Impact of IL28B Genotype and Pre-treatment
Serum IP-10 in Treatment-Naïve Genotype 1
HCV Patients Treated with TMC435 in
Combination with Peginterferon a-2a and
Ribavirin in the PILLAR Study
Jeroen AERSSENS,1 Greg FANNING,2 Annick SCHOLLIERS,3
Oliver LENZ,4 Monika PEETERS,5 Goedele DE SMEDT,6
Michael W FRIED7
1Department
of Translational Genomics & Genetics; 2Department of Infectious Disease and Vaccines;
3Department of Enabling Biology; 4Department of Clinical Virology; 5Department of Statistics;
6Department of Clinical Development, Tibotec, Beerse, Belgium; 7University of North Carolina at
Chapel Hill, Chapel Hill, NC, USA
EASL 2011
31 March 2011 - Berlin, Germany
Disclosures

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





Jeroen Aerssens
Greg Fanning
Annick Scholliers
Oliver Lenz
Monika Peeters
Goedele De Smedt
Michael W Fried
Employed by Tibotec, stock/shareholder J&J
Employed by Tibotec, stock/shareholder J&J
Employed by Tibotec
Employed by Tibotec, stock/shareholder J&J
Employed by Tibotec, stock/shareholder J&J
Employed by Tibotec, stock/shareholder J&J
Grants/Research Support, Consultant (Roche,
Merck, Human Genome Sciences, Vertex, Tibotec,
Bristol-Myers Squibb, Anadys, Conatus, Schering,
Pharmasset, Glaxo, Novartis), Stock/Shareholder
(Pharmasset)
TMC435 is an investigational product for hepatitis C virus (HCV) treatment,
under development by Tibotec (part of the Janssen Pharmaceutical
Companies of Johnson & Johnson)
Background: IL28B genotype and virologic
response during treatment with PegIFN/RBV
Treatment-naïve, HCV genotype 1, Caucasian patients (n=1171)
PegIFN/RBV treatment
RVR
cEVR
SVR
(week 4)
(week 12)
Proportion of patients achieving
virologic response (%)
p<0.0001
p<0.0001
p<0.0001
87%
69%
38%
5%
5%
TT
CT
28%
28%
CC
TT
33%
27%
CT
CC
TT
CT
CC
Thompson et al. Gastroenterology 2010; 139:120-129
cEVR, complete early virologic response; IL28B CC/CT/TT, rs12979860 polymorphism; PegIFN, pegylated interferon α-2a; RBV, ribavirin; RVR, rapid virologic
response; SVR, sustained virologic response
Background: Pre-treatment serum IP-10
and virologic response during treatment with
PegIFN/RBV
Treatment-naïve, HCV genotype 1, European patients (n=173)
PegIFN/RBV treatment
Proportion of patients achieving
virologic response (%): SVR
p=0.0002
p=0.003
IP-10 (pg/mL)
at baseline
100%
80%
60%
68%
55%
40%
20%
0%
21%
n=47
n=102
n=24
< 150 150-600 > 600
IP-10 at baseline (pg/ml)
Lagging et al. Hepatology 2006; 44:1617-1625
IP-10, interferon- inducible protein 10; PegIFN, pegylated interferon α-2a; RBV, ribavirin; SVR, sustained virologic response, HCV RNA <25 IU/mL (undetectable)
Background: Pre-treatment serum IP-10
improves predictive value of IL28B for
PegIFN/RBV treatment response
IL28B genotype and pre-treatment serum IP-10 are independent and additive
factors to predict sustained virologic response (SVR)
ViraHepC cohort (n=210)
HCV genotype 1
Overall SVR = 59%
% patients with SVR
90
80
70
60
50
40
30
20
10
0
CC
CT
TT
< 600 pg/ml
≥ 600 pg/ml
Darling et al. Hepatology 2011; 53:14-22
Likelihood ratio Chi2 = 55
p<0.0001
IL28B TT/CT/CC, rs12979860 polymorphism; IP-10, interferon- inducible protein 10; PegIFN, pegylated interferon α-2a; RBV, ribavirin
IL28B and IP-10 analyses: Objective

Evaluate the relationship of IL28B genotype and/or pretreatment serum IP-10 level with on-treatment virologic
response up to Week 24 in the TMC435 PILLAR study
–
–
TMC435 is a once-daily oral HCV NS3/4A protease
inhibitor
PILLAR (TMC435-C205; NCT00882908) is a Phase IIb,
randomised, double-blind, placebo-controlled study in
treatment-naïve genotype 1 HCV patients treated with
TMC435 in combination with PegIFN/RBV
Fried et al. AASLD 2010
IL28B, rs12979860 polymorphism; IP-10, interferon- inducible protein 10; PegIFN, pegylated interferon α-2a; RBV, ribavirin.
PILLAR study design
N=ITT
Consented for
DNA research
PegIFN/RBV
Post-therapy
FU
Post-therapy
FU
Post-therapy FU
N=78
N=58
PegIFN/RBV
Post-therapy
FU
Post-therapy
FU
Post-therapy FU
N=75
N=51
PegIFN/RBV
Post-therapy
FU N=77
Post-therapy
FU
Post-therapy FU
N=55
PegIFN/RBV
Post-therapy
FU N=79
Post-therapy
FU
Post-therapy FU
N=52
Post-therapy FU N=77
N=46
RGT*
TMC24/PR24 75 mg
TMC435 75 mg & PegIFN/RBV
Pbo &
PegIFN/RBV
TMC435 150 mg
& PegIFN/RBV
TMC12/PR24 150 mg
TMC24/PR24 150 mg
TMC435 150 mg & PegIFN/RBV
Pbo24 / PR48
Week
Pbo &
PegIFN/RBV
TMC435 75 mg
& PegIFN/RBV
TMC12/PR24 75 mg
PegIFN/RBV
Pbo & PegIFN/RBV
0
4
12
24
48
72
* RGT: Response-guided treatment duration in TMC435 arms

For IL28B and IP-10 analyses, dose groups were pooled

68% of patients (262 out of 386) consented for DNA research (including IL28B genotyping)
Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks; TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV
for 24 weeks (PegIFN/RBV, peginterferon a-2a [180 g/wk] + ribavirin [1000–1200 mg/day]); TMC24/PR24, TMC435 + PegIFN/RBV for 24 weeks; all TMC435 doses
administered once-daily; FU, follow-up; IL28B, rs12979860 polymorphism; IP-10, interferon- inducible protein 10; ITT, intent to treat; Pbo, placebo; TMC, TMC435.
PILLAR study: Demographics and baseline
disease characteristics for patients who consented
to DNA research
TMC435
75 mg/PR
N=109
TMC435
150 mg/PR
N=107
Pbo/PR
N=46
Male, %
White, %
Age, >40 years, %
Body mass index, median
53.2
94.5
62.4
25.4
55.1
95.3
68.2
24.7
56.5
95.6
65.2
25.9
IL28B rs12979860 genotype, CC, %‡
CT
TT
28.4
58.7
12.8
32.7
56.1
11.2
26.1
60.9
13.0
Baseline serum IP-10, ≥600 pg/ml at baseline, %
9.4
22.3*
9.0
HCV subtype 1a, %#
HCV subtype 1b, %#
44.9
55.1
46.2
53.8
39.1
60.9
HCV RNA, ≥800,000 IU/mL at baseline, %
83.5
88.8
80.4
Metavir fibrosis score F3, %†
17.4
14.0
8.7
Patient demographics
Disease characteristics
#As determined by NS5B sequence-based assay; †patients with cirrhosis (F4) were not eligible; ‡no significant differences between treatment groups; *higher frequency
of patients with high IP-10 in TMC435 150 mg group vs other groups (p<0.02)
IL28B TT/CT/CC, rs12979860 polymorphism; IP-10, interferon- inducible protein 10.
PILLAR: On-treatment virologic response
up to Week 24 by IL28B genotype
Virologic response: HCV RNA <25 IU/ml (detectable or undetectable)
Placebo
+ PegIFN/RBV
Proportion of patients (%)
n=12
n=28
n=6
N.S.
Pearson Chi2 test
p<0.01
p<0.04
The data analysis excluded missing values.
CC/CT/TT, rs12979860 polymorphism; N.S., not significant; PegIFN, pegylated interferon α-2a; RBV, ribavirin.
PILLAR: On-treatment virologic response
up to Week 24 by IL28B genotype
Virologic response: HCV RNA <25 IU/ml (detectable or undetectable)
TMC435 75 mg
+ PegIFN/RBV
Placebo
+ PegIFN/RBV
n=31
n=64
n=12
Proportion of patients (%)
TMC435 150 mg
+ PegIFN/RBV
n=28
n=35
n=60
n=12
n=14
n=6
N.S.
p<0.01
p<0.04
N.S.
p<0.003
p<0.003
The data analysis excluded missing values.
CC/CT/TT, rs12979860 polymorphism; N.S., not significant; PegIFN, pegylated interferon α-2a; RBV, ribavirin.
N.S.
Pearson Chi2 test
N.S.
N.S.
PILLAR: On-treatment virologic response
up to Week 24 by baseline serum IP-10
Virologic response: HCV RNA <25 IU/ml (detectable or undetectable)
Proportion of patients (%)
Placebo
+ PegIFN/RBV
n=40
n=4
N.S.
N.S.
Pearson Chi2 test
N.S.
The data analysed excluded missing values.
IP-10, interferon- inducible protein 10; N.S., not significant; PegIFN, pegylated interferon α-2a; RBV, ribavirin.
Baseline IP-10
Low (<600 pg/mL)
High (≥600 pg/mL)
PILLAR: On-treatment virologic response
up to Week 24 by baseline serum IP-10
Virologic response: HCV RNA <25 IU/ml (detectable or undetectable)
TMC435 75 mg
+ PegIFN/RBV
Proportion of patients (%)
Placebo
+ PegIFN/RBV
TMC435 150 mg
+ PegIFN/RBV
n=10
n=80
n=23
n=96
n=40
Baseline IP-10
Low (<600 pg/mL)
High (≥600 pg/mL)
n=4
Pearson Chi2 test
N.S.
N.S.
N.S.
N.S.
N.S.
N.S.
The data analysed excluded missing values.
IP-10, interferon- inducible protein 10; N.S., not significant; PegIFN, pegylated interferon α-2a; RBV, ribavirin.
N.S.
N.S.
N.S.
PILLAR: On-treatment virologic response up to Week 24
by IL28B genotype/baseline serum IP-10 combined:
Placebo + PegIFN/RBV
Virologic response: HCV RNA <25 IU/ml (detectable or undetectable)
Proportion of patients (%)
Week 4
Week 12
100
100
80
80
60
60
Week 24
100
100%
80
17%
20
5%
20
20%
CT
0
TT
< 600 pg/ml
≥ 600 pg/ml
50%
40
40%
CC
25%
CC
0%
77%
60
57%
40
40
100%
40%
20
CC
CT
0
TT
< 600 pg/ml
≥ 600 pg/ml
0
CT
TT
< 600 pg/ml
≥ 600 pg/ml
IL28B
IL28B CC/CT/TT, rs12979860 polymorphism; IP-10, interferon- inducible protein 10;
PegIFN, pegylated interferon α-2a; RBV, ribavirin
n
TT
CT
CC
IP-10 Low
5
23
12
IP-10 High
0
4
0
PILLAR: On-treatment virologic response up to Week 24
by IL28B genotype/baseline serum IP-10 combined:
TMC435 75 mg + PegIFN/RBV
Virologic response: HCV RNA <25 IU/ml (detectable or undetectable)
Proportion of patients (%)
Week 4
93%
100
80
60
Week 12
Week 24
100%
100%
100%
100
86% 100%
96%
60
40
100
60
67%
CC
CT
0
n=1
TT
< 600 pg/ml
≥ 600 pg/ml
100%
67%
40
40
20
100%
100%
96%
80
100%
80
67%
100%
100%
100%
20
CC
CT
0
20
CC
CT
0
n=1
n=1
TT
< 600 pg/ml
≥ 600 pg/ml
TT
< 600 pg/ml
≥ 600 pg/ml
IL28B
IL28B CC/CT/TT, rs12979860 polymorphism; IP-10, interferon- inducible protein 10;
PegIFN, pegylated interferon α-2a; RBV, ribavirin
n
TT
CT
CC
IP-10 Low
12
56
28
IP-10 High
1
6
3
PILLAR: On-treatment virologic response up to Week 24
by IL28B genotype/baseline serum IP-10 combined:
TMC435 150 mg + PegIFN/RBV
Virologic response: HCV RNA <25 IU/ml (detectable or undetectable)
Proportion of patients (%)
Week 4
96%
95%
100
100%
80
Week 12
100%
100%
95%
100
100%
100%
80
77%
Week 24
100%
100%
100
100%
80
77%
60
60
60
40
40
40
20
CC
CT
0
TT
< 600 pg/ml
≥ 600 pg/ml
20
CC
CT
0
TT
< 600 pg/ml
≥ 600 pg/ml
100%
95%
100%
90%
83%
20
CC
0
CT
TT
< 600 pg/ml
≥ 600 pg/ml
IL28B
IL28B CC/CT/TT, rs12979860 polymorphism; IP-10, interferon- inducible protein 10;
PegIFN, pegylated interferon α-2a; RBV, ribavirin
n
TT
CT
CC
IP-10 Low
19
100
55
IP-10 High
5
19
9
Summary

During the first 24 weeks of treatment in the PILLAR study:
–
In the control group, treated with placebo and PegIFN/RBV,
IL28B CC genotype and low baseline serum IP-10 levels were
associated with the highest virologic response
–
In patients treated with TMC435 in combination with
PegIFN/RBV, high virologic response rates were observed,
regardless of IL28B genotype and/or baseline serum IP-10
–
The highest response for IL28B TT genotype was observed in
TMC435 150 mg group
IL28B, rs12979860 polymorphism; IP-10, interferon- inducible protein 10; PegIFN, pegylated interferon α-2a; RBV, ribavirin
Conclusions

The addition of TMC435 to PegIFN/RBV reduces the
impact of IL28B genotype and/or baseline serum IP-10
on virologic response up to 24 weeks of treatment

Evaluation of the potential impact of these markers on
sustained virologic response (SVR) in triple combination
therapy will be assessed in the Phase IIb and Phase III
trials
IL28B, rs12979860 polymorphism; IP-10, interferon- inducible protein 10; PegIFN, pegylated interferon α-2a; RBV, ribavirin
Acknowledgements


The patients and their families
The PILLAR investigators and their study staff
New Zealand
• Olga V. Korochkina, Nizhny
• Mark E. Jonas, Cincinnati
• P. Michielsen, Edegem
• Ed Gane, Auckland
• Novgorod
• Fred Poordad, Los Angeles
• H. Orlent, Brugge
• Catherine Stedman, Christchurch
Spain
• Coleman Smith, Plymouth
• H. Reynaert, Bruxelles
• Graeme Dickson, Hamilton
• Maria Buti, Barcelona
• Jawahar Taunk, Palm Harbor
• J. Decaestecker, Roeselare
Norway
• Moises Diago, Valencia
• Lawrence Wruble, Germantown
Denmark
• Trond Bruun, Bergen
• Ricardo Moreno-Otero, Madrid
• Ziad Younes, Germantown
• Jan Gerstoft, Copenhagen
• Bent von der Lippe, Kirkeveien
• Manuel Romero, Sevilla
Canada
• Alex Lund Laursen, Aarhus
• Zbigniev Konopski, Trondheimsveien • Jose Luis Calleja, Madrid
• Pierre Cote, Montreal
• Lars Mathiesen, Hvidovre
• Kjell Block Hellum, Sykehusveien
Germany
• Gideon Hirschfield, Toronto
• Axel Møller, Kolding
• Jon Florholmen, Tromso
• Keikawus Arasteh, Berlin
• Maged Peter Ghali, Montreal
• Peer Brehm Christensen, Odense
Poland
• Thomas Berg, Berlin
• Sam Lee, Calgary
France
• Robert Flisiak, Bialystok
• Peter Buggisch, Hamburg
• Morris Sherman, Toronto
• Yves Benhamou, Paris
• Andrzej Horban, Warszawa
• Hartwig Klinker, Würzburg
Australia
• Christian Trepo, Lyon
• Waldemar Halota, Bydgoszcz
• Andreas Trein, Stuttgart
• Greg Dore, Darlinghurst
• Wieslaw Kryczka, Kielce
• Tobias Goeser, Köln
• Paul Desmond, Fitzroy
• Jean Pierre Bronowicki, Vandoeuvre Les
Nancy
• Maciej Jablkowski, Lodz
• Stefan Mauss, Düsseldorf
• Stuart Roberts, Melbourne
• Christophe Hezode, Creteil
• Ewa Janczewska-Kazek, Czeladz
• Dr Jens Rasenack, Freiburg
• Jacob George, Westmead
• Patrick Marcellin , Clichy
Russia
• Stefan Zeuzem, Frankfurt
• Graeme Macdonald, Woolloongabba
• Jean-Didier Grange, Paris
• Alexey A. Yakovlev, Saint Petersburg • Hans-Jürgen Stellbrink, Hamburg
• Alice Lee, Concord
• Jean Pierre Zarski, Grenoble
• Vladimir V. Rafalskiy, Smolensk
Austria
• Albert Tran, Nice
USA
• Evgeny E. Voronin, Saint Petersburg • Daniel Pambianco, Charlottesville
• Peter Ferenci, Wien
• N Zakharova, Saint Petersburg
• Edwin DeJesus, Orlando
• Hermann Laferl, Wien
• Igor G. Nikitin, Moscow
• Kyle Etzkron, Jacksonville
Michael Gschwantler, Wien
• Pavel O. Bogomolov, Moscow
• Michael Fried, Chapel Hill
Belgium
• Vladimir T. Ivashkin, Moscow
• Andrei Gasic, Longview
• F. Nevens, Leuven
• Vyacheslav G. Morozov, Samara
• Nigel Girgrah, New Orleans
• Y. Horsmans, Bruxelles
• Ira M. Jacobson, New York
• C. Moreno, Bruxelles
• Donald M. Jensen, Chicago
• H. Van Vlierberghe, Ghent
• Editorial support was provided by Dr.
Bethan Lowder at Complete Medical
Communications, funded by Tibotec.
• Maria Beumont-Mauviel, Joan Cannon,
Ronald Kalmeijer, Eric Lefebvre, Karen
Lindsay, Karen Manson, Gaston
Picchio and Vanitha Sekar contributed
to development of the presentation.