Transcript Advances in the treatment of chronic hepatitis C: Update to the Committee PEG-Intron/Rebetol

PEG-Intron/Rebetol
Advances in the treatment of
chronic hepatitis C:
Update to the Committee
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PEG-Intron/Rebetol
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Treating chronic hepatitis C
10 years of progress
% Sustained vriologic response
100
80
61%
52%
60
41%
40
16%
20
0
25%
6%
Intron A
24 weeks
1991
Intron A
48 weeks
PEG-Intron
Intron A +
Rebetol
PEG-Intron PEG-Intron
+ Rebetol
+ Rebetol
>10.6 mg/kg
2001
PEG-Intron/Rebetol
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Advancements in the treatment of
chronic hepatitis C
Participant Introduction
Dr. Penelope J. Giles
Dr. Janice K. Albrecht
Director, Regulatory Affairs
Vice President, Clinical Research
Schering-Plough Team
Dr. J.J. Garaud
Dr. Kenneth Koury
Dr. Mark Laughlin
Exec. V.P., Clinical Research
Director, Biostatistics
Director, Clinical Pharmacology
Consultants
Dr. J. McHutchison
Dr. L.J. Wei
Medical Director, Liver Transplantation, Scripps Clinic
Professor, Biostatistics, Harvard School of Public Health
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Indication: Chronic Hepatitis C
(Treatment Naïve Adults)
Approved Dose
PEG-Intron 1.5g/kg Once Weekly
plus
Rebetol 800mg/day
48 Weeks
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Treatment chronic hepatitis C
Information provided to the committee
 Intron A + Rebetol
• Treatment of Relapse Patients
• NEJM 1998, Davis et al
• Treatment of Naïve Patients
• NEJM 1998, McHutchison et al
• Lancet 1998, Poynard et al
 PEG-Intron Monotherapy
• Treatment of Naïve Patients
• Hepatology 2001, Lindsay et al
 PEG-Intron + Rebetol
• Treatment of Naïve Patients
• Lancet 2001, Manns et al
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The PEG-Intron molecule
PEG-Interferon alfa-2b 1.5 μg/kg
pg/ml interferon α-2b
Interferon alfa-2b 3MIU
1000
T½ 40 hours
100
10
1
0
20 40 60 80 100 120 140 160 180
Hours
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Intron A 3MU TIW
Sustained virologic response by patient weight
% Sustained vriologic
response
40
30
25%
19%
20
12%
9%
10
0
<55kg
(n=40)
55-75kg
(n=300)
75-95kg
(n=334)
Patient weight
Intron A 3 MU TIW 48 weeks
>95kg
(n=132)
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PEG-Intron monotherapy
study design
Screening
Endpoint
PEG 0.5g/kg QW
N= 315
PEG 1.0g/kg QW
N= 297
PEG 1.5g/kg QW
N= 304
Intron-A 3MIU TIW
N= 303
48 weeks
24 weeks
Follow-up
Primary Endpoint: Loss of serum HCV-RNA 24 weeks post-treatment
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PEG-Intron monotherapy
virologic response
% patients HCV negative*
Intron A
PEG 0.5
PEG 1.0
PEG 1.5
60
49%
41%
33%
24%
50
40
30
20
10
0
0
4
12
24
Treatment week
*HCV <100 copies/ml
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EOT
FU24
10
PEG-Intron monotherapy
virologic response
% patients HCV negative*
Intron A
PEG 0.5
PEG 1.0
PEG 1.5
60
50
40
25%
23%
18%
12%
30
20
10
0
0
4
12
24
Treatment week
*HCV <100 copies/ml
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EOT
FU24
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PEG-Intron monotherapy
Factors Associated with
Sustained Virologic Response*

HCV
Genotype - Non-1*

HCV-RNA
level - Lower*

Cirrhosis
or bridging fibrosis - Absence**

Age
- Younger ***
X
Body
weight - Lighter (p=0.9336)
*
Multivariate logistic regression, n=914
* p0.0001
** p<0.006
*** p<0.05
PEG-Intron/Rebetol
PEG-Intron dose selection
 PEG-Intron doses selected for use in
combination with Rebetol
• 1.5 g/kg - had maximum antiviral activity
particularly in HCV-1
• 0.5 g/kg - had similar antiviral activity to
Intron A and was better tolerated
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PEG-Intron/Rebetol
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PEG-Intron plus Rebetol
Intron A + Rebetol 1000-1200mg/daily
3MIU TIW (48 wks)
Screening
N=505
PEG-Intron + Rebetol 1000-1200mg/daily
1.5 g/kg QW (4 wks)
0.5 g/kg QW (44 wks)
N=514
PEG-Intron + Rebetol 800mg/daily
1.5 g/kg QW (48 weeks)
Endpoint
Follow-up
48 weeks
N=511
24 weeks
Primary Endpoint: Loss of serum HCV-RNA 24 weeks post-treatment
PEG-Intron/Rebetol
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Demographics
Intron A/R
(n=505)
PEG 0.5/R
(n=514)
PEG 1.5/R
(n=511)
Age
43
44
43
22-68
22-67
22-68
63%
67%
67%
91%
88%
89%
Mean
82
83
82
Range
43-163
38-181
43-159
Mean (yrs.)
Range
Gender
Male
Race
Caucasian
Weight (kg)
PEG-Intron/Rebetol
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Disease Characteristics
Intron A/R
(n=505)
PEG 0.5/R
(n=514)
PEG 1.5/R
(n=511)
HCV genotype
Geno 1
68%
68%
68%
Geno 2/3
29%
30%
29%
3%
2%
3%
69%
67%
68%
28%
30%
29%
Geno 4/5/6
HCV RNA copies/ml
>2 million
Fibrosis/Cirrhosis*
Present
* Knodell HAI F3/4
PEG-Intron/Rebetol
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% Sustained virologic response
Sustained Virologic Response
52% *
60
46%
46%
40
20
0
Intron A + Rebetol
1,000-1,200 mg
PEG 0.5 + Rebetol
1,000-1,200 mg
PEG 1.5 + Rebetol
800 mg
* PEG 1.5/800 vs. I/R p=0.03
PEG-Intron/Rebetol
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% Sustained virologic response
Sustained Virologic Response
54% *
60
47%
47%
40
20
0
Intron A + Rebetol
1,000-1,200 mg
PEG 0.5 + Rebetol
1,000-1,200 mg
PEG 1.5 + Rebetol
800 mg
* PEG 1.5/800 vs. I/R p=0.01
PEG-Intron/Rebetol
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Variables associated with sustained
response logistic regression analysis
Univariate
Multivariate


Genotype
•



lighter

absence
Lower
lighter
Bridging fibrosis/cirrhosis*
•
•
lower
Baseline Weight**
•
Age*
•

non-1*
Baseline HCV level*
•
Bridging fibrosis/cirrhosis*
•

lower
Baseline Weight*
•

•
Baseline HCV level*
•

non-1*
Genotype
Absence
Age**
•
Lower
Gender**
•
Female
*p 0.001 **p=0.01
*p 0.001 **p<0.05
PEG-Intron/Rebetol
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Effect of Rebetol dose mg/kg on virologic response
(Logistic regression analysis)
% Sustained virologic
response
100%
Rebetol 10.6 mg/kg
PEG 1.5 g/kg
80%
60%
Intron-A 3MU TIW
40%
20%
0%
5
7
9
11
13
15
17
Rebetol mg/kg
19
21
23
25
27
PEG-Intron/Rebetol
20
All genotypes
% Sustained virologic response
Sustained virologic response
Controlling for Rebetol dose (mg/kg)
80%
60%
61%
*
54%
50%
47%
47%
I/R
PEG 1.5/R
40%
27%
n=511
n=323
n=188
20%
n=505
0%
All
n=22
10.6mg/kg
n=483
>10.6mg/kg
Rebetol dose/weight (mg/kg)
*p=0.01
PEG-Intron/Rebetol
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HCV-1
% Sustained virologic response
Sustained virologic response
Controlling for Rebetol dose (mg/kg)
60%
48%
42% *
40%
38%
33%
34%
I/R
PEG 1.5/R
24%
20%
n=348
n=343
0%
All
n=226
n=15
10.6mg/kg
n=122
n=328
>10.6mg/kg
Rebetol dose/weight (mg/kg)
*p=0.02
PEG-Intron/Rebetol
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HCV-2/3
Sustained virologic response
Controlling for Rebetol dose (mg/kg)
% Sustained virologic response
100%
82%
79% 82%
88%
81%
80%
60%
40%
20%
50%
n=147
n=146
0%
All
n=89
n=6
10.6mg/kg
n=58
n=140
>10.6mg/kg
Rebetol dose/weight (mg/kg)
I/R
PEG 1.5/R
PEG-Intron/Rebetol
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Sustained virologic response
Controlling for Rebetol dose (mg/kg)
Intron A
Rebetol
PEG-Intron 1.5 g/kg
Rebetol 800mg
PEG-Intron 1.5 g/kg
Rebetol (mg/kg)
10.6
>10.6
HCV-1
 2 million
45%
73%
74%
71%
> 2 million
29%
30%
27%
37%
 2 million
80%
91%
89%
94%
> 2 million
77%
76%
74%
81%
HCV-2/3
PEG-Intron/Rebetol
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Relapse
Controlling for Rebetol dose and genotype
Intron/
R1000-1200
PEG 1.5/
R800
PEG 1.5/
R 10.6
PEG 1.5/
R >10.6
All patients
14%
18%
22%
12%
Genotype 1
21%
24%
28%
17%
Genotype 2/3
7%
11%
14%
7%
PEG-Intron/Rebetol
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Efficacy summary
 PEG-Intron 1.5 g/kg/Rebetol is significantly more
effective than Intron A/Rebetol and
PEG-Intron 0.5 g/kg /Rebetol
• Approved Regimen: 48 weeks of treatment
 PEG-Intron 1.5g/kg once weekly
plus
 Rebetol 800mg/day
 Further analyses suggest that weight based dosing of
ribavirin (mg/kg) results in improved sustained
virologic response
PEG-Intron/Rebetol
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PEG-Intron/Rebetol
Safety
PEG-Intron/Rebetol
27
Adverse events
Incidence >10% difference between groups
Intron/R
N=505
Application site
Injection site inflammation
Injection site reaction
Body as a whole
Fever
Rigors
Weight decrease
GI side effects
Nausea
Skin
Alopecia
PEG 1.5/R
800 mg
N=511
PEG 1.5/R
<10.6 mg/kg
N=323
PEG 1.5/R
>10.6 mg/kg
N=188
18%
36%
25%
58%
28%
61%
20%
54%
33%
41%
20%
46%
48%
29%
49%
51%
28%
41%
43%
30%
33%
43%
44%
43%
32%
36%
31%
45%
Incidence  10% in any treatment group:
Injection site inflammation, Injection site reaction , mouth dry, sweating, Asthenia,
fatigue, fever, headache, flu-like symptoms, rigors, RUQ pain, weight decrease, dizziness,
abdominal pain, anorexia, diarrhea, nausea, vomiting, arthralgia, musculoskeletal pain,
myalgia, anxiety, concentration impaired, depression, emotional liability, insomnia,
irritability, infection viral, coughing, dyspnea, pharyngitis, alopecia, pruritis, rash, dry skin
PEG-Intron/Rebetol
28
Discontinuations and dose modifications
due to adverse events
Intron/R
N=505
PEG 1.5/R
800 mg
N=511
PEG 1.5/R
PEG 1.5/R
<10.6 mg/kg >10.6 mg/kg
N=323
N=188
Discontinuations
13%
14%
15%
14%
Dose Modifications
34%
42%
38%
49%
PEG-Intron/Rebetol
29
Dose modification
>2% difference between groups
Intron/R
N=505
PEG 1.5/R
800 mg
N=511
PEG 1.5/R
PEG 1.5/R
<10.6 mg/kg >10.6 mg/kg
N=323
N=188
Neutropenia
8%
18%
16%
21%
Anemia
13%
9%
7%
12%
Platelet
1%
3%
4%
2%
Body as a Whole
6%
9%
9%
10%
Gastrointestinal
4%
7%
6%
9%
Psychiatric Events
4%
5%
4%
6%
PEG-Intron/Rebetol
30
Adverse hematologic effects
Neutrophils
Intron /R
Neutrophils
109/L
N=505
PEG 1.5/R
800 mg
N=511
PEG 1.5/R
PEG 1.5/R
<10.6 mg/kg >10.6 mg/kg
N=323
N=188
% Patients with
<750 at any time
8%
18%
17%
21%
% Patients with
<500 at any time
2%
4%
3%
7%
Discontinued
for Neutropenia
0.2%
1%
0.3%
2%
(1)*
(5)
(1)
(4)
*Number of patients
PEG-Intron/Rebetol
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Adverse hematologic effects
Hemoglobin
Intron /R
N=505
PEG 1.5/R
800 mg
N=511
PEG 1.5/R
PEG 1.5/R
<10.6 mg/kg >10.6 mg/kg
N=323
N=188
Decrease below
10g Hemoglobin
12%
9%
6%
14%
Discontinued
for Anemia
0.2%
0.8%
0%
2%
(1)*
(4)
(0)
(4)
*Number of patients
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Safety Summary

The types of adverse events observed in the I/R and PEG 1.5/R groups
are similar, but there is a somewhat higher incidence with PEG1.5/R

Neutropenia (<750) was more frequent with PEG 1.5/R than with I/R for
both the fixed-dose and weight-based dose analyses

With weight-based Rebetol >10.6 mg/kg there was an increased
occurrence of anemia and neutropenia than with PEG 1.5/800

Discontinuations due to adverse events were low and similar between the
groups; dose modifications due to the adverse events were more frequent
with PEG 1.5/R

The higher incidence of AE’s associated with PEG 1.5/R for either fixeddose or weight-based Rebetol were adequately managed by dose
modifications
PEG-Intron/Rebetol
Post-marketing studies
 Study 1-(n~4000) PEG1.5g/kg QW
• Rebetol 800mg vs. weight-based dosing (800 to 1400mg)
• (n~1000) evaluate effect of duration (6 vs.12 months) for
patients with favorable prognostic factors
 Study 2-(n~1500)
• PEG1.5g/kg vs. PEG1.0g/kg
• Rebetol dose regimen determined from study 1
• Evaluate effect of therapy in African Americans (n~100)
 PK food effect of ribavirin (fasted vs. low fat vs. high fat)
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34
Dr. J. McHutchison
Medical Director, Liver Transplantation,
Scripps Clinic, La Jolla, California
35
The Decision to Treat Hepatitis C
 Complex
 Controversial
 Host
 Severity disease
 Co-morbid conditions
 Viral
 Genotype
 Therapy
 Efficacy
 Side effects
 Cost
36
Weighing the Risks and Benefits
Likelihood of response
side effects
investments
Sustained response
ALT normal
HCV RNA neg
Histologic improvement
Improved HQOL
Durable
37
Decision to Treat
 Majority hepatitis C patients
 Unfavorable profile
 Genotype 1
 Significant investment and
commitment
 Time (48 weeks)
 More “aggressive” therapy
 Patient
 Doctor
 Other Staff
38
Decision to Treat Hepatitis C
 Practitioner and patients
 “Do our best first time around”
39
How can we achieve the greatest benefit
whilst diminishing the risk?
Provide best
support/education
available
Prescribe most
effective dose of
peginterferon
Provide most
appropriate dose
of ribavirin
Manage side effects
via dose reduction
rather than
discontinuation
Discontinue
treatment early in
those unlikely to
respond