Highlights of AASLD 2012
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Highlights of AASLD 2012
CCO Official Conference Coverage
of the 2012 Annual Meeting of the American Association for the
Study of Liver Diseases
November 9-13, 2012
Boston, Massachusetts
In partnership with
This program is supported by educational grants from
This program is supported by an educational grant from
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Faculty
Graham R. Foster, FRCP, PhD
Professor of Hepatology
The Liver Unit
Consultant Hepatologist
Queen Marys University of London
London, United Kingdom
Paul Y. Kwo, MD
Professor of Medicine
Medical Director of Transplantation
Division of Medicine/Gastroenterology/Hepatology
Indiana University School of Medicine
Indianapolis, Indiana
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Faculty Disclosures
Graham R. Foster, FRCP, PhD, has disclosed that he has
received consulting fees and fees for non-CME services from
Boehringer Ingelheim, Bristol-Myers Squibb, Gilead
Sciences, Janssen, Merck, Novartis, Roche, and Vertex;
and grants for research support from Janssen and Roche.
Paul Y. Kwo, MD, has disclosed that he has received
consulting fees from Abbott, Bristol-Myers Squibb, Gilead
Sciences, Merck, Novartis, and Vertex; fees for non-CME
services from Bristol-Myers Squibb, Merck, and Vertex;
grants for research support from Abbott, Bristol-Myers
Squibb, Gilead Sciences, Merck, Roche, and Vertex.
Hepatitis C
Current Therapy
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OPTIMIZE: Telaprevir BID vs Telaprevir q8h
in Tx-Naive Pts With GT1 HCV Infection
 Randomized, multicenter, open-label phase III noninferiority trial
Stratified by fibrosis status
(F0-F2 vs F3-F4), IL28B
GT (CC, CT, TT)
Wk 12
Wk 24
RVR
Treatmentnaive
patients with
chronic GT1
HCV infection
(N = 740)
Telaprevir 750 mg q8h +
PegIFN/RBV
(n = 371)
Buti M, et al. AASLD 2012. Abstract LB-8.
Follow-up
PegIFN/RBV
No
RVR
RVR
Telaprevir 1125 mg BID +
PegIFN/RBV
(n = 369)
Wk 48
PegIFN/RBV
No
RVR
PegIFN/RBV
Follow-up
PegIFN/RBV
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OPTIMIZE: Efficacy of Telaprevir BID vs
Telaprevir q8h in GT1 HCV Infection
 SVR12 rates similar with TVR BID and q8h dosing regimens in all
subgroups
 Similar safety and tolerability profile in both treatment arms
100
92
87
80
SVR12 (%)
TVR q8h/PR
TVR BID/PR
68
68
78
65
81
66
60
59
58
61/
103
61/
105
40
20
0
n/ 92/
N = 106
97/
105
CC
141/ 139/
208 206
CT
37/
57
38/
58
TT
IL28B GT
Buti M, et al. AASLD 2012. Abstract LB-8. Reproduced with permission.
209/ 213/
268 264
F0-2
F3/4
Liver Disease Status
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Retrospective Analysis of TVR in Pts With
GT1 HCV and Compensated Cirrhosis
 Retrospective study from single liver transplantation clinic
 eRVR: 35% (14/40 pts)
100
 EOT response: 75% (6/8 pts)
– SAE (n = 12)
– Lack of viral response (n = 11)
– Pt preference (n = 6)
– Loss of insurance (n = 2)
Gallegos-Orozco JF, et al. AASLD 2012. Abstract 53.
80
Patients (%)
 Reasons for discontinuation
100
72
62
60
40
22
20
n/ N=
0
50/
50
36/
50
31/
50
11/
50
16
8/
50
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N-CORE: 24 vs 48 Wks of PegIFN alfa-2a +
RBV in GT2/3 Patients Without RVR
 Multicenter, international, randomized, open-label phase
IIIb trial
Wk 24
Tx-naive patients with
chronic GT2/3 HCV
infection who initiated
pegIFN/RBV therapy and
did not achieve RVR but
did achieve EVR
(N = 235)*
Wk 48
Wk 72
Stop therapy; 48-wk follow-up
(n = 95)
Continue PegIFN/RBV
(n = 93)
Stop therapy; 24-wk follow-up
*47 patients dropped out and did not reach randomization at Wk 24.
Cheinquer H, et al. AASLD 2012. Abstract 156.
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N-CORE: SVR24 Rates Comparable With
24 or 48 Wks of PegIFN alfa-2a/RBV
100
SVR24 (%)
80
73
63
61
60
52
24-wk pegIFN/RBV
48-wk pegIFN/RBV
54
52
40
20
n/N =
0
49/
95
57/
93
ITT
(n = 188)
Odds Ratio
49/
95
51/
81
Per Protocol
(n = 176)
49/
90
46/
63
Study Completer
(n = 153)
0.68
0.63
0.44
95% CI
0.38-1.21
0.35-1.16
0.22-0.89
P Value
.1934
.1461
.0231
 Higher incidence of AEs, SAEs, AE-related dose reductions in 48-wk arm
Cheinquer H, et al. AASLD 2012. Abstract 156. Reproduced with permission.
Hepatitis C Current Therapy:
Anemia Management
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Anemia Management in HCV Pts Treated
With BOC: Erythropoietin vs RBV Reduction

Subanalysis within randomized trial of GT1 HCV therapy–naive pts receiving
4 wks of lead-in, then either 44 wks of triple therapy or RGT (24-44 wks)[1,2]
Stratified by black vs nonblack,
anemia onset ≤ 16 wks vs > 16 wks
from initiation of lead-in
Pts with Hb ≤10 g/dL*
during BOC-based therapy
(N = 500)
RBV Dose Reduction (by 200-400 mg/day)
(n = 249)†
Erythropoietin 40,000 IU/wk
(n = 251)†

Secondary anemia management with RBV dose reduction, erythropoietin
administration, or transfusion, allowed if Hb ≤ 8.5 g/dL

Patients discontinued if Hb ≤ 7.5 g/dL
*Baseline Hb requirements: 12-15 g/dL for women, 13-15 g/dL for men.
†RBV Dose Reduction included 23 pts with cirrhosis; Erythropoietin included 25 pts with cirrhosis.
1. Poordad F, et al. AASLD 2012. Abstract 154. 2. Lawitz E, et al. AASLD 2012. Abstract 50.
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SVR Rates With RBV Dose Reduction or
Erythropoietin for Anemia Management

Similar SVR rates (71%) with both strategies[1,2]
– Similar SVR rates regardless of timing of anemia management, number of RBV
dose reductions, or lowest RBV dose received
– Lower SVR rates if < 50% of per protocol total RBV dose received

Higher SVR rate if anemia management initiated with undetectable HCV RNA[2]
100
SVR (%)
80
86
71
86
RBV dose reduction
Erythropoietin
71
56
60
56
40
20
n/N =
0
178/ 178/
249 251
111/ 107/
129 124
67/ 71/
120 121
All Pts
Undetectable
Detectable
1. Poordad F, et al. EASL 2012. Abstract 1419. 2 Poordad F, et al. AASLD 2012. Abstract 154. Reproduced
with permission.
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SVR Rates With RBV Dose Reduction or
Erythropoietin in Cirrhotics
 SVR rates similar with each anemia management strategy in both
cirrhotic and noncirrhotic patients
 Higher proportion of cirrhotic patients received secondary anemia
management (44% vs 26%; P = .009)
 RBV dose reduction should be primary strategy for managing anemia,
but erythropoietin may be strongly considered as secondary treatment
SVR, % (n/N)
Noncirrhotic
(n = 438)
Cirrhotic
(n = 48)
RBV dose reduction
73 (162/221)
57 (13/23)*
Erythropoietin
72 (157/217)
64 (16/25)*
*P = .5966 for difference between arms among pts with cirrhosis.
Lawitz E, et al. AASLD 2012. Abstract 50.
HCV/HIV-Coinfected Patients
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Study 110: Telaprevir + PegIFN/RBV in
GT1 HCV Tx-Naive HCV/HIV Coinfection

Multicenter, randomized, double-blind, placebo-controlled phase II trial
Wk 60
Wk 48 (SVR12)
Wk 12
Part A: No Current ART
HCV/HIV-coinfected patients,
CD4+ cell count ≥ 500 cells/mm3,
HIV-1 RNA ≤ 100,000 copies/mL
(N = 13)
Part B: Stable ART
HCV/HIV-coinfected patients on
stable ART,*
CD4+ cell count ≥ 300 cells/mm3,
HIV-1 RNA ≤ 50 copies/mL
(N = 47)
TVR† 750 mg
q8h +
PegIFN/RBV
WK 72
(SVR24)
PegIFN/RBV
(n = 7)
Follow-up
Placebo +
PegIFN/RBV
PegIFN/RBV
(n = 6)
TVR† 750 mg
q8h +
PegIFN/RBV
PegIFN/RBV
(n = 31)
Follow-up
Placebo +
PegIFN/RBV
*Either EFV/TDF/FTC or ATV/RTV + TDF + (FTC or 3TC).
†TVR dose increased to 1125 mg q8h with EFV.
Sulkowski MS, et al. AASLD 2012. Abstract 54.
PegIFN/RBV
(n = 16)
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Study 110: SVR24 With TVR + PegIFN/RBV
in HCV GT1/HIV-Coinfected Patients

Higher SVR24 rate with TVR-based
therapy
Telaprevir + PR
Placebo + PR
100
SVR24 (%)
80

– TVR plasma levels similar in
patients with or without ART
80
74
71
50
45
40
– EFV and ATV/RTV plasma
levels similar in patients with
or without TVR
69
60
50
33

No HIV breakthroughs in patients
using ART during HCV treatment

Safety and tolerability similar to
treatment in patients with HCV
monoinfection
20
n/N =
0
No significant drug–drug
interactions with TVR and ART
28/ 10/
38 22
5/
7
2/
6
11/ 4/
16 8
12/ 4/
15 8
Sulkowski MS, et al. AASLD 2012. Abstract 54. Reproduced with permission.
Novel DAAs + PegIFN/RBV
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ATOMIC: Sofosbuvir (GS-7977) Plus PR in
Treatment-Naive Genotype 1 Patients

Interim analysis of randomized, open-label phase IIb study with sofosbuvir
(nucleoside polymerase inhibitor)
Wk 24
Wk 12
SOF + PegIFN/RBV
(n = 52)
Treatmentnaive,
noncirrhotic
patients*
(N = 332)
SOF + PegIFN/RBV
(n = 125)
SOF + PegIFN/RBV
(n = 155)
SOF
(n = 75)
SOF + RBV
(n = 75)
*All infected with GT1 HCV, except for 11 patients with GT4 HCV and 5 with GT6 HCV in 24-wk arm of SOF + pegIFN/RBV.
Hassanein T, et al. AASLD 2012. Abstract 230.
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ATOMIC: Sofosbuvir (GS-7977) Plus PR in
Treatment-Naive Genotype 1 Patients
SVR12 in ~ 90% patients with 12 or 24 wks of treatment

High rates of SVR12 in genotype 4/6 with 24 wks of treatment

Sofosbuvir well tolerated up to 24 wks
HCV RNA < LOD (%)

100
98 99 99
80
40
SOF + PR
24 wks
40
SOF + PR
12 + 12 wks
20
100
GT4 HCV
(n = 11)
60
GT6 HCV
(n = 5)
0
EOT

100
82
60
20
100
80
SOF + PR
12 wks
0

100
90 92 91
EOT
SVR12
11 patients (1 in 12-wk group) who
attained SVR12 subsequently lost to
follow-up

No relapse after SVR12 in any group

Hassanein T, et al. AASLD 2012. Abstract 230.
SVR12
11/11 patients with genotype 4 HCV
achieved RVR and EOT response
–
2 LTFU without posttreatment data
No relapse after SVR12 in either group
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ELECTRON: Sofosbuvir, GS-5885, and
RBV in Noncirrhotic Pts With GT1 HCV
 Interim analysis of nonrandomized phase II study with sofosbuvir
(nucleoside polymerase inhibitor) ± GS-5885 (NS5A inhibitor)
Wk 12
Patients, %
EOT SVR4 SVR12
Treatment naive (n = 25)
SOF + RBV
100
88
84
Null responders (n = 10)
SOF + RBV
100
10
10
Treatment naive (n = 25)
SOF + GS-5885 + RBV
100
100
Null responders (n = 9)
SOF + GS-5885 + RBV
100
100*
 No SAEs related to study drugs; AE profile consistent with RBV
toxicity profile
*Data reported for 3 pts only. Data collection ongoing.
Gane EJ, et al. AASLD 2012. Abstract 229.
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ELECTRON: Sofosbuvir in Patients With
GT2/3 HCV
 Interim analysis of nonrandomized phase II study with SOF
(nucleoside polymerase inhibitor) ± GS-5885 (NS5A inhibitor)
Wk 4
(n = 10)
(n = 10)
Wk 8
SOF + PegIFN + RBV
Treatmentexperienced,
GT2/3 HCV
SVR, %
100 (SVR24)
SOF + PegIFN + RBV
(n = 9) SOF + PegIFN + RBV
Treatment-naive,
GT2/3 HCV
(N = 95)
Wk 12
SOF + RBV
SOF + RBV
100 (SVR24)
100 (SVR24)
(n = 11)
SOF + RBV
100 (SVR24)
(n = 10)
SOF + Reduced-Dose RBV (800 mg/day)
60 (SVR8)
(n = 10)
SOF
60 (SVR24)
(n = 25)
SOF + RBV
64 (SVR12)
(n = 10)
SOF + PegIFN + RBV
100 (SVR24)
(n = 25)
SOF + RBV
Gane EJ, et al. AASLD 2012. Abstract 229. Reproduced with permission.
68 (SVR12)
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MATTERHORN: Danoprevir/RTV,
Mericitabine, and PegIFN/RBV in GT1 HCV

Randomized, open-label phase II trial of RTV-boosted danoprevir (protease
inhibitor), mericitabine (nucleoside polymerase inhibitor), and pegIFN/RBV
Wk 24
Noncirrhotic pts with
GT1 HCV and previous
partial response to
pegIFN/RBV
(N = 151)
Wk 48
Danoprevir/RTV +
Mericitabine + RBV* (n = 52)
Danoprevir/RTV +
PegIFN/RBV (n = 49)
Danoprevir/RTV +
Mericitabine + PegIFN/RBV (n = 50)
Noncirrhotic pts with
GT1 HCV and previous
null response to
pegIFN/RBV
(N = 228)
Danoprevir/RTV +
Mericitabine + RBV* (n = 77)
Danoprevir/RTV +
Mericitabine + PegIFN/RBV (n = 77)
Danoprevir/RTV +
Mericitabine + PegIFN/RBV (n = 74)
PegIFN/RBV
*GT1a HCV pts added pegIFN/RBV due to high relapse rates and are excluded from this analysis.
Feld JJ, et al. AASLD 2012. Abstract 81.
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MATTERHORN: Response to DNV/RTV,
MCB, and PegIFN/RBV in GT1 HCV

Response rates highest with 4-drug
therapy and lowest with pegIFN-free
therapy in both cohorts
–

DNV/RTV + MCB + RBV
Response (%)
All regimens generally well tolerated
–
3 potentially treatment-related SAEs
DNV/RTV + MCB + pegIFN/RBV
–
5 discontinuations due to AEs
87 94 94
86
Prior Null Response
88
GT1b
96
100
84
80
0
55
56
39
40
n/N =
91
96
GT1a
100
80
60
20
Less relapse with addition of MCB
DNV/RTV + pegIFN/RBV
Prior Partial Response
100
Higher response with pegIFN-containing
regimens in GT1b vs 1a
20/ 46/ 47/
23 49 50
EOT
9/ 27/ 43/
23 48 50
28/ 73/
32 76
17/ 62/
31 74
SVR12
EOT
SVR12
SVR12 (%)

75
73
18/
24
32/
44
60
40
20
n/N =
0
30
19/
21
Feld JJ, et al. AASLD 2012. Abstract 81. Reproduced with permission.
25/
26
30/
30
8/
27
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Daclatasvir and Asunaprevir in GT1 HCV
Previous Null Responders

AI447-011: randomized, open-label phase IIa study with daclatasvir (NS5A
inhibitor) and asunaprevir (NS3 protease inhibitor)
Wk 24
Daclatasvir 60 mg QD +
Asunaprevir 200 mg BID*
(n = 18)
Daclatasvir 60 mg QD +
Asunaprevir 200 mg QD*
(n = 20)
Noncirrhotic pts with
GT1 HCV and
previous null response
to pegIFN/RBV
(N = 101)
Daclatasvir 60 mg QD +
Asunaprevir 200 mg BID + PegIFN/RBV
(n = 20)
Daclatasvir 60 mg QD +
Asunaprevir 200 mg QD + PegIFN/RBV
(n = 21)
Daclatasvir 60 mg QD +
Asunaprevir 200 mg BID + RBV
(n = 22)
*Only pts with GT1b HCV included in dual-therapy arms.
Lok AS, et al. AASLD 2012. Abstract 79.
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Outcomes With Daclatasvir + Asunaprevir
± PegIFN or RBV in Null Responders

High response rates with 4-drug
regimen of DCV + ASV + pegIFN/RBV

Lower response rates with 2-drug
regimen (all GT1b pts)
–
HCV RNA < LLOQ (%)
100

Better response with ASV 200 mg BID
vs ASV 200 mg QD
100 100
90
DCV + ASV (BID) + PR
DCV + ASV (QD) + PR
DCV + ASV (BID)
DCV + ASV (QD)
95
89
78
80
70
65
0
21/
21
EOT
18/
20
20/
21
SVR24
16/
18
14/
20
EOT
14/
18
13/
20
SVR12
Lok AS, et al. AASLD 2012. Abstract 79.
–
All triple-therapy pts offered pegIFN
–
No virologic breakthrough with addition
of pegIFN

3 relapses

20/
20
10 GT1a pts with virologic breakthrough
Virologic breakthrough in 8 pts in 2-drug
arms but none in 4-drug arm
40
n/N =
–

60
20
SVR data from 3-drug arm not reported
due to high rate of virologic
breakthrough in GT1a but not in GT1b
–
1 with DCV + ASV QD
–
2 with DCV + ASV + PR
All regimens generally well tolerated,
with no discontinuations due to toxicity
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PILLAR/ASPIRE: Simeprevir + PegIFN/RBV
in Pts With GT1 HCV, F3/4 Fibrosis

Subanalysis of randomized, placebo-controlled phase IIb trials of simeprevir
(protease inhibitor)

Relatively high SVR24 rates in pts with advanced fibrosis
– In ASPIRE, 4/13 (31%) F4 null responders achieved SVR24
Placebo + PR
Simeprevir 150 mg QD + PR
SVR24 by METAVIR Score
80
100
71
79
56
60
40
20
n/N =
0
62
4
5/
7
15/
19
1/
23
38/
68
0/
10
24/
39
SVR24 (%)
SVR24 (%)
100
SVR24 by Prior IFN Response in
Pts With F3/F4
80
60
20
n/N =
33
10
40
0/
10
17/
26
0
ASPIRE
ASPIRE Tx
Relapser
Tx Exp’d,
Exp’d,
F3 + F4
F4 Only
Poordad F, et al. AASLD 2012. Abstract 83. Reproduced with permission.
PILLAR
Naive, F3
67
65
1/
10
14/
21
Partial
Responder
0/
3
7/
21
Null
Responder
Novel DAAs + Ribavirin
Interferon-Free Regimens
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AVIATOR: IFN-Free Regimens With
ABT-450/RTV, ABT-267, ABT-333, and RBV

Interim analysis of randomized, open-label, phase II study with RTV-boosted
ABT-450 (protease inhibitor), ABT-267 (NS5A inhibitor), and ABT-333
(nonnucleoside polymerase inhibitor)
Wk 8
Wk 12
ABT-450/RTV 150/100 mg QD +
ABT-267 + ABT-333 + RBV (n = 80)
ABT-450/RTV 150/100 mg QD +
ABT-333 + RBV (n = 41)
Cohort 1:
Treatment-naive
GT1 HCV pts
(N = 438)
ABT-450/RTV 100/100 mg QD or 200/100 mg QD +
ABT-267 + RBV (n = 79)
ABT-450/RTV 150/100 mg QD +
ABT-267 + ABT-333 (n = 79)
ABT-450/RTV 100/100 mg QD or 150/100 mg QD +
ABT-267 + ABT-333 + RBV (n = 79)
ABT-450/RTV 100/100 mg QD or 150/100 mg QD +
ABT-267 + ABT-333 + RBV (n = 80)
Kowdley KV, et al. AASLD 2012. Abstract LB-1.
Wk 24
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AVIATOR: IFN-Free Regimens With
ABT-450/RTV, ABT-267, ABT-333, and RBV
 Interim analysis of randomized, open-label, phase II study with RTVboosted ABT-450 (protease inhibitor), ABT-267 (NS5A inhibitor), and
ABT-333 (nonnucleoside polymerase inhibitor)
Wk 12
ABT-450/RTV 200/100 mg QD +
ABT-267 + RBV
(n = 45)
Cohort 2:
Treatment-exp’d
GT1 HCV pts
with previous
null response
(N = 133)
ABT-450/RTV 100/100 mg QD or 150/100 mg QD +
ABT-267 + ABT-333 + RBV
(n = 45)
ABT-450/RTV 100/100 mg QD or 150/100 mg QD +
ABT-267 + ABT-333 + RBV
(n = 43)
Kowdley KV, et al. AASLD 2012. Abstract LB-1.
Wk 24
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AVIATOR: SVR12 Rates With
ABT-450/RTV, ABT-267, ABT-333, and RBV

SVR12 rates higher in pts with GT1b HCV but also high in pts with GT1a HCV
–

12-wk regimen with all 3 DAAs + RBV produced highest SVR12 rates
No drug-related SAEs reported; 2 pts discontinued tx due to drug-related AEs
Treatment-Naive Patients
SVR12 (%)
100
80
100
96
86
96
82 100
100
88
100
Null Responders
100
88
96
98 100
100
96 100
81 100
100
89
100
89
79
85
83
n = 56 24
29 12
52 27
52 25
54 25
26 18
28 17
1a 1b
1a 1b
1a 1b
1a 1b
1a 1b
1a 1b
1a 1b
ABT-450
ABT-267
ABT-333
RBV
ABT-450
ABT-333
RBV
ABT-450
ABT-267
RBV
ABT-450
ABT-267
ABT-333
ABT-450
ABT-267
ABT-333
RBV
ABT-450
ABT-267
RBV
ABT-450
ABT-267
ABT-333
RBV
84
60
81
40
20
0
8 wks
12 wks
12 wks
Kowdley KV, et al. AASLD 2012. Abstract LB-1. Reproduced with permission.
Observed data
(above bar)
ITT (within bar)
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Daclatasvir + Sofosbuvir ± RBV in
Treatment-Naive Patients With GT1-3 HCV
AI444-040: interim analysis of randomized, open-label phase IIa trial of daclatasvir (NS5A
inhibitor) and sofosbuvir (nucleotide polymerase inhibitor)
Wk 1
SOF
Treatment-naive
noncirrhotic patients
with GT1 HCV
(N = 126)
Wk 12
SOF + DCV (n = 15)
SOF + DCV (n = 14)
SOF + DCV + RBV (n = 15)
SOF + DCV (n = 41)
SOF + DCV + RBV (n = 41)
Treatment-naive
noncirrhotic patients
with GT2/3 HCV
(N = 44)
SOF
Sulkowski MS, et al. AASLD 2012. Abstract LB-2.
SOF + DCV (n = 16)
SOF + DCV (n = 14)
SOF + DCV+ RBV (n = 14)
Wk 24
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SVR Rates With 12 or 24 Wks of
Daclatasvir + Sofosbuvir ± RBV

GT1
100
HCV RNA < LLOQ (%)

Very high SVR24 rates with all 24-wk
regimens across genotypes
Similar high SVR4 rates with 12-wk
regimens
–
GT2/3
100 100 100
100 100
93
100 100
94
100
88
93
SVR12 in all 68 pts who have reached
time point
100
80
80
60
60
40
40
20
20
0
0
EOT*
SVR24
EOT*
SVR24
SOF LI + DCV
SOF + DCV
SOF + DCV + RBV
*EOT includes pts who discontinued early, with last visit considered EOT.
Sulkowski MS, et al. AASLD 2012. Abstract LB-2.
100 100
EOT*
98
95
SVR4
SOF + DCV (12 wk)
SOF + DCV + RBV (12 wk)
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NIH SPARE: Interim Data on Sofosbuvir
and RBV in Difficult-to-Treat GT1 Pts

Subjects primarily GT1a (70%), male (63%), black (83%), IL28B CT/TT (80%)

BMI > 30: 48%; advanced liver disease: 23%; HCV RNA > 800,000 IU/mL: 62%
Viral Response, %
Part 1 (early-stage fibrosis)
Sofosbuvir 400 mg + RBV 1000/1200 mg (n = 10)
Wk 24
EOT
SVR4
90
SVR12
90
Part 2 (all stages of fibrosis)
Sofosbuvir 400 mg + RBV 600 mg (n = 25)
88
56
Sofosbuvir 400 mg + RBV 1000/1200 mg (n = 25)
96
72

In viral kinetic study involving 10 low-dose and 15 full-dose RBV subjects, HCV RNA
decrease was rapid with median HCV RNA reduction of 4.14 log10 IU/mL by Day 7

Both regimens well tolerated and resulted in significant improvement of hepatic
inflammation (P < .0001)
Osinusi A, et al. AASLD 2012. Abstract LB-4.
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ZENITH: VX-222 + Telaprevir + RBV in
Tx-Naive Pts With GT1a or GT1b HCV

Interim analysis of triple-therapy arm of randomized phase II study with VX-222
(nonnucleoside polymerase inhibitor) and BID telaprevir[1]
–
Previous report demonstrated high rate of virologic breakthrough with dual therapy (VX-222 +
TVR), but 4-drug therapy (VX-222 + TVR + pegIFN/RBV) associated with SVR12 rates of 83%
to 90% with no virologic breakthrough[2]
Wk 12
Wk 36
Tx-naive
noncirrhotic pts
with GT1a HCV
VX-222 400 mg BID +
Telaprevir 1125 mg BID +
RBV
(n = 23)
End treatment if HCV RNA
undetectable at Wks 2 and 8 (n = 6)
Tx-naive
noncirrhotic pts
with GT1b HCV
VX-222 400 mg BID +
Telaprevir 1125 mg BID +
RBV
(n = 23)
End treatment if HCV RNA
undetectable at Wks 2 and 8 (n = 5)
PegIFN/RBV for 24 wks if HCV RNA
detectable at Wk 2 or 8 (n = 14*)
PegIFN/RBV for 24 wks if HCV RNA
detectable at Wk 2 or 8 (n = 13*)
*3 pts in the GT1a arm and 5 pts in the GT1b arm discontinued treatment at or before Wk 12.
1. Jacobson IM, et al. AASLD 2012. Abstract 231. 2. Di Bisceglie A, et al. EASL 2011. Abstract 1363.
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ZENITH: Response to VX-222 + TVR + RBV
in Patients With GT1a and GT1b HCV


Comparable SVR12 rates in GT 1a and 1b
No SAEs; safety and tolerability better than previously observed with 4-drug regimen
(with pegIFN)
Virologic Outcome, % (n/N)
VX-222 + TVR + RBV in GT1b
(n = 23)
VX-222 + TVR + RBV in GT 1a
(n = 23)
70 (16/23)
73 (17/23)
 SVR12 with no pegIFN/RBV add on
100 (5/5)
67 (4/6)
 SVR12 with pegIFN/RBV add on (48 wks)
85 (11/13)
93 (13/14)
 Wk 4 (RVR)
91 (21/23)
91 (21/23)
 Wk 12 (cEVR)
83 (19/23)
83 (19/23)
 Wks 2 and 8
83 (19/23)
65 (15/23)
 Wk 4 (RVR)
91 (21/23)
57 (13/23)
 Wk 12 (cEVR)
83 (19/23)
83 (19/23)
 Wks 2 and 8
22 (5/23)
26 (6/23)
SVR12
HCV RNA < 25 IU/mL
HCV RNA undetectable
Jacobson IM, et al. AASLD 2012. Abstract 231.
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SOUND-C2: Faldaprevir + BI 207127 ± RBV
in Tx-Naive Pts With GT1 HCV

Randomized, open-label phase IIb trial of faldaprevir (NS3/4A protease
inhibitor) with BI 207127 (nonnucleoside polymerase inhibitor)
Wk 16
Stratified by HCV subgenotype
and IL28B genotype
Wk 28
Wk 40
Faldaprevir 120 mg QD +
BI 207127 600 mg TID + RBV
(n = 81)
Faldaprevir 120 mg QD +
BI 207127 600 mg TID + RBV
(n = 80)
Faldaprevir 120 mg QD +
BI 207127 600 mg TID + RBV
(n = 77)
Tx-naive pts
with GT1 HCV
(N = 362)
Faldaprevir 120 mg QD +
BI 207127 600 mg BID + RBV
(n = 78)
Faldaprevir 120 mg QD +
BI 207127 600 mg TID, no RBV
(n = 46)
Zeuzem S, et al. AASLD 2012. Abstract 232.
Randomization to this arm
stopped early due to FDA
concerns regarding lack of RBV
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SOUND-C2: Final Efficacy Analysis of
Faldaprevir + BI 207127 ± RBV in GT1 HCV

Higher SVR in pts with GT1b HCV and in pts with IL28B genotype CC

Favorable safety/tolerability with low rate of discontinuation with BID dosing
SVR12 (%)
PP
ITT
GT 1a
100
100
80
80
Non-CC
GT 1b
CC
100
85
66
69
69
72
59
59
40
44
52
40
84
80
69
57
56
60
69
60
75
38
44
47
43
60
67
57
67
55
63
64
58
48
40
33
39
20
20
11
0
0
0
PP
48/
n/N = 73
47/
68
40/
58
54/
75
18/
41
BI 207127 dosing TID
Duration (wks) 16
RBV +
TID
28
+
TID
40
+
BID
28
+
TID
28
‒
20
ITT 13/ 35/
n/N = 34 47
TID
16
+
14/ 33/
32 48
16/ 24/
34 43
13/ 41/
30 48
2/ 16/
18 28
TID
28
+
TID
40
+
BID
28
+
TID
28
‒
Zeuzem S, et al. AASLD 2012. Abstract 232. Reproduced with permission.
ITT 34/ 14/
n/N = 60 21
TID
16
+
32/ 14/
58 21
28/ 12/
58 19
38/ 16/
59 19
11/ 7/
33 12
TID
28
+
TID
40
+
BID
28
+
TID
28
‒
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SOUND-C2 Subanalysis: Efficacy of
Treatment in Patients With Cirrhosis

Among 33 cirrhotic patients, outcomes with faldaprevir + BI 207217 + RBV
similar to noncirrhotic patients
– SVR12 rates higher in GT1b vs GT1a HCV

Higher rate of discontinuations and SAEs with TID dosing
Cirrhosis
GT1a
No cirrhosis
100
100
67
52
57
33
40
20
11/
n/
N = 21
124/
217
6/
9
48/
69
1/
3
40
17/
43
0
86
80
80
70
SVR12 (%)
SVR12 (%)
80
60
GT1b
68
57
60
50
43
43
n/ 3/
N= 7
8/
14
2/
4
4/
5
0/
0
1/
3
11
40/ 84/
93 124
11/ 37/
26 43
2/
18
15/
25
0
Cirrhosis
BI 207127 Dosing
TID
Duration (wks) 16, 28, 40
RBV
+
42
33
40
20
60
BID
28
+
TID
28
-
TID
16, 28, 40
+
BID
28
+
Soriano V, et al. AASLD 2012. Abstract 84. Reproduced with permission.
No Cirrhosis
TID
28
-
TID
16, 28, 40
+
BID
28
+
TID
28
-
Interferon- and Ribavirin-Free
Regimens
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Daclatasvir, Asunaprevir, and BMS-791325
in Treatment-Naive Patients With GT1 HCV
 Interim analysis of Part 1 of AI443-014: randomized, open-label,
phase IIa study with daclatasvir (NS5A inhibitor), asunaprevir (NS3
protease inhibitor), and BMS-791325 (nonnucleoside polymerase
inhibitor)
Stratification by HCV
subgenotype (1a vs 1b)
Treatment-naive
noncirrhotic pts
with GT1 HCV
(N = 32)
Wk 12
Daclatasvir 60 mg QD +
Asunaprevir 200 mg BID +
BMS-791325 75 mg BID
(n = 16)
Daclatasvir 60 mg QD +
Asunaprevir 200 mg BID +
BMS-791325 75 mg BID
(n = 16)
Everson GT, et al. AASLD 2012. Abstract LB-3.
Wk 24
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Response to Daclatasvir, Asunaprevir, and
BMS-791325 in Modified ITT Analysis
24-Wk Treatment
(n = 16)
100

100
94
94
94
80
60
40
20
0
Wk 4
Wk 12
EOT
SVR4
Missing data
HCV RNA < LLOQTD or TND (%)
HCV RNA < LLOQTD or TND (%)
HCV RNA < LLOQTD or TND
12-Wk Treatment
(n = 16)
100
100
88
100
94
Wk 4
Wk 12
EOT
SVR4
94
80
60
40
20
0
SVR12
Both regimens generally well tolerated, with no discontinuations due to AEs
– Infrequent SAEs, grade 3/4 AEs, or grade 3/4 lab abnormalities
Everson GT, et al. AASLD 2012. Abstract LB-3. Reproduced with permission.
New Peginterferons
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D-LITE: PegIFN lambda-1a + RBV +
Daclatasvir or Asunaprevir in GT1 HCV

Interim analysis of randomized, double-blind phase IIb study with pegIFN
lamba-1a (a type III IFN) plus daclatasvir (NS5A inhibitor), asunaprevir (NS3
protease inhibitor)
Wk 24
Stratified by HCV GT1
subgenotype, IL28B genotype
Daclatasvir 60 mg QD +
PegIFN lambda-1a 180 µg SC QW +
RBV
(n = 41)
Tx-naive pts
with GT1 HCV
(N = 119)
Asunaprevir 200 mg BID +
PegIFN lambda-1a 180 µg SC QW +
RBV
(n = 38)
PDR: follow-up
No PDR*: PegIFN lambda-1a/RBV
PDR: follow-up
No PDR*: PegIFN lambda-1a/RBV
PegIFN alfa-2a 180 µg SC QW +
RBV
(n = 40)
*PDR: HCV RNA < LLOQ (-TD or -TND) at Wk 4, < LLOQ-TND at Wk 12.
Vierling JM, et al. AASLD 2012. Abstract LB-9.
Wk 48
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D-LITE: Virologic Outcomes in Patients
With Protocol-Defined Response


Most patients achieved PDR, qualified for shortened therapy
Higher SVR12 rates in GT1b HCV, but high response rates regardless of IL28B genotype
Outcome, %
PegIFN lamba-1a + RBV + Daclatasvir
(n = 41)
PegIFN lamba-1a + RBV + Asunaprevir
(n = 38)
90
84
(n = 37)
(n = 32)
 RVR
73
91
 cEVR
100
100
 eRVR
73
91
 SVR4
78
84
 SVR12
76
75
 1a
65 (15*/23)
67 (14†/21)
 1b
93 (13*/14)
91 (10*/11)
 Non-CC
75 (9/12)
90 (9/10)
 CC
76 (19/25)
68 (15/22)
PDR
PDR+ pts only
SVR12 by HCV subtype, % (n/N)
SVR12 by IL28B genotype, % (n/N)
Vierling JM, et al. AASLD 2012. Abstract LB-9.
*6 IL28B CC; †5 IL28B CC.
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D-LITE: Substudy in Japanese Patients
With GT1 HCV

In small Japanese substudy,
100% SVR4 rates in both arms
PegIFN lambda-1a + RBV + daclatasvir
PegIFN lambda-1a + RBV + asunaprevir
Virologic Response
Patients (%)
100
100
100 100
100 100
83
80
40
0
 Daclatasvir arm better tolerated
than asunaprevir arm
– 1 SAE in asunaprevir arm
– More grade 3/4 AEs with
asunaprevir (80% vs 13%)
60
20
 In asunaprevir arm, the 1 patient
without PDR discontinued due to
AE at Wk 3
n/ 8/
N= 8
5/
6
PDR
8/
8
5/
5
EOTR
8/
8
SVR4
PDR+ Only
Izumi N, et al. AASLD 2012. Abstract 234.
5/
5
– More grade 3/4 lab abnormalities
with asunaprevir
Hepatitis B Treatment
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Response-Guided PegIFN-Based Therapy
in HBeAg-Positive Patients
 Pooled analysis of 3 global randomized studies (N = 803)[1]
– Phase III study of pegIFN[2]
– HBV 99-01 study[3]
– Neptune study[4]
 Response observed in
– 23% with HBeAg loss with HBV DNA < 2000 IU/mL (n = 182)
– 5% with HBsAg loss at 6 mos posttreatment (n = 39)
 HBsAg levels at Wks 12 and 24 predicted response to therapy
 HBV genotypic–specific stopping rules proposed
– Low response rates if HBsAg > 20,000 IU/mL at Wk 24 in all genotypes
1. Sonneveld MJ, et al. AASLD 2012. Abstract 23. 2. Lau GK, et al. N Engl J Med. 2005;352:2682-2695.
3. Janssen HL, et al. Lancet. 2005;365:123-129. 4. Liaw YF, et al. Hepatology. 2011;54:1591-1599.
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HBsAg Decline During PegIFN Therapy
Varies According to HBV Genotype
HBsAg decline differed by HBV
genotype

Sustained HBsAg decrease seen in
pts with response to pegIFN but
typically not in nonresponders
HBsAg Decline (log IU/mL)


0.0
Wk 24 HBsAg level predicted
response at 6 mos posttreatment,
regardless of genotype
Outcome, %
HBsAg Level at Wk 24, IU/mL
GT D (n = 110)
< 1500
(n = 253)
150020,000
(n = 373)
> 20,000
(n = 162)
P
Value
HBeAg loss
and HBV DNA
< 2000 IU/mL
45
16
3
< .001
HBsAg loss
15
0
0
< .001
-0.5
GT C (n = 386)
-1.0
GT B (n = 205)
-1.5
GT A (n = 103)
PegIFN therapy
-2.0
BL
12
24
EOT
EOF
Wks
Sonneveld MJ, et al. AASLD 2012. Abstract 23. Reproduced with permission.
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