Advantages of New Generation
Direct Acting Antivirals (DAAs)
Tarik Asselah
MD, PhD
Service d’Hépatologie & INSERM U773,
CRB3
Hôpital Beaujon, Clichy
tarik.asselah@bjn.aphp.fr
Where we are : The Present
Triple therapy : PI + PEG-IFN + RBV
• Increased Efficacy in G1 patients (> 30%)
– G1 naïves
– G1 relapsers
• Shorten duration (> 50%)
• Predictors of non response
– Cirrhosis
– Subtype 1a
– Previous non response
Where we are : The present
Limitations of Triple therapy
• Efficacy only in G1 patients
• Low SVR in difficult to treat patients
– Cirrhosis
– Previous null responders
• Side Effects
• Costs
New Generation DAAs
New Generation DAAs
• Introduction : Targets for DAAs
• Protease inhibitors
• Polymerase inhibitors
• NS5A inhibitors
• IFN free combination
• Conclusion
Viral Cycle
Asselah T et al. Liver International 2012
Immune Response to HCV
Asselah T et al. GUT 2009
Asselah T et al. GUT 2009
Targets for DAAs
NS5A
Inhibitors
Protease
Inhibitors
NS3-4A
Protease
NS5A
Polymerase
Inhibitors
NS5B
Polymerase
Asselah T et al. Liver International 2012
New DAAs
Efficacy
Genotype
dependency
Barrier to
resistance
+++
+++2
++2
NS5A
+++
+++3
++3
NS5B
(nucleosides)
+++1
+++
+++
++
+
+
NS3/4A
(protease
inhibitors)
NS5B
(nonnucleosides)
1e.g.
PSI-7977, PSI-938; 2e.g. MK-5172, ACH-1625; 3e.g. PPI-461
New drugs
Phase I
Phase II
Phase III
Protease
inhibitors
ACH-1625
VX-985
BMS-650032
Danoprevir
GS 9256
GS 9451
MK5172
ABT 450
BI 201335
TMC435
Polymerase
inhibitors
non nuc
IDX375
ABT-333
ABT-072
ANA598
BMS-791325
BI207127
Filibuvir
VX-759
VX-222
Polymerase
inhibitors
nuc
NS5A inhibitors
Mericitabine
PSI-7977
PSI 938
ABT-267
PPI-461
BMS-790052
BMS-824393
CF102
New Agents
G1 naïves
Not head-to-head comparisons
100
71-83 68-85 65-85 75-86 61-84
SVR (%)
80
42-83
53-76
63-75
60
38-50
56
40
20
0
BOC or
TVR [1,2]
1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.
3. Sulkowski M, et al. EASL 2011. Abstract 60. 4. Terrault N, et al. AASLD 2011. Abstract 79.
5. Vierling JM, et al. AASLD 2011. Abstract LB-17. 6. Fried M, et al. AASLD 2011. Abstract LB-5.
7. Manns MP, et al. AASLD 2010. Abstract 82. 8. Jacobson I, et al. EASL 2010. Abstract 2088.
9. Lawitz E, et al. EASL 2011. Abstract 445. 10. Pol S. ICAAC 2011. Abstract HI-376.
11. Flisiak R, et al. EASL 2011. Abstract 4.
New Generation DAAs
• Introduction : Targets for DAAs
• Protease inhibitors
• Polymerase inhibitors
• NS5A inhibitors
• IFN free combination
• Conclusion
New Generation of DAAs
•
•
Protease inhibitors
•
TMC 435
•
BI 201335
•
Danoprevir
•
MK 7009
Polymerase inhibitors
•
•
PSI-7977
NS5A inhibitor
Daclatasvir
TMC435 (G1 naïves)
SVR (ITT)
100
90
p = 0,008
n.s.
p < 0,001
86
82
80
p = 0,013
75
81
SVR (%)
70
65
60
50
40
30
20
10
0
TMC435 75 mg
12 w
P/R
(n = 78)
TMC435 75 mg TMC435 150 mg TMC435 150 mg
24 w
12 w
24 w
P/R
P/R
P/R
(n = 75)
(n = 77)
(n = 79)
Placebo
P/R
(n = 77)
Fried et al. AASLD 2011, LB5
BI201335 (G1 naïves)
BI 12 weeks
BI 24 weeks
100
Patients (%)
82
80
72
73
65
60
40
20
0
58/81
eRVR
64/78
53/81
57/78
SVR
Dieterich et al. AASLD 2011, A36
Danoprevir (DNV, RG7227) (G1 naïves)
A : 300 mg + P/R (n = 72)
SVR
B : 600 mg + P/R (n = 72)
C : 900 mg + P/R (n = 50)
100
85
88
80
96
87
86
68
79
74
D : Placebo mg + P/R (n = 31)
89
76
SVR (%)
65
42
60
40
18
20
0
7
53 63 43
72 72 50
RVR
2
31
47 57 9
72 72 50
49 61 38 13
72 72 50 31
eRVR
SVR24
41 55 8
47 57 9
N/A
SVR24
Patients eRVR*
*Patients RVRe : patients with HCV RNA undetectable from W4 to W20
Terrault et al. AASLD 2011, A79
MK 7009 (G1 experienced)
SVR
120
* p < 0,001 vs PR
100
100
71,1*
100
84,6*
93
80
87
86
83 86
78*
80
87
66,7*
67
60
60
50
40
All
Relapsers
Partial Responders
Breakthroughts
Null responders
50
40
37
40
19*
20
0
31
29
11
38 14 7 5 12
MK-7009
600 mg x 2/j
+ PR 24 w
39 16 6 7 10
MK-7009
600 mg x 2/j
+ PR 48 w
39 16 8 5 10
37 16 5 6 10
MK-7009
300 mg x 2/j
+PR 48 w
MK-7009
600 mg x 2/j
+ PR 48 w
28 16 5 7
0
PR 48 sem
Lawitz et al. AASLD 2011, LB13
Summary: New Generation PI triple therapy (G1 naïves)
Drug
SVR
Duration of trt (weeks)
TMC- 435
82%
75%
81%
86%
85-96% ( RVRe+: 79-86%)
TMC(75mg/j) 12 /PR24
TMC (75mg/j) 24 /PR 24
TMC (150mg/j) 12/PR24
TMC (150mg/j) 24/PR24
BI201335
71%
73%
83%
93% ( RVRe+: 87% )
Vaniprevir
(MK-7009)
61%
80%
78%
84%
MK (300mg x2/j) 4/PR44
MK (600mgx2/j) 4/PR44
MK (600mg/j) 4/PR44
MK (800mg/j) 4/PR44
Danoprevir
(RG-7227)
66%
85%
42%
RG (300mgx3/j) 12/PR24-48 TGR
RG (600mgx2/j) 12/PR24-48 TGR
PR 48
BI (120mg) 24/ PR 24ou 48
BI (240mg + PIB) 24 / PR 24 ou 48
BI (240mg/j) 24 / PR 24 ou 48 ± PR
BI (240 mg ) 24 /PR 24
Fried et al. AASLD 2011 LB5
Sulkowski et al. EASL 2011 USA, A60
Manns et al. AASLD 2010, A82
Terrault et al. AASLD 2011 A79
New Generation of DAAs
•
•
Protease inhibitors
•
TMC 435
•
BI 201335
•
Danoprevir
•
MK 7009
Polymerase inhibitors
•
•
PSI-7977
NS5A inhibitor
Daclatasvir
PSI-7977 (G2 and G3 naïves)
n = 11
SVR 12
PSI-7977 + RBV + PEG-INF
n = 10
PSI-7977 + RBV + PEG-INF
PSI-7977 + RBV
+ PEG-INF
n=9
SVR 12
PSI-7977 + RBV
SVR 12
PSI-7977 + RBV
n = 10
SVR 12
PSI-7977 + RBV
W0
W4
W8
W12
W24
Gane et al. AASLD 2011, A34
PSI-7977 (G2 and G3 naïves)
PSI-7977
RBV + PEG
12 w
(n = 11)
Weeks
SVR 24
PSI-7977
RBV + PEG
8w
(n = 10)
PSI-7977
RBV + PEG
4w
(n = 9)
PSI-7977
RBV
without PEG
(n = 10)
n
% < LOD*
n
% < LOD*
n
% < LOD*
n
% < LOD*
6/6
100
5/5
100
5/5
100
4/4
100
*LOD : limit of detection
Gane et al. AASLD 2011, A34
PSI-7977 (G1 naïves)
SVR 12
RVR
(%)
100
98
98
92
88
91
91
RVRe
91
EOT
80
SVR12
60
50
40
19
20
0
200 mg
+ PEG/RBV
400 mg
+ PEG/RBV
PEG/RBV
* 50% des patients PR ont atteint la fin de traitement S48
Lawitz et al. AASLD 2011, A225
Quadriple therapy : PEG-IFN+ RBV+
NS5A (Daclatasvir) + PI inhibitors (Asunaprevir)
G1 non responders

Daclatasvir (BMS-790052) QD (NS5A inhibitor) + asunaprevir (BMS-650032) BID
(NS3 protease inhibitor) ± pegIFN/RBV for 24 wks
US Study[1]
100
90
Japan Study[2]
90*
Daclatasvir + Asunaprevir
SVR24 (%)
80
Daclatasvir + Asunaprevir + PR
60
40
36
20
0
N/A
*all genotype 1b patients.
1. Lok A, et al. NEJM 2012.
2. Chayama K, et al. Hepatology 2012.
New Generation DAAs
• Introduction : Targets for DAAs
• Protease inhibitors
• Polymerase inhibitors
• NS5A inhibitors
• IFN free combination
• Conclusion
IFN free combination
Combinations
Design
Population Genotype
PI + I Nuc ± RBV 12 ou 24 w
Null R
1
PI + Non Nuc ± RBV 24 or 48 w
PI + Non Nuc 12 + PR 12 or 24 w
PI + Non Nuc + RBV 12 w
PI + Non Nuc + RBV 12 w
Naïves
Naïves
Naïves / NR
Naïves
1
1
1
1
Null R
R Naïves
Naïves
1
1, 2, 3
1
PI + NS5B I Nuc
TMC-435+ PSI-7977
PI + NS5BI Non Nuc
BI- 201335 + BI-207127
Telaprevir + VX -222
ABT-450/r + ABT-333
ABT-450/r + ABT-072
PI + NS5A I
BMS-650032+ BMS-790052
ABT-450/r + ABT-267
BMS-650032 +
791325+790052
PI + NS5A ± PR 24 w
PI + NS5A ± RBV 12 w
2 PI + NS5A 12 ou 24 w
IFN free combination: Proof of Concept
RG7128 and Danoprevir
1
Placebo
Réduction ARN VHC
0
-1
-2
-3
-4
1000b/600b-TE
-5
1000b/900b-TE
1000b/900b-Na
-6
-7
0
2
4
6
8
Days
10
12
14
Gane et al. Lancet 2010
BI 201335 + BI 207127 + RBV (G1 naïves)
6/15
14/17
10/15
17/17
11/15
17/17
Zeuzem S, et al. Gatroenterology 2011
Avoid cross resistance : NS3/4A protease inhibitors
Ph Halfon, S Locarnini J Hepatol 2011
Where we go : The Future
Ten Commandments for the Magic Drug
Where we go : The Future
Ten Commandments for the Magic Drug
1
High Efficacy
2
Pan-Genotypic
3
Favorable safety profile
4
Low resistance (high genetic barrier)
5
Oral regimen (IFN free)
6
Once a day (Good pharmacokinetic)
7
Short duration
8
Few drug-drug interraction
9
Available for (ELD) cirrhosis and HIV-HCV
10
Low price (access program)