Jean-Michel Pawlotsky, Shiv K. Sarin, Graham R. … · Jean-Michel Pawlotsky, Shiv K. Sarin, Graham...
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Jean-Michel Pawlotsky, Shiv K. Sarin, Graham R. Foster, Cheng-Yuan Peng, Jens Rasenack, Robert Flisiak, Teerha Piratvisuth, Heiner Wedemeyer,
Wan-Long Chuang, Wei Zhang and Nikolai V. Naoumov
Abstract 233
Patients stratified according to viral load and HCV genotype 2 or 3*Loading dose: ALV 600 mg BID for 1 week; †RVR by LOQ (<25 IU/mL) after 4 weeks of treatment; QD=once daily; RBV=ribavirin 800 mg/day; PegIFN=pegylated interferon α2a 180 μg/week; LOQ=limit of quantification
RVR† at W4
ALV 1000 n=83
ALV 600+RBV n=84
ALV 800+RBV n=94
ALV 600+PegIFN n=39
W48W24 W36ALVloading*
PegIFN+RBV n=40
PegIFN + RBV
RVR ALV 1000 mg QD
No RVR ALV 600 mg QD + PegIFN/RBV
RVR ALV 600 mg QD + RBV
No RVR ALV 600 mg QD + PegIFN/RBV
No RVR ALV 600 mg QD + PegIFN/RBV
RVR ALV 800 mg QD + RBV
RVR ALV 600 mg QD + PegIFN
W6
No RVR ALV 600 mg QD + PegIFN/RBV
Post-treatment follow up
SVR12 SVR24
Pawlotsky JM, et al. 63rd AASLD; Boston, MA; November 9-13, 2012:. Abst. 233.
80%85%
81% 80%
58%
11% 8% 6%10%
25%
0%10%20%30%40%50%60%70%80%90%
ALV 1000 alone/addPeg/RBV (n=83)
ALV600+RBValone/add Peg-IFN
(n=84)
ALV800+RBValone/add Peg-IFN
(n=94)
ALV+Peg-IFNalone/add Peg/RBV
(n=39)
Peg-IFN+RBV (n=40)
SVR24 Relapse
Pawlotsky JM, et al. 63rd AASLD; Boston, MA; November 9-13, 2012:. Abst. 233.
LOQ=limit of quantification (<25 IU/mL)-4.5
-4
-3.5
-3
-2.5
-2
-1.5
-1
-0.5
00 1 2 3 4 5 6
Mea
n ch
ange
from
bas
elin
e in
HC
V R
NA
(log 1
0IU
/mL)
Treatment week
ALV1000ALV600 + RBV
ALV800 + RBV
Pawlotsky JM, et al. 63rd AASLD; Boston, MA; November 9-13, 2012:. Abst. 233.
Alisporivir exposure (Cmin) strongly predicted high RVR
Low baseline viral load strongly predicted high RVR
High RBV mg/kg dose is associated with high RVR
Odds ratio 90% CI P value
Log (ALV Cmin at Week 4, ng/mL) 1.8 [1.3, 2.4] 0.002
Baseline HCV RNA (log10 IU/mL) 2.9 [2.1, 4.2] <0.0001
RBV mg/kg dose 1.1 [1.04, 1.16] 0.003
Age (year) 1.03 [1.01, 1.06] 0.04
Pawlotsky JM, et al. 63rd AASLD; Boston, MA; November 9-13, 2012:. Abst. 233.
LOQ=limit of quantification (<25 IU/mL)
29%
37%42%
32%
49%46%
0%
10%
20%
30%
40%
50%
60%
ALV1000 (n=82) ALV600+RBV (n=84) ALV 800+RBV (n=94)
Proportion of patients with HCV RNA <LOQ
Week 4 Week 6
Pawlotsky JM, et al. 63rd AASLD; Boston, MA; November 9-13, 2012:. Abst. 233.
Per protocol = patients with RVR who completed scheduled 24-week treatment and SVR24 assessment; Patients missing the SVR24 assessment were counted as treatment failure;SVR24 according to limit of quantification (<25 IU/mL); VB = viral breakthrough
71%
90% 87%
0 3% 0
24%
3%9%
0%10%20%30%40%50%60%70%80%90%
100%
ALV1000(n=17)
ALV 600+RBV(n=29)
ALV 800+RBV(n=32)
Prop
ortio
n of
pat
ient
s (%
)
Per protocol
SVR24 VB RelapseITT SVR24 68% 90% 78%
Pawlotsky JM, et al. 63rd AASLD; Boston, MA; November 9-13, 2012:. Abst. 233.
90% 92% 94%
0 0 08% 8% 4%
0%10%20%30%40%50%60%70%80%90%
100%
ALV 1000 add-on IFN(n=51)
ALV 600+RBV add-on IFN(n=47)
ALV 800+RBV add-on IFN(n=48)
Prop
ortio
n of
pat
ient
s (%
)
Per protocol
SVR24 VB Relapse
Per protocol = patients with RVR who completed scheduled 24-week treatment and SVR24 assessment; Patients missing the SVR24 assessment were counted as treatment failure;SVR24 according to limit of quantification (<25 IU/mL); VB = viral breakthrough
ITT SVR24 90% 86% 89%
Pawlotsky JM, et al. 63rd AASLD; Boston, MA; November 9-13, 2012:. Abst. 233.
Mean AEs/perpatient
2.0
5.4
3.1
5.2
3.4
8.6
Adverse Events (n)
ALV 1000, IFN-free (n=22)
ALV with add-onPeg/RBV (n=55)
ALV + RBVadd-on Peg (n=51)
ALV 600+RBVIFN-free (n=30)
ALV 800+RBVIFN-free (n=37)
ALV + RBVadd-on Peg (n=37)
0 50 100 150 200 250 300 350
B
C
A
Pawlotsky JM, et al. 63rd AASLD; Boston, MA; November 9-13, 2012:. Abst. 233.
All reported SAEs were in the IFN-containing arms
IFN-containing arms, n (%)(N=234)
IFN-free arms, n (%)(N=91)
Clinical AEsPsychiatric disorders 89 (38.0) 22 (24.2)Fatigue 85 (36.3) 12 (13.2)Headache 73 (31.2) 12 (13.2)Pyrexia 60 (25.6) 4 (4.4)Nausea 50 (21.4) 17 (18.7)Decreased appetite 50 (21.4) 9 (9.9)Pruritus 46 (19.7) 6 (6.6)Myalgia 40 (17.1) 6 (6.6)Rash 36 (15.4) 2 (2.2)Diarrhoea 35 (15.0) 4 (4.4)Arthralgia 35 (15.0) 3 (3.3)Asthenia 29 (12.4) 10 (11.0)Influenza-like illness 29 (12.4) 3 (3.3)
Pawlotsky JM, et al. 63rd AASLD; Boston, MA; November 9-13, 2012:. Abst. 233.
Laboratory - Hematology
Anemia
ALV + IFN(n=158)
ALV IFN-free(n=247)
ALV IFN-free(n=89)
24 486 Week
6
Thrombocytopenia
ALV IFN-free(n=89)
ALV IFN-free(n=247)
ALV + IFN(n=158)
24 48Week
Neutropenia
24 486 Week
ALV IFN-free(n=247)
ALV + IFN(n=158)
ALV IFN-free(n=89)
Pawlotsky JM, et al. 63rd AASLD; Boston, MA; November 9-13, 2012:. Abst. 233.
ULN=upper limit of normal; BL=baseline; W=week; EOT=end of treatment
-100
102030405060708090
100110
BL WI W2 W3 W4 W6 W8 W12 W16 W20 EOT
Bili
rubi
n le
vel (
µmol
/L)
Treatment Week
ALV 1000 mg (N=82) ALV 600 mg + pegIFN (N=39)ALV 600 mg + RBV (N=84) ALV 800 mg + RBV (N=94)pegIFN + RBV (N=37)
5xULN
3xULN
Total bilirubin level
Pawlotsky JM, et al. 63rd AASLD; Boston, MA; November 9-13, 2012:. Abst. 233.
0100200300400500600700800900
100011001200
BL WI W2 W3 W4 W6 W8 W12 W16 W20 EOT W28 W36
Fast
ing
trig
lyce
rides
(mg/
dL)
Time
PegIFN+RBV
500 mg/dL
350 mg/dL
150 mg/dL
0100200300400500600700800900
100011001200
BL WI W2 W3 W4 W6 W8 W12 W16 W20 EOT W28 W36Fa
stin
g tr
igly
cerid
es (m
g/dL
)
Time
ALV +/- RBV, IFN-free
500 mg/dL
350 mg/dL
150 mg/dL
0100200300400500600700800900
100011001200
BL WI W2 W3 W4 W6 W8 W12 W16 W20 EOT W28 W36
Fast
ing
trig
lyce
rides
(mg/
dL)
Time
ALV/RBV with add-on Peg-IFN
500 mg/dL
350 mg/dL
150 mg/dL
Pawlotsky JM, et al. 63rd AASLD; Boston, MA; November 9-13, 2012:. Abst. 233.
Alisporivir + Ribavirin treatment achieves high rates of SVR in patients with early HCV clearance, with low viral breakthrough or post-treatment relapse
Alisporivir exposure and Ribavirin dose are the most important determinants for RVR
The results provide insights into Alisporivir attributes as interferon-free treatment option:
Antiviral activity of cyclophilin inhibition with Alisporivir is associated with down-regulation of Interferon-Stimulated GenesLow rates of viral breakthrough, mostly associated with low Alisporivir exposure, further highlight the high barrier to resistance
The safety profile of Alisporivir, IFN-free was markedly better compared to IFN-containing regimens
Pawlotsky JM, et al. 63rd AASLD; Boston, MA; November 9-13, 2012:. Abst. 233.