EASL 2015. HCV Investigational Agents

clinicaloptions.com/hepatitis
HCV Investigational Agents
April 22-26, 2015
Vienna, Austria
Highlights From EASL:
CCO Independent Conference Coverage
of the 2015 Annual Meeting of the European Association for the Study of
the Liver*
*CCO is an independent medical education company that
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professionals through conference coverage and other
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This program is supported by educational grants from
AbbVie, Gilead Sciences, and Merck.

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Faculty
Andrew J. Muir, MD
Chief, Division of Gastroenterology
Associate Professor of Medicine
Department of Medicine
Director, Gastroenterology/
Hepatology Research
Duke Clinical Research Institute
Duke University School of Medicine
Durham, North Carolina
David R. Nelson, MD
Professor of Medicine
Assistant Vice President for
Research
University of Florida
Gainesville, Florida
Norah Terrault, MD, MPH
Professor of Medicine and Surgery
Director, Viral Hepatitis Center
Division of Gastroenterology
University of California, San
Francisco
San Francisco, California

Disclosures
Andrew J. Muir, MD, has disclosed that he has received funds for
research support from AbbVie, Achillion, Bristol-Myers Squibb, Gilead
Sciences, GlaxoSmithKline, Hologic, Intercept, Janssen, Merck, NGM
Biopharm, and Roche and has received consulting fees from AbbVie,
Achillion, Bristol-Myers Squibb, Gilead Sciences, Intercept, Janssen,
Lumena, Merck, Regulus Therapeutics, Salix, and Theravance.
David R. Nelson, MD, has disclosed that he has received funds for
research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences,
Janssen, and Merck.
Norah Terrault, MD, MPH, has disclosed that she has received funds for
research support from AbbVie, Biotest, Esai, Gilead Sciences, Novartis,
and Vertex and has received consulting fees from Achillion, Biotest,
Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck.

Summary of Direct-Acting Antivirals
Discussed in This Slideset
Drug Class Dosing
Daclatasvir NS5A inhibitor 60 mg QD
Elbasvir NS5A inhibitor 50 mg QD*
Grazoprevir NS3/4A protease inhibitor 100 mg QD*
GS-5816 NS5A inhibitor 100 mg QD‡
GS-9451 NS3/4A protease inhibitor 80 mg QD
GS-9857 NS3/4A protease inhibitor 100 mg QD
GS-9669 NS5B nonnucleoside polymerase inhibitor 500 mg QD
Ledipasvir NS5A inhibitor 90 mg QD†
Sofosbuvir NS5B nucleotide polymerase inhibitor 400 mg QD†‡
*Grazoprevir and elbasvir may be coformulated.
†
Ledipasvir and sofosbuvir may be coformulated.
‡
Sofosbuvir and GS-5816 may be coformulated.

Phase II/III Studies of
Grazoprevir/Elbasvir

Grazoprevir/Elbasvir Studies: Overview
Study Name Description
C-EDGE TN
12 wks of grazoprevir/elbasvir in treatment-naive pts with
GT1, 4, or 6 HCV infection
C-EDGE TE
12 or 16 wks of grazoprevir/elbasvir ± RBV in pts with GT1, 4, or 6 HCV and
previous failure of pegIFN/RBV
C-EDGE Coinfection
12 wks of grazoprevir/elbasvir in HCV treatment-naive pts coinfected with HIV
and GT1, 4, or 6 HCV
C-SALVAGE
12 wks of grazoprevir/elbasvir + RBV in pts with GT1 HCV and previous failure
of HCV PI + pegIFN/RBV
C-SCAPE
12 wks of grazoprevir ± elbasvir ± RBV in treatment-naive, noncirrhotic pts with
GT2, 4, 5, or 6 HCV
C-WORTHY C
8 wks of grazoprevir/elbasvir ± RBV in treatment-naive, noncirrhotic pts with
GT1b HCV
C-SWIFT
Short-duration therapy with grazoprevir/elbasvir + sofosbuvir in treatment-
naive, GT1 or 3 HCV–infected pts ± cirrhosis
C-SURFER
12 wks of grazoprevir/elbasvir in pts with GT1 HCV infection
and stage 4 or 5 CKD

C-EDGE TN: 12-Wk Grazoprevir/Elbasvir
for Treatment-Naive Pts With GT1/4/6 HCV
 International, randomized, blinded, placebo-controlled, parallel-group phase III
trial
 Pts well matched at baseline: 91% infected with GT1a or 1b HCV, 68% HCV
RNA > 800,000 IU/mL, 22% cirrhotic
 Fewer white pts in immediate vs deferred treatment arm (60% vs 70%,
respectively)
(n = 316)
Placebo
(n = 105)
Coformulated grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily.
Treatment-naive
GT1, 4, or 6
HCV–infected
pts
(N = 421)
Open-label period
Treatment
Wk 12
Follow-up
Wk 4
Follow-up
Wk 16
Zeuzem Z, et al. EASL 2015. Abstract G07.
Randomized period

C-EDGE TN: Efficacy Results
Zeuzem Z, et al. EASL 2015. Abstract G07. Reproduced with permission.
 Subgroup analysis: significantly lower SVR12 rates in pts with baseline HCV RNA >
800,000 IU/mL
‒ No differences according to race, IL28B status, presence of cirrhosis
 Lower SVR12 rates in pts having baseline NS5A RAVs associated with > 5-fold loss of
susceptibility to elbasvir
SVR12(%)
All Pts GT1a GT1b GT4 GT6
95 92 99 100
80
299/
316
144/
157
129/
131
18/
18
8/
10n/N =
SVR12 With 12 Wks of Grazoprevir/Elbasvir According to Genotype
100
80
60
40
20
0
Non-virologic failure 4 3 1 0 0
Breakthrough 1 1 0 0 0
Relapse 12 9 1 0 2

C-EDGE TN: Adverse Events
 Grazoprevir/elbasvir generally well
tolerated in cirrhotic, noncirrhotic pts
– No serious treatment-related AEs
– 1% discontinued active drugs for AEs
Zeuzem Z, et al. EASL 2015. Abstract G07. Reproduced with permission.
Adverse
Events, %
Noncirrhotic Pts Cirrhotic Pts
GZR/EBV
(n = 246)
Pbo
(n = 83)
GZR/EBV
(n = 70)
Pbo
(n = 22)
≥ 1 AE 71 69 54 68
Drug-related
AE
39 39 26 41
SAE 3 4 3 0
Drug-related
SAE
0 0 0 0
Discontinued
for AE
1 0 1 5
Death < 1 0 1 0
Parameter, %
GZR/EBV
(n = 316)
Pbo
(n = 105)
Common AEs (> 5%)
 Headache 17 18
 Fatigue 16 17
 Nausea 9 8
 Arthralgia 6 6
Late ALT or AST elevation
 > 2 to 5 x ULN 1.0 3.8
 > 5 x ULN 1.3 0
Total bilirubin elevation
 > 2 to 5 x baseline 0.9 0
 > 5 x baseline 0.3 0
Decreased hemoglobin
 Grade 1/2 2.9 3.8
 Grade 3/4 0 0

C-EDGE TE: Grazoprevir/Elbasvir ± RBV
for Treatment-Experienced Pts
 International, randomized, open-label, parallel-group, phase III trial
 Pts well matched at baseline: ~ 90% infected with GT1a or 1b HCV, ~ 35% cirrhotic
 Fewer GT4 HCV–infected pts in 16-wk arms, no GT6 HCV–infected pts in 12-wk arms
(n = 105)
Grazoprevir/Elbasvir + RBV
(n = 104)
PegIFN/RBV-
experienced pts
with GT1, 4, or 6 HCV
infection
(N = 420)
(n = 105)
Wk 12
(n = 106)
Wk 16
Kwo P, et al. EASL 2015. Abstract P0886.
Coformulated grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily; weight-based RBV

0
100
80
60
40
20
C-EDGE TE: Efficacy Results
 Subgroup analysis: 99% SVR12 in black pts and no evidence of reduced efficacy at high baseline
HCV RNA (cutoff = 2 million IU/mL)
 Among pts with GT1a HCV infection, previous response and cirrhosis status did not impact SVR12
rates
 SVR12 rate reduced (52.4%) in GT1a HCV–infected pts with baseline NS5A variants associated
with > 5-fold change in elbasvir susceptibility
Kwo P, et al. EASL 2015. Abstract P0886. Reproduced with permission.
GZR/EBV GZR/EBV + RBV GZR/EBV + RBVGZR/EBV
92
97/
105
98/
104
97/
105
103/
106
94 9792
SVR12(%) 12 Wks 16 Wks
n/N =
Breakthrough 0 0 1 0
Rebound 0 0 2 0
Relapse 6 6 4 0
LTFU/Early DC 2 0 1 3

C-EDGE TE: Adverse Events
Kwo P, et al. EASL 2015. Abstract P0886. Reproduced with permission.
AEs, %
12 Wks of
GZR/EBV
(n = 105)
12 Wks of
GZR/EBV + RBV
(n = 104)
16 Wks of
GZR/EBV
(n = 105)
16 Wks of
GZR/EBV + RBV
(n = 106)
Serious AE 3.8 2.9 2.9 3.8
Death 0 0 0 0
Discontinued due to AE 1.0 1.0 0 4.6
Hemoglobin < 10 g/dL 0 8.7 0 20.8
Total bilirubin > 5 x
baseline
0 0 0 0
Late ALT or AST
elevation > 5 x ULN
0 1 4 0
Common AEs*
 Fatigue 19.0 26.9 16.2 30.2
 Headache 21.0 20.2 19.0 18.9
 Nausea 8.6 14.4 3.8 17.0
*Occurring in > 10% of pts.

C-EDGE Coinfection: Grazoprevir/Elbasvir
for Pts Coinfected With HCV/HIV
 Multicenter, single-arm, open-label phase III trial
 66% with GT1a HCV, 60% had HCV RNA > 800,000 IU/mL, 16% cirrhotic
(n = 218)
HCV treatment-naive pts
coinfected with HIV and
GT1, 4, or 6 HCV
(N = 218)
Wk 12
Rockstroh JK, et al. EASL 2015. Abstract P0887. Reproduced with permission.
Coformulated grazoprevir/elbasvir dosed orally 100/50 mg once daily
Baseline ART
Undetectable HIV-1 RNA on ART (%) 96.8
 Abacavir containing 21.6
 Tenofovir DF containing 75.2
 Raltegravir 51.8
 Dolutegravir 27.1
 Rilpivirine 17.4

0
100
80
60
20
C-EDGE Coinfection: Key Findings
 No subgroup provided an efficacy
advantage or disadvantage
 New NS3, NS5A RAVs detected at
failure in 5 of 6 pts who relapsed
 Short-lived HIV-1 RNA increases
occurred in 2 pts on ART during
grazoprevir/elbasvir treatment: both
resuppressed HIV-1 RNA without
change of ART
 During 12 wks of treatment, no
significant changes in CD4+ cell count
(n = 207)
 Grazoprevir/elbasvir well tolerated: no
pt discontinued for AEs and no serious
treatment-related AEs
Rockstroh JK, et al. EASL 2015. Abstract P0887. Reproduced with permission.
SVR12(%)
136/
144
42/
44
27/
28
All Pts GT1a GT1b GT4
95.0 94.4 95.5 96.4
207/
218
SVR12 With 12 Wks GZR/EBV
According to Genotype
LTFU or DC* 4 3 1 0
Breakthrough 0 0 0 0
Relapse 6 4 1 1
Reinfection 1 1 0 0
*Unrelated to virologic failure.
n/N =
40

C-SALVAGE: Grazoprevir/Elbasvir + RBV
After DAA Failure in Pts With GT1 HCV
 International, open-label, single-arm phase II study
Forns X, et al. EASL 2015. Abstract O001. Reproduced with permission.
Grazoprevir/elbasvir orally dosed 100 mg/50 mg once daily, weight-based RBV.
(n = 79)
Pts with GT1 HCV and
previous PI +
pegIFN/RBV therapy
(N = 79)
Wk 12
Baseline Characteristic, %
All Pts
(N = 79)
Evaluable Pts*
Baseline NS3 RAVs
(n = 34)
No Baseline NS3 RAVs
(n = 44)
HCV genotype
 1a 38.0 67.6 15.9
 1b 62.0 32.4 84.1
Cirrhosis 43.0 44.1 43.2
Previous PI
 Boceprevir 35.4 29.4 38.6
 Telaprevir 54.4 55.9 54.5
 Simeprevir 10.1 14.7 6.8
Previous virologic failure 83.5 94.1 75.0
*1 pt did not have baseline NS3 sequencing data available.

100
60
40
20
0
80
C-SALVAGE: Efficacy Results
Previous Therapy
Previous All-
Cause Treatment
Failures, N
Baseline RAVs, % SVR12 in Pts With
Baseline RAVs, %
NS3 NS5A
Boceprevir 28 37.0 10.7 90.9*
Telaprevir 43 44.2 10.7 90.0*
Simeprevir 8 62.5 0 100
All pts 79 43.6 10.1 91.7*2 boceprevir-treated pts and 4 telaprevir-treated pts harbored quasispecies at baseline with mutations in both the NS3
and NS5A genes.
SVR12(%)
76/
79
Prior Non-
virologic
Failure
All
Pts
Prior
Virologic
Failure
10096.2 95.5
63/
66
13/
13n/N =

C-SALVAGE: Adverse Events
Adverse Events,* %
All Pts
(N = 79)
Any event relating to study drug 57.0
Occurring in ≥ 10% of pts
regardless of causality
 Fatigue 27.8
 Headache 19.0
 Asthenia 15.2
 Nausea 11.7
Serious adverse events†
5.1
Discontinuation due to toxicity†
1.3
Death 0
Grade 3/4 Laboratory
Abnormalities, %
All Pts
(N = 79)
Grade 3 Grade 4
Total bilirubin 5.1 1.3
Direct bilirubin 2.5 0
AST/ALT 0 0
Lipase 5.1 0
Prothrombin time 0 1.3
Hemoglobin 2.5 0
Leukopenia 0 1.3
Thrombocytopenia 1.3 0
*Occurring up to 2 wks after treatment end.
†
None attributed to study drug.

C-SCAPE: Grazoprevir ± Elbasvir ± RBV
for Pts With GT2/4/5/6 HCV
 Open-label, randomized, phase II trial
 In the GT4/5/6 group, 53% of pts were infected with GT4 HCV
 Efficacy reduced in pts infected with GT2 HCV with baseline HCV RNA > 2 million IU/mL
 Grazoprevir/elbasvir active in GT5 and 6 HCV, although pt numbers were small
GT2 (n = 56*)
(n = 30)
Grazoprevir + RBV
(n = 26)
(n = 18)
Wk 12
(n = 18)
GT4 (n = 20)
GT5 (n = 8*)
GT6 (n = 8*)
Treatment-naive,
noncirrhotic, HCV-
infected pts
(N = 98)
*mITT population: 6 pts were excluded due to improper genotyping. Grazoprevir dosed 100 mg orally once
daily; elbasvir dosed 50 mg orally once daily; RBV dosed at 800-1400 mg/day based on weight.
Brown A, et al. EASL 2015. Abstract P0771.
SVR12, %
80
73
GT4/5/6
100/100/75
GT4/5/6
90/25/75

C-WORTHY C: 8-Wk Grazoprevir/
Elbasvir ± RBV for GT1b HCV
 Randomized, open-label, phase II trial
 Higher HCV RNA levels for grazoprevir/elbasvir without vs with RBV at baseline
 All pts who did not achieve SVR12 relapsed (n = 4); 1 pt had an NS5A RAV at baseline
and failure
 1 SAE in grazoprevir/elbasvir + RBV group; considered unrelated to treatment
 No discontinuations due to AEs or deaths
Vierling J, et al. EASL 2015. Abstract P0769.
(n = 30)
(n = 31)
Grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily.
Treatment-naive,
noncirrhotic
GT1b HCV–infected
pts
(N = 61)
Wk 8
SVR12, %
93
94

C-SWIFT: Short-Duration GZR/EBV + SOF
in GT1 or 3 HCV Infection
Treatment-naive
noncirrhotic pts
with GT1 HCV
(n = 61)
Grazoprevir/Elbasvir + SOF
(n = 31)
(n = 30)
(n = 21)
Wk 4 Wk 6 Wk 8
Treatment-naive
cirrhotic pts with
GT1 HCV
(n = 41)
(n = 20)
(n = 15)
Treatment-naive
noncirrhotic pts
with GT3 HCV
(n = 29)
Coformulated grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily; sofosbuvir 400 mg orally once daily.
(n = 14)
Treatment-naive
cirrhotic pts with
GT3 HCV
(n = 12)
(n = 12)
Wk 12
Poordad F, et al. EASL 2015. Abstract O006.
 Open-label phase II trial

C-SWIFT: GZR/EBV + SOF Efficacy
Results
 Pts well matched at baseline: population primarily white (93% to 100%); of pts with GT1 HCV
infection, 76% to 84% had GT1a HCV; IL28B non-CC varied between arms (21% to 50%)
 All pts who failed treatment relapsed; among GT1 HCV relapses, 30% developed NS5A RAVs at
failure (most in 4-wk treatment group)
 Higher baseline HCV RNA (> 2 million IU/mL) and presence of cirrhosis resulted in lower SVR12
rates for pts with GT3 HCV
Poordad F, et al. EASL 2015. Abstract O006. Reproduced with permission.
SVR12(%)
100
80
60
40
20
0
4 Wks 6 Wks 6 Wks 8 Wks 8 Wks 12 Wks 12 Wks
Genotype 1 Genotype 3
33
26/
30
16/
20
17/
18
14/
15
14/
14
10/
11*
87 80
94 93 100 91
10/
30*
*Excluded pts who discontinued due to reasons other than virologic failure.
Noncirrhotic
Cirrhotic
n/N =

C-SWIFT: GZR/EBV + SOF Adverse Events
Poordad F, et al. EASL 2015. Abstract O006. Reproduced with permission.
Parameter, n (%)
All Pts
(N = 143)
Genotype 1 HCV Infection Genotype 3 HCV Infection
Noncirrhotic
4 and 6 Wks
(n = 61)
Cirrhotic
6 and 8 Wks
(n = 41)
Noncirrhotic
8 and 12 Wks
(n = 29)
Cirrhotic
12 Wks
(n = 12)
Most common AEs
 Headache 4 (3) 1 (2) 3 (7) 1 (3) 1 (8)
 Fatigue 2 (1) 2 (3) 0 0 1 (8)
 Nausea 2 (1) 2 (3) 1 (2) 1 (3) 1 (8)
Serious AEs 2 (1) 0 2*†
(5) 0 0
Discontinuations due to AE 1 (1) 0 1†
(2) 0 0
Deaths 0 0 0 0 0
Hemoglobin < 10 g/dL 0 0 0 0 0
Total bilirubin > 5 x
baseline
0 0 0 0 0
ALT/AST > 5 x ULN 0 0 0 0 0
*Pyelonephritis (n = 1).
†
B-cell lymphoma (n = 1). Study drug discontinued after treatment Wk 4.

C-SURFER: Grazoprevir/Elbasvir in Pts
With GT1 HCV and Stage 4 or 5 CKD
 Multicenter, part-randomized, parallel-group, placebo-controlled, phase III trial
 Treatment arms well matched at baseline
– Pts split evenly by GT1a and 1b infection (52% for GT1a); 6% had compensated cirrhosis
– 75% and 77% were on hemodialysis; 32% to 36% were diabetic
– 81% and 82% were CKD stage 5 (eGFR < 15 mL/min/1.73 m2
, or on hemodialysis); 18% and
19% were CKD stage 4 (eGFR 15-29 mL/min/1.73 m2
)
Roth D, et al. EASL 2015. Abstract LP02.
(n = 111)
Placebo
(n = 113)
GT1 HCV-infected
pts with
stage 4/5 CKD
(n = 224) Grazoprevir/Elbasvir
(n = 113)
Grazoprevir/elbasvir dosed orally 100 mg/50 mg once daily. This study also included a pharmacokinetic analysis (n = 11)
in which pts were treated as in the randomized grazoprevir/elbasvir study group.
Treatment
Wk 12
Follow-up
Wk 4
Follow-up
Wk 16
Open-label period
Randomized period

20
Modified Full
Analysis Set
Full Analysis
Set
n/N =
C-SURFER: Efficacy Results
Roth D, et al. EASL 2015. Abstract LP02. Reproduced with permission.
GZR/EBR 12 wks
Modified analysis set: pts in pharmacokinetic substudy and pts randomized to immediate treatment who received
≥ 1 drug dose; excludes pts who died or discontinued where cause not related to study treatment.
Full analysis set: all pts receiving ≥ 1 drug dose.
*1 pt relapsed on each arm.
†
6 pts in the full analysis set discontinued unrelated to treatment: lost to follow-up (n = 2), n = 1 each for death,
noncompliance, withdrawal by subject, and withdrawal by physician (owing to violent behavior).
SVR12(%)
9499
115/
116*
115/
122*†
100
6/6
100
61/61
98.2
54/55
98.9
86/87
97.6
40/41
Cirrhotic GT 1a
HCV
GT 1b
HCV
DiabeticOn
hemodialysis
100
80
60
40
0

C-SURFER: Adverse Events
Roth D, et al. EASL 2015. Abstract LP02. Reproduced with permission.
AE, %
Grazoprevir/Elbasvir (Randomized Treatment)
(n = 111)
Placebo
(n = 113)
Serious AEs 14.4 16.8
Discontinuation due to AE 0 4.4
Death 0.9 2.7
Common AEs* 75.7 84.1
 Headache 17.1 16.8
 Nausea 15.3 15.9
 Fatigue 9.9 15.0
 Insomnia 6.3 10.6
 Dizziness 5.4 15.9
 Diarrhea 5.4 13.3
Hb grade decrease from
baseline
 1 grade 24.3 26.5
 2 grades 12.6 7.1
 3 grades 3.6 1.8
 4 grades 0 0.9
*Reported in ≥ 10% of pts in either arm.

Treatment Simplification
Strategies

SYNERGY: 4-6 Wks of LDF/SOF + GS-9451
± GS-9669 in GT1 HCV
 Single-center, open-label, phase IIa trial
 At baseline, > 60% GT1a HCV; 76% to 80% black pts, except 6-wk treatment-experienced arm,
which had 40% black pts; 4- and 6-wk arms had 40% to 44% and 20% to 24% pts with > 6 million
IU/mL, respectively
 Most pts in the F3-F4 fibrosis treatment groups had F3 fibrosis (64% to 68%)
 Univariate analysis: HCV RNA < 6 million IU/mL and GT1b HCV predicted response
Kattakuzhy S, et al. EASL 2015. Abstract P0875.
Tx-naive GT1 pts with
F0-F2 fibrosis
(N = 50)
LDV/SOF + GS-9451
(n = 25)
LDV/SOF + GS-9451 + GS-9669
(n = 25)
Nonrandomized
Tx-naive GT1 pts with
F3-F4 fibrosis
(N = 25)
LDV/SOF + GS-9451
(n = 25)
Tx-exp’d GT1 pts with
F3-F4 fibrosis
(N = 25)
LDV/SOF + GS-9451
(n = 25)
Wk 6Wk 4
SVR12, %
Coformulated LDF/SOF 90/400 mg QD; GS-9451 80 mg QD; GS-9669 500 mg QD.
LTFU, % Relapse, %
Pts Not Achieving
SVR12
40
20
68
80
0
4
8
0
60
76
24
20

Short-Duration Sofosbuvir/GS-5816 +
GS-9857 in GT1 HCV Pts
 Single-center, nonrandomized, open-label phase II trial
 Key baseline characteristics
– IL28B CC: treatment-naive pts: noncirrhotic (33%), cirrhotics (53%); treatment-experienced pts
(20%)
– 73% to 93% pts had GT1a HCV infection; 17% of pts in treatment-experienced group had
cirrhosis
Gane EJ, et al. EASL 2015. Abstract LP03.
Sofosbuvir/GS-5816 + GS-9857
(n = 15)
(n = 15)Tx-naive noncirrhotic
GT1 pts
(N = 30)
(n = 30)
(n = 15)
Wk 6Wk 4
Tx-naive cirrhotic GT1 pts
(N = 30)
Tx-exp’d GT1 pts ± cirrhosis
(N = 30)
Sofosbuvir/GS-5816 400 mg/100 mg FDC tablet QD; GS-9857 100 mg QD.

GS-9857: Efficacy Results
 All pts who did not achieve SVR12 relapsed
 SVR12 rates for treatment-experienced pts: no cirrhosis, 68% (17/25
pts); cirrhosis, 60% (3/5 pts)
SVR12, n/N (%)
Treatment Naive,
No Cirrhosis
Treatment Naive,
Cirrhosis
Treatment
Experienced
± Cirrhosis
4 wks 4/15 (27)
6 wks 14/15 (93) 13/15 (87) 20/30 (67)

GS-9857: Adverse Events
 No serious adverse events or discontinuations for toxicity
 9% experienced grade 3/4 laboratory abnormalities; 4 of 7
events constituted transient lipase elevations
 Overall, adverse events occurred in 77% of pts
 Adverse events occurring in ≥ 5% of pts (N = 75) included
nausea (25%), headache (24%), fatigue (16%), diarrhea
(9%), viral infection (7%), abdominal discomfort (5%), and
mouth ulcers (5%)

Evolving Options in
Difficult-to-Treat Patients

SOF + NS5A Inhibitors ± RBV in Pts With
GT1/3 HCV and Decompensated Cirrhosis
 Observational cohort study of National Health Service of England (N = 467)
 At physician’s discretion, pts received 12 wks SOF + LDV or DCV ± RBV
Baseline
Characteristic
All Pts
(N = 467)
Genotype 1
(n = 235)
Genotype 3
(n = 189)
Other Genotypes
(n = 43)
CTP B, % 66.2 68.5 64.0 62.8
CTP C, % 9.9 8.1 12.7 7.0
Mean MELD score
(range)
11.9 (6-36) 11.3 (6-24) 12.6 (6-36) 11.9 (6-22)
Regimen, % of
total population
SOF + LDV + RBV 54.0 35.1 13.1 5.8
SOF + DCV +
RBV
36.8 9.6 24.4 2.8
RBV-free regimen 9.2 5.6 3.0 0.6
Foster GR, et al. EASL 2015. Abstract O002. Reproduced with permission.

N =
100
80
60
40
20
0
Decompensated Cirrhosis: Efficacy
SVR12 among pts with other HCV GTs: 89% (n = 27) with SOF + LDV + RBV; 85%
(n = 13) with SOF + DCV + RBV; 100% (n = 3) SOF + DCV
12-wk SOF + LDV + RBV
All GT1 GT3
SVR12,%(ITT)
P < .05
59
43
70 71
252 28 172 15 164 21 45 5 61 7 114 7
12-wk SOF + LDV 12-wk SOF + DCV + RBV 12-wk SOF + DCV
80
71
74 73
86
81 82
60

Decompensated Cirrhosis: Safety
 91% of pts received RBV
– 6% discontinued RBV
– 30% had hemoglobin ≤ 10 g/dL
 Longer follow-up required to evaluate risk:benefit
– 20% reduced RBV dose
– 5% had hemoglobin ≤ 8 g/dL
SAEs by Follow-up Wk 4
Events,
n (% of All SAEs)
Pts,
n (% of All Pts)
All SAEs 175 119 (26)
SAE likely related to liver disease and/or tx 138 (79) 100 (21)
Ascites 55 (31) 38 (8)
Hepatic encephalopathy 28 (16) 23 (5)
Infection 26 (15) 23 (5)
Liver transplantation -- 16 (3)
Death -- 14 (3)

Compassionate Use Program: SOF + DCV
± RBV for GT3 HCV Infection
 Interim analysis of nonrandomized, multicenter, compassionate use program
 Pts had GT3 HCV infection and ≥ F3 liver disease, extrahepatic manifestation of HCV
disease, HCV recurrence following liver transplantation, or indication for liver or kidney
transplantation (N = 601)
 76% of pts were cirrhotic; 73% were treatment experienced
 Pts received sofosbuvir + daclatasvir ± ribavirin for 12 or 24 wks
 Treatment discontinuations to date
– Adverse events: n = 1; death: n = 2; pt decision: n = 1
Hezode C, et al. EASL 2015. Abstract LP05.
SVR4, % (n/N)
12 Wks of Sofosbuvir +
Daclatasvir ± Ribavirin
24 Wks of Sofosbuvir +
Daclatasvir ± Ribavirin
Noncirrhotic pts 11/12 (92) 5/6 (83)
Cirrhotic pts 22/29 (76) 52/59 (88)

ALLY-1: SOF + DCV + RBV in Cirrhotic or
Posttransplant HCV-Infected Pts
 Multicenter, open-label phase III trial
 Enrolled advanced cirrhosis (n = 60) or post–liver transplant (n = 53) pts
– 95% and 96% of pts were white, 40% and 42% were treatment naive, 75% and
77% were infected with GT1 HCV
 Treatment
– All pts: 12 wks of daclatasvir 60 mg QD + sofosbuvir 400 mg QD + RBV
– Initial RBV dose 600 mg/day, adjusted to 1000 mg/day based on hemoglobin levels and
creatinine clearance
– Pts with advanced cirrhosis who interrupted treatment due to liver transplantation
could receive 12 additional wks of therapy immediately after transplantation
– Individuals relapsing following 12 wks of daclatasvir + sofosbuvir + RBV offered
re-treatment with the same regimen for 24 wks
Poordad F, et al. EASL 2015. Abstract LO8.

ALLY-1: Key Results
 In subgroup analysis of pts in the advanced cirrhosis group, those who were
Child-Pugh class C (n = 16) or had albumin < 2.8 g/dL (n = 18) had SVR12 rates of 56%
 10/10 pts who relapsed in the advanced cirrhosis group had NS5A RAVs at virologic
failure; 4 of 10 pts had NS5A RAVs at baseline
 3/3 pts who relapsed in the posttransplantation group had NS5A RAVs at virologic
failure; none had NS5A RAVs at baseline
Poordad F, et al. EASL 2015. Abstract LO8. Reproduced with permission.
Genotype
100
80
60
40
20
0
SVR12(%)
All Pts
Advanced
Cirrhosis
Post-
transplant
50/60 50/53
83
94
n/N =
4 6
Advanced Cirrhosis
Cohort
4/
4
100
26/
34
76
1a 1b 2 3 4 6 1a 1b 2 3
11/
11
100
4/
5
80
5/
6
83
0/
0
30/
31
97
9/
10
90
0/
0
10/
11
91
0/
0
1/
1
100
Posttransplant Cohort
Child-Pugh Class
Advanced
Cirrhosis Cohort
11/
12
92
A B C
30/
32
94
9/
16
56

ANRS CUPILT: SOF + DCV Treatment for
HCV Recurrence After Liver Transplant
 Multicenter, open-label, nonrandomized study
SOF + DCV
(n = 11)
SOF + DCV+ RBV
(n = 3)
Pts with HCV
recurrence posttransplant,
no coinfection with HIV
(N = 130) SOF + DCV
(n = 64)
Wk 12
SOF + DCV+ RBV
(n = 52)
Wk 24
SOF dosed 400 mg/day; DCV dosed 60 mg/day; renal function-based RBV dosing.
Treatment type and duration at discretion of investigator; 3 pts in 24-wk groups received ≥ 36 wks of
treatment.
Coilly A, et al. EASL 2015. Abstract G15.
 Most pts were GT1a (27% to 29%) or GT1b (47% to 49%)

SOF + DCV SOF + DCV
+ RBV
Naive 1a 1b 3 4 5 ≤ F2 F3 F4
96
ANRS CUPILT: Efficacy Results
 From baseline to follow-up wk 24, albumin improved from 37 g/L to 40 g/L
Coilly A, et al. EASL 2015. Abstract G15. Reproduced with permission.
100
80
60
40
20
0
SVR12(%)
Overall, Wk 24
97 96
Tx History Genotype Fibrosis Stage
Exp’d
96 97 97 97 91 91 100 93 98
65/
68
60/
62
35/
36
61/
63
10/
11
10/
11
1/
1
44/
46
27/
29
39/
40
62/
64
50/
52n/N =
All Pts

ANRS CUPILT: Variation in
Immunosuppressive Agent Dosing
Coilly A, et al. EASL 2015. Abstract G15. Reproduced with permission.
Cyclosporine Tacrolimus Everolimus MMF
Baseline/Wk 4100
80
60
40
20
0
%VariationinDosing
4
-4
19
34
-5
21
0 2
Baseline/EOT

ALLY-2: Daclatasvir + Sofosbuvir for
HIV/HCV Coinfection
 Multicenter, randomized phase III study
 Treatment arms well matched at baseline and GT1 HCV infection most prevalent
(> 80% per arm)
 Cirrhosis more common on treatment-experienced arm (29% vs 9% to 10% for treatment-naive
arms)
 Almost all pts received ART (atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, efavirenz,
nevirapine, rilpivirine, raltegravir, dolutegravir, or NRTIs only)
Wyles DL, et al. EASL 2015. Abstract LP01.
Daclatasvir + Sofosbuvir
(n = 101)
(n = 50)
HCV treatment-naive,
HCV/HIV-coinfected
pts
(n = 151)
(n = 52)
Daclatasvir 60 mg QD, with dose adjustment for ART use: 30 mg QD with ritonavir-boosted
PIs, 90 mg QD with NNRTIs except rilpivirine. Sofosbuvir 400 mg QD.
Wk 8
HCV treatment-experienced,
HCV/HIV-coinfected
pts
(n = 52)
Wk 12

ALLY-2: Key Results
 No significant differences in SVR12 rates by HCV genotype, HCV disease characteristics, CD4+ cell
count, or ART use in either 8-wk or 12-wk arms
 Ongoing control of HIV disease maintained without need for ART modification
 28 of 32 pts with NS5A RAVs achieved SVR12
– Among 4 pts with NS5A RAVS who did not achieve SVR12, 3 were in 8-wk arm
– Emergent NS5A Q30 RAVs detected in 3 of 13 pts with virologic failure
Wyles DL, et al. EASL 2015. Abstract LP01. Reproduced with permission.
Naive, 12 wks of DCV + SOF
Naive, 8 wks of DCV + SOF
Exp’d, 12 wks of DCV + SOF
Genotype 1 All Treated
100
80
60
40
20
0
SVR12(%)
96.4
75.6
97.7 97.0
76.0
98.1
80/
83
31/
41
43/
44
98/
101
38/
50
51/
52n/N =

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