Fred Poordad, Michael W. Fried, Stefan Zeuzem, Peter

Fred Poordad, Michael W. Fried, Stefan Zeuzem, Peter

Fred Poordad, Michael W. Fried, Stefan Zeuzem, Peter Ferenci,
Oliver Lenz, Rekha Sinha, Katleen Callewaert, Monika Peeters,
Maria Beumont-Mauviel
Abstract 83
PILLAR: treatment-naïve patients (including F3)
12
0
Week
24
72
48
PR
Post-therapy FU
75 mg, n=78
150 mg, n=77
SMV + PR
PR
Post-therapy FU
75 mg, n=75
150 mg, n=79
Pbo + PR
PR
Post-therapy FU
Control, n=77
SMV + PR
Pbo + PR
SMV either 75 mg QD or 150 mg QD
RGT in SMV arms
ASPIRE: treatment-experienced patients
(prior relapsers, partial and null responders; including F3 and F4)
SMV + PR
Pbo + PR
SMV + PR
Post-therapy FU
100 mg, n=66
150 mg, n=66
100 mg, n=65
150 mg, n=68
Post-therapy FU
100 mg, n=66
150 mg, n=65
Post-therapy FU
Control, n=66
Post-therapy FU
Pbo + PR
SMV + PR
Pbo + PR
SMV either 100 mg QD or 150 mg QD
Poordad F, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 83.
Patients achieving SVR24, %
Placebo PR
100
80
Simeprevir 150 mg* PR
79
71
62
56
60
40
20
0
5/7
15/19
PILLAR treatmentnaïve: F3
4
1/23
38/68
ASPIRE treatmentexperienced: F3/F4
pooled
0/10
24/39
ASPIRE treatmentexperienced: F4 only
*Treatment arms within PILLAR and ASPIRE with different durations pooled
PR, pegylated interferon α-2a + ribavirin; SVR24, HCV RNA <25 IU/mL undetectable 24 weeks after planned end of treatment
Poordad F, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 83.
Patients achieving SVR24, %
Placebo PR
100
Simeprevir 150 mg* PR
80
67
65
60
40
33
20
0
10
0/10
17/26
Relapser
1/10
14/21
Partial responder
0/3
7/21
Null responder
31% (4/13) null responders with cirrhosis (F4) achieved SVR24
*Treatment arms across ASPIRE with different durations combined
PR, pegylated interferon α-2a + ribavirin ; SVR24, HCV RNA <25 IU/mL undetectable 24 weeks after planned end of treatment
Poordad F, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 83.
Vicente Soriano, Ed Gane, Peter Angus, Felix Stickel,
Jean-Pierre Bronowicki, Stuart Roberts, Michael Manns,
Stefan Zeuzem, Richard Vinisko, Ivona Herichova, Wulf Böcher,
Jerry Stern, and Federico Mensa
Abstract 84
No. with cirrhosis
(n=9)
Faldaprevir 120 mg QD +
BI 207127 600 mg TID + RBV
(n=7)
Faldaprevir 120 mg QD + BI 207127 600 mg TID + RBV
(n=5)
Faldaprevir 120 mg QD + BI 207127 600 mg TID + RBV
(n=9)
Faldaprevir 120 mg QD + BI 207127 600 mg BID + RBV
Follow-up
(n=3)
Faldaprevir 120 mg QD + BI 207127 600 mg TID, no RBV
Follow-up
Day 1
Follow-up
Week 16
Follow-up
Follow-up
Week 28
Week 40
Phase IIb, multicenter, open-label, randomized (1:1:1:1:1)
ƒ
Treatment-naïve patients with chronic HCV GT-1
Compensated cirrhosis allowed, 18–75 years of age, HCV RNA >100 000 IU/mL
Stopping rule: HCV RNA detectable between Weeks 6 and 8
Primary endpoint: SVR 12 weeks after treatment completion
Soriano V, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 84.
GT-1a
GT-1b
Cirrhosis
100
No cirrhosis
86
90
80
80
68
SVR (%)
70
50
60
57
60
50
43
43
40
42
33
30
20
11
10
0
BI 207127 dosing
Duration (weeks)
RBV
3/7
8/14
TID
16, 28, & 40
+
2/4
4/5
0/0
BID
28
+
1/3
TID
28
-
40/93 84/124
11/26 37/43
TID
16, 28, & 40
+
BID
28
+
2/18
15/25
TID
28
-
Soriano V, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 84.
Patrick Marcellin, John M Vierling, Bruce R Bacon, Michael Manns,
Christine Fandozzi, Jacqueline Gress, Luzelena Caro, Christopher Gilbert,
Peggy Hwang, Janice Wahl, Michael P Cooreman, Niloufar Mobashery
Abstract 766
MK-5172 is a once-daily, potent, next-generation NS3/4A protease inhibitor (PI)
Potent in vitro activity against a broad enzyme panel including all major hepatitis C virus (HCV) genotypes (G)1
In vitro activity against resistance-associated variants (RAVs) found in patients who failed therapy with
first-generation PIs (boceprevir,telaprevir, and TMC-435)2
5 log10 drop in HCV RNA levels in patients with HCV G1 following monotherapy of ≥30 mg once daily (qd)
for 7 days3
Interim
Analysis
Week Week
4
8
Assess Primary
Futility Analysis
Week Week
12
16
Arm 1:
MK-5172 100mg QD+ PR
PR
Arm 2:
MK-5172 200mg QD+ PR
PR
Arm 3:
MK-5172 400mg QD+ PR
PR
Arm 4:
MK-5172 800mg QD+ PR
PR
Arm 5:
PR
Assess
Futility
Week
24
Week
28
Week
36
Week
48
Week
72
48 Weeks – follow-up
24 weeks’ follow-up
48 Weeks – follow-up
24 weeks’ follow-up
48 Weeks – follow-up
24 weeks’ follow-up
48 Weeks – follow-up
24 weeks’ follow-up
44 Weeks – follow-up
Arm 5:
Boceprevir 800mg TID+ PR
PR
24 weeks’ follow-up
Marcellin P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 766.
Figure 6. Sustained virologic response at week 4 follow-up (SVR4) according to
genotype 1 subtype (G1a vs non-G1a) – combined cohort, FAS population.
TD(u)
TND
94.7%
96.3%
0.0
0.0
2.5
50
100%
0.0
80.0%
88.5%
100%
0.0
0.0
0.0
100.0
85.0
94.7
0.0
95.0%
0.0
91.7%
0.0
64.1%
0.0
100.0
96.3
92.9%
78.6%
7.2
80.0
88.5
100.0
95.0
92.9
0.0
91.7
71.4
64.1
60.0
25/39
12/20
MK-5172
100mg + PR
MK-5172
400mg + PR
13/14
19/20
11/12
Non-G1a
11/14
G1a
15/15
Non-G1a
23/26
G1a
G1a
MK-5172
200mg + PR
14/14
Non-G1a
8/10
G1a
26/27
Non-G1a
36/38
Non-G1a
23/23
G1a
35/40
Non-G1a
25
0
MK-5172
800mg + PR
BOC, boceprevir; PR, peginterferon alfa-2b + ribavirin; RGT, response-guided therapy; SC, second cohort;
TD(u), HCV target detected unquantifiable; TND, HCV target not detected; VC, vanguard cohort
Marcellin P, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 766.
60.0%
Non-G1a
75
100%
0.0
G1a
Patients, (%)
87.5%
G1a
100
BOC + PR
RGT
J.J. Feld, I.M. Jacobson, D.M. Jensen, G.R. Foster, S. Pol, E. Tam,
H. Berak, J.M. Vierling, J.A. Tavel, M.T. Navarro, S. Shahdad,
R. Kulkarni, S. Le Pogam, I. Najera, C.Y. Lim, N.S. Shulman, E.S. Yetzer
Abstract 81
Randomized (1:1:1), open-label, multicenter, parallel study of two cohorts
Stratification: G1a/G1b and IL28B
Cohort A: G1 prior partial responders
n=52
IFN-free: MCB + DNVr + RBV
Follow-up
n=49
Triple: DNVr + P/R
Follow-up
n=50
QUAD: MCB + DNVr + P/R
Follow-up
G1a pts added P/R and are
excluded from this analysis
Cohort B: G1 prior null responders
n=77
IFN-free: MCB + DNVr + RBV
Follow-up
n=77
QUAD: MCB + DNVr + P/R
Follow-up
n=74
QUAD: MCB + DNVr + P/R
0
12
G1a pts added P/R and are
excluded from this analysis
Follow-up
P/R
24
36
Weeks
48
DNVr = danoprevir/ritonavir 100 mg/100 mg bid; MCB = mericitabine 1000 mg bid;
P/R = peginterferon alfa-2a (40KD) 180 μg/week plus ribavirin 1000 mg or 1200 mg/day
ClinicalTrials.gov Identifier: NCT01331850
G1a patients in IFN-free arms offered 24-week P/R + assigned treatment due to unacceptable relapse rates
Meld J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 81.
Ongoing
72
Prior partial response
Patients with a virologic
response, %
100
Prior null response
88
87
80
68
55
60
44
39
40
20
n
N
20
23
10
23
9
23
28
32
21
31
17
31
EOT
SVR4
SVR12
EOT
SVR4
SVR12
0
IFN-free*: DNVr + MCB + RBV
Characteristics: partial vs. null responders
Similar IL28B genotype, BMI, age
Partials: higher baseline viral load (Median: 7.0 vs. 6.7 IU/mL; ≥7 log10 IU/mL: 52% vs. 34%)
Meld J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 81.
Patients with an SVR12, %
Genotype 1b
100
91
96
Genotype 1a
100
80
60
73
18
24
32
44
+ MCB
∆ 45%
40
20
75
30
n
N
19
21
25
26
30
30
8
27
0
Partial
Partial
Null
Partial
Partial
Null
responders responders responders responders responders responders
Triple: DNVr + P/R
Meld J, et al. 63rd AASLD; Boston, MA; November 9-13, 2012; Abst. 81.
QUAD: DNVr + MCB + P/R