Transcript SILEN-C1: Early Antiviral Activity and Safety of BI 201335

SILEN-C1: sustained virological response
(SVR) and safety of BI 201335 combined
with peginterferon alfa 2a and ribavirin
(PegIFN/RBV) in treatment-naïve patients
with chronic genotype-1 HCV infection
M.S. Sulkowski,1 C. Emanoil,2 T. Asselah,3 F.A. Caruntu,4 J. Lalezari,5 P. Ferenci,6
A. Streinu-Cercel,4 H. Fainboim,7 H. Tanno,8 L. Preotescu,4 B. Leggett,9 F. Bessone,10 S.
Mauss,11 J.O. Stern,12 C. Häfner,13 Y. Datsenko,13 G. Nehmiz,13 W. Böcher,13 G. Steinmann13
On behalf of the SILEN-C1 study group
Hopkins University, Baltimore, MD, USA; 2“Dr. Victor Babes” Hospital for Infectious and Tropical
Diseases, Bucharest, Romania; 3Hôpital Beaujon, Clichy Cedex, France, 4“Prof. Dr. Matei Bals” Institute of
Infectious Diseases, Bucharest, Romania; 5Quest Clinical Research, San Francisco, CA, USA; 6Medical
University of Vienna, Vienna, Austria; 7Hospital Francisco J. Muniz, Uspallata, Argentina; 8Hospital Provincial
Del Centenario, Rosario, Argentina; 9Royal Brisbane & Women's Hospital, Brisbane, QLD, Australia; 10Instituto
CAICI, Rosario, Argentina; 11Center for HIV and Hepatogastroenterology, Düsseldorf, Germany; 12Boehringer
Ingelheim Pharmaceuticals, Ridgefield, CT, USA; 13Boehringer Ingelheim Pharma, Biberach, Germany
1Johns
Speaker declaration
I have financial relationships within the last 12 months
relevant to my presentation with Boehringer Ingelheim
Pharmaceuticals.
My presentation includes discussion of off-label
or investigational use of:
• BI 201335
• Peginterferon alfa 2a
• Ribavirin
SILEN-C1 trial
Double-blind, placebo-controlled phase IIb study in
treatment-naïve, HCV genotype-1 (GT-1) patients
n = 71
Placebo + PegIFN/RBV
PegIFN/RBV
n = 69
* 120 mg QD LI BI 201335 + PegIFN/RBV
PegIFN/RBV
n = 143
* 240 mg QD LI BI 201335 + PegIFN/RBV
PegIFN/RBV
n = 146
240 mg QD BI 201335 + PegIFN/RBV
PegIFN/RBV
D1 D4
Week 24
Week 48
lead-in period (LI) of PegIFN alfa 2a (180 μg/week) plus ribavirin (1,000 mg or 1,200 mg/day);
Re-randomisation 1:1 of patients with eRVR (extended rapid virological response) to 24 versus 48 weeks
of PegIFN/RBV
QD, once daily
*3-day
Main inclusion criteria
• Age 18 to 65 years
• GT-1 chronic hepatitis C infection
• Naïve to interferon and/or ribavirin
• HCV RNA ≥ 100,000 IU/mL
• Liver biopsy < 2 years without cirrhosis
Baseline characteristics
PegIFN/RBV
120 mg QD LI 240 mg QD LI
240 mg QD
n = 71
n = 69
n = 143
n = 146
Mean age (years)
45.6
46.3
44.7
46.3
Male gender (%)
57.7
58.0
51.7
54.1
White
80.3
84.1
83.2
83.6
Asian
11.3
13.0
14.7
11.6
Black
5.6
1.4
0.7
2.7
6.41
6.19
6.45
6.41
1a
45.1
27.5
46.9
34.9
1b
53.5
72.5
52.4
62.3
Otherb
1.4
0
0.7
2.7
Ethnicity (%)
Mean HCV RNA (log10)
Genotype,a (%)
aBased
on NS3/4A sequencing; bOther genotypes were 3A (n = 2), 4A (n = 1); 6L (n = 1); 6Q (n = 1). 1 patient was
confirmed as GT-1 but was neither 1a or 1b (subgenotype could not be determined)
Virological responsea
PegIFN/RBV
120 mg QD LI
240 mg QD LI
240 mg QD
P = 0.001
Proportion of patients (%)
P = 0.021
100
80
80
87
78
83
71
73
56
60
40
20
0
16
11/71
55/69
111/142 124/142
eRVR
aPer
P = 0.081
40/71
49/69 103/142 118/142
SVR
protocol: excluding 5 patients with non-GT-1 as per NS3/4A sequencing; eRVR: HCV RNA < 25 IU/mL at
Week 4 and undetected at Weeks 8 to 20
SVR in eRVR patientsa randomised to
24 or 48 weeks of PegIFN/RBV
240 mg QD LI
240 mg QD
P = 0.743
Proportion of patients (%)
P = 0.051
100
93
96
90
53/57
46/48
53/59
82
80
60
40
20
40/49
0
24 weeks
a78%
48 weeks
and 87%, respectively, eligible for re-randomisation to 24 and 48 weeks’ PegIFN/RBV
Virological failures
Proportion of patients (%)
PegIFN/RBV
a≥
120 mg QD LI
240 mg QD LI
240 mg QD
100
80
60
40
20
0
14.1
2.8 5.8 4.2 2.8
Breakthrougha
on BI 201335
0
2.9
0
0.7
Breakthrougha on
PegIFN/RBV
7.2 10.6 7.7
Relapseb
1 log10 rebound from nadir, or rebound to ≥ 100 IU/mL if nadir < lower limit of detection (LLOD) on treatment,
confirmed in a second sample; bRebound at end of all treatment from nadir < LLOD after end of treatment
Adverse eventsa
PegIFN/RBV
(%)
All patients (nb)
120 mg QD LI 240 mg QD LI
(%)
(%)
240 mg QD
(%)
71
68
138
149
Nausea
19.7
25.0
47.1
44.3
Vomiting
5.6
20.6
18.1
22.8
Diarrhoea
18.3
13.2
31.9
26.8
Jaundice
1.4
5.9
18.8
24.2
0
0
0
0
16.9
20.6
28.3
26.8
2.8
0
2.9
0
8.0
3.6
14.1
4.0
16.9
32.4
34.8
37.6
Severe
Rashc
Moderate
Severe
Pruritus
events ≥ 10% compared with PegIFN/RBV; bNumber quoted is according to given treatment;
cNo cases of Stevens-Johnson syndrome, erythema multiforme or drug rash with eosinophilia and
systemic symptoms
aAdverse
Adverse events: overall summary
PegIFN/RBV
(%)
120 mg QD LI 240 mg QD LI
(%)
(%)
240 mg QD
(%)
All patients (na)
71
68
138
149
With severe adverse
events
4.2
11.8
15.9
12.8
Fatalities
1.4
0
0
0
Discontinuations for
adverse events
1.4
4.4
11.6
5.4
0
0
0
1.4
0
0
0
4.4
3.6
0
0
7.7
3.4
0.7
0.7
0.7
Discontinuations for
Rash
Photosensitivity
Jaundice
Others
aNumber
quoted is according to given treatment
Effect of BI 201335 on bilirubin
metabolism and ALT
Total bilirubin mg/dL
(normal range 0.1–1)
PegIFN/RBV
240 mg QD LI
240 mg QD
Mean total bilirubin (mg/dL)
4
3.5
3
2.5
2
1.5
1
0.5
0
BL
ALT U/L
(normal range 0–56)
120 mg QD LI
Day
4
Week
1
Week Week Week Week Week
2
4
8
10
12
Week Week Week Week
16
20
24
28
Mean ALT (U/L) +/– SE
140
120
100
80
60
40
20
0
BL
Day
4
Week
1
Week Week Week Week Week
2
4
8
10
12
BL, baseline; ALT, alanine amino transferase
Week Week Week Week
16
20
24
28
Sane R, et al. EASL 2011. Abstract 1236
Mean haemoglobin (g/dL)
Effect of BI 201335 on haemoglobin
20
PegIFN/RBV
120 mg QD LI
240 mg QD LI
240 mg QD
18
16
14
12
10
BL
Day
4
Week
1
Week
2
Week
4
Week
8
Week
10
Week
12
Week
16
Week
20
Week
24
Week
28
PegIFN/RBV
120 mg QD LI
240mg QD LI
240 mg QD
n/N
%
n/N
%
n/N
%
n/N
%
Patients requiring RBV
dose reduction
20/71
28.2
15/69
21.7
34/143
23.8
36/146
24.7
ESAsa
6/71
8.5
6/69
8.8
5/137
3.6
8/150
5.4
aPatients
using ESAs during the BI 201335 treatment period
BL, baseline; RBV, ribavirin; ESAs, erythropoiesis stimulating agents
Discussion: virological response
• High SVR rates at all doses evaluated
• Up to 83% at 240 mg QD
• At 240 mg QD, 87% of patients achieved eRVR and
required only 24 weeks’ PegIFN/RBV
• eRVR-guided treatment duration of 24 weeks achieved
equivalent SVR rates as 48 weeks’ PegIFN/RBV
with 240 mg QD
• 3-day PegIFN/RBV lead-in did not increase
virological response
Discussion: safety and tolerability
• Most adverse events were those commonly related to
PegIFN/RBV therapy
– No excess effect on haemoglobin
• Mild-to-moderate jaundice and rash are the main
adverse events associated with BI 201335
• Jaundice due to isolated indirect hyperbilirubinaemia
without liver injury
• Phase III trials testing 120 mg QD and 240 mg QD
without lead-in are underway
Acknowledgements
• Patients and study investigators at study centres in the following countries:
Argentina
Jorge Daruich
Hugo Tanno
Hugo Fainboi
Marcelo Silva
Fernando Bessone
Australia
Jacob George
William Sievert
Barbara Leggett
Graeme MacDonald
Stephen Riordan
Sally Bell
Joe Sasadeusz
Amany Zekry
Simone Strasser
Austria
Peter Ferenci
Michael Gschwantler
Andreas Maieron
Canada
Curtis Cooper
Jenny Heathcote
Stephen Shafran
Bernard Willems
Keith Tsoi
Czech Republic
Jan Galsky
Petr Kumpel
France
Tarik Asselah
Yves Benhamou
Stanislas Pol
Marc Bourlière
Jean-Pierre Bronowicki
Dominique Larrey
Jean-Michel Pawlotsky
Christophe Hezode
Jean-Didier Grange
Christian Trepo
Germany
Keikawus Arastéh
Thomas Berg
Michael P. Manns
Dieter Häussinger
Stefan Zeuzem
Michael Gregor
Ansgar Lohse
Marcus Schuchmann
Johannes Wiegand
Stefan Mauss
Ulrich Spengler
Wolfgang E. Schmidt
Elmar Zehnter
Netherlands
Henk W. Reesink
Portugal
Armando Carvalho
Fernando Ramalho
Filipe Calinas
Cristina Valente
José Sarmento
Republic of Korea
Jeong Heo
DoYoung Kim
SeongGyu Hwang
SookHyang Jeong
Young Oh Kweon
Kwan Sik Lee
HanChu Lee
SeungWoon Paik
SungWon Cho
YounJae Lee
Mong Cho
Romania
Adrian Streinu-Cercel
Liliana Preotescu
Florin Alexandru Caruntu
Ceasu Emanoil
Spain
Jose Luis Calleja
Jose María Sanchez Tapias
Javier García-Samaniego
Switzerland
Beat Müllhaupt
Daniel Genné
Enos Bernasconi
Jürg Reichen
Markus Flepp
United Kingdom
William Rosenberg
Mark Wright
Fiona Gordon,
Graham Foster
Stephen Ryder
Kosh Agarwal
United States
Mark Sulkowski
Douglas Dieterich
David Wright
Donald Jensen
Jacob Lalezari
• Boehringer Ingelheim for sponsoring the study and their clinical and statistical teams for study
monitoring, data collection and analysis
• Editorial support provided by StemScientific