A Predictable Journey with PEGINTRON

1
A Predictable Journey with PEGINTRON
Philippe MERLE, M.D. Ph.D., Hepatology Unit (Pr
Christian TREPOs group), Lyon, France
2
Therapeutic indications

• Chronic hepatitis C associated with significant
  liver parenchyma lesions related to activity and
  fibrosis (METAVIR gt A1-F1)
• Clinical situations in which the virologic goal
  seems prioritary pre-liver transplantation,
  extra-hepatic manifestations, profession related
  to health care

3
Therapeutic schedule

• Association of PEG-IFN ribavirin
• Limitation factors 80/80/80 rules of
  administration schedule

4
Classification of Response According to Viral
Kinetics
Neumann et al. AASLD 2003. Zeuzem et al. AASLD
2003.
5
Genotype 1
SVR PEG-IFN (1,5 µg/kg/w ou 180
µg) Ribavirin (800 -1400 mg/d)
48 51 48 weeks

Genotype 2 - 3
SVR PEG-IFN (1,5 µg/kg/w ou 180
µg) Ribavirin (800 -1400 mg/d)
77 82 24 weeks

Genotype 4
SVR PEG-IFN (1,5 µg /kg/w ou 180
µg) Ribavirin ( 800 -1200 mg/d )
60 ? 48 weeks

6
EVR at 12 weeks PEGINTRON? 1.5 ?g/kg Rebetol?
gt 10.6 mg/kg/d
W72
Start of treatment
W12
No SVR 20
EVR 82
SVR 80
Subgroup from Mannss study
SVR 0
No EVR 18
No SVR 100
HCV-RNA undetectable or decrease gt 2 log of
HCV-RNA
Wong J, Davis G, Hepatology 2002 36, 4, 2
A-472
7
EVR for the two types of pegylated IFN Genotype
1
Ferenci, Shiffman, Fried, et al., AASLD 2001
Wong, Davis, McHutchison et al., AASLD 2002, Muir
NEJM 2004
8
Global EVR for the two types of pegylated IFN
all genotypes
Ferenci, Shiffman, Fried, et al., AASLD 2001
Davis, Wong, McHutchison et al., Hepatology 2003.
9
(No Transcript)
10
(No Transcript)
11
(No Transcript)
12
(No Transcript)
13
CONCLUSION ON HIGH PREDICTABILITY OF VIRAL
RESPONSE
For patients A rapid viral response within 4
weeks gives patients early assurance that
treatment is working For physicians High
positive and negative predictive value at week 12
give physicians the control to make treatment
decisions with confidence
14
CONCLUSION ON DEPENDABLE RESULTS
For patients The dependable results and low
relapse rate give responding patients the
assurance that they will achieve SVR For
physicians The dependable results and the low
relapse rate reinforce the physicians choice of
treatment in their hepatitis C patients
15
Might we safely decrease the duration of
treatment by PEG-IFN and RBV for a subset of
patients who need anti-HCV therapy ?
16
Short duration therapeutic schedules and
predictive factors of SVR for genotypes 2-3
17
(No Transcript)
18
Treatment genotypes 2-3 12 weeks vs 24 weeks

• Prospective controlled randomized study 283
  patients genotype 2-3 1 µg/kg/w ribavirin
  1-1,2 g/d

D0
W4
W12
W24
133 pts
PCR
-
213 pts

283 pts
80 pts
70 pts
Treatment
D0
W24
W4
W12
19
Baseline Characteristics of the Patients
Mangia A. N Engl J Med 20053522609-17.
20
Baseline Characteristics of the Patients
Mangia A. N Engl J Med 20053522609-17.
21
Initial Viral Decline PCR Negativity at Week-4
Mangia A. N Engl J Med 20053522609-17
22

Std duration PEG-IFN alfa-2b 1.0 ?g/kg
Ribavirin 1000-1200 mg (24 weeks) Var 12
PEG-IFN alfa-2b 1.0 ?g/kg Ribavirin 1000-1200
mg (12 weeks) Var 24 PEG-IFN alfa-2b 1.0
?g/kg Ribavirin 1000-1200 mg (24 weeks)
178/283
133/213
45/70
ALL
Std Duration
Variable Duration
Mangia et al NEJM 2005
23
Sustained Viral Response
Std duration PEG-IFN alfa-2b 1.0 ?g/kg
Ribavirin 1000-1200 mg (24 weeks) Var 12
PEG-IFN alfa-2b 1.0 ?g/kg Ribavirin
1000-1200 mg (12 weeks) Var 24
PEG-IFN alfa-2b 1.0 ?g/kg Ribavirin 1000-1200
mg (24 weeks)

41/45
113/133
217/283
51/80
12/25
Variable 12-week Tx
Duration 24-week Tx
ALL
Standard Duration
Responders
Mangia et al NEJM 2005
24
Sustained Virologic Response
Standard Duration
Variable Duration
Mangia A. N Engl J Med 20053522609-17.
25
Conclusions

• In patients with genotype 2 or 3, length of
  treatment may be safely reduced according to the
  HCV-RNA status after 4 weeks, independently of
  genotype and levels of viremia
• Week-4 HCV-RNA negativity is highly predictive of
  SVR

26
AASLD 2005, A849, A. Anfriulli et al., Italy
Aims Identification of predictors of SVR, RVR
and relapse following short treatments for
genotypes 2 and 3
Patients 403 patients treated by PEG-IFN alfa2b
RBV for 12 vs 24 weeks depending on HCV-RNA at
W4
Primary end-point SVR
27
AASLD 2005, A849, A. Anfriulli et al., Italy
SVR rates
90
Plt0.0001
80
70
60
50
85
40
62
30
20
10
0
RVR
RVR-
28
AASLD 2005, A849, A. Anfriulli et al., Italy
SVR rates
90
P0.004
80
70
60
50
82
40
67
30
20
10
0
mild fibrosis
bridging fibrosis
29
AASLD 2005, A849, A. Anfriulli et al., Italy
30
AASLD 2005, A849, A. Anfriulli et al., Italy
SVR rates
100
P0.05
80
60
81
40
73
20
0
HCV-2
HCV-3
31
AASLD 2005, A849, A. Anfriulli et al., Italy
SVR rates
100
P0.05
80
60
80
40
67
20
0
low viremia
high viremia
32
AASLD 2005, A849, A. Anfriulli et al., Italy

• - Logistic regression model, independent
  predictors of SVR
• RVR
• mild fibrosis
• HCV-2
• Independent predictors of RVR
• absence of severe fibrosis
• INDEPENDENT OF VIRAL LOAD
• Independent predictors of relapse
• severe fibrosis
• low ALT

33
Short duration therapeutic schedules and
predictive factors of SVR for genotype 1
34
New results from 24 weeks of weight adjusted
peginterferon a-2b ribavirin therapy in
genotype 1 low viral load patients
35
Background

• Previous 48 week treatment studies suggest that
  low viral load genotype 1 patients have high
  sustained virologic response rates (SVR) similar
  to that reported in genotype 2/3 patients
• Recent data demonstrated that genotype 2/3
  patients respond similarly with 24 weeks of
  therapy as historical 48-week treated controls
• No similar data exist for low viral load genotype
  1 patients

Zeuzem S. et al, DDW2005, Abstract S1542 J.
Hepatol in press (november 2005)
36
Study Design
PEG-IFN ?-2b 1.5 ?g/kg QW ribavirin 800-1,400
mg/day, N235
24 weeks Treatment
24 weeks Follow-up
Analysis
Historical control 48 weeks PEG-IFN ?-2b 1.5
?g/kg QW ribavirin 800 mg/day, N38
48 weeks Treatment
24 weeks Follow-up
Primary Endpoint SVR
Zeuzem S. et al, DDW2005, Abstract S1542.
Zeuzem S. et al, DDW2005, Abstract S1542 J.
Hepatol in press (november 2005)
37
Methods

• Naïve low viral load genotype 1 patients (
  600.000 IU/mL)
• Plasma HCV-RNA was determined at treatment weeks
  4, 12, 24 and follow-up weeks 12 and 24 using
  quantitative Taqman assay (sensitivity 29 IU/ml).
  
• Genotype was determined by sequencing the PCR
  product. 

Zeuzem S. et al, DDW2005, Abstract S1542.
Zeuzem S. et al, DDW2005, Abstract S1542 J.
Hepatol in press (november 2005)
38
End of Treatment and Sustained Virologic Response
Rates, 24 vs 48 Weeks of Tx
24 Weeks Tx
48 Weeks Historical Control
100
80
80
50
60
of Patients
40
20
0
EOT
SVR
Zeuzem S. et al, DDW2005, Abstract S1542.
Zeuzem S. et al, DDW2005, Abstract S1542 J.
Hepatol in press (november 2005)
39
Relapse Rate, 24 vs 48 Weeks of Tx
Zeuzem S. et al, DDW2005, Abstract S1542.
Zeuzem S. et al, DDW2005, Abstract S1542 J.
Hepatol in press (november 2005)
40
Percentage of Patients HCV RNA Negative by Time,
24 Weeks Tx
Zeuzem S. et al, DDW2005, Abstract S1542.
Zeuzem S. et al, DDW2005, Abstract S1542 J.
Hepatol in press (november 2005)
41
Sustained Virologic Response Rates by Time to HCV
RNA Negativity24 vs 48 Weeks of Tx
24 Weeks Tx.
48 Weeks Historical Control
Zeuzem S. et al, DDW2005, Abstract S1542.
Zeuzem S. et al, DDW2005, Abstract S1542 J.
Hepatol in press (november 2005)
42
SVR in patients who achieved HCV-RNA Negativity
at week-4 and week-24
HCV RNA ve at Wk 4 24
PegIntron, Summary of Product Characteristics
43
SVR in patients who achieved HCV-RNA Negativity
at week-4 and week-24
7
week 48 (SVR)
PegIntron, Summary of Product Characteristics
44
Discontinuation and dose reductions for adverse
events
Zeuzem S. et al, DDW2005, Abstract S1542.
Zeuzem S. et al, DDW2005, Abstract S1542 J.
Hepatol in press (november 2005)
45
Conclusion

• Overall, 24 week treatment with PEGINTRON 1.5
  µg/kg/week plus ribavirin 800-1400 mg/day in low
  viral load genotype 1 patients achieves similar
  EOT response, but lower SVR compared to a 48-week
  treated historical control
• For patients who become HCV RNA negative at
  week-4, treatment for 24 weeks has SIMILAR HIGH
  EFFICACY compared to 48 week therapy
• Discontinuation and dose reductions for adverse
  events were lower with 24 weeks treatment (3,
  25) than the historical control (14, 49).

Zeuzem S. et al, DDW2005, Abstract S1542.
Zeuzem S. et al, DDW2005, Abstract S1542 J.
Hepatol in press (november 2005)
46
New Approved Labeling for PegIntron in the EU

• Therapy with Pegylated Interferon alfa-2b is now
  approved for a 24 week treatment course in
  genotype 1 low viral load (lt 600, 000 IU/ml)
  patients who become HCV RNA negative at treatment
  week 4 and remain HCV RNA negative at week 24

47
Conclusion

• Short duration therapy combining PEGINTRON and
  Rebetol can be shortened to 12 weeks for
  genotypes 2 and 3, and 24 weeks for genotype 1
• ONLY for patients who are HCV-RNA negative at W4