Transcript Slide 1

Direct Acting Antivirals: What are
they? What is their place in HCV
management?
Mark Sulkowski, MD
Associate Professor of Medicine
Johns Hopkins University School of Medicine
Limitations of PegIFN + Ribavirin
(with or without protease inhibitors)
• Antiviral activity is host + virus genotype dependent
– IL28B CC genotype > TC and TT
• Safety and tolerability risk outweighs treatment
benefit for some individuals
– “IFN unwilling and/or unable”
• Finite number of expert healthcare providers
• Cost
Therapeutic Targets for DAAs
•
Prevent viral entry
–
–
•
Prevent translation of viral RNA
–
•
NS3/4 protease inhibitors
Inhibit HCV-RNA polymerase
–
–
–
–
•
Polyclonal and monoclonal antibodies
SRB1 receptor blockers
Nucleoside analogue NS5B polymerase
inhibitors
Non-nucleoside analogue NS5B
polymerase inhibitors
NS5A inhibitor
Cyclophilin B inhibitors
Viral assembly/release
Pereira AA, et al. Nat Rev Gastroenterol Hepatol. 2009;6:403-411.
Direct Acting Antivirals for Hepatitis C
Nature Reviews Drug Discovery 10, 93-94 (February 2011) | doi:10.1038/nrd3361
New Targets
•
•
•
•
•
•
Peginterferon lambda (PegIL-29)
Protease inhibitors
Polymerase inhibitors
NS5A inhibitors
Cyclophilin inhibitors
DAA Combinations
Peginterferon lambda + RBV
Virologic response by IL28B Genotype in patients with HCV Genotypes 1, 4
Solid bars: CC
Hatched bars: CT/TT
Percentage of patients ± 95% CI
RVR
cEVR
100
90
80
70
60
50
40
30
20
10
0
120 μg
n = 19
46
180 μg
PegIFN-λ
22
38
Zeuzem et al. EASL 2011
240 μg
17
40
180 μg
PegIFN-α-2a
18
57
120 μg
180 μg
PegIFN-λ
240 μg
19
22
17
46
38
40
180 μg
PegIFN-α-2a
18
57
Platelets (GI/L)
Total
Neutrophils (GI/L)
Hemoglobin (g/L)
Changes in Hematologic Parameters Over Time and
Hematology-associated PegIFN and RBV Dose Reductions
PegIFN-λ 120 µg
PegIFN-λ 240 µg
150
PegIFN-λ 180 µg
PegIFN-α-2a
PegIFN
α-2a
PegIFN-λ
140
120 µg 180 µg 240 µg 180 µg
130
120
0
2
4
6
8
10
5
4
3
2
1
LLN
12
LLN
0
2
4
6
8
10
12
10
LLN
12
300
250
200
150
0
2
4
6
8
Study Week
Zeuzem et al EASL 2011
Lab Toxicity, %
Hemoglobin low
RBV dose reduction, %
(due to Hb abnormality)
Neutrophils Low
Platelets Low
PegIFN dose reduction, %
(due to hematologic
abnormality)
(N=128) (N=131) (N=134) (N=133)
20.5
15.4
12.9
43.9
2.3
1.5
0.7
12.8
0
0
0.8
0
0
0
15.2
14.4
0
0
0
17.3
New Targets
•
•
•
•
•
•
Peginterferon lambda (PegIL-29)
Protease inhibitors
Polymerase inhibitors
NS5A inhibitors
Cyclophilin inhibitors
DAA Combinations
PILLAR Study: TMC435 + PegIFN/RBV
PILLAR Week 24 Analysis: Proportion of Patients Achieving Virologic
Response at Weeks 4 and 12
Week 4
***
100
10
80
***
20
***
16
Week 12
***
***
2
17
***
1
***
3
***
11
60
40
77
68
76
91
79
96
94
97
58
20
11
5
0
TMC 12/ TMC 24/ TMC 12/ TMC 24/
PR24
PR24
PR24
PR24
75 mg
75 mg
150 mg 150 mg
(n=77)
(n=75)
(n=76)
(n=75)
<25 IU/mL undetectable
Pbo 24/
PR48
(n=75)
TMC 12/ TMC 24/ TMC 12/ TMC 24/
PR24
PR24
PR24
PR24
75 mg
75 mg
150 mg 150 mg
(n=78)
(n=73)
(n=77)
(n=77)
<25 IU/mL detectable
Fried et al. AASLD 2010
Fried MW, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-5.
>25 IU/ml
Pbo 24/
PR48
(n=74)
PILLAR Study: Role of IL28B Genotype
Mean(+/- SE) Change in Plasma HCV RNA
(log10 IU/mL) from Baseline
PILLAR Week 24 Analysis: Mean Change in HCV RNA
from Baseline According to IL28B Genotype*
Placebo
0
-2
CC
CT
TT
-4
-6
0
4
8
12
16 20 24
Week
All TMC 435 (75 mg)
0
-2
-2
-4
-4
-6
-6
0
4
8
12
16 20 24
Week
Fried et al. AASLD 2010
Fried MW, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-5.
All TMC 435 (150 mg)
0
0
4
8
12
Week
16 20 24
SILEN-C1: BI-1335 + PegIFN/RBV with
or without 3-day lead-in
100
88
83
80 78
80
71 73
55
60
40
24
20
15
9
15
8
0
eRVR
PR
BI1335 120 mg LI
Sulkowski et al. EASL 2011
SVR
BI1335 240 mg LI
Relapse
BI1335 240 mg No LI
New Targets
•
•
•
•
•
•
Peginterferon lambda (PegIL-29)
Protease inhibitors
Polymerase inhibitors
NS5A inhibitors
Cyclophilin inhibitors
DAA Combinations
Mericitabine + PegIFN/RBV for HCV genotype 1
patients
A: 500mg BID+ P/R 12 wk (n=80)
B: 1000mg BID+ P/R 8 wk (n=81)
C: 1000mg BID+ P/R 12 wk (n=82)
% Patients with virologic response (<15IUmL)*
D: 1000mg BID+ P/R 12 wk (n=81)
E: P/R 48 wk (n=84)
100%
88%
83%
80%
68%
62%
62%
62%
80%
60%
49%
39%
40%
18%
20%
0%
0
0
*Roche COBAS® HCV Test; LLOD = 15 IU/mL
ITT population, n=408
2
4
6
Study Week
Jensen DM, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. 81.
8
10
12
PSI-7977 Phase 2b Study
GT-1 treatment-naïve
Weeks
24
12
0
N=50
PSI-7977 200 mg QD
+ PEG-IFN -2a + RBV
PEG-IFN -2a + RBV
N=50
RG7128 400 mg QD
+ PEG-IFN -2a + RBV
PEG-IFN -2a + RBV
STOP
Non-RVR PEG-IFN -2a + RBV
STOP
Non-RVR PEG-IFN -2a + RBV
PEG-IFN -2a + RBV
N=25
GT-2/3 treatment-naïve open-label
N=25
PSI-7977 400 mg QD
+ PEG-IFN -2a + RBV
SVR
Follow-Up
• 150 patients GT-1, 2 & 3, treatment-naïve
– Response-guided
– IL28B stratified (GT-1, 125 patients)
• Primary efficacy endpoint : Safety and tolerability
Lalezari et al. EASL 2011
72
48
“12+0”
SVR
Follow-Up
PSI-7977 + PegIFN + RBV
• 121 patients with HCV
genotype 1
– 41% IL28B CC
• No viral breakthrough
observed
• No safety signal
detected
Week 4
100
98
80
60
40
20
19
0
PSI7977 200 or 400 mg/P/R
PR
New Targets
•
•
•
•
•
•
Peginterferon lambda (PegIL-29)
Protease inhibitors
Polymerase inhibitors
NS5A inhibitors
Cyclophilin inhibitors
DAA Combinations
BMS-790052 Replication Complex Inhibitor:
Change in HCV RNA after administration of single dose
M Gao et al. Nature 000, 1-5 (2010) doi:10.1038/nature08960
NS5A replication complex inhibitor +
PegIFN/RBV
SVR
100
92
83
80
60
42
40
25
20
0
PR (n=12)
Pol et al. EASL 2011
NS5A 1 mg (n=12) NS5A 10 mg (n=12) NS5A 60 mg (n=12)
New Targets
•
•
•
•
•
•
Peginterferon lambda (PegIL-29)
Protease inhibitors
Polymerase inhibitors
NS5A inhibitors
Cyclophilin inhibitors
DAA Combinations
Alisporivir (DEB025): Oral cyclophilin B inhibitor
• Synthesized from
cyclosporin A
– No immunosuppressive
activity; Potent Cyp
inhibition
• Active all HCV genotypes
• In vitro resistance in the
NS5A region
• Also active against HIV
Flisiak et al. Hepatology. 2009 May;49(5):1460-8.
Alisporivir + PegIFN/RBV in HCV
genotype 1, treatment naïve patients
SVR
76
80
69
60
55
53
40
20
0
PR
Flisiak R et al. EASL 2011
APV 48 wks
APV 24 wks
RGT
New Targets
•
•
•
•
•
•
Peginterferon lambda (PegIL-29)
Protease inhibitors
Polymerase inhibitors
NS5A inhibitors
Cyclophilin inhibitors
DAA Combinations
INFORM-1: RG7128 + RG7227
• 1st clinical trial to investigate the combination of DAA in the absence of
interferon and ribavirin
•
•
Assessed safety and antiviral activity of RG7128 + RG7227 x13d
Rx-naïve, null and relapser GT-1 HCV patients (N ~90)
• No evidence of resistance breakthrough in any cohort
Gane et al. The Lancet 15 Oct 2010
Telaprevir + VX-222 with or with
PegIFN/RBV
RVR
Breakthrough
100
86
87
40
31
80
59
60
20
17
40
20
17
0
0
TLV + TLV + QUAD
222 low 222 high low
QUAD
high
0
TLV + TLV + QUAD
222 low 222 high low
0
QUAD
high
SOUND C-1: PI (1335) + nonnucleoside polymerase (7127) + RBV
Day 8
Day 15
Day 22
Day 29
27%
40%
67%
73%
18%
82%
100%
100%
Group 1:
7127 (400 mg TID) +
1335 + RBV
(N=15)
Group 2:
7127 (600 mg TID) +
1335 + RBV
(N=17)
HCV RNA < 25 IU/mL, undetectable
Two genotype 1a patients in the low dose group had viral rebound during treatment
Zeuzem S., et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-7.
PI + NS5A inhibitor ± PegIFN/RBV in
prior null responder
Group A: No PegIFN/RBV, n = 11
Group B: PegIFN/RBV, n =10
8
8
↓ Indicates Initiation of
PegIFN/RBV
↓
7
7
6
6
5
Log10 HCV RNA
Log10 HCV RNA
↓
↓
4
3
2
LOQ
LOD
LOQ 26 IU/mL
LOD < 10 IU/mL
1
0
5
4
LOQ 26 IU/mL
LOD < 10 IU/mL
3
2
LOQ
LOD
1
0
1
2
3
4
5
6
7
8
9
10
11
12
Week
Lok AS, et al. 61st AASLD; Boston, MA; October 29 – November 2, 2010; Abst. LB-8.
0
0
1
2
3
4
5
6
Week
7
8
9
10
11
12
PI + NS5A inhibitor ± PegIFN/RBV in
prior null responder
• No PegIFN/RBV
– 4/11 patients had SVR-12 with no PegIFN/RBV
• 1a, 2/3 SVR with 1 relapse; 1b; 2/2
– 6/11 patients had breakthrough with PegIFN/RBV
added  4 achieve undetectable HCV RNA
(treatment ongoing)
• QUAD therapy (PegIFN/RBV)
– 10/10 patients had SVR-12
Lok AS, et al. EASL; Berlin, Germany 2011
Future HCV therapies
• Multiple agents in phase 2 or later
development
– Effective across viral genotypes and subtypes
– Different resistant variants
– Improved safety and tolerability
– Oral (with the exception of IFN λ)
– Less frequent dosing
• Increase HCV treatment rates with IFN alfa
free regimens