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OPERA-1 trial
(Study TMC435-C201):
interim analysis of safety
and antiviral activity of
TMC435 in treatment-naïve
genotype-1 HCV patients
M. Manns,1 H. Reesink,2 C. Moreno,3 T. Berg,4
Y. Benhamou,5 Y. Horsmans,6 G. Dusheiko,7
R. Flisiak,8 P. Meyvisch,9 O. Lenz,9 V. Sekar,10
G. van ’t Klooster,9 K. Simmen,9 R. Verloes9
1Medizinische
Hochschule Hannover, Germany; 2Amsterdam Medical Center,
Amsterdam, The Netherlands; 3Erasme Hospital, Université Libre de
Bruxelles, Belgium; 4Charité-Universitätsmedizin Berlin, Campus VirchowKlinikum, Germany; 5Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris,
France; 6Saint-Luc Université Catholique de Louvain, Belgium; 7Royal Free
Hospital, London, UK; 8 Medical University of Bialystok, Poland;
9Tibotec, Mechelen, Belgium; 10Tibotec Pharmaceuticals, USA
OPERA-1: TMC435 is a potent HCV NS3/4A inhibitor
• Non-covalent binding
NS3/4A protease inhibitor
• EC50 = 8 nM in genotype-1 replicon
• In vitro: synergistic with IFNα
and an NS5B inhibitor;
additive with RBV
• 3.9 log10 IU/mL decline in HCV RNA after 5 days’
monotherapy with TMC435 200 mg QD in genotype-1
infected treatment-experienced patients
• Pharmacokinetic profile allows for QD dosing
HCV, hepatitis C virus; IFNα, interferon α; QD, once daily; RBV, ribavirin
Lin et al. AAC 2009; Reesink et al. EASL 2008; Van ’t Klooster et al. AASLD 2008
OPERA-1 (Study TMC435-C201)
• Phase IIa, double-blind, placebo-controlled, proof-of-concept
trial
• treatment-naïve and treatment-experienced patients,
genotype-1 infection
• Data presented for treatment-naïve patients
• Cohort 1: TMC435 25 and 75 mg QD
• Cohort 2: TMC435 200 mg QD
• Standard entry criteria for PEG-IFN/RBV studies
• documented chronic HCV infection
• compensated liver disease including cirrhosis
PEG-IFN, pegylated interferon
OPERA-1 (Cohorts 1 and 2): objectives
• To study the dose dependency of the antiviral effect of
TMC435 QD in treatment-naïve genotype-1 HCV-infected
patients
• Panel A: during 1 week of monotherapy, plus 3 weeks combined
with SoC
• Panel B: combined with SoC over 4 weeks of treatment
• To determine the antiviral activity, safety and tolerability of
TMC435 QD
SoC, standard of care (pegylated interferon-2a + ribavirin)
OPERA-1 (Cohorts 1 and 2): study design
Treatment-naïve, genotype-1 HCV-infected patients
• Cohort 1: TMC435 25 and 75 mg QD
• Cohort 2: TMC435 200 mg QD
TMC435 25 mg QD
TMC435 25 mg QD + SoC
SoC
N=9
TMC435 75 mg QD
TMC435 75 mg QD + SoC
SoC
N=10
TMC435 200 mg QD
TMC435 200 mg QD + SoC
SoC
N=8
Placebo
Placebo + SoC
SoC
N=9
TMC435 25 mg QD+ SoC
SoC
N=9
TMC435 75 mg QD+ SoC
SoC
N=9
TMC435 200 mg QD+ SoC
SoC
N=10
Placebo + SoC
SoC
N=10
Panel B
Panel A
N=ITT
0
1
Week
SoC = pegylated interferon-2a + ribavirin (PEG-IFN-2a + RBV)
ITT, intent-to-treat population
4
24 or 48
OPERA-1 (Cohorts 1 and 2): demographics and baseline
disease characteristics
Cohort 1
PARAMETER
Cohort 2
Placebo
(N=13)
25 mg QD
(N=18)
75 mg QD
(N=19)
Placebo
(N=6)
200 mg QD
(N=18)
76.9
92.3
72.2
94.4
57.9
100.0
83.3
100.0
55.6
88.9
HCV subtype*, %
1a
1b
1 other
58.3
41.7
0
33.3
61.1
5.6
36.8
63.2
0
83.3
16.7
0
27.8
66.7
5.6
HCV RNA, log10 IU/mL, median
<800 000, %
800 000, %
6.6
15.4
84.6
6.7
5.6
94.4
6.4
26.3
73.7
6.4
33.3
66.7
6.6
11.1
88.9
Duration of HCV infection, years,
median
13.0
12.3
8.4
5.5
2.5
Cirrhosis, %
53.8
61.1
47.4
33.3
16.7
Patient demographics
Male, %
Caucasian, %
Disease characteristics
*Based on part of NS5B sequence
OPERA-1 (Cohorts 1 and 2): mean change in HCV RNA
from baseline to Day 7 (mono- and triple therapy)
Mean HCV RNA (log10 IU/mL)
change from baseline
1
0
0.02
-1
-1.72
-2
-2.63
-3
-3.43
-3.47
-4
-4.13
-4.55
-4.68
-5
-6
0
2
3
7
Day
Panel A: TMC435 monotherapy phase
Panel B: TMC435 combined with SoC
Panel A
Placebo
TMC435 25 mg
TMC435 75 mg
TMC435 200 mg
Panel B
Placebo
TMC435 25 mg
TMC435 75 mg
TMC435 200 mg
Mean (± SE) HCV RNA (log10 IU/mL)
change from baseline
OPERA-1 (Cohorts 1 and 2): mean change in HCV RNA
from baseline to Day 28 (mono- and triple therapy)
Panel A
Placebo
TMC435 25 mg
TMC435 75 mg
TMC435 200 mg
1
Panel B
Placebo
TMC435 25 mg
TMC435 75 mg
TMC435 200 mg
0
-1
-2
-2.74
-3
-3.64
-4
-4.26
-4.48
-4.74
-4.60
-5.52
-5.44
-5
-6
0
3
7
14
Day
Panel A: 1 week of TMC435 monotherapy followed by 3 weeks combined with SoC
Panel B: 4 weeks of TMC435 combined with SoC
21
28
OPERA-1 (Cohorts 1 and 2): response to treatment
at Day 28
Panel A
Patients
(%)
Panel B
_
>10 - <25 IU/mL
<10 IU/mL
100
80
60
40
20
0
Placebo 25 mg 75 mg 200 mg
n=8
n=9
n=9
n=8
Placebo 25 mg 75 mg 200 mg
n=9
TMC435 QD
n=9
n=9
n=10
TMC435 QD
• 6/9 patients in the 25 mg arm, 9/9 patients in the 75 mg arm and 10/10 patients
in the 200 mg arm of Panel B had HCV RNA <10 IU/mL at Week 12 (4-weeks
TMC435 + SoC, 8-weeks SoC only)
Panel A: 1 week of TMC435 monotherapy followed by 3 weeks combined with SoC
Panel B: 4 weeks of TMC435 combined with SoC
OPERA-1 (Cohorts 1 and 2): virology findings during the
first 4 weeks of treatment
•
•
No viral breakthroughs were observed in Panel B (4 weeks TMC435 + SoC)
5 viral breakthroughs were observed in Panel A (1 week TMC435 monotherapy
followed by 3 weeks TMC435 + SoC)
• 2 patients in 25 mg group
• 2 patients in 75 mg group
• 1 patient in 200 mg group
•
Among the viral breakthroughs in Panel A, emerging NS3 mutations† were
observed in all 5 patients
•
•
•
•
•
R155K (intermediate FC‡)
R155K + D168N (intermediate FC‡)
D168E (intermediate FC‡)
Q80R/K + D168E (high FC‡)
D168V (high FC‡)
Viral breakthrough: >1 log10 IU/mL increase in HCV RNA from nadir or >100 IU/mL in patients with previous HCV RNA <10 IU/mL
FC, fold change; intermediate FC: >10-100; high FC: >100
†based on in vitro passage experiments; ‡based on in vitro replicon SDM data for TMC435
OPERA-1 (Cohorts 1 and 2): adverse event (AE) summary
Cohort 1
Cohort 2
Placebo
(N=13)
25 mg QD
(N=18)
75 mg QD
(N=19)
Placebo
(N=6)
200 mg QD
(N=18)
0
0
7.7
0
0
0
0
0
10.5*
0
0
0
0
0
0
0
11.1*
0
0
0
38.5
30.8
7.7
15.4
50.0
44.4
27.8
27.8
47.4
21.1
26.3
31.6
50.0
16.7
16.7
0
16.7
27.8
27.8
22.2
Parameter, %
Any AE
Grade 3 or 4
Discontinuation due to AE
Serious AE
Death
Most common AEs†
Headache
Fatigue
Nausea
Influenza-like illness
• No evidence of hepatobiliary, renal, haematopoietic or cardiac disturbances
*Neutropenia
†Reported
in 4 subjects, related to PEG-IFN -2a, not or doubtfully related to TMC435
in >10 patients (all TMC435 groups combined)
OPERA-1 (Cohorts 1 and 2): total bilirubin at
baseline (Day 0) and Day 28
Panel A
Mean 40
mol/L
(± SE)
30
Panel B
ULN
20
10
0
•
•
*Baseline
Day 0 28
Placebo
n=6
0 28
25 mg
n=9*
0 28
75 mg
n=10
0 28
200 mg
n=8
0 28
Placebo
n=7
0 28
25 mg
n=9
0 28
75 mg
n=9
0 28
200 mg
n=10
Bilirubin levels decreased after the end of treatment with TMC435
Elevations in direct and indirect bilirubin levels were also observed, particularly in
the highest dose group
sample missing from 1 patient; ULN, upper limit of normal = 21 mol/L
OPERA-1 (Cohorts 1 and 2): ALT at baseline (Day 0)
and Day 28
Mean 250
U/L
(± SE) 200
Panel A
Panel B
150
100
50
ULN
0
Day 0 28
*Baseline
ULN
0 28
0 28
0 28
0 28
0 28
0 28
0 28
Placebo
25 mg
75 mg
200 mg
Placebo
25 mg
75 mg
200 mg
n=6
n=9*
n=10
n=8
n=6
n=9**
n=10
n=8
sample missing from 1 patient; **baseline sample missing from 2 patients
ALT, alanine aminotransferase
OPERA-1 (Cohorts 1 and 2): summary
TMC435 demonstrated potent antiviral activity in monotherapy and in
combination with SoC over 4 weeks of treatment
•
TMC435 25, 75 and 200 mg QD resulted in greater HCV RNA reductions than SoC alone
•
Dose-dependent antiviral activity was observed after 1 week of TMC435 monotherapy
•
In the 75 and 200 mg groups, all patients achieved HCV RNA levels <25 IU/mL and 8/9
and 7/10 respectively were undetectable at the end of 4-week triple therapy (Panel B)
Once-daily administration of TMC435 in combination with SoC in treatmentnaïve genotype-1 patients over 28 days was generally safe and well tolerated
•
TMC435 was not associated with AE-related treatment discontinuations
•
Most reported AEs were mild to moderate
•
Most common AEs included headache, fatigue, nausea and influenza-like illness
•
Bilirubin elevations were observed in some patients receiving TMC435, mostly with the
200 mg dose, and were generally mild and reversible in nature
•
Substantial decreases in transaminases were observed in patients receiving TMC435
OPERA-1 (Cohorts 1 and 2): conclusions
• In treatment-naïve patients infected with HCV
genotype-1, TMC435 in combination with SoC over
4 weeks of treatment:
• demonstrated potent antiviral activity
• was generally safe and well tolerated
• was not associated with AE-related treatment discontinuations
• These results support the development of TMC435
for treatment-naïve patients infected with HCV
genotype-1
Acknowledgements
The patients and their families
France
The OPERA-1 investigators and their study staff
Yves BENHAMOU, Paris
Patrice COUZIGOU, Pessac
Patrick MARCELLIN, Clichy
Jean-Michel MOLINA, Paris
Stanislas POL, Paris
Anne RACHLINE, Paris
Christian TREPO, Lyon
Netherlands
Henk REESINK, Amsterdam
Poland
Robert FLISIAK, Bialystok
Andrzej HORBAN, Warszawa
Maciej JABLKOWSKI, Lodz
Wieslaw KRYCZKA, Kielce
UK
Matthew CRAMP, Plymouth
Geoffrey DUSHEIKO, London
Graham FOSTER, London
Mark NELSON, London
Belgium
Yves HORSMANS, Brussels
Christophe MORENO, Brussels
Hans ORLENT, Bruges
Hans VAN VLIERBERGHE, Ghent
Germany
Thomas BERG, Berlin
Michael BIERMER, Berlin
Peter BUGGISCH, Hamburg
Andreas ERHARDT, Düsseldorf
Atef HALABI, Kiel
Michael Peter MANNS, Hannover
Karl-Heinz MOLZ, München
Jens RASENACK, Freiberg
Medivir AB, Sweden
Tibotec