SILEN-C1: Early Antiviral Activity and Safety of BI

Report
FALDAPREVIR PLUS PEGYLATED
INTERFERON ALFA-2A AND RIBAVIRIN
IN CHRONIC HCV GENOTYPE-1
TREATMENT-NAÏVE PATIENTS
FERENCI P 1 , ASSELAH T 2 , FOSTER GR 3 , ZEUZEM S 4 , SARRAZIN C 4 ,
MORENO C 5 , OUZAN D 6 , MAEVSKAYA M 7 , CALINAS F 8 , MORANO LE 9 ,
CRESPO J 10 , DUFOURJ -F 11 , BOURLIERE M 12 , AGARWAL K 13 , FORTON D 14 ,
SCHUCHMANN M 15 , ZEHNTER E 16 , NISHIGUCHI S 17 , OMATA M 18 , STERN J 19 ,
DATZENKO Y 20 , SCHERER J 19 , QUINSON AM 19
1 Me d i c a l
U n i ve r s i t y o f V i e n n a , V i e n n a , A u s t r i a ; 2 H e p a t o l o g y D e p a r t m e n t , B e a u j o n H o s p i t a l , A P - H P ,
U n i ve r s i t y P a r i s D i d e r o t 7 a n d I N S E R M U 7 7 3 , C R B 3 , C l i c h y, F r a n c e ; 3 Q u e e n Ma r y, U n i ve r s i t y o f
L o n d o n , L o n d o n , U K ; 4 JW G o e t h e U n i ve r s i t y H o s p i t a l , F r a n k f u r t , G e r m a n y; 5 H ô p i t a l U n i ve r s i t a i r e
E r a s m e , B r u s s e l s , B e l g i u m ; 6 I n s t i t u t A r n a u l t T za n c k , S t L a u r e n t d u V a r , F r a n c e ; 7 F i r s t Mo s c o w S t a t e
Me d i c a l U n i ve r s i t y, Mo s c o w, R u s s i a ; 8 C e n t r o H o s p i t a l a r d e L i s b o a C e n t r a l , L i s b o n , P o r t u g a l ;
9 H o s p i t a l Me i xo e i r o , V i g o , S p a i n ; 1 0 H o s p i t a l U n i v. D e V a l d e c i l l a , S a n t a n d e r , S p a i n ;
1 1 U n i ve r s i t ä t s k l i n i k f ü r V i s ze r a l e C h i r u r g i e u n d Me d i zi n , B e r n , S wi t ze r l a n d ; 1 2 H o p i t a l S a i n t J o s e p h ,
Ma r s e i l l e , F r a n c e ; 1 3 K i n g ' s C o l l e g e H o s p i t a l , L o n d o n , U K ; 1 4 S t G e o r g e ' s H o s p i t a l , L o n d o n , U K ;
1 5 U n i ve r s i t y H o s p i t a l Ma i n z, Ma i n z, G e r m a n y; 1 6 S c h we r p u n k t p r a xi s H e p a t o l o g i e , D o r t m u n d , G e r m a n y;
1 7 H yo g o C o l l e g e o f Me d i c i n e , H yo g o , J a p a n ; 1 8 Y a m a n a s h i C e n t r a l a n d K i t a H o s p i t a l s , Y a m a n a s h i ,
J a p a n ; 19B o e h r i n g e r I n g e l h e i m P h a r m a c e u t i c a l s I n c , R i d g e f i e l d , C T , U S A ; 20B o e h r i n g e r I n g e l h e i m
Pharmaceuticals GmbH & Co KG, Biberach, Germany
1
Introduction to faldaprevir
 Faldaprevir (FDV; BI 201335) is a
potent and selective inhibitor of HCV
NS3/4A1
 FDV has antiviral activity against HCV
genotypes (GT) 1, 2, 4, 5 and 6 in vitro1
 The pharmacokinetics of FDV allow
oral, once-daily administration
 High efficacy and favourable tolerability was shown in Phase II
studies of FDV in combination with pegylated interferon α2a and
ribavirin (PegIFN/RBV)2
2
1. White PW, et al. Antimicrob Agents Chemother 2010;54:4611–4618; 2. Sulkowski et al Hepatology 2013 Jan 28 (epub)
Study design
PR, pegylated interferon α2a 180 µg/week and weight-based ribavirin
Arm 1
ETS
Arm 2
(n=261)
PR
Placebo + PR
(n=133)
Placebo + PR
Observation Period
Faldaprevir
120 mg QD + PR
PR
Faldaprevir
120 mg QD + PR
No ETS
(n=262)
Faldaprevir
240 mg QD + PR
Placebo + PR
No ETS
Day 1
Observation Period
Observation Period
ETS
Arm 3
Observation Period
Week 12
PR
Week 24
Observation Period
Week 48

Patients enrolled from Europe and Japan

Eligibility: Treatment naive, GT1 infection, no HBV or HIV coinfection,
adult, platelets >90,000 cells/mm3

3
Week 72
Primary endpoint: SVR 12 weeks after completion of all treatment
Baseline data
Placebo
n=132
120 mg FDV
n=259
240 mg FDV
n=261
Male, n (%)
75 (57)
121 (47)
146 (56)
Caucasian, n (%)
103 (78)
203 (78)
205 (79)
Region, n (%)
Japan
Europe
24 (18)
108 (82)
52 (20)
207 (80)
50 (19)
211 (81)
Mean age, years (SD)
46.6 (12.53)
47.9 (11.44)
48.3 (11.89)
Mean BMI, kg/m2 (SD)
24.6 (4.25)
24.9 (4.21)
25.2 (4.63)
45 (34)
86 (65)
87 (34)
171 (66)
90 (34)
171 (66)
6.4 (3.4–7.7)
6.4 (3.3–7.5)
6.4 (3.0–7.4)
Baseline HCV RNA, n (%) ≥800 000 IU/mL
101 (77)
201 (78)
185 (71)
IL28B (rs12979860), n (%)
CC
Non-CC
46 (35)
86 (65)
107 (41)
151 (58)
101 (39)
160 (61)
Fibrosis stage, n (%)
≥F3
25 (19)
45 (17)
42 (16)
8 (6)
16 (6)
15 (6)
HCV GT-1 subtypea, n (%)
1a
1b
Median baseline HCV RNA levels,
log10 IU/mL (range)
Cirrhosis, n (%)
Yes
4
aHCV
GT-1 subtype analyses by sequencing of NS3
Primary endpoint
SVR12 (ITT)
(∆ = 26.7; 95% CI, 17.1–36.3; p<0.0001)
(∆ = 28.6; 95% CI, 19.0–38.2; p<0.0001)
100
79
80
SVR12 (%)
80
60
52
40
20
0
5
69/132
204/259
210/261
Placebo
FDV 120 mg
FDV 240 mg
SVR12 rates adjusted for race and genotype
ITT, intention-to treat
Early Treatment Success, Week 4 HCV RNA
Both FDV groups
Early Treatment Success (ETS): HCV RNA <25 IU/mL at Week 4
and undetectable at Week 8; patients with ETS in active treatment
arms were eligible to stop all treatment at Week 24
No ETS
12%
ETS, Week 4
<25 IU/mL, detected 13%
75%
6
ETS, Week 4
undetected
SVR12 in patients with ETS (received 24 weeks total
treatment duration)
Proportion of patients (%)
100
87
89
226/259
233/261
FDV 120 mg
FDV 240 mg
89
80
60
40
20
0
ETS
7
86
194/226
FDV 120 mg
208/233
FDV 240 mg
ETS + SVR12a
ETS, early treatment success: HCV RNA <25 IU/mL (detected or undetected) at Week 4
and <25 IU/mL (undetected) at Week 8. aDenominator = patients with ETS
Proportion of patients with SVR (%)
SVR12 among ETS patients:
BLQ (detected) vs BLD at Week 4
100
80
91
77
72
60
40
20
0
30/39
21/29
155/171
167/178
FDV 120 mg
FDV 240 mg
FDV 120 mg
FDV 240 mg
Week 4 ≤25 IU/mL, detected
8
94
Week 4, undetected
ETS, early treatment success: HCV RNA <25 IU/mL (detected or undetected) at Week 4
and <25 IU/mL (undetected) at Week 8
SVR12 according to HCV genotype-1 subtype (ITT)
100
84
83
76
80
SVR12 (%)
69
60
60
40
36
20
0
16/45
60/87
68/90
52/86
143/171
142/171
Placebo
FDV
120 mg
FDV
240 mg
Placebo
FDV
120 mg
FDV
240 mg
GT-1a
9
GT-1b
Other genotype-1 subtype = one patient in placebo arm and one patient in FDV 240 mg arm. Both achieved SVR12
Virological failure
Placebo
FDV 120 mg
GT-1a
50
40
30
20
10
0
13
10 9
8
11
1 0
Null/partial Breakthrough
response
10
18
15
Relapse
Proportion of patients (%)
Proportion of patients (%)
FDV 240 mg
GT-1b
50
40
30
20
12
10
0
7
6
4 4
7 6
0 0
Null/partial Breakthrough
response
Stopping rules:
• Null or partial response defined as lack of Early Virological Response, i.e. absence of HCV RNA
drop by ≥2 log10 from baseline at Week 12
• Breakthrough indicates confirmed ≥1 log10 rebound at any time during FDV or PegIFN/RBV treatment
Relapse
No significant effect of Q80K on SVR12 in GT-1a
100
23% (49/212) of GT-1a patients had Q80K at baseline
82
80
75
SVR12 (%)
69
73
60
40
20
0
42/61
FDV 120 mg
56/75
FDV 240 mg
Q80 wild type
11
16/22
9/11
FDV 120 mg
FDV 240 mg
Q80K
SVR12 according to IL28B genotype rs12979860 (ITT)
100
90
95
76
80
70
79
69
SVR12 (%)
63
60
51
40
28
20
0
29/46
96/107 96/101
35/68 85/122 87/126
Placebo FDV
FDV
120 mg 240 mg
Placebo FDV
FDV
120 mg 240 mg
CC
12
CT
5/18
22/29
27/34
Placebo FDV
FDV
120 mg 240 mg
TT
SVR12 for FDV 120 mg vs 240 mg
n/N (%)
FDV 120 mg
FDV 240 mg
60/87 (69)
143/171 (84)
68/90 (76)
142/171 (83)
157/203 (77)
44/52 (85)
158/205 (77)
47/51 (92)
96/107 (90)
85/122 (70)
22/29 (76)
96/101 (95)
87/126 (69)
27/34 (79)
172/212 (81)
30/45 (67)
9/16 (56)
187/219 (85)
23/42 (55)
6/15 (40)
Estimated difference in SVR12 (95% CI)
Genotype
1a
1b
Race
Caucasian
Asian
IL28B
CC
CT
TT
Fibrosis stage
<F3
≥F3
Cirrhosis
Baseline HCV RNA
<800 000 IU/mL
≥800 000 IU/mL
13
54/58 (93)
150/201 (75)
70/76 (92)
140/185 (76)
-100% -80% -60% -40% -20%
Favours 120 mg
0
20% 40% 60% 80% 100%
Favours 240 mg
Adverse event summary
N (%)
Placebo
n=132
120 mg FDV
n=259
240 mg FDV
n=261
Any AE
123 (93)
251 (97)
253 (97)
AEs leading to discontinuation
of all medication
5 (4)
10 (4)
14 (5)
AEs leading to discontinuation
of FDV or PBO only
0
2 (1)
8 (3)
8 (6)
17 (7)
17 (7)
64 (48)
134 (52)
144 (55)
8 (6)
21 (8)
23 (9)
Photosensitivity
0
0
2 (1)
Gastrointestinal
4 (3)
18 (7)
31 (12)
Anaemia
15 (11)
33 (13)
32 (12)
Jaundice
0
5 (2)
7 (3)
Serious AEs
AEs of at least moderate
intensitya
Rash
aDAIDS
Grade 2 to 4; protocol defined AEs of special interest
14 DAIDS, Division of AIDS table for grading the severity of adult and pediatric adverse events
Rash
N (%)
N (%) of patients with
event*
Mild
Moderate
Severe
Potentially life-threatening
N (%) of patients who
discontinued due to event
*All events resolved
15
Placebo
n=132
120 mg FDV
n=259
240 mg FDV
n=261
29 (22)
83 (32)
86 (33)
21 (16)
6 (5)
2 (2)
0
62 (24)
19 (7)
2 (1)
0
63 (24)
21 (8)
2 (1)
0
1 (1)
3 (1)
2 (1)
Grade ≥3 lab abnormalities during first 24 weeks
of treatment
N (%)
White blood cells
<1,499/mm3
Platelets
<49,999/mm3
Neutrophils
<749/mm3
Lymphocytes
<499/mm3
ALT
>5.1 x ULN
Total bilirubin
>2.6 x ULN
16
Placebo
n=132
120 mg FDV
n=259
240 mg FDV
n=261
4 (3)
10 (4)
11 (4)
4 (3)
4 (2)
7 (3)
24 (18)
53 (20)
31 (12)
15 (11)
49 (19)
48 (18)
4 (3)
5 (2)
2 (1)
1 (1)
29 (12)
138 (53)
*Laboratory value categories based on the DAIDS grading system
Changes in haemoglobin
Placebo
FDV 120 mg
FDV 240 mg
Mean haemoglobin
± SD (g/dL)
18
16
14
12
10
8
0
4
8
12
20
16
24
Weeks
N (%)
Placebo
n=132
120 mg FDV
n=259
240 mg FDV
n=261
38 (29)
64 (25)
57 (22)
Led to permanent RBV D/C
0 (0)
3 (1)
2 (1)
Led to RBV dose reduction
32 (24)
44 (17)
39 (15)
Received blood transfusion
1 (1)
2 (1)
2 (1)
Received EPO
4 (3)
10 (4)
12 (5)
Anaemia adverse event
17
Mean bilirubin ± SD (mg/dL)
Bilirubin changes over time
Total Conjugated
bilirubin bilirubin
5
Placebo
FDV 120 mg
FDV 240 mg
4
3
2
1
0
0
4
8
12
Weeks
18
16
20
24
Summary and conclusions
 FDV is highly efficacious in European and Japanese patients
infected with HCV GT-1
 Almost 90% of FDV-treated patients were eligible for
shortened treatment
 The 240 mg dose showed no benefit over 120 mg
for any subgroup
 FDV was well tolerated with few discontinuations due to AEs
at both dosages
 No incremental haemoglobin reduction was observed with FDV
and PegIFN/RBV compared with PegIFN/RBV alone
 Bilirubin elevations were benign and transient
19
Acknowledgements
• The patients enrolled in the STARTVerso1 trial
• Study investigators:
Austria
Peter Ferenci
Michael Gschwantler
Hermann Laferl
Andreas Maieron
Belgium
Jean Delwaide
Yves Horsmans
Peter Michielsen
Christophe Moreno
Frederik Nevens
Hans Van Vlierberghe
France
Armand Abergel
Tarik Asselah
Marc Bourliere
Jean-Didier Grangé
Dominique Guyader
Christophe Hezode
Dominique Larrey
Victor Ledinghen
Philippe Mathurin
Sophie Métivier
Denis Ouzan
Vlad Ratziu
Albert Tran
Germany
Keikawus Arastéh
Thomas Berg
Johannes Bogner
•
•
20
Rainer Günther
Dieter Häussinger
Dietrich Hüppe
Dietmar Klass
Ansgar Lohse
Stefan Mauss
Marcus Schuchmann
Jürgen Siebler
Ulrich Spengler
Christian Trautwein
Elmar Zehnter
Stefan Zeuzem
Japan
Akihiro Deguchi
Yukio Gibo
Yuichi Hirose
Tatsuya Ide
Takafumi Ichida
Shogo Iwabuchi
Michio Kato
Norifumi Kawade
Yasuteru Kondo
Makoto Kuboki
Hitoshi Mochizuki
Mitsuhiko Moriyama
Kazuyoshi Nagayama
Yoichi Nishigaki
Shuhei Nishiguchi
Kazunori Noguchi
Masao Omata
Yoshinori Sakai
Yoshiyuki Sakai
Yasuhito Tanaka
Kunihiko Tsuji
Yoshiyuki Ueno
Hiroshi Yatsuhashi
Osamu Yokosuka
Hirohito Yoneyama
Portugal
Filipe Calinas
Armando Carvalho
Tiago Bana e Costa
Guilherme Macedo
Leopoldo Matos
Célia Oliveira
José Presa
Luís Tavares
Romania
Florin Caruntu
Emanoil Ceausu
Liliana Preotescu
Adrian Streinu-Cercel
Russia
Pavel Bogomolov
Marina Maevskaya
Vadim Pokrovsky
Olga Sagalova
Alexey Yakovlev
Natalia Zakharova
Spain
Javier Crespo
Moises Diago
Jaime Enriquez
Luis Enrique Morano
Jose Domingo Pedreira
Manuel Romero
Ricard Solá
Vicente Soriano
Switzerland
Andreas Cerny
Jean-François Dufour
Daniel Genné
Beat Müllhaupt
David Semela
United Kingdom
Kosh Agarwal
Jane Collier
Fiona Gordon
Daniel Forton
Graham R. Foster
Mark Nelson
Stephen Ryder
Javier Vilar
Mark Wright
Alison Uriel
Boehringer Ingelheim for sponsoring the study and their clinical and statistical teams for study monitoring, data collection, and analysis
Editorial support provided by Katharine Howe of Adelphi Communications Ltd and funded by Boehringer Ingelheim

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