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Efficacy and Safety of TMC435 in Combination
With Peginterferon a-2a and Ribavirin in
Treatment-naïve Genotype-1 HCV Patients:
24-Week Interim Results from the PILLAR Study
M.W. Fried,1 M. Buti,2 G.J. Dore,3 P. Ferenci,4
I. Jacobson,5 P. Marcellin,6 S. Zeuzem,7
O. Lenz,8 M. Peeters,8 V. Sekar,9 G. De Smedt8
1University
of North Carolina at Chapel Hill, North Carolina, USA; 2Hospital Vall d'Hebron and
Ciberehd, Barcelona, Spain; 3St Vincent's Hospital, Sydney, Australia and National Centre in HIV
Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia; 4Allgemeines
Krankenhaus der Stadt Wien, Wien, Austria ; 5Weill Cornell Medical College, New York, USA; 6Hopital
Beaujon, Clichy, Paris, France; 7Klinikum der Johann-Wolfgang-Goethe-Universität - Med. Klinik I,
Frankfurt, Germany; 8Tibotec, Beerse, Belgium; 9Tibotec Inc., Titusville, New Jersey, USA
Disclosure Information
• Michael Fried
Grants/Research Support, Consultant (Roche, Merck, Human Genome Sciences,
Vertex, Tibotec, Bristol Myers Squibb, Anadys, Conatus, Schering, Pharmasset,
Glaxo, Novartis), Stock/Shareholder (Pharmasset)
• Maria Buti
Advisory Board and Speaker (MSD, Gilead, BMS)
• Greg Dore
Advisory Committee, Grant/Research Support, Teaching and Speaking, Travel
Scholarship (Roche, Merck, Bristol-Myer Squibb, Gilead)
• Peter Ferenci
Advisory Committee and Review Panels, Unrestricted Grant/Research Support,
Teaching and Speaking, Consulting, Patent Held (Roche, Vertex/Tibotec,
Madaus-Rottapharm, Boehringer Ingelheim, MSD/previously SPI)
• Ira Jacobson
Grant/Research Support, Member of Speaker’s Bureau, Consultant/Advisor
(Schering/Merck, Tibotec, Roche/Genentech, Pharmasset, Anadys, Boehringer
Ingelheim, Novartis, Gilead, Vertex, GlobeImmune, Human Genome Sciences,
Bristol Myers Squibb, Pfizer, Zymogenetics, Abbott, sanofi-aventis)
• Patrick Marcellin
Grant, Investigator, Speaker, and Expert (Roche, Schering Plough, Gilead, BMS,
Vertex, Novartis, Pharmasset, Tibotec, MSD, Boehringer Ingelheim, Biolex,
Intermune, Zymogenetics)
• Stefan Zeuzem
Consultancy, Member of Speaker’s Bureau (Abbott, BMS, Gilead, Merck, Pfizer,
Roche, Tibotec, Vertex)
• Oliver Lenz
Employed by Tibotec
• Monika Peeters
Employed by Tibotec
• Vanitha Sekar
Employed by Tibotec
• Goedele De Smedt
Employed by Tibotec
PILLAR (Study TMC435-C205):
Objectives & Endpoints
• Objective
– To assess efficacy and safety of protease inhibitor TMC435
once-daily in combination with PegIFN/RBV* in treatmentnaïve patients infected with HCV genotype-1
• Study design
– Ongoing international, Phase IIb, randomized, double-blind,
placebo-controlled clinical trial
• Primary endpoint
– Sustained virologic response at Week 72
• Key secondary endpoints
– Antiviral activity throughout study
– Viral breakthrough and relapse rates
– Safety and tolerability
– Pharmacokinetics
Results of a planned Week 24 interim analysis are reported today
*PegIFN/RBV, peginterferon a-2a (180 g/wk) + ribavirin (1000–1200 mg/day); HCV, hepatitis C virus
PILLAR: Study Design
Planned interim analysis
All available data included
Pbo &
PegIFN/RBV
TMC12/PR24 75 mg TMC435 75 mg &
PegIFN/RBV
TMC24/PR24 75 mg
TMC435 75 mg & PegIFN/RBV
TMC12/PR24 150 mg TMC435 150 mg &
PegIFN/RBV
TMC24/PR24 150 mg
TMC435 150 mg & PegIFN/RBV
Pbo24/PR48
Week
Pbo &
PegIFN/RBV
12
Post-therapy FU
N=78
Post-therapy FU
N=75
Post-therapy FU
N=77
Post-therapy FU
N=79
Post-therapy FU
PegIFN/RBV
Pbo & PegIFN/RBV
0
N=ITT
24
48
N=77
72
Response-guided treatment duration in TMC435 arms
• End treatment at Week 24, if
o HCV RNA <25 IU/mL detectable or undetectable at Week 4, and
o HCV RNA <25 IU/mL undetectable at Weeks 12, 16, and 20
• All other patients continued Peg/RBV for up to 48 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 were administered once-daily; Pbo24/PR48, placebo and PegIFN/RBV
for 24 weeks followed by PegIFN/RBV for 24 weeks; FU, follow-up; ITT, intent to treat; Pbo, placebo; RNA, ribonucleic acid; TMC, TMC435
PILLAR: Demographics and Baseline Disease
Characteristics
TMC12/
PR24
75 mg
N=78
TMC24/
PR24
75 mg
N=75
TMC12/
PR24
150 mg
N=77
TMC24/
PR24
150 mg
N=79
Pbo24/
PR48
N=77
All
subjects
N=386
51.3
89.7
47.0
25.9
62.7
94.7
46.0
24.2
55.8
96.1
47.0
24.7
55.7
92.4
47.0
24.9
50.6
96.1
45.0
25.6
55.2
93.8
46.5
25.0
HCV subtype 1a, %*
HCV subtype 1b, %*
46.8
53.2
45.9
54.1
48.0
52.0
48.1
51.9
38.2
61.8
45.4
54.6
HCV RNA, log10 ≥800,000 IU/mL
at baseline, median, %
82.1
84.0
89.6
91.1
81.8
85.8
Metavir score F3, %†
12.8
22.7
9.1
15.2
9.1
13.7
IL28B at baseline, CC, %‡
22.4
35.3
40.0
25.0
26.1
29.8
Parameter
Patient demographics
Male, %
White, %
Age, years, median
Body mass index, median
Disease characteristics
*As determined by NS5B sequence-based assay
† Patients with cirrhosis (F4) were not eligible
‡ Polymorphism on chromosome 19 s12979860, data available for patients who consented only (67.9%)
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 were administered once-daily; Pbo24/PR48, placebo and PegIFN/RBV
for 24 weeks followed by PegIFN/RBV for 24 weeks; no. of subjects completing therapy at Week 24 was according to response-guided treatment algorithm
Mean (+/- SE) change in plasma
HCV RNA (log10 IU/mL) from baseline
PILLAR Week 24 Analysis: Mean Change in
Plasma HCV RNA From Baseline
0
TMC12/PR24 75 mg
TMC24/PR24 75 mg
TMC12/PR24 150 mg
TMC24/PR24 150 mg
Pbo24/PR48
-1
-2
-3
-4
-5
-6
-7
0
4
8
12
16
20
24
Week
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 were administered once-daily; Pbo24/PR48, placebo and PegIFN/RBV
for 24 weeks followed by PegIFN/RBV for 24 weeks; SE, standard error
PILLAR Week 24 Analysis: Proportion of Patients
Achieving Virologic Response at Weeks 4 and 12
Week 12
Week 4
***
***
***
***
***
Proportion of patients (%)
100
80
10
20
16
2
17
***
***
1
3
***
11
60
40
77
68
76
91
79
96
94
97
58
20
11
5
0
TMC12/
PR24
75 mg
(n=77)
HCV RNA
TMC24/
PR24
75 mg
(n=75)
TMC12/
PR24
150 mg
(n=76)
TMC24/
PR24
150 mg
(n=75)
Pbo24/
PR48
(n=75)
<25 IU/mL undetectable
TMC12/
PR24
75 mg
(n=78)
TMC24/
PR24
75 mg
(n=73)
TMC12/
PR24
150 mg
(n=77)
<25 IU/mL detectable
TMC24/
PR24
150 mg
(n=77)
Pbo24/
PR48
(n=74)
>25 IU/mL
***TMC435 vs placebo: p≤0.001; TMC12/PR24, TMC435 for 12 weeks in addition to Peg/RBV for 24 weeks; TMC24/PR24, TMC435 for 24 weeks in addition to
Peg/RBV for 24 weeks; HCV RNA determined using Roche TaqMan v2
PILLAR Week 24 Analysis: Proportion of
Patients Achieving Virologic Response at Week 24
Week 24
Proportion of patients (%)
100
3
3
80
60
94
97
94
95
TMC12/
PR24
150 mg
(n=69)
TMC24/
PR24
150 mg
(n=73)
40
82
20
0
TMC12/
PR24
75 mg
(n=77)
HCV RNA
TMC24/
PR24
75 mg
(n=72)
<25 IU/mL undetectable
Pbo24/
PR48
(n=73)
<25 IU/mL detectable
>25 IU/mL
TMC12/PR24, TMC435 for 12 weeks in addition to Peg/RBV for 24 weeks; TMC24/PR24, TMC435 for 24 weeks in addition to Peg/RBV for 24 weeks;
HCV RNA determined using Roche TaqMan v2
PILLAR Week 24 Analysis: Proportion of Patients Achieving
Undetectable HCV RNA After Planned End of Treatment
• Between 79% and 86% of patients in TMC435 arms ended
therapy at Week 24 as per protocol-defined response criteria
Follow-up after planned
end of treatment†
SVR4
(4 weeks after planned end
of treatment)
SVR12
(12 weeks after planned
end of treatment)
TMC12/
PR24
75 mg
N=78
TMC24/
PR24
75 mg
N=75
TMC12/
PR24
150 mg
N=77
TMC24/
PR24
150 mg
N=79
91%
93%
93%
91%
(59/65*)
(56/60*)
(57/61*)
(62/68*)
97%
93%
89%
88%
(32/33*)
(27/29*)
(32/36*)
(28/32*)
* Denominator based on number of patients that stopped treatment for any
reason by Week 24 and reached specified timepoint
TMC12/PR24, TMC435 for 12 weeks in addition to PegIFN/RBV for 24 weeks; TMC24/PR24, TMC435 for 24 weeks in addition to PegIFN/RBV for 24 weeks;
SVR, sustained virologic response; †not yet defined in the placebo group in this Week 24 analysis as planned end of treatment has not been reached
Proportion of patients with
viral breakthrough,*
cumulative (%)
PILLAR Week 24 Analysis: Viral Breakthrough
50
40
30
20
10
7.8%
6.4%
2.7%
3.9%
2.5%
0
TMC12/PR24
75 mg
TMC24/PR24
75 mg
Weeks 1-4
TMC12/PR24
150 mg
Weeks 1-12
TMC24/PR24
150 mg
Pbo24/PR48
Weeks 1-24
*Viral breakthrough: confirmed increase of >1 log from nadir or >100 IU/mL if undetectable; 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 were administered once-daily; Pbo24/PR48, placebo and PegIFN/RBV for 24 weeks followed by PegIFN/RBV for 24 weeks
PILLAR Week 24 Analysis: Mean Change in HCV RNA
from Baseline According to IL28B Genotype*
Placebo
Mean (+/- SE) change in plasma HCV RNA
(log10 IU/mL) from baseline
0
-2
CC
CT
TT
-4
-6
0
4
8
12
Week
16
20
24
All TMC435 75 mg
All TMC435 150 mg
0
0
-2
-2
-4
-4
-6
-6
0
4
8
12 16
Week
20
24
0
4
*Data shown for patients who consented only (67.9%); CC/TT/CT, polymorphism on chromosome 19 s12979860
8
12 16
Week
20
24
PILLAR Week 24 Analysis: Adverse Events
Preferred term, %
TMC12/
PR24
75 mg
N=78
TMC24/
PR24
75 mg
N=75
TMC12/
PR24
150 mg
N=77
TMC24/
PR24
150 mg
N=79
All TMC435
N=309
Pbo24/
PR48
N=77
Adverse events leading to permanent discontinuation of TMC435/Pbo
Discontinuation
9.0
2.7
9.1
7.6
7.1
7.8
45.3
46.7
42.7
22.7
20.0
45.5
41.6
23.4
39.0
26.0
40.5
48.1
34.2
30.4
30.4
46.0
41.7
31.7
31.1
27.5
50.6
46.8
37.7
44.2
27.3
17.3
20.0
29.9
22.1
30.4
17.7
28.5
19.4
27.3
20.8
Most common adverse events*
Headache
Fatigue
Influenza-like
illness
Pruritus
Nausea
52.6
30.8
26.9
32.1
33.3
Adverse events of interest
Rash (any type)†
Anemia‡
35.9
17.9
*Reported in ≥25% of subjects in the ‘All TMC435’ group (all dose groups combined)
† Rash (any type) combines all reported types of rash
‡ Reported as an adverse event by study investigator if laboratory abnormalities considered clinically relevant
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 were administered once-daily; Pbo24/PR48, placebo and PegIFN/RBV
for 24 weeks followed by PegIFN/RBV for 24 weeks
PILLAR Week 24 Analysis: Laboratory
Parameters, Bilirubin Over Time
Mean (+/- SE) values of bilirubin
(μmol/L)
• Mild and reversible increases in bilirubin (direct and indirect) were
noted in TMC435 150 mg dose arms
Pbo24/PR48
TMC 75 mg
TMC 150 mg
30
25
Upper limit of normal
20
15
10
5
Lower limit of normal
0
0 1 2
4
6
8
12
16
20
24
Week
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 were administered once-daily; Pbo24/PR48, placebo and PegIFN/RBV
for 24 weeks followed by PegIFN/RBV for 24 weeks; SE, standard error; to convert from bilirubin mol/L to mg/dL, divide by 17.1
PILLAR Week 24 Analysis: Laboratory
Parameters, Bilirubin Over Time
Mean (+/- SE) values of bilirubin
(μmol/L)
• Mild and reversible increases in bilirubin (direct and indirect) were
noted in TMC435 150 mg dose arms
TMC12/PR24 75 mg
TMC24/PR24 75 mg
TMC12/PR24 150 mg
TMC24/PR24 150 mg
Pbo24/PR48
TMC 75 mg
TMC 150 mg
30
25
Upper limit of normal
20
15
10
5
Lower limit of normal
0
0 1 2
4
6
8
12
16
20
24
Week
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 were administered once-daily; Pbo24/PR48, placebo and PegIFN/RBV
for 24 weeks followed by PegIFN/RBV for 24 weeks; SE, standard error; to convert from bilirubin mol/L to mg/dL, divide by 17.1
Mean (+/- SE)
values of
bilirubin
(μmol/L)
PILLAR Week 24 Analysis: Laboratory Parameters,
Bilirubin, ALT, and ALP Over Time (TMC12/PR24 150 mg)
Upper limit of normal
20
10
Mean (+/- SE)
values of ALT
(IU/mL)
60
Mean (+/- SE)
values of ALP
(IU/mL)
90
140
120
100
80
60
40
20
Upper limit of normal
30
Upper limit of normal
0 1 2
4
6
8
12
Week
16
20
24
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]); ALT, alanine aminotransferase; ALP, alkaline phosphatase ; SE, standard error; to convert from bilirubin mol/L to mg/dL, divide by 17.1
PILLAR Week 24 Analysis: Efficacy Summary
TMC435 administered once-daily with PegIFN/RBV over
12 or 24 weeks demonstrated potent antiviral activity
• At Weeks 4 and 12, HCV RNA was <25 IU/mL (undetectable)
for the majority of patients in TMC435 groups
• The majority of patients in TMC435 groups met the criteria to
stop treatment at Week 24
• In patients who completed therapy at or before Week 24,
response rates remained high 12 weeks after planned end of
therapy
• Addition of TMC435 to PegIFN/RBV increased response rates
in all IL28B genotypes
PILLAR Week 24 Analysis: Safety Summary
No clinically relevant difference in safety and
tolerability between TMC435 and placebo groups
•
Frequency of rash, gastrointestinal events, and anemia were
similar to placebo group
•
Mild and reversible increases in bilirubin concentration
observed with 150 mg dose
•
ALT concentration decreased in all treatment groups
•
Discontinuation in TMC435 groups was low and similar to
placebo group
Planning of Phase III studies of TMC435 is underway
Acknowledgements
The patients and their families
The PILLAR investigators and their study staff
New Zealand
Olga V. Korochkina, Nizhny
Ed Gane, Auckland
Catherine Stedman, Christchurch
Novgorod
Ira M. Jacobson, New York
Belgium
Gregory Fanning, Richard
Donald M. Jensen, Chicago
F. Nevens, Leuven
Hoetelmans, Ronald
Y. Horsmans, Bruxelles
Kalmeijer, Eric Lefebvre,
Spain
Mark E. Jonas, Cincinnati
Graeme Dickson, Hamilton
Maria Buti, Barcelona
Fred Poordad, Los Angeles
C. Moreno, Bruxelles
Karen Manson, Gaston
Norway
Moises Diago, Valencia
Coleman Smith, Plymouth
H. Van Vlierberghe, Ghent
Picchio, Setareh
Trond Bruun, Bergen
Ricardo Moreno-Otero, Madrid
Jawahar Taunk, Palm Harbor
P. Michielsen, Edegem
Seyedkazemi, and Brian
Bent von der Lippe, Kirkeveien
Manuel Romero, Sevilla
Lawrence Wruble, Germantown
H. Orlent, Brugge
Woodfall (Tibotec) have also
Zbigniev Konopski, Trondheimsveien
Jose Luis Calleja, Madrid
Ziad Younes, Germantown
H. Reynaert, Bruxelles
contributed to development
Kjell Block Hellum, Sykehusveien
Germany
Canada
J. Decaestecker, Roeselare
of the presentation, and
Jon Florholmen, Tromso
Keikawus Arasteh, Berlin
Pierre Cote, Montreal
Denmark
editorial assistance was
Poland
Thomas Berg. Berlin
Gideon Hirschfield, Toronto
Jan Gerstoft, Copenhagen
provided by Bethan Lowder
Robert Flisiak, Bialystok
Peter Buggisch, Hamburg
Maged Peter Ghali, Montreal
Alex Lund Laursen, Aarhus
at Complete Medical
Andrzej Horban, Warszawa
Hartwig Klinker, Würzburg
Sam Lee, Calgary
Lars Mathiesen, Hvidovre
Communications.
Waldemar Halota, Bydgoszcz
Andreas Trein, Stuttgart
Morris Sherman, Toronto
Axel Møller, Kolding
Wieslaw Kryczka, Kielce
Tobias Goeser, Köln
Australia
Peer Brehm Christensen,
Maciej Jablkowski, Lodz
Stefan Mauss, Düsseldorf
Greg Dore, Darlinghurst
Ewa Janczewska-Kazek, Czeladz
Dr. Jens Rasenack, Freiburg
Paul Desmond, Fitzroy
France
Russia
Stefan Zeuzem, Frankfurt
Stuart Roberts, Melbourne
Yves Benhamou, Paris
Alexey A. Yakovlev, Saint-Petersburg Hans-Jürgen Stellbrink, Hamburg
Jacob George, Westmead
Christian Trepo, Lyon
Vladimir V. Rafalskiy, Smolensk
USA
Graeme Macdonald, Woolloongabba Jean Pierre Bronowicki,
Evgeny E. Voronin, Saint-Petersburg
Daniel Pambianco, Charlottesville Alice Lee, Concord
N Zakharova, Saint-Petersburg
Edwin DeJesus, Orlando
Austria
Christophe Hezode, Creteil
Igor G. Nikitin, Moscow
Kyle Etzkron, Jacksonville
Peter Ferenci, Wien
Patrick Marcellin , Clichy
Pavel O. Bogomolov, Moscow
Michael Fried, Chapel Hill
Hermann Laferl, Wien
Vladimir T. Ivashkin, Moscow
Andrei Gasic, Longview
Michael Gschwantler, Wien
Vyacheslav G. Morozov, Samara
Nigel Girgrah, New Orleans
Odense
Vandoeuvre Les Nancy
Jean-didier Grange, Paris
Jean Pierre Zarski, Grenoble
Albert Tran, Nice