P-1
EASL and The Future of HCV Treatment
Douglas T. Dieterich, M.D Professor of Medicine
Division of Liver Diseases, Gastroenterology and Infectious Diseases
Department of Medicine Mount Sinai School of Medicine
New York, New York
Case Discussions
• Miles 64y/o successful garment executive with HCV for >30 years
• Treated with IFN TIW and RBV :partial responder in 1990’s
• Declined therapy with Peg in 2001 • Cirrhosis and HCC 2005 : RFA successful • Declined therapy in 2005 (DAA’s coming) • Declined therapy with DAA in 2011 (IFN Free) • 2013 HCC in portal vein now getting palliative
Y90 and sorafenib
3
DAAs as Components of New Treatment Paradigm for Hepatitis C
IFN-based 1 DAA + SOC
2 DAAs + SOC
2011 2015
Peg-IFN + RBV (SOC)
2009
DAA=direct-acting antiviral; SOC=standard of care (Peg-IFN + RBV)
Time
Prospect of shorter treatment duration for a greater proportion of patients
IFN-free? IFN-free?
~2013
Evolving Treatment Landscape of Direct Acting Anti-Viral Agents
DAA = direct-acting anti-viral agents. 5
ABT450/r (ABT)
Preclinical
Phase I
Phase II
Phase III
Approved
Nuc- Polymerase inhibitors
Non Nuc- Polymerase inhibitors Protease
inhibitors
NS5A inhibitor
Others
DAA combinations
IFN lamba (BMS)
Alisporivir cyclophilins
MSD
Idenix
AZD07259 NSSA (AZN)
Daclatasvir (BMS)
Presidio GSK
BMS824393 NSSA (BMS)
Enanta
Vertex
Vertex
BMS
Roche
Gilead
Boceprevir (MSD)
Simeprevir (J&J/Tobizer)
GS9256 (Gilead)
MK5172 (MSD)
Vaniprevir (MSD)
Telaprevir (J&J/Vertex)
Asunaprevir (BMS)
Faldaprivir (BI)
Sovaprevir (Achillion) Danoprevir (Roche/Intermune)
Tegobuvir (Gilead)
Setrobuvir (Roche)
VX222 (Vertex)
BI201127 (BI)
IDX375 (Idenix/NVS)
ABT333. ABT7072 (ABT)
BMS-791325 (nuc/non-nuc BMS))
Mericitabine (Roche/Pharmasset)
Sofosbuvir (Gilead)
BI
R0622 (Roche) Medivir (Tibotec)
GL59393 (GSK)
Biocryst
BI Abbott
The first all-oral combination therapies of NUC+NS5A and PI+non-NUC are expected to reach the market in 2013
6 Source: L.E.K. interviews and analysis
2015 2016 2017 2014 2018
Second wave Third wave
2013
PI
NUC
NS5A
Non-NUC
NUC+NS5A
NS5A+PI+ non-NUC
Non-NUC+PI
MK-7009 (Merck)
NUC+PI
Single agents
Combinations
IDX-963 (Idenix)
IDX-719 (Idenix)
IDX-437 (Idenix)
GS9256, GS9451 (Gilead)
GS9669 (Gilead)
BMS-032 (BMS)
8742 (Merck)
MK-5172 (Merck)
TMC435 (JNJ)
BI-335 (BI)
RG7227 (Roche)
239 (Novartis)
ACH-2684 (Achillion)
383 (BioCryst)
ABT-267+ABT-450+ABT-333 (Abbott)
BMS-052+BMS-032+BMS-325 (BMS)
VX-135+TMC435 (Vertex, JNJ)
BI-335 and BI-7127 (BI)
RG7128+RG7227 (Roche)
TMC-055 (JNJ)
ACH-1625 (Achillion)
Idenix NS5A-PI combo (+/- NUC and/or non-NUC)
Incivek (Vertex) and Victrelis
(Merck) launched in 2011
GS7977 (Gilead)
VX-135 (Vertex) RG7128
(Roche)
BMS-052 (BMS)
RG7790 (Roche)
GS9190 (Gilead)
BI-7127 (BI)
BMS-325 (BMS)
ABT-333 (Abbott)
VX-222 (Vertex)
All Phase II with expected
launch in 2016
GS5885 (Gilead)
ABT-267 (Abbott)
BMS-393 (BMS)
3102, 2928
(Achillion)
6805 (GSK) 668, 461
(Presidio)
GS7977+GS5885 (NUC+NS5A,
Gilead)
ABT-450+ABT-072 (PI+non-NUC,
Abbott)
First all-oral combinations
VX-135+6805 (Vertex, GSK)
GS9256+GS9190 (Gilead)
ABT-450 (Abbott)
ABT-072 (Abbott)
VX-135+GSK-6805 (Vertex, GSK)
First oral NUC
Second generation PIs
Idenix’s combo is expected to
launch in 2017 Single agent
Combination
Updated from Manns MP et al: Nature Reviews Drug Discovery, 2007
Patients achieving SVR (%)
100
80
60
40
20
0 24 48 78 Peg-IFN IFN +
ribavirin Peg-IFN + ribavirin Weeks
IFN monotherapy
6-19 11-19 10-22
18-39 35-43
61-79
33-36
76-82
42-46
*Range of values reported; lower bar represents lower value;
Peg-IFN + ribavirin
+ PI
67-75
Fig. 2
All genotypes
Genotype 2/3
Genotype 1
NS3/4A NS5B
NS5A CypA
miR122
Viral RNA
Lipid droplets
virions
NS2
ER
Nucleus
SR-BI
CD81
CLDN1
OCLN
SR-BI Blocker •ITX-5061 (1)
Anti miR122 agents •Miravirsen (2)
NS3/4A PI‘s •Boceprevir (4) •Telaprevir (4) •Simeprevir (3) •Faldaprevir (3) •Asunaprevir (3) •ABT-450 (3) •Danoprevir (2) •GS-9451 (2) •MK-5172 (2) •ACH-2684 (1)
Polymerase inhibitors •Nucleosides −Sofosbuvir (3) −Mericitabine (2) −VX-135 (1)
•Non-nucleosides −ABT-333 (3) −BI-207127 (3) −ABT-072 (2) −BMS-791325 (2) −GS-9669 (2) −Setrobuvir (2) −VX-222 (2)
Cyclophilin A inhibitors •Alisporivir (3/hold) •SCY-635 (2)
NS5A inhibitors •Daclatasvir (3) •GS-5885 (3) •ABT-267 (3) •PPI-668 (1)
Fig. 3A
ribosome
endosome
Other
Other
Other
Other
Other
Other
Other
Other
non-
spec
ific
dru
gs
Boceprevir
Ribavirin
spec
ific
dru
gs
Telaprevir
PEG-Alpha
ABT-450/r
Simeprevir
Daclatasvir
PEG-Lambda
Fig. 4
pre 2011 2011 2012 2013 2014 2015 2016
Sofosbuvir
Asunaprevir
GS-5885
ABT-267
Faldaprevir
ABT-333
NS3/4A PI
Non-specific agent
Non-Nuc NS5B inhibitor
NS5A inhibitor
Nucleoside NS5B inhibitor
Daclatasvir (NS5A inhibitor) + Asunaprevir (PI) ± PR in null responders: phase IIa study
0 24 Study weeks
CHC,
G1,
nul
l res
pond
er
to P
R,
no c
irrho
tics,
N=2
1
Daclatasvir 60 mg qd plus Asunaprevir 600 mg bid
Daclatasvir 60 mg qd + Asunaprevir 600 mg bid plus PR
Randomisation Null response defined as <2 log10 decline in HCV RNA following 12 weeks of treatment with PR Lok A, et al. EASL 2011, oral
Virologic Response before and after treatment
0
20
40
60
80
100
120
RVR eRVR cEVR EOTR SVR 12 SVR 24
NS5A+PIQUAD
64 60 60
36 36 36
90 90*
46
100 100
46
•Group A: 4(2/9 GT1a and 2/2 GT1b) patients achieved SVR12 and SVR24 •Group B; 10/10 achieved SVR12 and 9 had SVR24
•1 patient had HCVRNA<LLQ at post treatment week 24, and undetectable 35 d later
The world changed again in November 2011 in San Francisco : Electron
Time Wk
Sofosbuvir RBV
12 weeks PEG
Sofosbuvir RBV
8 weeks PEG
Sofosbuvir RBV
4 weeks PEG
Sofosbuvir RBV
NO PEG
n %<LOD n %<LOD n %<LOD n %<LOD
2 9/11 82 7/8 88 8/9 89 8/10 80
4 11/11 100 10/10 100 9/9 100 10/10 100
8 11/11 100 10/10 100 9/9 100 10/10 100
12 11/11 100 10/10 100 9/9 100 10/10 100 SVR4 11/11 100 10/10 100 9/9 100 10/10 100
SVR8 11/11 100 10/10 100 9/9 100 10/10 100
SVR12 11/11 100 10/10 100 9/9 100 10/10 100 SVR24 6/6 100 5/5 100 5/5 100 4/4 100
ELECTRON 100% concordance of SVR12 with SVR24
Gane EJ, et al. 62nd AASLD; San Francisco, CA; November 4-8, 2011. Abst. 34.
On Treatment Viral Suppression
Once-Daily Sofosbuvir Plus Ribavirin Given for 12 or 24 Weeks in Treatment-Naïve Patients
With HCV Infection: the QUANTUM Study
ATOMIC Study Design
• Non-cirrhotic, treatment-naïve patients with HCV genotype 1 were randomized 1:2:3 into open-label arms
• HCV RNA analyzed by TaqMan® HCV Test 2.0 (LOD: 15 IU/mL)
Group A N = 52
Group B N = 125*
Group C N = 155†
Day 1 Wk 24 Wk 12
SOF + PEG + RBV
SOF + PEG + RBV
SOF + PEG + RBV
SOF (n = 75) SOF + RBV (n = 75)
GT 1
GT 1, 4, 6
GT 1
*Of the 125 patients enrolled in Arm B, 11 were genotype 4 and five were genotype 6 †Five of the 155 patients were not re-randomized at Week 12 Hassanein T, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 230.
94% 98% 97% 98% 99% 99%
94% 94% 93% 90% 92% 91%
0%10%20%30%40%50%60%70%80%90%
100%
SOF+PEG+RBV12 Wks
SOF+PEG+RBV24 Wks
SOF+PEG+RBV12+12 Wks
Patie
nts
with
HC
V R
NA
<LO
D (%
)
Week 4 EOT SVR4 SVR12
11 patients (1 in the 12 Wk group) who achieved SVR12 were subsequently lost to follow-up resulting in SVR24 rate of 88% with 12 weeks of treatment No relapse after SVR12 was seen in any group Hassanein T, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 230.
90% of Patients Achieved SVR12: Sofosbuvir + PEG + RBV 12-Week Regimen
Sofosbuvir Phase 3 Programs: GT2/3
Genotype 2/3 (naïve)
Genotype 2/3 (IFN ineligible/intolerant)
Sofosbuvir 400mg QD + RBV
Peg-IFN + RBV
N=256
N=243
N=207
N=71
SVR12
SVR12
12 24 36
Sofosbuvir placebo + RBV placebo
SVR12
SVR12
POSITRON
FISSION
Sofosbuvir 400mg QD + RBV
Study Weeks
Genotype 2/3 (treatment-experienced)
N=103
N=98 Sofosbuvir 400mg QD +
RBV
SVR12
SVR12
FUSION Sofosbuvir 400mg QD
+ RBV
16 28
FISSION SVR12 Results: Treatment naive GT 2/3
67%
97%
56%
47%
67%
78%
63%
38%
0%
20%
40%
60%
80%
100% SOF+RBVPeg-IFN+RBV
Overall GT2 GT3 Cirrhosis
Patie
nts
Ach
ievi
ng S
VR12
(%)
•1 on-treatment virologic failure in SOF+RBV arm due to nonadherence •Most common AEs occurring in ≥ 10% subjects were fatigue, headache, nausea, insomnia, and dizziness (all more common in PEG+RBV arm)
12 Wks 24 Wks
Press Release. These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.
170/ 253
162/ 243
P <0.001* Primary
Endpoint
POSITRON SVR12 Results: GT 2/3 IFN Intolerant/Unwilling
78%
93%
61% 61%
0%
20%
40%
60%
80%
100%
Overall
Patie
nts
Ach
ievi
ng S
VR12
(%)
GT2 GT3 Cirrhosis •SVR12 rate in placebo recipients was 0% •No on-treatment virologic failure in SOF+RBV arm (all relapses) •Most common AEs occurring in ≥10% subjects were fatigue, nausea, headache, insomnia, pruritus, and anemia
Press Release. These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.
161/ 207 n/N =
Confidential 24
FUSION SVR12 Results: Treatment experienced GT 2/3
50%
86%
30% 31%
73%
94%
62%66%
0%
20%
40%
60%
80%
100% 12 Weeks SOF+RBV16 Weeks SOF+RBV
Overall GT2 GT3 Cirrhosis
Patie
nts
Ach
ievi
ng S
VR12
(%)
•No on-treatment virologic failure (all relapses) •Most common AEs occurring in ≥15% subjects were fatigue, headache, insomnia, nausea
Press Release. These data are available in press release format only, have not been peer reviewed, may be incomplete, and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.
50/ 100
69/ 95
Confidential 26
Treatment With Sofosbuvir + Peginterferon + Ribavirin for 12 Weeks Achieves 90% SVR12 in Treatment-Naïve Genotype 1, 4, 5, and 6 HCV-Infected Patients: The
NEUTRINO Study
SOF + RBV (treatment-naïve)
SOF + RBV (null responders)
84% SVR12
10% SVR12
Week 0 Week 4 Week 8 Week 12
n = 10
n = 25
ELECTRON: Genotype 1 Cohorts
SOF + GS-5885 + RBV (treatment-naïve)
SOF + GS-5885 + RBV (null responders) n = 10
n = 25
32
12-week groups (G and H) were enrolled and independently randomized after 24-week groups (A, C, and E) RBV: 1000-1200 mg/d, weight-based (GT 1); 800 mg/d (GT 2/3).
Daclatasvir + Sofosbuvir with or without Ribavirin in HCV genotype 1, 2 or 3
SVR12 Week 24 SVR24 SVR4 SVR48
Chronic HCV GT 2/3
(N = 44)
n = 16 Follow-up
Follow-up
Follow-up
n = 14
n = 14
Group B: SOF 400 mg QD × 7 d, then DCV 60 mg QD + SOF 400 mg QD
Group D: DCV 60 mg QD + SOF 400 mg QD
Group F: DCV 60 mg QD + SOF 400 mg QD + RBV
Chronic HCV GT 1a/1b (N = 126)*
n = 41
n = 15
n = 14
Follow-up
n = 41
n = 15
Follow-up
Follow-up
Follow-up
SVR4 Week 12
Follow-up
Group C: DCV 60 mg QD + SOF 400 mg QD
Group E: DCV 60 mg QD + SOF 400 mg QD + RBV
Group A: SOF 400 mg QD ×7 d, then DCV 60 mg QD + SOF 400 mg QD
SVR48 SVR12 SVR24
Group G: DCV 60 mg QD + SOF 400 mg QD
Group H: DCV 60 mg QD + SOF 400 mg QD + RBV
Sulkowski M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. LB-2.
Genotype 2/3: Virologic Response During and After Treatment (mITT)
• Group B: 1 patient (GT3) relapsed; NS5A-A30K polymorphism (associated with DCV resistance) detected at baseline and PT Week 4. 1 patient (GT3) met protocol definition of virologic breakthrough; added pegIFN alfa/RBV – achieved SVR24
• Group F: 2 lost to follow-up after EOT; 1 returned at PT Week 24 with HCV RNA < LLOQ-TND a End-of-treatment (EOT) includes patients who discontinued early, with last visit considered EOT; TD, target detected; TND, target not detected.
0
20
40
60
80
100
HCV
RNA
< LL
OQ
(%
Pat
ient
s)
94 88 88 86 93 88
SVR4 Week 4 SVR12
N =
EOT a 16 14 14
SVR24
16 14 14 16 14 14 16 14 14 16 14 14
D: DCV + SOF
B: SOF LI + DCV
F: DCV + SOF + RBV
Missing
% of patients with HCV RNA < LLOQ-TND
88 79 64 94 93 100 100 88 79 93 88 86 100 88 93
86
Sulkowski M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. LB-2.
2 patients missing at PT Week 4— both achieved SVR12; 1 patient undetectable at PT Week 2 and with HCV RNA detected at PT Week 4 (not confirmed)—achieved SVR12
68 patients have reached PT Week 12—all 68 have achieved SVR12
a End-of-treatment (EOT) includes patients who discontinued early, with last visit considered EOT.
12-week Groups (G and H)
Genotype 1: Virologic Response During and After Treatment,12- and 24-Week Groups (mITT)
SVR4
HCV
RNA
< LL
OQ
(% p
atie
nts)
0
20
40
60
80
100
Week 4 SVR12
N =
EOT a
15 14 15 41 41
SVR24
15 14 15 15 14 15 41 41 15 14 15 41 41 15 14 15
C: DCV + SOF
A: SOF LI + DCV
E: DCV + SOF + RBV
G: DCV + SOF (12-wk)
H: DCV + SOF + RBV (12-wk)
Missing
87 93 73 78 76 100 100 100 100 100 100 95 98 100 100 100 100 100 93 100 100
95 98 95
% of patients with HCV RNA <
LLOQ-TND
Sulkowski M, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. LB-2.
EOT
Sustained Virologic Response With Daclatasvir Plus Sofosbuvir ± Ribavirin (RBV) in Chronic HCV Genotype (GT) 1-Infected Patients Who
Previously Failed Telaprevir (TVR) or Boceprevir (BOC)
HCV
RNA
< LL
OQ
(%
pat
ient
s)
Week 2 SVR4
N =
Week 4 21 20 SVR12
100 100 100 100
21 20
21 20
21 20
21 20
DCV + SOF
DCV + SOF + RBV
Missing
100
91
80
95
* 1 patient missing at post-treatment (PT) Week 12: HCV RNA was undetectable at PT Week 4 and at PT Week 24 (preliminary)
■21/41 patients have reached PT Week 24; all have achieved SVR24
100 95*
-6
-5
-4
-3
-2
-1
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14
NS3 polymorphisms
No NS3 polymorphisms
Med
ian
chan
ge in
HCV
RN
A (lo
g 10IU
/mL)
Virologic Response by Presence or Absence of Baseline NS3 Polymorphisms
Patients with NS3 polymorphisms, n V36M-R155K 6
R155K 3
V36L-R155K 1
T54S-R155K 1
T54S-V55I-R155K 1
V36M 1
V36M-V55I 1
V36M-V55A-R155K 1
V36M-R155K-I170T 1
V36A 1
V55A 1
V170T 1
Study Day
(n=19)
(n=22)
First dose
ABT450/r (PI) + ABT267 (NS5A)+/- ABT333 (NNI) +- RBV in Treatment and Prior Null Responders
Trea
tmen
t-na
ïve
Nul
l Re
spon
der
ABT-450/r Dose (QD) N
ABT-267 25mg QD; ABT-333 400mg BID; RBV weight-based 1000-1200 mg daily dose divided BID All patients to be followed through 48 weeks post-treatment
ABT-450 ABT-267 ABT-333 RBV
Wk 0 Wk 8 Wk 12 Wk 24
80
79
79
79
80
41
45
45
43
Regimen/Duration
150/100
150/100
100/100,200/100
150/100
100/100,150/100
100/100,150/100
200/100
100/100,150/100
100/100,150/100
Kowdley K, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. LB-1.
ABT-450 ABT-267 ABT-333 RBV
ABT-450 ABT-267 ABT-333 RBV
ABT-450 ABT-267 ABT-333
ABT-450 ABT-267 ABT-333 RBV
ABT-450 ABT-267 ABT-333 RBV
ABT-450 ABT-267 ABT-333 RBV
ABT-450 ABT-267 ABT-333 RBV
ABT-450 ABT-267 ABT-333 RBV
SVR12 Rates (ITT) for 8- and 12-Week Arms
88,6 85,4 89,9 88,5 97,4
88,6 93.3
0102030405060708090
100
Naïve 450+267+333+RBV 8 Week Naïve 450+333+RBV Naïve 450+267+RBVNaïve RBV-free Naïve 450+267+333+RBV 12 WeekNull 450+267+RBV Null 450+267+333+RBV 12 Week
Per
cent
age
of p
atie
nts
(ITT)
ac
hiev
ing
SV
R12
Treatment-naϊve Patients Null Responders
ABT-450 ABT-267
RBV
ABT-450 ABT-267 ABT-333
ABT-450 ABT-267 ABT-333
RBV
ABT-450
ABT-333 RBV
ABT-450 ABT-267 ABT-333
RBV
ABT-450 ABT-267 ABT-333
RBV
ABT-450 ABT-267
RBV
8 weeks 12 weeks 12 weeks N=80 N=41 N=79 N=79 N=79 N=45 N=45
Kowdley K, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. LB-1.
Simeprevir (TMC435) with peginterferon/ribavirin for chronic HCV genotype 1 infection in treatment-naïve
patients: results from QUesT-1, Phase III
COSMOS: Sofosbuvir + Simeprevir ± RBV in GT1 Null-Responders
96 93
0
25
50
75
100
RBV + RBV -
Phase IIa Study: Sofosbuvir 400 mg QD + Simeprevir 150 mg QD ± RBV x 12 wks
Lawitz et al., CROI 2013, Abstract 155LB
26/27
SVR8wks (%)
13/14
2013
• Simeprevir filed NDA in US in March • Sofosbuvir filed NDA in US April 4 • FDA meeting tentatively October 24,25 • SMV PDUFA Date November 28 • SOF PDUFA Date December 6 • Will you use these two together off label? • Will insurers pay for it?
Lonestar Press Release Treatment Duration
Weeks Population numbers
SVR % SVR weeks
SOF+LDV 8 G1 naive 19/20 95 8
SOF+LDV RBV 8 G1 naive 21/21 100 8
SOF+LDV 12 G1 naive 19/19 100 4
SOF+LDV 12 G1 experienced 18/19 95 4
SOF+LDV RBV 12 G1 experienced 20/21 95 4
New Nucs
Second Generation NS5As
The Future (as I see it)
PI+PEG+RBV PI2+PEG+RBV
DAA1 + DAA2 + RBV
2011 2012 2013 2014 2015 2016 2017 2018 2019
PEG/RBV 0 10 20 30 40 50 60 70 80 90 100
% Nuc + P/R For G 1 Nuc + RBV For G 2/3
A Potential Evolution Scenario
HCV Therapy for Genotype 1
PEG-IFN
+
Pol Inhibitor
+/- ribavirin
+ +
or
Prot Inhibitor
+
Pol Inhibitor
+
Prot Inhibitor
All Oral
Therapy
1989-1998 1998-2001 2001- present 2008-2009 2011-2014 2014+
Oral immune modulators
Other direct antivirals
10%
35%
42-50%
Estimated 65-70%
Estimated 85-90%
0
10
20
30
40
50
60
70
80
90
100
1st Stage 2nd Stage 3rd Stage 4th Stage 5th Stage 6th Stage
Sust
aine
d Vi
rolo
gic
Resp
onse
in G
1 (S
VR)
