Transcript PPT - ACoP

Inception of an HCV Platform Model for IL-28B Genotype
Treatment Duration Optimization and Cure Rate Maximization
1Hui
1Bristol-Myers
INTRODUCTION (CDC 2002)

2.7 million infected with chronic hepatitis C (CHC) in the
United States

Peginterferon α-2a (PEG-IFN; weekly subcutaneous
injection) + ribavirin (RBV; twice daily oral) given for up
to 52 weeks is the current standard-of-care treatment for
CHC

Treatment success based on treatment duration,
adverse events, host and viral genotypes

Effective therapy is sustained virologic response (SVR,
undetectable HCV RNA at 24 weeks post treatment)
and occurs in 40-50% viral genotypes 1 and 4, and 7080% for genotypes 2 and 3 treated
Squibb, Princeton, NJ, USA 2Quantitative Solutions, Inc., Menlo Park, CA, USA
METHODS (continued)
RESULTS (continued)
Figure 2: HCV Quantitative Framework
Table 2: Roche VK model simulations of SVR
with/without dropouts
Exposure-vs.Response
Clinical Trial
Simulation
HCV
Unified Platform
dT
 s  d  T   V  T
dt
dI
  V  T    I
dt
dV
 (1-  )  p  I  c V
dt
The inception of an HCV disease-model platform based
on a viral kinetic model for PEG-IFN+RBV, using
individual data and bridging to new situations with
published summary data to project SVR for different
treatment scenarios. This approach provides a
quantitative framework for HCV drug development
thereby complementing the FDA AIMS initiative.
Semi-mechanistic model
(Snoeck, et. al)


By using VK and clinical outcomes from 5,500 CHC patients in a
clinical database
12 weeks
CC
SVR with
dropouts
43% [37-53]
25% [11-42]
74% [66-81]
43% [30-58]
50% [44-59]
57% [48-69]
55% [46-64]
44% [29-56]
ε
= DosePEG-IFN/(ED50PEG-IFN+DosePEG-IFN)

Longer duration appear to provide no better benefit
ρ
= DoseRBV/(ED50RBV+DoseRBV)

Shorter durations are anticipated to have much lower SVR

Dose reductions were not incorporated

CC genotype as 100% increase in infected cell death rate (Thompson 2010)

SVR not adjusted for other factors (baseline viral load, degree of fibrosis, race,
gender, etc.)
93%
received 24 weeks of treatment or more
61%
received 48 weeks of treatment or more
47%
received PEG-IFN monotherapy
RESULTS
53%
received PEG-IFN+RBV combotherapy
Figure 1: VK model simulations of SVR without dropouts
Figure 3: Range of SVR responses in the clinical
database
Compare SVR projections vs. literature values
Figure 1: Integrated disease-model platform for HCV
EOT
0
4
8
12
20
28
36
44
52
20
0
0
60
Ribavirin
68
48
72
EOT
0
4
8
12
20
28
36
44
52
60
68
Table 3: Comparison of SVR from the Roche model with
SVR from clinical database
Time (wk)
DAA
Each scenario utilizes 100 simulated trials, each trial with 100 subjects. Trials use model parameters
sampled over parameter uncertainty. Band represent 5th to 95th percentile confidence interval. The
center line represents the median prediction. EOT is end of treatment.
Figure 2: Dropout rates from the literature database for
various PEG-IFN treatment durations
Virus Genotype
24
T ime (week)
Time (wk)
Drug(s)
SVR (%)
40
60
80
60
40
Dropout rates
20

0
Virus genotypes (1&4/2&3)
% Patients with Undetectable HCV RNA

80
Host genotypes (CC/non-CC), which represent SNPs variations on chromosome
19
60

40
Treatment durations
20

PEGASYS 180ug, G2/3, 48wk Treatment Duration + 24 wk Followup
100
100
PEGASYS 180ug, G1/4, 48wk Treatment Duration + 24 wk Followup
80
100
Pegasys,
180180mg,
µg, GTP GT
1/4 P 1/4
Pegasys,
Perform SVR outcome projections, using R, for different:
Interferons
1,4
1,4
2,3
2,3
CC
CC
CC
Dropout
rate
25%
12%
12%
8%
25%
12%
8%
5%
to 24 weeks of treatment appears to be the optimal
duration for CC genotype
Drug effects described by Emax model
0

48 weeks
24 weeks
24 weeks
16 weeks
48 weeks
24 weeks
16 weeks
SVR without
dropouts
58% [37-70]
29% [11-48]
84% [66-92]
47% [33-63]
67% [58-79]
65% [54-79]
59% [50-69]
46% [30-59]
 16
% Patients with Undetectable HCV RNA

Genotype
GT 1&4 patients may require a longer duration to
achieve SVR
Model assumptions:
Implement the published Roche viral kinetic (VK) model:

Duration
 Some
METHODS

Predictors of
Response
Literature
Database
OBJECTIVE

Phyllis Chan, PhD
Route 206 & Province Line Road
P.O. Box 5400, Princeton, N.J. 08543-5400
[email protected]
Min Chan, PhD, 1Xiaodong Wang, PhD, 2Nelson Jumbe, PhD, 2Russell Wada, PhD,
1Alaa Ahmad, PhD, and 1Vikram Kansra, PhD
Treatment
Duration
48 weeks
24 weeks
# Arms
18
5
Observed
Total N
Range
14-79%
2924
13-59%
495
Weighted
Modeled SVR
Mean
48%
43% [37-53]
33%
25% [11-42]
 SVR

Roche VK model assumes PEG-IFN dose-dependently
inhibits the production of virions
dT
 s  d  T   V  T
dt
dI
  V  T    I
dt
dV
 (1 -  )  p  I  c  V
dt

Pegasys,
180mg
Pegasys,
180
ug
Infected
Hepatocyte
Discontinuations on Treatment (%)
0 10 20 30 40 50 60
Host Genotype
VK model assumes RBV dose-dependently renders a
fraction of newly produced virions non-infectious
V  VI  VNI
dT
 s  d  T    VI  T
dt
dI
   VI  T    I
dt
dVI
 (1 -  )  (1  ε )  p  I  c  VI
dt
dVNI
   ( 1   )  p  I  c  VNI
dt
predictions of the implemented model with dropout
agrees with observed SVR from HCV clinical database
 The
Roche model may slightly underestimate SVR rates
CONCLUSIONS
0
12
24
T ime (week)
36

The model links PEG-IFN+RBV doses and viral kinetics
and integrates clinical data and literature information
across different PEG-IFN treatment durations and
host/virus genotypes to provide an assessment of
SVR24 projections and variability to support HCV drug
development

This framework is being expanded to include directly
acting antivirals and other anti-HCV agents in
development.
48
Table 1: Dropout model for PEG-IFN
Treatment
Duration
48 weeks
36 weeks
24 weeks
20 weeks
16 weeks
12 weeks
8 weeks
# Arms
Total N
16
2774
Weighted
Mean
27%
12
1737
12%
6
953
6%
Linear Model
25%
18%
12%
10%
8%
5%
4%

Dropout rates were linearly interpolated

Dropouts captured as no SVR irrespective of viral load
REFERENCES

Center for Disease Control. Medical Management of Chronic
Hepatitis B and Chronic Hepatitis C. 2002.

Snoeck E, Chanu P, Lavielle M, Jacqumin P, Jonsson EN, Jorga K,
Goggin T, Grippo J, Jumbe NL, Frey N. A comprehensive hepatitis
C viral kinetic model explaining cure. Clin Pharm Ther. 2010
Jun;87(6):706-13.

Thompson AJ, Muir AN, Sulkowski MS, et al. Interleukin-28B
polymorphism improves viral kinetics and is the strongest
pretreatment predictor of sustained virologic response in genotype
1 hepatitis C virus. Gastroenterology. 2010 Jul;139(1):120-9.
10/05/2009 - N7