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Peg-IFNa-2a (PEGASYS) in CHB Review of
Data Presented at the 40th Annual EASL meeting
1317 April 2005, Paris, France

George V. Papatheodoridis, MD Assistant
Professor in Medicine Gastroenterology 2nd
Academic Department of Medicine Hippokration
General Hospital, Athens, Greece Beirut, July
1st, 2005
3
EASL Meeting, April 2005, Paris

• Abstracts on Pegasys in CHB
• Study 240 (HBeAg-positive CHB)
• GKK Lau et al. PEGASYS vs. PEGASYS plus
  lamivudine vs. lamivudine in HBeAg-positive CHB
  Effect of previous treatment and drug exposure on
  sustained response
• G Cooksley et al. Effect of genotype and other
  baseline factors on response to PEGASYS in
  HBeAg-positive CHB Results from a large,
  randomised study
• M Fried et al. Greater viral suppression with
  lamivudine /- PEGASYS does not translate into
  improved rates of sustained HBeAg seroconversion
  results from a large, multinational study
• T Piratvisuth et al. Effect of ALT flares on
  efficacy and safety of PEGASYS, PEGASYS plus
  lamivudine and lamivudine in HBeAg-positive CHB

4
EASL Meeting, April 2005, Paris

• Abstracts on Pegasys in CHB (cont.)
• Study 241 (HBeAg-negative CHB)
• P Marcellin et al. Sustained response to PEGASYS
  in HBeAg-negative CHB B. One-year follow-up data
  from a large, randomised multinational study
• P Farci et al. On-treatment predictors of
  sustained biochemical and virological response in
  patients with HBeAg-negative CHB treated with
  PEGASYS
• Studies 240 241
• S Hadziyannis et al. Sustained HBsAg
  seroconversion in patients with chronic hepatitis
  B treated with PEGASYS
• Independent Study in HBeAg-negative CHB
• RM Ribeiro et al. Hepatitis B viral kinetics
  under different approved antiviral treatment
  regimens in HBeAg-negative patients with CHB
  explain treatment antiviral mechanisms

5
Peginterferon Alfa-2a Alone, Lamivudine Alone,
and the Two in Combination in Patients with
HBeAg-Negative Chronic Hepatitis B Patrick
Marcellin, M.D., George K.K. Lau, M.D., Ferruccio
Bonino, M.D., Patrizia Farci, M.D., Stephanos
Hadziyannis, M.D., Rui Jin, M.D., Zhi-Meng Lu,
M.D., Teerha Piratvisuth, M.D., Georgios
Germanidis, M.D., Cihan Yurdaydin, M.D., Moises
Diago, M.D., Selim Gurel, M.D., Ming-Yang Lai,
M.D., Peter Button, M.Sc., Nigel Pluck, M.D., for
the Peginterferon Alfa-2a HBeAg-Negative Chronic
Hepatitis B Study Group
6
Study Design
Patients with HBeAg-negative CHB were randomised
using a 111 ratio ITT population n537
End of Treatment 48 weeks
End of Follow-up 72 weeks
Randomised
PEGASYS 180 ?g qw oral placebo qd
24 weeks follow-up
PEGASYS 180 ?g qw lamivudine 100 mg qd
lamivudine 100 mg qd
0
24
48
72
Study weeks
7
Key Inclusion Criteria

• HBsAg ve for ?6 months
• HBeAg ve, anti-HBe ve for ?6 months
• HBV DNA gt100,000 cp/mL
• (COBAS AMPLICOR HBV MONITOR)
• Serum ALT gt1 but ?10 x ULN at screening
• Less than 20 with serum ALT 12 x ULN
• Liver biopsy proven CHB
• Prominent necroinflammatory component

8
Key Exclusion Criteria

• Decompensated liver disease
• Co-infection with HCV, HDV or HIV
• Anti-HBV therapy in 6 months prior to study

9
Baseline Characteristics
Marcellin et al. NEJM 2004351120617
10
Co-primary Endpoint - Normal ALT 24 Weeks After
End of Treatment (Week 72)
P0.004
60
59
Patients ()
44
n177
n179
n181
lamivudine
PEGASYS placebo
PEGASYS lamivudine
Marcellin et al. NEJM 2004351120617
11
Co-primary Endpoint - HBV DNA Response 24 Weeks
After End of Treatment (Week 72)
P0.007
P0.849
P0.003
44
43
Patients ()
29
n177
n179
n181
PEGASYS placebo
PEGASYS lamivudine
lamivudine
HBV DNA response defined as lt20,000 cp/mL
Marcellin et al. NEJM 2004351120617
12
HBV DNA lt400 copies/ml 24 Weeks After End of
Treatment (Week 72)
Plt0.001
P0.909
Plt0.001
20
19
Patients ()
7
n177
n179
n181
PEGASYS placebo
PEGASYS lamivudine
lamivudine
Marcellin et al. NEJM 2004351120617
13
Combined Response 24 Weeks After End of
Treatment (Week 72)
38
36
Patients ()
23
n177
n179
n181
PEGASYS placebo
PEGASYS lamivudine
lamivudine
Combined response defined as ALT normalisation
and HBV DNA lt20,000 cp/mL
Marcellin et al. NEJM 2004351120617
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Study Design
Patients with HBeAg-positive CHB were randomised
using a 111 ratio ITT population n814
End of Treatment 48 weeks
End of Follow-up 72 weeks
Randomised
PEGASYS 180 ?g qw oral placebo qd
24 weeks follow-up
PEGASYS 180 ?g qw lamivudine 100 mg qd
lamivudine 100 mg qd
0
24
48
72
Study weeks
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18
Baseline Characteristics
19
HBeAg Seroconversion at End of Follow-up (Week
72) All Patients
Plt0.001
PNS
P0.023
32
27
Patients with HBeAg seroconversion ()
19
n271
n271
n272
PEGASYS placebo
PEGASYS lamivudine
lamivudine
20
(No Transcript)
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Conclusions

• In both HBeAg-negative HBeAg-positive CHB
• PEGASYS monotherapy achieves significantly higher
  response rates at 24 weeks post-treatment, as
  compared with lamivudine monotherapy
• The combination of PEGASYS lamivudine does not
  improve response rates compared with PEGASYS
  alone

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Conclusions

• No unexpected adverse events are observed with
  PEGASYS, and the addition of lamivudine did not
  alter the safety profile
• The data support the use of PEGASYS asfirst-line
  therapy in both patients with HBeAg-negative and
  HBeAg-positive CHB

23
Annual EASL Conference, April 2005, Paris

• Peginterferon Alfa-2a (40KD) (PEGASYS) vs.
  Peginterferon alfa-2a Plus Lamivudine vs.
  Lamivudine in HBeAg-positive Chronic HBV Effect
  of Previous Treatment and Drug Exposure on
  Sustained Response
• GKK Lau, T Piratvisuth, K-X Luo, P Marcellin, S
  Thongsawat, E Gane, MW Fried, G Cooksley, P
  Button, Y-F Liaw
• Abstract 31 (oral presentation)

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HBeAg Seroconversion at Week 72 in Patients with
Prior Exposure to Anti-HBV Therapy
PEGASYS placebo
Lamivudine
PEGASYS lamivudine
Plt0.001
P0.065
P0.009
P0.047
43
37
34
32
32
30
Patients with HBeAg seroconversion ()
27
25
19
17
16
13
n271
n271
n272
n31
n30
n24
n42
n32
n32
n57
n50
n64
Pts with prior exposure to lamivudine
All patients
Pts with prior anti-HBV therapy
Pts with prior exposure to conv. IFN?
P value for PEGASYS placebo vs lamivudine
includes lamivudine and conventional or
pegylated IFN
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HBeAg Seroconversion at End of Follow-up (Week
72) Effect of PEGASYS Exposure
33
28
Patients with HBeAg seroconversion ()
17/60
70/211
90 PEGASYS dose (7776 ?g)
lt90 PEGASYS dose (lt7776 ?g)
The bars represent 95 confidence intervals
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Effect of Previous Treatment on Sustained
Response Summary

• Prior treatment with lamivudine or interferon
  does not substantially affect HBeAg
  seroconversion rates
• HBeAg seroconversion rates in patients without
  prior anti-HBV therapy appear to be almost
  identical to those seen in the overall population
• HBeAg seroconversion rates are significantly
  higher with PEGASYS alone than with lamivudine
  monotherapy, irrespective of previous anti-HBV
  therapy

27
Effect of PEGASYS Drug Exposure on Sustained
Response Summary

• Drug exposure in the study was very high
• 78 of patients received 90 of the total
  PEGASYS dose
• A high rate (28) of HBeAg seroconversion was
  achieved with PEGASYS even in patients who
  received lt90 of the drug dose
• Because of the relatively small number of
  patients receiving lt90 of the PEGASYS dose, it
  is difficult to determine an exposure/efficacy
  relationship

28
Annual EASL Conference, April 2005, Paris

• Effect of Genotype and Other Baseline Factors on
  Response to Peginterferon Alfa-2a (40KD)
  (PEGASYS) in HBeAg-positive Chronic Hepatitis B
  Results from a Large, Randomised Study
• G Cooksley, M Manns, GKK Lau, Y-F Liaw, P
  Marcellin, W-C Chow, S Thongsawat, E Gane,
  MW Fried, F Zahm
• Abstract 71 (oral presentation)

29
Factors Predictive of Response in HBeAg() CHB

• Common across conventional IFN?, lamivudine,
  adefovir1,2
• High pretreatment ALT values
• For response to conventional IFN? and lamivudine1
• Low pretreatment serum HBV DNA levels
• High degree of necroinflammatory activity
• Infection as an adult
• For response to conventional IFN? only1, 36
• Genotype B (vs C)
• Genotype A (vs D)

1. EASL Consensus Statement J Hepatol 2003 (EASL
Guidelines) 2. Marcellin EASL 2002 3. Craxi J
Hepatol 2003 4. Erhardt Hepatology 2000 5. Hou
Hepatology 2001 6. Cooksley J Viral Hepat 2003
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HBeAg Seroconversion after 24 Weeks of
Follow-upBest Responses in Patients with High
Baseline ALT
PEGASYS placebo
PEGASYS lamivudine
lamivudine
41
37
Patients with HBeAg seroconversion ()
30
29
28
27
20
20
16
19/96
36/121
30/111
20/129
24/58
25/67
13/47
27/92
19/93
25 x ULN
gt5 x ULN
?2 x ULN
ALT
31
HBeAg Seroconversion after 24 Weeks of
Follow-upBest Responses in Patients with Low
Baseline HBV DNA
HBeAg seroconversion 24 weeks after the end of
treatment
53
36
31
Patients ()
28
27
21
17
17
10
7/71
24/78
39/138
40/147
21/123
11/63
14/68
37/70
20/56
gt9.07 to 10.26 (2nd 3rd Quartiles)
gt10.26 (4th Quartile)
9.07 (1st Quartile)
HBV DNA (log10 cp/mL)
32
Parameters Significantly Associated with
Sustained HBeAg Seroconversion (SR) in the MV
Analysis

• Treatment with PEGASYS
• 2-fold higher odds (chance) of SR than lamivudine
  
• ALT at baseline
• Chance of SR increased by 2.7-fold for each log10
  ALT (IU/L) increase
• Patients with ALT 500 IU/L had a 2.7-fold
  higher chance of SR than those with an ALT 50
  IU/L
• HBV DNA at baseline
• Chance of SR increased by 20 for each log10
  (copies/mL) decrease
• HBeAg levels at baseline
• Chance of SR increased by 50 for each log10
  (IU/mL) decrease

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HBeAg Seroconversion after 24 Weeks of Follow-up
(Week 72) Effect of HBV Genotype
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
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Summary (i)

• High ALT, low HBV DNA and low HBeAg levels at
  baseline are strong independent predictors of
  HBeAg seroconversion
• Regardless of baseline ALT, HBV DNA or HBeAg
  levels, rates of HBeAg seroconversion are higher
  with PEGASYS than with lamivudine
• Among patients with low HBV DNA levels (lt9 logs),
  HBeAg seroconversion is achieved in gt50 of those
  treated with PEGASYS alone
• Among patients with ALT levels gt5 xULN, HBeAg
  seroconversion is achieved in gt40 of those
  treated with PEGASYS alone

35
Summary (ii)

• HBeAg seroconversion rates with PEGASYS
  monotherapy are substantially higher in patients
  infected with genotype A compared with those
  infected with genotypes B, C or D
• More than half of the patients infected with
  genotype A treated with PEGASYS achieve sustained
  HBeAg seroconversion
• Patients infected with HBV genotypes B and C
  respond equally well to PEGASYS, in contrast to
  what has been observed with conventional IFNa

36
Annual EASL Conference, April 2005, Paris
Greater Viral Suppression with LAM /- PEGASYS
does not translate into Improved Rates of
Sustained HBeAg Seroconversion MW Fried, GKK
Lau, T Piratvisuth, K-X Luo, WC Chow, SW Paik,
WY Chang, R Flisiak, N Pluck, T Berg Abstract
488 (poster presentation)
37
HBV DNA Levels On Treatment and HBeAg
Seroconversion at End of Follow-up
12
HBeAg Seroconversion Rates at End of Follow-up
On-treatment
Plt0.001
10
32
P0.023
27
8
Mean HBV DNA (log10 copies/mL)
19
6
4
n271
n271
n272
2
PEGASYS
PEGASYS LAM
LAM
0
6
12
18
24
30
36
42
48
54
60
66
72
Study week
all numbers shown are log10 reduction from
baseline
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HBV DNA suppression HBeAg seroconversionConclus
ions

• HBV-DNA suppression is greater with PEGASYSLAM
  or LAM alone compared to PEGASYS monotherapy
  (7.2, 5.8 and 4.5 mean log reduction at EOT)
• However, HBeAg seroconversion 24 wks after EOT is
  higher with PEGASYS (32) than with LAM (19) or
  combination therapy (27)
• The more potent HBV-DNA suppression does not
  translate into improved HBeAg seroconversion
  rates
• The superior benefit seen with PEGASYS may be due
  to its dual mode of action (antiviral
  immunomodulatory)

39
Annual EASL Conference, April 2005, Paris
Effect of ALT Flares on Efficacy and Safety of
PEGASYS /- Lamivudine, or Lamivudine alone in
HBeAg-positive CHB T Piratvisuth, K-X Luo, P
Marcellin, WY Chang, T Berg, R Flisiak, Y-C
Chao, SW Paik, S Thongsawat, P McCloud Abstract
523 (poster presentation)
40
Marked ALT flares (maximum ALT) during therapy
(weeks 0-48)
PEGASYSplacebo (n271) PEGASYSlamivudine
(n271) Lamivudine (n271)
P0.037
18
Patients,
13
11
6
5
4
gt10 x ULN gt5 x baseline ALT
41
Peak ALT during treatment and HBeAg
seroconversion 24 weeks after the end of
treatment (week 72)
42
Marked ALT flares (maximum ALT) after therapy
(weeks 49-72)
PEGASYSplacebo (n271) PEGASYSlamivudine
(n271) Lamivudine (n271)
15
Patients,
13
12
11
11
7
gt10 x ULN gt5 x baseline ALT
43
Liver decompensation in patients with
post-therapy (weeks 49-72) marked ALT flares

• Patients with
• 
  decompensation Outcome
• PEGASYSplacebo 1
  Resolved 1
• PEGASYSlamivudine 3
  Resolved 3
• Lamivudine 4
  Resolved 2
• 
  Death 1
• 
  OLT 1

44
ALT flares safety-efficacy of therapy in
HBeAg()CHB Conclusions

• Marked on-treatment ALT elevations are generally
  more frequent with PEGASYS monotherapy and are
  more common in patients with HBeAg seroconversion
  24 weeks after the end of treatment
• In contrast, marked follow-up flares are
  generally more frequent with lamivudine and may
  lead to irreversible liver failure

45
Annual EASL Conference, April 2005, Paris

• Sustained HBsAg seroconversion in patients with
  chronic hepatitis B treated with peginterferon
  alfa-2a (40KD) (PEGASYS)
• S Hadziyannis, GKK Lau, P Marcellin, T
  Piratvisuth,
• G Cooksley, F Bonino, A Chuttaputti, M Diago, R
  Jin,
• N Pluck
• Abstract 491 (poster presentation)

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Objective

• To investigate the occurrence of HBsAg
  seroconversion in 1,351 patients with
  HBeAg-positive or HBeAg-negative CHB treated for
  48 weeks with peginterferon alfa-2a (40KD)
  (PEGASYS) alone, PEGASYS plus lamivudine or
  lamivudine alone

47
Methods

• Patients with HBeAg-positive (n814) or
  HBeAg-negative (n537) CHB were treated in two
  large, randomised, partially double-blind
  multinational studies
• All patients were positive for HBsAg and negative
  for anti-HBs antibody at baseline
• Patients were considered to have sustained HBsAg
  seroconversion only if they were both HBsAg
  negative and anti-HBs positive at 24 wks after
  the end of treatment (wk 72)

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Sustained HBsAg seroconversion (24 weeks after
EOT in patients with HBeAg-positive CHB
49
Sustained HBsAg Seroconversion According to
Ethnicity and Genotype
50
HBsAg seroconversion in CHB -Conclusions

• HBsAg seroconversion can be achieved in patients
  with HBeAg-positive or HBeAg-negative CHB treated
  with a PEGASYS-containing regimen for 48 weeks
• In contrast, HBsAg seroconversion is not observed
  in patients treated with lamivudine monotherapy
  for 48 weeks
• HBsAg seroconversion rates are affected by
  ethnicity and infecting HBV genotype. In patients
  with HBeAg-positive CHB, the highest rates of
  HBsAg seroconversion are observed in Caucasians
  and in those infected with HBV genotype A

51
EASL Meeting, April 2005, Paris
Hepatitis B Viral Kinetics under Different
Approved Antiviral Treatment Regimens in
HBeAg-negative Patients with CHB Explain
Treatment Antiviral Mechanisms RM Ribeiro, G
Germanidis, KA Powers, B Pellegrin, K
Arvanitakis, AS Perelson, JM Pawlotsky Abstract
526 (poster presentation)
52
Aim - Methods

• Aim To assess early HBV kinetics in response to
  treatments in HBeAg-negative CHB patients
• 46 Greek pts with HBeAg(-)CHB prospectively
  included
• 48 weeks of treatment with
• IFN?-2a, 4.5 MU tiw (n 9)
• LAM 100 mg qd (n9)
• IFN?-2a LAM (n8)
• PEG-IFN?-2a, 180 µg/wk (n6)
• PEG-IFN?-2a LAM (n7)
• LAM Adefovir, 10 mg qd (n7)
• Analysis of HBV dynamics

53
HBV Kinetics under Therapy - Results

• HBV DNA decrease over the first 48 hours differed
  significantly by treatment regimen (p0.003),
  with the largest decrease in the LAM group (-1.3
  log10) and the smallest decrease in the
  PEG-IFN?-2a group (-0.48 log)
• Differences became less pronounced with time and,
  at 1 month, all groups had similar viral decays
  (between -2.9 and -3.5 log), except IFN?
  monotherapy (-1.5 log)

54
HBV Kinetics under Therapy Conclusions

• Nucleos(t)ide analogues (LAM or ADV) have better
  initial antiviral efficacy than PEG-IFN?-2a in
  HBeAg-negative CHB patients, but
• This difference is lost upon treatment
  continuation, probably because PEG-IFN?-2a
  results in greater loss of infected cells,
  a result in keeping with its
  immunomodulatory properties

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Thank you very much for your attention