Jean-Michel Pawlotsky, Shiv K. Sarin, Graham R. … · Jean-Michel Pawlotsky, Shiv K. Sarin, Graham R. Foster, Cheng-Yuan Peng, Jens Rasenack, Robert Flisiak, Teerha Piratvisuth,

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



RVR ALV 800 mg QD + RBV

RVR ALV 600 mg QD + PegIFN

W6


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


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


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


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


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%


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%


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


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)


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)


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


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


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


Documents

Jean-Michel Pawlotsky, Shiv K. Sarin, Graham R. … · Jean-Michel Pawlotsky, Shiv K. Sarin, Graham R. Foster, Cheng-Yuan Peng, Jens Rasenack, Robert Flisiak, Teerha Piratvisuth,