1 advances in the treatment of chronic hepatitis c: update to the committee...
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1
Advances in the treatment of chronic hepatitis C:
Update to the Committee
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
2
Treating chronic hepatitis C10 years of progress
0
20
40
60
80
100
% S
ust
ain
ed
vri
olo
gic
res
po
nse
PEG-Intron+ Rebetol
>10.6 mg/kg
61%
PEG-Intron+ Rebetol
52%
Intron A +Rebetol
41%
PEG-Intron
25%
Intron A24 weeks
Intron A48 weeks
6%16%
1991 2001
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
3
Advancements in the treatment of chronic hepatitis C Participant Introduction
Schering-Plough TeamDr. J.J. Garaud Exec. V.P., Clinical ResearchDr. Kenneth Koury Director, BiostatisticsDr. Mark Laughlin Director, Clinical Pharmacology
Dr. Penelope J. Giles Director, Regulatory AffairsDr. Janice K. Albrecht Vice President, Clinical Research
ConsultantsDr. J. McHutchison Medical Director, Liver Transplantation, Scripps ClinicDr. L.J. Wei Professor, Biostatistics, Harvard School of Public Health
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
4
Indication: Chronic Hepatitis C(Treatment Naïve Adults)
Approved Dose
PEG-Intron 1.5g/kg Once Weekly
plus
Rebetol 800mg/day
48 Weeks
5
Treatment chronic hepatitis CInformation 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
Hours
0 20 40 60 80 100 120 140 160 180
pg
/ml
inte
rfer
on
α-2
b
1
10
100
1000
Interferon alfa-2b 3MIU
PEG-Interferon alfa-2b 1.5 μg/kg
T½ 40 hours
7
Intron A 3MU TIWSustained virologic response by patient weight
0
10
20
30
40
% S
us
tain
ed
vri
olo
gic
re
sp
on
se
<55kg (n=40)
55-75kg(n=300)
75-95kg(n=334)
>95kg(n=132)
Patient weight
9%12%
19%
25%
Intron A 3 MU TIW 48 weeks
8
PEG-Intron monotherapystudy design
Primary Endpoint: Loss of serum HCV-RNA 24 weeks post-treatment
48 weeks 24 weeksEndpoint
Follow-up
Screening
PEG 0.5g/kg QW N= 315
PEG 1.0g/kg QW N= 297
PEG 1.5g/kg QW N= 304
Intron-A 3MIU TIW N= 303
9
PEG-Intron monotherapyvirologic response
0
10
20
30
40
50
60
0 4 12 24 36 EOT FU24
Treatment week
% p
atie
nts
HC
V n
egat
ive*
Intron A PEG 0.5 PEG 1.0 PEG 1.5
49%41%
33%24%
*HCV <100 copies/ml
10
PEG-Intron monotherapyvirologic response
0
10
20
30
40
50
60
0 4 12 24 36 EOT FU24
Treatment week
% p
atie
nts
HC
V n
egat
ive*
Intron A PEG 0.5 PEG 1.0 PEG 1.5
25%23%18%12%
*HCV <100 copies/ml
11
PEG-Intron monotherapyFactors Associated with
Sustained Virologic Response*
HCV Genotype - Non-1*
HCV-RNA level - Lower*Cirrhosis or bridging fibrosis - Absence**Age - Younger ***
Body weight - Lighter (p=0.9336)
* Multivariate logistic regression, n=914
* p0.0001** p<0.006*** p<0.05
X
12
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
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
13
PEG-Intron plus Rebetol
PEG-Intron + Rebetol 1000-1200mg/daily
0.5 g/kg QW (44 wks)1.5 g/kg QW (4 wks) N=514
PEG-Intron + Rebetol 800mg/daily
N=5111.5 g/kg QW (48 weeks)
Screening
Intron A + Rebetol 1000-1200mg/daily
N=5053MIU TIW (48 wks)
Endpoint
Follow-up
48 weeks 24 weeks
Primary Endpoint: Loss of serum HCV-RNA 24 weeks post-treatment
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
14
Demographics
Age
Gender
Race
Weight (kg)
828382Mean
434443Mean (yrs.)
67%67%63%Male
89%88%91%Caucasian
43-163 38-181 43-159Range
22-68 22-67 22-68Range
Intron A/R(n=505)
PEG 0.5/R (n=514)PEG 1.5/R (n=511)
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
15
Disease Characteristics
HCV RNA copies/ml
HCV genotype
Fibrosis/Cirrhosis*
* Knodell HAI F3/4
29%30%29%Geno 2/3
68%68%68%Geno 1
68%67%69%>2 million
29%30%28%Present
Geno 4/5/6 3% 2% 3%
Intron A/R(n=505)
PEG 0.5/R (n=514)PEG 1.5/R (n=511)
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
16
Sustained Virologic Response
0
20
40
60
% S
us
tain
ed
vir
olo
gic
re
sp
on
se
Intron A + Rebetol1,000-1,200 mg
PEG 0.5 + Rebetol1,000-1,200 mg
PEG 1.5 + Rebetol800 mg
52%46%46%
* PEG 1.5/800 vs. I/R p=0.03
*
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
17
Sustained Virologic Response
0
20
40
60
% S
us
tain
ed
vir
olo
gic
re
sp
on
se
Intron A + Rebetol1,000-1,200 mg
PEG 0.5 + Rebetol1,000-1,200 mg
PEG 1.5 + Rebetol800 mg
54%47%47%
* PEG 1.5/800 vs. I/R p=0.01
*
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
18
Variables associated with sustained response logistic regression analysis
Univariate Genotype
• non-1*
Baseline HCV level*
• lower
Baseline Weight*
• lighter
Bridging fibrosis/cirrhosis*
• absence
Age*
• Lower
Gender**
• Female*p 0.001 **p=0.01
Multivariate Genotype
• non-1*
Baseline HCV level*
• lower
Baseline Weight**
• lighter
Bridging fibrosis/cirrhosis*
• Absence
• Age**
• Lower
*p 0.001 **p<0.05
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
19
Effect of Rebetol dose mg/kg on virologic response(Logistic regression analysis)
Rebetol mg/kg
0%
20%
40%
60%
80%
100%
% S
ust
ain
ed v
iro
log
ic
resp
on
se
5 7 9 11 13 15 17 19 21 23 25 27
PEG 1.5 g/kg
Intron-A 3MU TIW
Rebetol 10.6 mg/kg
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
20
All genotypesSustained virologic response
Controlling for Rebetol dose (mg/kg)
*p=0.01Rebetol dose/weight (mg/kg)
47%54%
27%
50% 47%
61%
0%
20%
40%
60%
80%
% S
us
tain
ed
vir
olo
gic
re
sp
on
se
All 10.6mg/kg >10.6mg/kg
I/R
PEG 1.5/R
*
n=505n=505
n=511n=511
n=22n=22
n=323n=323
n=483n=483
n=188n=188
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
21
HCV-1Sustained virologic response
Controlling for Rebetol dose (mg/kg)
*p=0.02
33%
42%
24%
38%34%
48%
0%
20%
40%
60%
% S
us
tain
ed
vir
olo
gic
re
sp
on
se
All 10.6mg/kg >10.6mg/kg
I/R
PEG 1.5/R
*
n=343n=343
n=348n=348
n=15n=15
n=226n=226
n=328n=328
n=122n=122
Rebetol dose/weight (mg/kg)
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
22
HCV-2/3Sustained virologic response
Controlling for Rebetol dose (mg/kg)
Rebetol dose/weight (mg/kg)
79% 82%
50%
82% 81%88%
0%
20%
40%
60%
80%
100%
% S
us
tain
ed
vir
olo
gic
re
sp
on
se
All 10.6mg/kg >10.6mg/kg
I/R
PEG 1.5/R
n=146n=146
n=147n=147
n=6n=6
n=89n=89
n=140n=140
n=58n=58
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
23
Sustained virologic response Controlling for Rebetol dose (mg/kg)
Intron ARebetol
PEG-Intron 1.5 g/kgRebetol 800mg
PEG-Intron 1.5 g/kgRebetol (mg/kg)
10.6 >10.6
2 million
> 2 million
HCV-1
HCV-2/3
80%
77% 74%
89%
81%
94%
76%
91%
2 million
> 2 million
45%
29%
74%
27%
71%
37%
73%
30%
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
24
RelapseControlling for Rebetol dose and genotype
Genotype 2/3
Genotype 1 21% 28% 17%
7% 14% 7%11%
24%
Intron/ PEG 1.5/ PEG 1.5/ PEG 1.5/ R1000-1200 R800 R 10.6 R >10.6
All patients 14% 22% 12%18%
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
25
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 1.5g/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/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
26
PEG-Intron/Rebetol Safety
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
27
Adverse eventsIncidence >10% difference between groups
Application site Injection site inflammation 18% 25% 28% 20% Injection site reaction 36% 58% 61% 54%Body as a whole Fever 33% 46% 49% 41% Rigors 41% 48% 51% 43% Weight decrease 20% 29% 28% 30%GI side effects Nausea 33% 43% 44% 43%Skin Alopecia 32% 36% 31% 45%
PEG 1.5/R<10.6 mg/kg
N=323
PEG 1.5/R>10.6 mg/kg
N=188
Intron/R
N=505
PEG 1.5/R800 mgN=511
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
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
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Discontinuations and dose modificationsdue to adverse events
Dose Modifications
Discontinuations 13% 15% 14%
34% 38% 49%42%
14%
PEG 1.5/R<10.6 mg/kg
N=323
PEG 1.5/R>10.6 mg/kg
N=188
Intron/R
N=505
PEG 1.5/R800 mgN=511
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
29
Dose modification>2% difference between groups
PEG 1.5/R<10.6 mg/kg
N=323
PEG 1.5/R>10.6 mg/kg
N=188
Intron/R
N=505
8% 18% 16% 21%
13% 9% 7% 12%
1% 3% 4% 2%
6% 9% 9% 10%
4% 7% 6% 9%
Neutropenia
Anemia
Platelet
Body as a Whole
Gastrointestinal
PEG 1.5/R800 mgN=511
Psychiatric Events 4% 5% 4% 6%
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
30
Adverse hematologic effects Neutrophils
Discontinued for Neutropenia
% Patients with<500 at any time
8% 18% 17% 21%
2% 4% 3% 7%
0.2% 1% 0.3% 2%
(1)* (5) (1) (4)
% Patients with <750 at any time
Neutrophils 109/L
PEG 1.5/R<10.6 mg/kg
N=323
PEG 1.5/R>10.6 mg/kg
N=188
Intron /R
N=505
PEG 1.5/R800 mgN=511
*Number of patients
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
31
Adverse hematologic effects Hemoglobin
Decrease below10g Hemoglobin
Discontinuedfor Anemia
12% 9% 6% 14%
0.2% 0.8% 0% 2%
(1)* (4) (0) (4)
PEG 1.5/R<10.6 mg/kg
N=323
PEG 1.5/R>10.6 mg/kg
N=188
Intron /R
N=505
PEG 1.5/R800 mgN=511
*Number of patients
PEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
32
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 fixed-dose or weight-based Rebetol were adequately managed by dose modifications
33
Study 1-(n~4000) PEG1.5g/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)
• PEG1.5g/kg vs. PEG1.0g/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)
Post-marketing studiesPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/RebetolPEG-Intron/Rebetol
34
Dr. J. McHutchison
Medical Director, Liver Transplantation, Scripps Clinic, La Jolla, California
35
The Decision to Treat Hepatitis C
ComplexComplexControversialControversialHostHost
Severity diseaseSeverity diseaseCo-morbid conditionsCo-morbid conditions
ViralViralGenotype Genotype
TherapyTherapyEfficacyEfficacySide effectsSide effectsCostCost
36
Weighing the Risks and BenefitsWeighing the Risks and Benefits
Likelihood of responseside effectsside effectsinvestmentsinvestments
Sustained responseSustained responseALT normalALT normalHCV RNA negHCV RNA negHistologic improvementHistologic improvementImproved HQOLImproved HQOLDurable Durable
37
Decision to TreatDecision to Treat
Majority hepatitis C patientsMajority hepatitis C patientsUnfavorable profileUnfavorable profileGenotype 1Genotype 1
Significant investment and Significant investment and commitmentcommitmentTime (48 weeks)Time (48 weeks)More “aggressive” therapyMore “aggressive” therapyPatientPatientDoctorDoctorOther StaffOther Staff
38
Decision to Treat Hepatitis C
Practitioner and patientsPractitioner and patients““Do our best first time around”Do our best first time around”
39
How can we achieve the greatest benefit How can we achieve the greatest benefit whilst diminishing the risk?whilst diminishing the risk?
Provide best support/education
availablePrescribe 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