2 GJ 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 Smedt 8 Ef ficacy and Safety of TMC435 in Combination With Peginterferon ID: 816229
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Slide1
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
Ef
ficacy 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
1
University of North Carolina at Chapel Hill, North Carolina, USA
;
2
Hospital Vall d'Hebron and Ciberehd, Barcelona, Spain
;
3
St Vincent's Hospital, Sydney, Australia and National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, Australia
;
4
Allgemeines Krankenhaus der Stadt Wien, Wien, Austria
;
5
Weill
Cornell Medical College, New York, USA
;
6
Hopital Beaujon, Clichy, Paris, France
;
7
Klinikum
der Johann-Wolfgang-Goethe-Universität - Med.
Klinik I, Frankfurt, Germany
;
8
Tibotec,
Beerse,
Belgium;
9
Tibotec
Inc., Titusville,
New Jersey, USA
Slide2Disclosure InformationMichael 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
Slide3*PegIFN/RBV, peginterferon -2a (180 g/wk) + ribavirin (1000–1200 mg/day); HCV, hepatitis C virus
PILLAR (Study TMC435-C205):
Objectives & EndpointsObjectiveTo assess efficacy and safety of protease inhibitor TMC435 once-daily in combination with PegIFN/RBV* in treatment-naïve patients infected
with
HCV genotype-1
Study
design
O
ngoing 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
Slide4TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -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
Response-guided treatment duration in TMC435
arms
End treatment at Week 24,
if
HCV RNA <
25 IU/mL
detectable or undetectable at Week
4,
and
HCV RNA <25 IU/mL undetectable at Weeks 12, 16, and 20All other patients continued Peg/RBV for up to 48 weeks
PILLAR: Study Design
Planned interim analysisAll available data included
Week
0
12
24
72
48
Pbo & PegIFN/RBV
TMC435 75 mg & PegIFN/RBV
TMC435 75 mg & PegIFN/RBV
TMC435 150 mg & PegIFN/RBV
Post-therapy FU
PegIFN/RBV
N=78
N=75
N=79
N=77
N=ITT
TMC12/PR24 75 mg
TMC24/PR24 75 mg
TMC24/PR24 150 mg
Pbo24/PR48
Pbo & PegIFN/RBV
TMC435 150 mg & PegIFN/RBV
Pbo & PegIFN/RBV
N=77
TMC12/PR24 150 mg
Post-therapy FU
Post-therapy FU
Post-therapy FU
Post-therapy FU
Slide5Parameter
TMC12/PR2475 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
Patient demographics
Male
,
%
White
, %
Age
, years, median
Body mass index,
median
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
Disease characteristics
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
54.6HCV RNA, log10 ≥800,000 IU/mL at baseline, median, %82.184.089.691.181.885.8Metavir score F3, %†12.822.79.115.29.113.7IL28B at baseline, CC, %‡22.435.340.025.026.129.8
TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -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
*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%)
PILLAR: Demographics and Baseline Disease Characteristics
Slide6TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -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 errorPILLAR Week 24 Analysis: Mean Change in Plasma HCV RNA From Baseline0
-1
-2
-3
-4
-5
-6
-7
TMC12/PR24 75 mg
TMC24/PR24 75 mg
TMC12/PR24 150 mg
TMC24/PR24 150 mg
Pbo24/PR48
24
20
16
12
8
4
0
Mean (+/- SE) change in plasma HCV RNA (log
10
IU/mL) from baseline
Week
Slide710080
60
40200
TMC12/PR24 75 mg (n=77)
TMC24/PR24 75 mg (n=75)
TMC12/PR24 150 mg (n=76)
TMC24/PR24 150 mg (n=75)
Pbo24/PR48
(n=75)
TMC12/PR24 75 mg (n=78)
TMC24/PR24 75 mg (n=73)
TMC12/PR24 150 mg (n=77)
TMC24/PR24 150 mg (n=77)
Pbo24/PR48
(n=74)
<25 IU/mL undetectable
<25
IU/
mL
detectable
>25 IU/mL
Week 4
Week 12
Proportion of patients (%)
HCV
RNA
***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 Weeks 4 and 12
***
***
***
***
***
***
***
***
Slide8Week 24Proportion of patients (%)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
100
80
60
40
20
0
TMC12/PR24 75 mg (n=77)
TMC24/PR24 75 mg (n=72)
TMC12/PR24 150 mg (n=69)
TMC24/PR24 150 mg (n=73)
Pbo24/PR48
(n=73)
PILLAR Week 24 Analysis: Proportion of
Patients Achieving Virologic Response at Week 24
<25 IU/mL undetectable
<25
IU/
mL
detectable
>25 IU/mL
HCV
RNA
Slide9Between 79% and 86% of patients in TMC435 arms ended therapy at Week 24 as per protocol-defined response criteriaTMC12/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
PILLAR Week 24 Analysis: Proportion of Patients Achieving Undetectable HCV RNA After Planned End of Treatment
Follow-up 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
SVR4
(4 weeks after planned end of treatment)
SVR12
(12 weeks after planned end of treatment)
91%
(59/65*)
97%
(32/33*)
93%
(56/60*)
93%
(27/29*)
93%
(57/61*)
89%
(32/36*)
91%
(62/68*)
88%
(28/32*)
* Denominator based on number of patients that stopped treatment for any reason by Week 24 and reached specified
timepoint
Slide10*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
-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: Viral Breakthrough
50
40
30
20
10
0
TMC12/PR24
75 mg
TMC24/PR24
75 mg
TMC12/PR24
150 mg
TMC24/PR24
150 mg
Pbo24/PR48
Proportion of patients with viral breakthrough,* cumulative (%)
Weeks 1-4
Weeks 1-12
Weeks 1-24
6.4%
2.7%
7.8%
2.5%
3.9%
Slide11*
Data shown for patients who consented only
(67.9%); CC/TT/CT, polymorphism on chromosome 19 s12979860
PILLAR Week 24 Analysis: Mean Change in HCV RNA from Baseline According to
IL28B
Genotype*
Mean (+/- SE) change in plasma HCV RNA (log
10
IU/mL) from baseline
0
-2
-4
-6
0
4
8
12
16
20
24
Placebo
All TMC435 75 mg
0
-2
-4
-6
0
4
8
12
16
20
24
Week
0
-2
-4
-6
0
4
8
12
16
20
24
All TMC435 150 mg
Week
Week
CC
CT
TT
Slide12TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -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
*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
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
Most common adverse events*
Headache
Fatigue
Influenza-like illness
Pruritus
Nausea
52.6
30.8
26.9
32.1
33.3
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
44.227.3Adverse events of interestRash (any type)†Anemia‡35.917.917.320.029.922.130.417.728.519.427.320.8
Slide13Mild and reversible increases in bilirubin (direct and indirect) were noted in TMC435 150 mg dose armsTMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV, peginterferon -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
30
25
20
15
10
5
0
24
20
12
4
0
Mean (+/- SE)
values
of
bilirubin
(
μ
mol/L)
Week
1
2
6
8
16
Pbo24/PR48
TMC 75 mg
TMC 150 mg
Upper limit of normal
Lower limit of normal
Slide14Mild and reversible increases in bilirubin (direct and indirect) were noted in TMC435
150 mg
dose armsTMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV
,
peginterferon
-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 17.1PILLAR Week 24 Analysis: Laboratory
Parameters, Bilirubin Over Time
30
25
20
15
10
5
0
24
20
12
4
0
Mean (+/- SE)
values
of
bilirubin
(
μ
mol/L)
Week
1
2
6
8
16
TMC12/PR24 75 mg
TMC24/PR24 75 mg
TMC12/PR24 150 mg
TMC24/PR24 150 mg
Pbo24/PR48
TMC 75 mg
TMC 150 mg
Upper limit of normal
Lower limit of normal
Slide15PILLAR Week 24 Analysis: Laboratory Parameters, Bilirubin, ALT, and ALP Over Time (
TMC12/PR24
150 mg
)
90
60
30
Mean (+/- SE) values of
ALT (IU/mL)
TMC12/PR24, TMC435 + PegIFN/RBV for 12 weeks followed by PegIFN/RBV for 24 weeks (PegIFN/RBV
,
peginterferon
-2a [
180
g/wk]
+ ribavirin [
1000–1200 mg/day]); ALT, alanine aminotransferase; ALP, alkaline
phosphatase
; SE, standard error; t
o convert from bilirubin
mol/L to mg/
dL
, divide by 17.1
140
20
Mean (+/- SE) values of
ALP (IU/mL)
0
1
2
4
6
8
12
16
20
24
Week
40
60
80
100
120
Upper limit of normal
Upper limit of normal
Mean (+/- SE) values of bilirubin (
μ
mol/L)
20
10
Upper limit of normal
Slide16TMC435 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 groupsThe 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
genotypesPILLAR Week 24 Analysis: Efficacy Summary
Slide17No clinically relevant difference in safety and tolerability between TMC435 and placebo groupsFrequency of rash, gastrointestinal events, and anemia were similar to placebo groupMild and reversible increases in bilirubin concentration observed with 150
mg doseALT concentration decreased in all treatment groups
Discontinuation in TMC435 groups was low and similar to placebo groupPlanning of Phase III studies of TMC435 is underway
PILLAR Week 24 Analysis: Safety Summary
Slide18The patients and their familiesThe PILLAR investigators and their study staffNew ZealandEd Gane, AucklandCatherine Stedman, ChristchurchGraeme Dickson, HamiltonNorway
Trond Bruun, Bergen
Bent von der Lippe, Kirkeveien Zbigniev Konopski, TrondheimsveienKjell Block Hellum, SykehusveienJon Florholmen, TromsoPolandRobert Flisiak, Bialystok
Andrzej Horban, Warszawa
Waldemar Halota, Bydgoszcz
Wieslaw Kryczka, Kielce
Maciej Jablkowski, Lodz
Ewa Janczewska-Kazek, Czeladz
Russia
Alexey A. Yakovlev, Saint-Petersburg
Vladimir V. Rafalskiy, Smolensk
Evgeny E. Voronin, Saint-Petersburg
N Zakharova, Saint-PetersburgIgor G. Nikitin, MoscowPavel O. Bogomolov, MoscowVladimir T. Ivashkin, Moscow
Vyacheslav G. Morozov, SamaraOlga V. Korochkina, Nizhny
NovgorodSpainMaria Buti, Barcelona
Moises Diago, Valencia
Ricardo Moreno-Otero, MadridManuel Romero, Sevilla
Jose Luis Calleja, Madrid
GermanyKeikawus Arasteh, Berlin
Thomas Berg. BerlinPeter Buggisch, Hamburg
Hartwig Klinker, Würzburg
Andreas Trein, Stuttgart
Tobias Goeser, Köln
Stefan Mauss, Düsseldorf
Dr. Jens Rasenack, FreiburgStefan Zeuzem, Frankfurt
Hans-Jürgen Stellbrink, HamburgUSA
Daniel Pambianco, CharlottesvilleEdwin DeJesus, Orlando
Kyle Etzkron, JacksonvilleMichael Fried, Chapel Hill
Andrei Gasic, LongviewNigel Girgrah, New Orleans
Ira M. Jacobson, New York
Donald M. Jensen, Chicago
Mark E. Jonas, Cincinnati
Fred Poordad, Los Angeles
Coleman Smith, Plymouth
Jawahar Taunk, Palm Harbor
Lawrence Wruble, Germantown
Ziad Younes, Germantown
Canada
Pierre Cote, MontrealGideon Hirschfield, Toronto
Maged Peter Ghali, MontrealSam Lee, Calgary
Morris Sherman, TorontoAustralia
Greg Dore, DarlinghurstPaul Desmond, Fitzroy
Stuart Roberts, MelbourneJacob George, WestmeadGraeme Macdonald, Woolloongabba
Alice Lee, ConcordAustria
Peter Ferenci, WienHermann Laferl, Wien
Michael Gschwantler, Wien
Belgium
F. Nevens, Leuven
Y. Horsmans, Bruxelles
C. Moreno, Bruxelles
H. Van Vlierberghe, Ghent
P. Michielsen, Edegem
H. Orlent, Brugge
H. Reynaert, Bruxelles
J. Decaestecker, Roeselare
DenmarkJan Gerstoft, Copenhagen
Alex Lund Laursen, Aarhus
Lars Mathiesen, HvidovreAxel Møller, Kolding
Peer Brehm Christensen, OdenseFrance
Yves Benhamou, ParisChristian Trepo, Lyon
Jean Pierre Bronowicki, Vandoeuvre Les NancyChristophe Hezode, CreteilPatrick Marcellin , Clichy
Jean-didier Grange, ParisJean Pierre Zarski, GrenobleAlbert Tran, Nice
Gregory Fanning,
Richard Hoetelmans, Ronald Kalmeijer,
Eric Lefebvre,
Karen Manson, Gaston Picchio, Setareh Seyedkazemi, and Brian Woodfall (Tibotec) have also contributed to development of the presentation, and editorial assistance was provided by Bethan Lowder at Complete Medical Communications.Acknowledgements