DAA’s in phase III,
the near future in IFN free regimen
12 june 2014
Pr Philippe Halfon, MD, PhD
Hôpital Europeen
Marseille, France
1 Introduction
2 Viral Cycle and DAAs
3 DAAs in Phase III
4 Special focus on HCV-G4
5 Conclusion
DAA’s in phase III,
the near future in IFN free regimen
Disclosures Philippe Halfon
– Speaker for : Roche, Merck, Janssen, Gilead, BMS
– Boardmember : Provepharm, SoulPharma
– Shareholder and Founder: Genoscience
Drug targets in the HCV lifecycle
RNA replication
Nucleocapsid
assembly
Core of the
virus released RNA uncoating
Translation
&
polyprotein
processing RNA synthesis
Liver cell
Transport and release
miR-122 inhibitor
(LNA)
Protease
inhibitors
NS5A
inhibitors
CD81 Receptors
NS5A
inhibitors
Early
inhibitors
NS5B
polymerase
inhibitors New Therapies & Targets
Life Cycle Step
Cyclophilin
inhibitors
Capsid RNA
Polymerase
Metalloprotease
Serine protease
RNA helicase
Envelope
Glycoproteins
E1 C E2
Nonstructural proteins Structural proteins 5’NTR 3’NTR
NS1 NS2 NS3 NS4A NS4B
Cofactors
NS5A NS5B
Protease Inhibitors
Telaprevir
Boceprevir
Simeprevir
Faldaprevir
Asunaprevir
ABT-450
MK-5172
Sovaprevir
ACH-2684
NS5A Inhibitors
Daclatasvir
Ledipasvir
ABT-267
GS-5816
ACH-3102
PPI-668
GSK-2336805
Samatasvir
MK-8742
Polymerase Inhibitors
Nucs Non-Nucs
Sofosbuvir ABT-333
VX-135 Deleobuvir
IDX-20963 BMS-791325
ACH-3422 PPI-383
GS-9669
TMC-647055
Direct-acting antivirals (DAAs)
Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2014
Triple Therapy:
1 DAA + PegIFN alfa/RBV IFN-Free Regimens (phase III)
Simeprevir (PI)
Faldaprevir (PI)
Sofosbuvir (NI)
Daclatasvir (NS5A)
MK 5172 (PI)
Danoprevir (PI)
Alisporivir (CYP)
Sofosbuvir + RBV
Sofosbuvir + GS-5885 ± RBV
ABT-450/RTV + ABT-267 ± ABT-333 ± RBV
Daclatasvir + Asunaprevir
Investigational HCV Regimens in Phase II & III Trials in 2014
Asselah and Marcellin P,. Liver International 2014
IFN-Free Regimens (phase II)
Simeprevir + Sofosbuvir
Daclatasvir + Sofosbuvir
Daclatasvir + Asunapreivr + BMS 791325
MK 5172 + MK 8742 ± RBV
PI,
1st Generation PI,
2nd Generation
NS5A Inhibitors
1st Generation
NS5A Inhibitors
2nd Generation
NS5B
Nucleoside
Inhibitors
NS5B
Non-Nucleoside
Inhibitors
Efficacy
Resistance
Profile
Pangenotypic
Efficacy
Adverse
events
Drug-drug
interactions
Good profile Average profile Least favorable profile
Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013
General Characteristics of Direct-Acting Antivirals
CHINA 30M
INDIA
18M
USA 5M
RUSSIA 6M
JAPAN
3M EGYPT
12M
PAKISTAN
9M
BRAZIL
4M
INDONESIA
9M
NIGERIA
3M
DR CONGO
4M
CAMEROON 3M
HCV worldwide: Limited access to new treatment options
in countries with the highest HCV prevalence
Asselah T et al. Liver International 2014, in press
Mylan, Sun Pharma and Dr Reddy : are negociating with
Gilead for a production of a generic of Sofosbuvir :
Objective price : 130 USD
Improved HCV treatments continue to be approved in 2014
Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec
Telaprevir
Boceprevir
Interferon Free
Triple therapy
Sofosbuvir
(G1,4,5,6)
Sofosbuvir
+
RBV
G2/3
Daclatasvir*
(G1, 2, 3, 4)
2011 2012 2013 2014 2015
IFN
-fre
e
IFN
-ba
se
d
Simeprevir*
(G1, 4)
European approvals
Protease inhibitor
Nuc inhibitors
NS5A
NS5B inhibitor
Nuc: nucleotide polymerase inhibitor; NS5A: hepatitis C virus non-structural protein 5a protease inhibitor
*Not yet approved in Europe
Current access to second-generation DAAs in Europe 2014
Sofosbuvir Simeprevir
DCV Asunaprevir
Sofosbuvir
Sofosbuvir
Sofosbuvir
Potency
Genotype Coverage
Resistance Barrier
Safety/Tolerability
Half life & Pills burden
Treatment Duration
Drug-drug Interaction
Highest Importance
Secondary Priorities
Cost
Priorities for Direct-Acting Antivirals
Schinazi R, Halfon P, Marcellin P, Asselah T. Liver International 2013
DAA’s in phase III,
the near future in IFN free regimen
1 Introduction
2 Viral Cycle and DAAs
3 DAAs in Phase III
4 Special focus on HCV-G4
5 Conclusion
12 12 12/24 12 12/24 24 12/24 12
24/48 24/48 24/48 12 24/48 24 12/24 12
Current options for genotype 1 treatment-naïve patients
Cross comparison of studies cannot be carried out Q8h, every 8 hours; bid, twice daily *Not yet approved in Europe; ‡duration in weeks ¶F4 excluding non-VF failures
1. Buti M, et al. Gastroenterology 2014;146:744–53; 2. Jacobson I, et al. AASLD 2013. Abstract
1122
3. Jensen D, et al. AASLD 2013. Abstract 1088; 4. Lawitz E, et al. N Engl J Med 2013;368:1878–87
5. Hézode C, et al. AASLD 2012. Abstract 755; 6. Sofosbuvir EU SmPC
7. Lawitz E, et al. EASL 2014. Abstract O165; 8. Sulkowski M, et al. NEJM 2014;370:211‒21
TVR/PR
(bid)
SMV*/PR FDV*
240 mg/PR
SOF/PR DCV*
60 mg/PR
OPTIMIZE1 NEUTRINO4 Pooled
QUEST1 & 22 COMMAND-15 STARTVerso
1&23
295/
327
274/
369
419/
521
378/
524
94/
146
16/
17 104/
159
QUANTUM &
NIAID Study
11-I-02586
COSMOS7
SV
R (
%)
SOF/RBV SOF/SMV*
±RBV¶
DAA
duration‡
Treatment
duration‡
41/
41
SOF + DCV
A14440408
Current and near future options for genotype 1 treatment-experienced patients
Cross comparison of studies cannot be carried out *Not yet approved in Europe ‡Excluding non-virologic failures ¶These data are from Japanese patients
1. Forns X, et al. Gastroenterology 2014. [Epub ahead of print] 2. Reddy K, et al. APASL 2014; 3. Jacobson I, et al. AASLD 2013. Abstract 1100
4. Suzuki F, et al. APASL 2012; 5. Lawitz E, et al. EASL 2014. Abstract
O165
Some data
on re-
treatment
with
SOF/PR, but
no Phase II
or III data
available 101/
145
102/
234
206/
260
69/
99
33/
57
48/
145 3/9 21/
22
Relapsers Partial
responders Nulls Non
responders Relapsers Partial
responders Nulls Nulls
SMV 150mg*/
SOF 400mg*
±RBV‡
SMV
150 mg*/PR
SMV
150 mg*/PR
FDV* 240mg/PR (12 week arm) DCV
60 mg*/PR¶
PROMISE1 ATTAIN2 STARTVerso-33 COSMOS5 COMMAND-24
DAA
duration‡
Treatment
duration‡
12 12 12/24 24 12/24
24/48 48 24/48 24/48 12/24
COSMOS cohort 2: no impact of RBV on SVR12
Excludes non-virologic failures Lawitz E, et al. EASL 2014. Abstract O165
Q80K METAVIR F4
METAVIR F4
Null responders
SV
R1
2 (
%)
11/
11
24 weeks
12/
12
10/
11
9/
9
6/
7
9/
9
4/
5
4/
4
4/
4
12 weeks
13/
14
11/
11
7/
8
7/
7
7/
8
4/
4
3/
3
SMV/SOF/RBV SMV/SOF
Without With Q80K
Without With Q80K
Potency of new therapies in patients who have previously failed treatment with First
generation DAAs
Sulkowski MS, et al. N Engl J Med 2014;370:211–21
SOF + DCV*
24 weeks
20/21
RBV – +
SV
R1
2 (
%)
21/21
No cirrhosis
Sofosbuvir + R
12 weeks
SVR
97% G2 Naive
Sofosbuvir + R
12 weeks 93% G2 IFN intolerant / Ineligible
Sofosbuvir + R
12/16 w
86% / 94% G2 NR
60%/ 78% G2 NR cirrhotic
Lawitz E et al. N Engl J Med. 2013;368(20):1878-1887
Jacobson IM, et al. N Engl J Med. 2013;368(20):1867-1877
Zeuzem S et al. Hepatology AASLD 2013 : Abst 1085
Genotype 2 patients
100
91
50
63
0
20
40
60
80
100
Genotype2 Genotype3
SOF+PEG/RBV12weeks.
SOF/RBV24weeks.
HC
V R
NA
< L
LQ (
%)
Esteban R, Espagne, EASL 2014, Abs. O8 actualisé
Sofosbuvir + R
12 weeks
SVR
56% G3 Naive
Sofosbuvir + R
12 weeks 61% G3 IFN intolerant / Ineligible
Sofosbuvir + R
12/16 w
30% / 62% G3 NR
19% /61% G3 NR cirrhotic
Lawitz E et al. N Engl J Med. 2013;368(20):1878-1887
Jacobson IM, et al. N Engl J Med. 2013;368(20):1867-1877
Zeuzem S et al. Hepatology AASLD 2013 : Abst 1085
Genotype 3
Sofosbuvir + R
24 weeks
93% G3 NR
92% (12/13) G3 Naive cirrhotic
60% (27/45) G3 NR cirrhotic
SVR according to fibrosis in GT-3 patients
Patients G3 : retreatment with sofosbuvir after sofosbuvir failure*
93
74
88
47
0
20
40
60
80
100
SOF+PEG/RBV12weeks. SOF+RBV24weeks.
Nocirrhosis Cirrhosis
13/14 7/8 17/23 7/15
HC
V R
NA
< L
LQ (
%)
Esteban R, Espagne, EASL 2014, Abs. O8 actualisé
n = 16 14 14 16 14 14 16 14 14 16 14 14 16 14 14
Week 4 EOT SVR4 SVR12 SVR24
Sofosbuvir* lead-In +
daclatasvir*
Daclatasvir +
sofosbuvir
Daclatasvir +
sofosbuvir + RBV
Missing
88
93
GT2/3 patients: effective IFN-free regimens in treatment-naive patients
Sulkowski MS, et al. AASLD 2012, oral LB-2. Available at: www.clinicaloptions.com/Hepatitis/Conference%20Coverage/
AASLD%202012/Conference%20Track/Capsules/LB2.aspx. [Accessed July 2013].
94
88 88
86 86
* Investigational compound not licensed in Europe.
EOT, end of treatment; LOD, limit of detection
Ruane Pj et al. J Hepatol 2014 EASL 2014 Absst 1243
Genotype 4
Sofosbuvir + R
12/24
weeks
79% / 59% G4 Naive/ NR 12w
100% / 87% G4 Naive/ NR 24 w
Daclatasvir + +/- RBV
12 weeks Sofosbuvir
Simeprevir + 12 weeks +/- RBV
Sofosbuvir
Improved HCV treatments continue to be developed
Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec Jan–Jun Jul–Dec
Telaprevir
Boceprevir
Interferon Free
Triple therapy
Faldaprevir*
(G1)
Sofosbuvir
(G1,4,5,6)
Sofosbuvir
+
RBV
G2/3 +
Asunaprevir*
Daclatasvir*
±
BMS-325*
Daclatasvir*
(G1, 2, 3, 4)
Sofosbuvir+
Ledipasvir
FDC*
Ombitasvir*
Dasabuvir*
+
ABT-450*/r
RBV
+
±
2011 2012 2013 2014 2015
IFN
-fre
e
IFN
-ba
se
d
Simeprevir*
(G1, 4)
European approvals
RBV
±
Protease inhibitor
Nuc inhibitors
NS5A
NS5B inhibitor
Nuc: nucleotide polymerase inhibitor; NS5A: hepatitis C virus non-structural protein 5a protease inhibitor
*Not yet approved in Europe
Sofosbuvir/Ledipasvir + RBV in GT-1 patients
High efficacy with 12 weeks without Ribavirin. 1 Mangia A, et al. EASL 2014, Abs. O164.
2Afdhal N, et al. EASL 2014, Abs. O109. 3 Kowdley KV, et al. EASL 2014, Abs. O56 .
ION-1 1
12 vs 24 weeks. G1 naive (865pts)
ION-2 2
12 vs 24 weeks. Trt experienced G1 (440 pts)
ION-3 3
8 vs 12 sem. G1 naive non cirrhotics (647pts)
98 %
99 %
99 %
97 %
99 %
99 %
94 %
96 %
94 %
93 %
SVR 12
SOF + LDV
SOF + LDV + RBV
SOF + LDV
SOF + LDV + RBV
SOF + LDV
SOF + LDV + RBV
SOF + LDV
SOF + LDV + RBV
SOF + LDV
SOF + LDV + RBV
SOF + LDV
0 8 12 24 weeks.
95 %
C-WORTHY : 2 DAA for 12 weeks
SVR 4-12
Population Fibrosis MK-5172 + MK-8742
+ RBV
MK-5172 + MK-8742 + 12 w.
(between 12-18)
Naive co-infected Non cirrhotic 97 % (28/29) 90 % (26/29)
Naive Non cirrhotic 94 % (80/85) 98 % (43/44)
Naive Cirrhotic 90 % (28/31) 97 % (28/29)
Null Responder Cirrhotic
Non cirrhotic 94 % (30/32)* 91 % (30/33)*
Hézode C, Créteil, EASL 2014, Abs. O10. Lawitz E, Etats-Unis, EASL 2014, Abs. O61. Sulkowski M, Etats-Unis, EASL 2014, Abs. O63.
* Among cirrhotic patients 44/46 (96 %)
3 DAA: ABT450/r, ombitasvir (ABT 267) and dasabuvir (ABT 333) For 12 weeks in GT-1 patients
SAPPHIRE-I (12 weeks)
PEARL-II (12 weeks)
TURQUOISE-II (12 & 24 weeks)
SAPPHIRE-II (12 weeks)
PEARL-III (12 weeks)
PEARL-IV
(12 weeks)
STUDY
3DAA + RBV (n = 473)
3DAA + RBV (n = 88)
3DAA + RBV, 12 weeks. (n = 208)
3DAA + RBV (n = 297)
3DAA + RBV (n = 210)
3DAA + RBV (n = 100)
Treatment
3DAA (n = 91)
3DAA (n = 209)
3DAA (n = 205)
3DAA + RBV, 24 weeks. (n = 172)
GT1 with compensated cirrhosis , naïve and Treatment-experienced (n = 380)
Treatment naive (n = 631)
Treatment-experienced (n = 394)
GT1b Treatment-experienced (n = 179)
GT1b Treatment naive (n = 419)
GT1a Treatment naive (n = 305)
Patients
3DAA = combination of ABT-450/ritonavir (150/100 mg) with ombitasvir (ABT-267) (25 mg) QD plus dasabuvir (ABT-333) (250 mg) TID with or without ribavirin
SVR12
96 %
96 %
96 %
100 %
99 %
97%
99 %
92 %
90%
96 %
EASL 2014
Interferon-free regimen in Naive GT-1 cirrhotic patients
Afdhal N, et al. EASL 2014, Abs. O109 Poordad F et al. EASL 2014, Abs. O163 Mangia A, et al. EASL 2014, Abs. O164 Lawitz E et al. EASL 2014, Abs. O165
SVR G1a G1b
94 100
94 100
92,2 92,9 100 100
90 97 97 97 100 100 100
66
0
20
40
60
80
100
28 31
28 29
30 31
29 30
3 3
5 5
6 6
2 3
59 64
52 56
22 22
18 18
32 34
33 33
31 33
36 36
SVR
G1a G1b
86 82
100 100 93,3
100 100 100
80
92,9 100 100
85,7
100 100 100 94 91 100 97 100 100
80
100
Relapsers or non responders bi or
tri
Relapsers bi
Partial R bi
Null R bi
Relapsers bi
Partial R bi
Null R bi
Null R bi
Null R bi
6 7
14 14
10 10
30 32
4 5
9 9
4 4
4 4
11 11
40 50
39 42
25 25
19 22
18 22
22 22
14 15
22 22
13 13
10 10
20 20
3 3
30 33
32 32
29 30
0
20
40
60
80
100
Interferon-free regimen in Treatment-experienced GT-1 cirrhotic patients
Afdhal N, et al. EASL 2014, Abs. O109 Poordad F et al. EASL 2014, Abs. O163 Mangia A, et al. EASL 2014, Abs. O164 Lawitz E et al. EASL 2014, Abs. O165
ABT-450/r (150/100 mg /d) ; ombitasvir (25 mg/d) ; RBV ( 1 000 or 1 200 mg/d)
(n = 44)
(n = 42)
(n = 49)
D1 Week 12
ABT-450/r + ombitasvir Naive
ABT-450/r + ombitasvir + RBV Naive
ABT-450/r + ombitasvir + RBV Relapsers/partial responders/nulls responders
Study design
ABT-450/r/ombitasvir + RBV For 12 weeks in GT-4 patients
• Phase II study
• 86 Naive patients, GT-4, F0-F3
• 49 Treatment failure patients, GT-4, F0-F3
Hézode C, et al. EASL 2014, Abs. O58
SVR 12
91% (40/44)
SVR 4
100% (42/42)
100% (37/37)
GS-5816 : a new pangenotypic NS5A I.
• Open label study
– SOF 400 mg + GS-5816 25 mg for12 weeks.
– SOF 400 mg + GS-5816 100 mg for12 weeks.
• Naive GT 1-6, non cirrhotic patients
Everson G, et al. EASL 2014, Abs. O111.
w24 D1 w12
SVR12
G2–6
(n = 45)
G3
(n = 54)
SOF + GS-5816 25 mg
SOF + GS-5816 100 mg
SOF + GS-5816 25 mg
SOF + GS-5816 100 mg
SOF + GS-5816 25 mg
SOF + GS-5816 100 mg
G1
(n = 55)
SVR 12
96 %
100 %
91 %
100 %
93 %
93 %
DAA + PR
Simeprevir
Faldaprevir
Sofosbuvir
IFN free
Sofosbuvir/ ledipasvir FDC ± RBV
ABT-450r/ABT-267 FDC + ABT-333 ±
RBV
Daclastavir + Asunaprevir
G1b
2015-2016
2014-2015
Simeprevir + Sofosbuvir
Daclatasvir
Other IFN-free combinations Other DAA + PR
Telaprevir
Boceprevir
Conclusion & Perspectives
Asselah and Marcellin P,. Liver International 2014
Daclatasvir + Sofosbuvir
MK 5172 + MK 8742 ± RBV
NS5A
+
NS5B Nuc
NS3-4/r
+
NS5B non NUC
+
≈100%
SVR
Treatment duration
12 weeks
(8-24?)
RBV +
PEG
IFN
+
HTA
+
Cure ?
HCV : yes
Liver disease : ?
< 5 %
Future
Chronic HCV infection can be cured … but challenges still remain
Older age:
polypharmacy Undiagnosed
patients
Intravenous
drug users
Advanced
disease
Coinfected
(e.g. HIV, HBV) Failing
patients
Ethnicity /
geographic
differences
Adherence
challenges?
100%
20%
10%
DIAGNOSIS
and therapy
Cure
All
HCV
patients
PEG-IFN/RBV
100%
20%
95% SVR
19%
100%
90%
85%
95% SVR
And increase of diagnosis
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