dose modification in 56 patients Temporary dose
modification in gt 70 patients
ALT elevations gt 10 x ULN n83/542
Dose modification in 43 patients
ALT elevations as
Serious Adverse Event n 3/542
Resolved following dose modification

• Peg IFN induced on treatment-ALT flares were not
  associated with serous safety issues in the
  majority of patients and were managed by
  temporary dose modification

Piratvisuth et al. EASL 2005, abstract 523
94
Peg IFN a-2a in HBeAg CHB Authors Conclusions
(1)

• Peg IFN showed significantly higher response
  rates 24 weeks after the end of treatment
  compared with lamivudine for 1
• HBeAg seroconversion
• HBV DNA response (lt100,000 cp/mL)
• More potent HBV DNA suppression (with LAM or
  combination) does not translate into higher HBeAg
  seroconversion rates 2
• HBsAg seroconversion reported in 16 patients with
  Peg IFN ( lamivudine), compared with no patients
  with lamivudine monotherapy

1- Lau et al. AASLD 2004 2- Fired et al. EASL
2005, abstract 488
95
Peg IFN a-2a in HBeAg CHB Authors Conclusion
(2)

• Combination of Peg IFN and LAM did not improve
  post-therapy response rates compared with Peg IFN
  alone 1
• Increased HBV DNA suppression with combination
  therapy resulted in a lower incidence of YMDD
  mutation than seen with LAM alone 2

1- Lau et al. AASLD 2004 2- Fried et al. EASL
2005, abstract 488
96
Peg IFN a-2a in HBeAg CHB Authors Conclusions
(3)

• Patients with genotype C receiving Peg IFN
  monotherapy responded equally well to treatment
  as genotype B 1
• High ALT, low HBV-DNA and low HBeAg levels at
  baseline were predictive of response in patients
  with HBeAg CHB 1
• Previous treatment with IFN or LAM did not
  substantially affect HBeAg seroconversion rates
  with Peg IFN 2
• Peg IFN can achieve HBsAg seroconversion in
  difficult to treat patients such as Asian
  patients 3

1- Cooksley et al. EASL 2005, abstract 71 2-
Lau et al. EASL 2005, abstract 31 3-
Hadziyannis et al. EASL 2005, abstract 491
97
Peg IFN a-2a in HBeAg CHB Authors Conclusions
(4)

• Peg IFN is welll-tolerated in patients with
  HBeAg CHB, with low rate of early withdrawals
  no unexpected adverse events were reported1
• Peg IFN induced on treatment ALT flares were not
  associated with safety issues and were managed by
  temporary dose modification 2
• Adherence was excellent 3

1- Lau et al. AASLD 2004, abstract 20 2-
Piratvisuth et al. EASL 2005, abstract 523 3 -
Lau et al. EASL 2005, abstract 31
98
Peg IFN a-2a in HBeAg CHBKEY MESSAGES

• Design Methods
• Treatment duration of Peg IFN course in HBeAg
  48 weeks.
• Standard IFN 4 to 6 months (16 to 24 weeks)
• What is the rational to double the treatment
  duration, considering that Peg IFN is supposed to
  more efficacious than IFN??
• Co-primary endpoint HBV DNA lt 5 log copies/mL
• Irrelevant threshold
• Assay used COBAS Amplicor with LLQ 200
  copies/mL

99
Peg IFN a-2a in HBeAg CHBKEY MESSAGES

• Virological response at End of treatment
• Peg IFN shows a slow and modest antiviral
  response
• Especially as the response is measured with the
  COBAS assay
• As such, LAM performed extremely well with a 5.8
  log reduction

100
Peg IFN a-2a in HBeAg CHBKEY MESSAGES

• HBeAg response
• 32 patients achieved HBeAg seroconversion at W72
• PEG IFN doesnt seem to be more efficient than
  IFN
• Patients who did seroconverted had a greater HBV
  DNA reduction at W48
• Predictive factors of HBeAg response
• High baseline ALT
• Low HBV DNA level
• HBeAg level
• Genotype A
• Predictive factors of response to IFN and to Peg
  IFN are the same

101
Peg IFN a-2a in HBeAg CHBKEY MESSAGES

• HBsAg response
• 3 patients achieved HBsAg seroconversion at W72
• ? Peg IFN does not provide additional benefit
  compared to standard IFN (cf Wong Meta-analysis)
• Only patients who achieved HBeAg seroconversion
  had an s seroconversion
• The vast majority were caucasian and genotype A
• Only 1 asian had a response vs 21 caucasian
• No patient with genotype D had a HBsAg response
• Asian ethnicity and genotype D are factors of
  non response to Peg IFN

102
Peg IFN a-2a in HBeAg CHBKEY MESSAGES

• Peg IFNLAM combination
• The combination showed a more profound HBV DNA
  reduction after 1 year therapy as compared with
  Peg IFN monotherapy (-7.2 log vs -4.5 log)
• Combining Peg IFN and LAM did not improve
  response rates over Peg IFN alone
• However Peg IFNLAM combination has demonstrated
  to prevent the emergence of YMDD mutants

103
Peg IFN a-2a in HBeAg CHBKEY MESSAGES

• Safety Profile of Peg IFN
• Safety profile of Peg IFN ltltlt LAM
• ALT flares are common during Peg IFN monotherapy
• 27 patients experienced an ALT flare gt 5 x ULN
• 18 ALT flare gt 10 x ULN
• Peg IFN shows a poor tolerability
• 6 treatment discontinuation
• 40 dose reduction due to side effects

104
Peg IFN a-2b in HBeAg CHB Study Design
EOT 52 weeks
EOF 78 weeks
Randomized
100 µg Peg IFN a-2b qw oral placebo qd (n136)
50 µg Peg IFN qw oral placebo qd
100
µ
g PEGASYS qw oral placebo
qd
(n )
26 week follow-up
100 µg Peg IFN a-2b qw 100 mg lamivudine
qd (n130)
50 µg Peg IFN qw 100 mg lamivudine qd
72
0
24
48
32
Study weeks
Janssen HLA, et al. Lancet 2005 365123-29
105
Peg IFN a-2b in HBeAg CHBKey Inclusion Criteria

• HBeAg positive
• Serum ALT gt 2 x ULN
• Age gt 16 years
• Compensated liver disease
• No antiviral therapy 6 months prior to entry
• No co-infection with HIV, HCV or HDV

Janssen HLA, et al. Lancet 2005 365123-29
106
Peg IFN a-2b in HBeAg CHBStudy Endpoints

• Primary Endpoint
• HBeAg loss
• Secondary Endpoints
• HBV DNA lt 200.000 copies/ml
• HBV DNA lt 400 copies/ml
• ALT normalization
• HBsAg loss

Janssen HLA, et al. Lancet 2005 365123-29
107
Peg IFN a-2b in HBeAg CHBBaseline
Characteristics
Peg-IFN LAM (n 130)
Peg-IFN (n 136)
Male 79 75 Age (yr) 33
32 Orientals 21 19 Weight
(kg) 73 73 Prior IFN () 21
21 Prior Lamivudine () 12 13
ALT (ULN) 3.2 3.3 Cirrhosis 10
12 HBV DNA (Log10) 9.2 9.2 Genotype A 35
33 B 9 9 C 16
14 D 38 40
median
108
Peg IFN a-2b in HBeAg CHBSerological Response
at End of Therapy
Peg IFN (n136)
Peg IFN LAM (n130)
100
80
P0.01
60
Patients ()
44
40
29
25
22
20
7
6
5
4
0
HBsAg loss
HBeAg loss
HBeAg
HBsAg
seroconversion
seroconversion
End of therapy 52 weeks
Janssen HLA et al., Lancet 2005365123-29
109
Peg IFN a-2b in HBeAg CHBSerological Response
at End of Follow-up
Peg IFN (n136)
Peg IFN LAM (n130)
100
80
60
Patients ()
36
35
40
29
29
20
7
7
7
5
0
HBeAg loss
HBeAg
HBsAg
HBsAg loss
seroconversion
seroconversion
End of Follow Up 78 weeks
Janssen HLA, et al. Lancet 2005 365123-29
110
Peg IFN a-2b in HBeAg CHBVirological Response
at End of Therapy
Peg IFN (n136)
Peg IFN LAM (n130)
100
80
74
60
plt0.001
Patients ()
plt0.0001
33
40
29
20
10
0
HBV DNA lt 400 c/mL
HBV DNA lt 200 000 c/mL
End of therapy 52 weeks
Taqman PCR assay
Janssen HLA, et al., Lancet 2005365123-29
111
Peg IFN a-2b in HBeAg CHBVirological Response
at End of Follow-up
Peg IFN (n136)
Peg IFN LAM (n130)
100
80
60
Patients ()
40
32
p043
27
20
9
7
0
HBV DNA lt 200 000 c/mL
HBV DNA lt 400 c/mL
End of Follow Up 78 weeks
Taqman PCR assay
Janssen HLA et al., Lancet 2005365123-29
112
Peg IFN a-2b in HBeAg CHBHBV DNA Level Over Time
Follow-up
On-treatment
12
Peg IFN
10
Peg IFN LAM
8
Mean HBV DNA (log c/mL)
6
4
2
0
0
8
16
24
32
40
48
56
64
72
80
weeks
Janssen HLA, et al., Lancet 2005365123-29
113
Peg IFN a-2b in HBeAg CHBBiochemical Response
Peg IFN (n136)
Peg IFN LAM (n130)
p0.005
51
p0.60
Patients ()
35
34
32
52 weeks end of therapy
78 weeks end of follow-up
Janssen HLA et al., Lancet 2005365123-29
114
PEG IFN a-2b in HBeAgHBeAg HBsAg loss at End
of Follow up by Genotype
()
A vs D p0.01 A vs C p0.006
47
44
28
25
14
9
3
2
n103
n23
n39
n90
Janssen et al., AASLD 2004
115
PEG IFN a-2b in HBeAgRole of HBV genotype on
HBsAg seroconversion

• All patients with HBsAg seroconversion had
• Normal ALT
• HBV DNAlt103 copies/mL
• Among responders with HBeAg loss the HBsAg
  seroconversion rate was
• 28 for genotype A
• 20 for genotype B
• 0 for genotype C
• 8 for genotype D

Janssen HL et al. AASLD 2004, Poster 1144
116
Peg IFN a-2b in HBeAg CHBSafety

• No deaths
• Serious adverse events
• 32 patients (12)
• 17 probably related to therapy all reversible
• Side effect profile similar to conventional IFN
• No difference in side effects between Peg IFN
  alone or combination Peg IFNLAM

Janssen HLA et al., Lancet 2005365123-29
117
Peg IFN a-2b in HBeAg CHBAuthor Conclusions

• One year Peg IFN is effective for HBeAg positive
  CHB
• In comparison to Peg IFN monotherapy,
  combination
• of Peg IFN LAM leads to higher end of
  treatment but equal sustained response
• Peg IFN and Peg IFNLAM combination are well
• tolerated
• Peg IFN monotherapy should be the standard
  therapy
• to achieve sustained response in HBeAg positive
  CHB

Janssen HLA et al., Lancet 2005365123-29
118
Peg IFN a-2b in HBeAg CHBKEY MESSAGES

• Efficacy of Peg IFN at End Of Follow-up
• 29 patients had HBeAg seroconversion at EOF
• 29 had HBV DNA lt 200,000 c/mL
• 7 patients HBV DNA lt 400 copies/mL
• 32 patients had Normalized ALT
• As shown and described in the literature with
  Standard IFN, About One third patients responded
  to Pegylated IFN

119
Peg IFN a-2b in HBeAg CHBKEY MESSAGES

• Predictive factors of response
• Genotype Response in Genotype A gt B gt C gt D
• High ALT level at baseline
• These results contrast with Cooksleys finding.
  In the Roche phase II study, the author attempted
  to demonstrate that patients with low ALT and
  high HBV DNA levels at baseline respond well to
  Peg IFN
• Hepsera showed efficacy regardless of HBV
  genotype
• (Westland, Gastroenterology, July 2003)

120
Peg IFN a-2b in HBeAgCHBKEY MESSAGES

• Combination PEG IFN LAM
• The combination Peg IFN LAM provides better
  results than Peg IFN monotherapy at the end of
  treatment (52 weeks)
• Combination therapy did not show any advantage on
  sustained response off therapy over the Peg IFN
  monotherapy arm.

121
Peg IFNs a in HBeAg CHBDesign Comparison
Peg IFN ?-2a (Lau et al, AASLD 2004) Peg IFN ?-2b (Janssen et al, Lancet 2005)
Study population 542 266
Comparator arm with established agent Yes (LAM) No
Length of treatment Length of follow up 48 weeks 24 weeks 52 weeks 26 weeks
ALT levels Included patients with low/minimally raised ALT 28 with ALT 2 x ULN 7 with ALT N at BL Patients included only if ALT levels 2 x ULN on 2 occasions 8 weeks prior to randomisation
Study dose 180 µg qw dose consistent throughout 100 µg qw dose reduced to 50 µg qw after 32 weeks
Study endpoints at end of follow-up 1. HBeAg seroconversion 1. HBeAg loss
Study endpoints at end of follow-up 2. HBV DNA lt100,000 cp/mL 2. HBV DNA lt200,000 cp/mL
Study endpoints at end of follow-up 3. HBV DNA lt400 cp/mL 3. HBV DNA lt400 cp/mL
122
Peg IFNs a in HBeAg CHBPatient Characteristics
At Baseline
Peg IFN ?-2a (Lau et al, AASLD 2004) Peg IFN ?-2b (Janssen et al, Lancet 2005)
Ethnicity Caucasian Asian 7 86 74 20
Genotype A B C D 7 28 59 4 34 9 15 39
Mean ALT at baseline (x ULN) 3.7 4.4
Mean HBV DNA at baseline (log copies/mL) 10.0 9.1
for all treatment arms combined
123
Peg IFNs a in HBeAg CHB Efficacy Summary at End
of Follow Up
Roche (Lau et al) Roche (Lau et al) Roche (Lau et al) Schering (Janssen et al) Schering (Janssen et al) Schering (Janssen et al)
Response parameter Peg IFN PLB (n271) Peg IFN LAM (n271) LAM (n272) Peg IFN PLB (n136) Peg IFN LAM (n130)
HBeAg seroconversion 32 27 19 29 29
HBV DNA response 32 34 22 27 32
ALT normalization 41 39 28 32 35
HBsAg seroconversion 3 3 0 5 7
HBV DNA lt 100,000 c/ml HBV DNA lt 200,000 c/mL
124
Peg Interferons in HBeAg - patients

• Roche Marcellin et al. NEJM 2005

125
Peg IFN a-2a in HBeAg- CHB Study Design

• Patients with HBeAg-negative CHB were randomized
  using a 111 ratio (n537)

EOF 72 weeks
EOT 48 weeks
Randomized
180 µg Peg IFN qw oral placebo qd
24 week follow-up
180 µg Peg IFN qw 100 mg lamivudine qd
100 mg lamivudine qd
0
24
48
72
Study weeks
Marcellin et al. NEJM 2004351120617
126
Peg IFN a-2a in HBeAg- CHB Study Endpoints

• Co-primary Endpoints
• ALT normalization at EOF
• HBV DNA lt 20,000 copies/mL (COBAS PCR Assay) at
  EOF
• Secondary Endpoints
• Histology
• HBsAg loss seroconversion at EOF
• HBV DNA lt 400 copies/mL
• Combined response
• ALT Normalization HBV DNA lt 20,000 copies/mL
  at EOF

Marcellin et al. NEJM 2004351120617
127
Peg IFN a-2a in HBeAg- CHB Co-primary Endpoint
Normal ALT At Week 72
P0.004
80
60
60
60
59
59
44
44
Percentage
40
20
n177
n179
n181
n177
n179
n181
0
LAM
Peg IFN
Peg IFNLAM
Marcellin et al. NEJM 2004351120617
128
Peg IFN a-2a in HBeAg- CHB HBV DNA lt 20,000
copies/mL
Peg IFN a-2a (n177)
Peg IFN a 2aLAM (n179)
LAM (n181)
92
100
P0.007
85
81
80
P0.849
P0.003
Patients ()
60
44
43
40
29
20
0
End of Treatment Week 48
End of Follow Up Week 72
Marcellin P, et al. NEJM 2004351120617
129
Peg IFN a-2a in HBeAg- CHB HBV DNA lt 400
copies/mL
Peg IFN a-2a (n177)
Peg IFN a-2aLAM (n179)
LAM (n181)
100
87
73
80
63
Patients ()
60
40
20
19
20
7
0
End of Treatment Week 48
End of Follow up Week 72
Marcellin P, et al. NEJM 2004351120617
130
Peg IFN a-2a in HBeAg- CHBHBV DNA Levels Over
Time
On-treatment
Follow-up
7
Peg IFN a2a
6
placebo (n177)
1.6
2.4
5
2.3
Peg IFN a 2a
Mean HBV DNA (log10 c/mL)
LAM (n 179)
4
4.1
3
LAM (n 181)
4.2
5.0
2
1
0
Study week
0
6
12
18
24
30
36
42
48
54
60
66
72
Marcellin et al. NEJM 2004351120617
131
Peg IFN a-2a in HBeAg- CHB HBsAg Response at
Week 72
Peg IFN a-2a (n177)
Peg IFN a 2aLAM (n179)
LAM (n181)
100
80
Patients ()
60
40
20
4
3
3
2
0
0
0
HBsAg Loss
HBsAg seroconversion
Marcellin P, et al. NEJM 2004351120617
132
Peg IFN a-2a in HBeAg- CHBHistological Response
(Ishak Score) at Week 72
56
Improvement
46
46
Peg IFN
Peg IFN LAM
LAM
17
15
12
LAM
Peg IFN LAM
Peg IFN
Patients ()
5
8
11
11
16
17
Fibrosis
Activity
Worsening
Defined as gt 2-point change in Ishak Activity
score.
Defined as gt 2-point change in Ishak fibrosis
score.
133
Peg IFN a-2a in HBeAg- CHBALT Flares on Treatment
Peg IFN a-2a (n177)
Peg IFN a 2aLAM (n179)
LAM (n181)
40
p0.001
30
30
25
p0.001
p0.001
p0.001
Percentage
20
12
12
10
6
4
0
gt5 to ?10 x ULN
gt10 x ULN
Marked ALT Elevations
Moderate ALT Elevations
Piratvisuth et al. AASLD 2004. Marcellin et al.
NEJM 2004351120617
134
Peg IFN a-2a in HBeAg- CHBRelationship between
On-therapy ALT elevations and response at EOF
Patients with Sustained ALT normalization at Week 72 Patients with Sustained ALT normalization at Week 72 Patients with Sustained ALT normalization at Week 72 Patients with Sustained ALT normalization at Week 72
Peg IFN (n177) Peg IFN LAM (n179) LAM (n181) All arms (n537)
All ALT patterns 59 60 44 54
gt 10 x ULN 73 75 73 73
gt 5 - lt 10 x ULN 55 51 43 51
lt 5 x ULN 59 63 42 53
p 0.004 vs LAM mono

• Sustained ALT normalization at week 72 was more
  common in patients with marked ALT flare ( gt 10 x
  ULN)
• A marked ALT elevation during therapy may be
  beneficial in patients with HBeAg - disease

Piratvisuth T et al. AASLD 2004, Abstract 1137
135
Peg IFN a-2a in HBeAg- CHBALT Flares During
Follow-up
Peg IFN a-2a (n177)
Peg IFN a 2aLAM (n179)
LAM (n181)
40
30
30
25
Percentage
20
p0.021
p0.033
12
12
10
6
4
0
gt5 to ?10 x ULN
gt10 x ULN
Marked ALT Elevations
Moderate ALT Elevations
Piratvisuth et al. AASLD 2004. Marcellin et al.
NEJM 2004351120617
136
Peg IFN a-2a in HBeAg- CHBPredictors of Response
at Week 72

• Predictors of combined response at EOF (all
  patients groups, n518)
• High baseline ALT
• Low baseline HBV DNA
• Younger age
• Female gender
• Predictors of combined response at EOF in
  patients treated with PEG or LAM mono
• HBV genotype emerged as an additional predictor
• B C gt D

Bonino et al. AASLD 2004
137
Peg IFN a-2a in HBeAg- CHB HBsAg Seroconversion
at W72 according to Genotype
Peg IFN (n177) Peg IFN LAM (n179) LAM(n181)
HBsAg seroconversion 5 (3)p0.03 3 (2) 0
Genotype AD
A 2/11 (18) 1/10 (10) -
B 1/43 (2) 2/41 (5) -
C 2/63 (3) 0/69 (0) -
D 0/55 (0) 0/54 (0) -
vs lamivudine

• HBsAg seroconversion rate was higher in patients
  with genotype A.

Hadziyannis et al. EASL 2005, abstract 491
138
Peg IFN a-2a in HBeAg- CHB HBsAg Seroconversion
according to Ethnicity
Peg IFN (n177) Peg IFN LAM (n179) LAM(n181)
HBsAg seroconversion 5 (3) 3 (3) 0
Ethnicity
Asian 3/108 (3) 2/112 (2) -
Causasian 2/66 (3) 1/65 (2) -
Hadziyannis et al. EASL 2005, abstract 491
139
Peg IFN a-2a in HBeAg- CHBOn-treatment HBV DNA
and Sustained Response to Peg IFN
80
70
57
60
53
53
46
patients with N ALT at Week 72
40
20
0
gt 400 to 100 000
gt 100 000 to 500 000
gt 400
gt 500 000
lt 400
HBV DNA at Week 12

• Rate of sustained biochemical response (W72) was
  higher in patients who had HBV DNA lt 400 at Week
  12 (70)
• However, 30 patients with HBV DNA lt 400 at W12
  did not go on to achieve a sustained biochemical
  response
• 46 patients achieved sustained biochemichal
  response, despite HBV DNA gt 500,000 at W 12

Farci et al. EASL 2005, Abstract 484
140
Peg IFN a-2a in HBeAg- CHBOn-treatment HBV DNA
and Sustained Response to Peg IFN
80
61
60
patients with HBV DNA lt 20,000 c/mL Week 72
40
34
31
30
29
20
0
gt 400 to 100 000
gt 100 000 to 500 000
gt 400
gt 500 000
lt 400
HBV DNA at Week 12

• Rate of sustained HBV DNA lt 20,000 c/mL at W72
  was higher in patients who had HBV DNA lt 400 at
  Week 12 (61)
• However, 39 patients with HBV DNA lt 400 at W12
  did not go on to achieve a sustained virological
  response
• 34 patients achieved sustained virological
  response, despite HBV DNA gt 500,000 at W 12

Farci et al. EASL 2005, Abstract 484
141
Peg IFN a-2a in HBeAg- CHB LT Study
Randomized
LT Study n304/537
EOT
EOF
180 µg Peg IFN qw oral PLB qd (n177)
63 (n111)
180 µg Peg IFN qw 100 mg LAM qd (n179)
62 (n111)
100 mg LAM qd (n181)
45 (n82)
0
48
72
96
Study weeks
Marcellin P, et al. EASL 2005 (Abstract 512)
142
Peg IFN a-2a in HBeAg- CHBVirological Response
At Week 96
100
6 months after EOT
12 months after EOT
80
60
patients
44
43
42
41
40
31
29
20
19
17
20
14
7
8
76/177
79/179
53/181
41/97
17/102
40/97
20/65
34/177
35/179
15/104
6/75
12/181
0
LAM
Peg IFN
Peg IFNLAM
LAM
Peg IFN
Peg IFNLAM
HBV DNA lt 20,000 copies/mL
HBV DNA lt 400 copies/mL
If week 96 value was missing, week 84 value was
used COBAS PCR assay
Marcellin P, et al. EASL 2005 (Abstract 512)
143
Peg IFN a-2a in HBeAg- CHB Normal ALT At Week 96
Week 72
Week 96
100
80
60
59
59
60
52
44
patients
43
40
20
n65
n177
n181
n99
n179
n98
0
Peg IFN
Peg IFNLAM
LAM
Marcellin P, et al. EASL 2005 (Abstract 512)
144
Peg IFN a-2a in HBeAg- CHBDurability of Response
patients
13/21
47/66
34/46
Marcellin P, et al. EASL 2005 (Abstract 512)
145
Peg IFN a-2a in HBeAg- CHBEmergence of Resistance
Peg IFN Peg IFN LAM LAM
YMDD at Week 48 NA lt1 (1/173) 18 (32/179)
YMDD by W48 in patients with HBV DNA gt 400c/mL NA 0 (n157) 5 (n133)
YMDD by W48 in patients with HBV DNA gt 400c/mL NA 13 (n8) 13 (n8)
plt0.001 for comparison with LAM
Germanidis G et al. AASLD 2004, Abstract 1131
146
Peg IFN a-2a in HBeAg- CHB Dose Modification

• All patients randomized to Peg IFN alone (n177)
  started treatment with 180 ?g once weekly.
• In total, 83 (47) of patients required a Peg IFN
  dose modification for adverse events and/or lab
  abnormalities.
• Lab abnormalities were main reasons (n65)
• Neutropenia 17
• ALT elevations 15
• Thrombocytopenia 19

Marcellin et al. NEJM 2004351120617
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