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. Verloes 9 OPERA-1 trial (Study TMC435-C201): interim analysis of safety and antiviral activity of TMC435 in treatment- naïve genotype-1 HCV patients 1 Medizinische Hochschule Hannover, Germany; 2 Amsterdam Medical Center, Amsterdam, The Netherlands; 3 Erasme Hospital, Université Libre de Bruxelles, Belgium; 4 Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Germany; 5 Centre Hospitalier Universitaire Pitié-Salpêtrière, Paris, France; 6 Saint-Luc Université Catholique de Louvain, Belgium; Royal Free Hospital, London,
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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.
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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
OPERA-1 trial (Study TMC435-C201):
interim analysis of safety and antiviral activity of
TMC435 in treatment-naïve genotype-1 HCV patients
1Medizinische Hochschule Hannover, Germany; 2Amsterdam Medical Center, Amsterdam, The Netherlands; 3Erasme Hospital, Université Libre de Bruxelles, Belgium; 4Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, 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 bindingNS3/4A 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, ribavirinLin et al. AAC 2009; Reesink et al. EASL 2008; Van ’t Klooster et al. AASLD 2008
OPERA-1 (Cohorts 1 and 2): demographics and baseline disease characteristics
PARAMETER
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)
Patient demographics
Male, %
Caucasian, %
76.9
92.3
72.2
94.4
57.9
100.0
83.3
100.0
55.6
88.9
Disease characteristics
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
*Based on part of NS5B sequence
-6
-5
-4
-3
-2
-1
0
1
-1.72
-3.47
-4.55-4.68
0.02
-2.63
-3.43
-4.13
-6
-5
-4
-3
-2
-1
0
1
OPERA-1 (Cohorts 1 and 2): mean change in HCV RNA from baseline to Day 7 (mono- and triple therapy)
Mea
n H
CV
RN
A (
log 1
0 IU
/mL)
ch
ange
from
bas
elin
e
0 2 3 7Day
PlaceboPanel A
TMC435 25 mgTMC435 75 mgTMC435 200 mg
PlaceboPanel B
TMC435 25 mgTMC435 75 mgTMC435 200 mg
Panel A: TMC435 monotherapy phasePanel B: TMC435 combined with SoC
OPERA-1 (Cohorts 1 and 2): mean change in HCV RNA from baseline to Day 28 (mono- and triple therapy)
Mea
n (±
SE
) H
CV
RN
A (
log 1
0 IU
/mL)
ch
ange
from
bas
elin
e
1
0 3 7 14 21 28Day
0
-1
-2
Placebo PlaceboPanel B
TMC435 25 mg
Panel A
TMC435 25 mgTMC435 75 mgTMC435 200 mg
TMC435 75 mgTMC435 200 mg
-3
-4
-5
-6
-3.64
-4.74-5.52-5.44
-2.74
-4.26-4.48-4.60
Panel A: 1 week of TMC435 monotherapy followed by 3 weeks combined with SoCPanel B: 4 weeks of TMC435 combined with SoC
OPERA-1 (Cohorts 1 and 2): response to treatment at Day 28
• 6/9 patients in the 25 mg arm, 9/9 patients in the 75 mg arm and 10/10 patientsin the 200 mg arm of Panel B had HCV RNA <10 IU/mL at Week 12 (4-weeks TMC435 + SoC, 8-weeks SoC only)
Patients(%)
Placebo 25 mg 75 mg 200 mg
Panel A
Placebo 25 mg 75 mg 200 mg
Panel B
TMC435 QDTMC435 QD
n=8 n=9 n=9 n=8 n=9 n=9 n=9 n=10
0
20
40
60
80
100 >10 - <25 IU/mL<10 IU/mL
_
Panel A: 1 week of TMC435 monotherapy followed by 3 weeks combined with SoCPanel B: 4 weeks of TMC435 combined with SoC
• 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
Viral breakthrough: >1 log10 IU/mL increase in HCV RNA from nadir or >100 IU/mL in patients with previous HCV RNA <10 IU/mLFC, 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): virology findings during the first 4 weeks of treatment
OPERA-1 (Cohorts 1 and 2): adverse event (AE) summary
Parameter, %
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)
Any AE
Grade 3 or 4
Discontinuation due to AE
Serious AE
Death
0
0
7.7
0
0
0
0
0
10.5*
0
0
0
0
0
0
0
11.1*
0
0
0
Most common AEs†
Headache
Fatigue
Nausea
Influenza-like illness
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
*Neutropenia in 4 subjects, related to PEG-IFN -2a, not or doubtfully related to TMC435†Reported in >10 patients (all TMC435 groups combined)
• No evidence of hepatobiliary, renal, haematopoietic or cardiac disturbances
0
10
20
30
40Mean mol/L(± SE)
280280280 280Placebo 25 mg 75 mg 200 mg
n=7 n=9 n=9 n=10
280280280280Placebo 25 mg 75 mg 200 mg
n=6 n=9* n=10 n=8
Panel A Panel B
OPERA-1 (Cohorts 1 and 2): total bilirubin at baseline (Day 0) and Day 28
ULN
• 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
Day
*Baseline sample missing from 1 patient; ULN, upper limit of normal = 21 mol/L
0
50
100
150
200
250
OPERA-1 (Cohorts 1 and 2): ALT at baseline (Day 0) and Day 28
280280280 280
Placebo 25 mg 75 mg 200 mg
n=6 n=9** n=10 n=8
280280280280
Placebo 25 mg 75 mg 200 mg
n=6 n=9* n=10 n=8
Day
Mean U/L(± SE)
ALT, alanine aminotransferase
*Baseline sample missing from 1 patient; **baseline sample missing from 2 patients
Panel A Panel B
ULN ULN
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 treatment-naïve 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