Non-Protease Novel Agents for Chronic Hepatitis C
Transcript of Non-Protease Novel Agents for Chronic Hepatitis C
Non-Protease Novel Agents for
Chronic Hepatitis C
HCV Resistance Workshop
Boston, Massachusetts
June 23, 2011
Ira Jacobson, M.D.
Vincent Astor Professor of Medicine
Chief, Division of Gastroenterology and Hepatology
Medical Director, Center for the Study of Hepatitis C
Weill Cornell Medical College New York Presbyterian Hospital
Core E1 E2 P
7
NS2 NS3 NS4A NS4B NS5A NS5B
Targets for New Hepatitis C Drugs
5– –3
Linear Telaprevir
Boceprevir
ACH-1625
GS-9256
Macrocyclic Danoprevir (RG7227)
TMC 435350
BI-201335
BMS-650032
Vaniprevir
BMS-790052
Active site
(nucleosides)
RG7128
IDX184
PSI-7977
Non-
nucleosides
ABT-333
ABT-072
GS 9190
ANA598
VCH-759
VCH-916
VX-222
Filibuvir
BI-207127
Protease
inhibitors
Polymerase
inhibitors
Cyclophilin Alisporivir
SCY-635
Not all-inclusive
Clemizole
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Current Paradigms of Novel HCV Drug
Development
PEG IFN + RBV
+ New Drug
PEG IFN + RBV
+ New Drug 1
+ New Drug 2
IFN-Free
Combinations
PEG IFN + RBV
+ New Drug
PEG IFN + RBV
+ New Drug 1
+ New Drug 2
IFN-Free
Combinations
PEG IFN + RBV
+ New Drug
PEG IFN + RBV
+ New Drug 1
+ New Drug 2
Some studies include combinations of these regimens
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Meracitabine (RG7128), Nucleoside Polymerase
Inhibitor, Combined With PR in Genotype 1/4
Phase IIb, treatment-naïve
Pockros P, et al. EASL 2011, Berlin, O1359
Meracitabine
1000 mg bid
+ PR (RGT based on eRVR)
PR
n=81 n=85
Interim analysis presented at EASL 2011
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Meracitabine (RG7128) With PR in G1/4
0
20
40
60
80
100
RVR eRVR Week
12
Week
24
MCB/PR
PR
HCV RNA neg
% 63
14
60
13
63
14
89
61
91
62
Pockros P, et al. EASL 2011, Berlin, O1359 • Tolerability similar to PR
• No resistance
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Meracitabine (RG7128) With PR in G1/4:
SVR in eRVR Group
0
20
40
60
80
100
SVR-12 Relapse
% 76
24
Pockros P, et al. EASL 2011, Berlin, O1359
37/49 12/49
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Meracitabine: eRVR and SVR
Association With IL28B
eRVR (%)
0
20
40
60
80
100
CC Non-CC
SVR After eRVR (%)
0
20
40
60
80
100
CC Non-CC
80
72
83
55
Pockros P, et al. EASL 2011, Berlin, O1359
15/18 18/33 12/15 13/18
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
The relapse rate with meracitabine was
higher than reported with the protease
inhibitors. Is this a “class effect” or
related to the properties of the drug?
8 Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
PSI-7977 (Nucleoside) + PEG IFN/RBV in
Treatment Naïve Patients (PROTON Study)
125 treatment-naïve patients with HCV GT1
Planned 12 Week Interim analysis: Nelson et al. EASL LB poster #1372
Week 0 12 48 72 24
PSI-7977 200 mg QD
Peg-IFN + RBV
PSI-7977 400 mg QD
Peg-IFN + RBV Peg-IFN + RBV
Peg-IFN + RBV
SVR
Follow-Up
Peg-IFN + RBV Non-RVR Peg-IFN + RBV
STOP
Non-RVR Peg-IFN + RBV
STOP
N=50
N=50
N=25
HCV GT1
25 treatment-naïve patients with HCV GT2/3
PSI-7977 400 mg QD
Peg-IFN + RBV N=25
Week 0 12
HCV GT2/GT3
SVR24 SVR12
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
PROTON:
Treatment-naïve HCV GT11
RVR cEVR EOT Relapse SVR12
HCV GT1
PSI-7977 200mg QD
PEG/RBV
n=48
98% 100%
HCV GT1
PSI-7977 400mg QD
PEG/RBV
n=47
98% 92%
HCV GT1
Placebo
PEG/RBV
n=26
19% 62%
Nelson D et al, EASL LB#1372
GT1 Portion of Trial Ongoing
Response was independent of IL28B genotype
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Week 2
Week 4 RVR
Week 12 cEVR/EOT
SVR12
n (evaluable) 24 24 24 24
HCV RNA < LOD 21 24 24 24
% Response 88% 100% 100% 100%
Lost to follow-up 1 1 1 1
% Response (ITT) 84% 96% 96% 96%
PROTON HCV GT2/GT3 - Antiviral Responses
24/25 enrolled subjects completed therapy
– One subject lost to follow-up after day 1
Consistent HCV RNA reduction: 24/24 RVR & cEVR(EOT)
– No difference in viral kinetics: GT 2 v GT 3; IL28B CC v T allele
No virologic breakthrough & no relapse through 12 weeks post-therapy
SVR12 in 24/24 subjects with evaluable data
Lalezeri J et al, J Hepatol 2011;54:S28
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
NUCLEAR: PSI-7977 + PSI-938 combination:
First purine/pyrimidine combination study
40 HCV G1 treatment-naive subjects; 8 active and 2 PBO per cohort
HCV RNA >50,000 IU/mL, no evidence of cirrhosis
All subjects offered full course of PR on Day 15
Lawitz E, et al. EASL 2011, Berlin, P1370
Cohort Day 7 Day 14 Total
< LOD Median < LOQ < LOD Median < LOD (%)
1 2 -4.5 5 4 -5.2 4/8 (50)
2 2 -4.6 8 8 -5.2 8/8 (100)
3 4 -4.7 8 7 -5.0 7/8 (88)
4 1 -4.4 8 5 -5.0 7/8 (88)
HCV RNA Δ from BL and subjects with HCV RNA <15 IU/mL (LOD)
PSI-938 300 mg QD
PSI-938 300 mg QD
PSI-7977 400 mg QD
PSI-7977 + PSI-938
PSI-7977 + PSI-938
PSI-938 + PSI-7977
Day 0 7 14
Cohort 1
Cohort 2
Cohort 3
Cohort 4
Phase IIB Trial of Tegobuvir (Non-nuclesoide) +
PR vs PR for Chronic Genotype 1
3 arms:
–PR 48 wks (n=64)
–PR + TGV (40mg bid) 48 wks (n=126)
–PR + TGV (40mg bid) RGT (n=62)
Demographics:
–Comparable except IL28B
12% more CC in PR arm (45% CC)
Lawitz E, et al. EASL 2011, Berlin, P445
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
HC
V R
NA
<25
IU
/mL
(%
)
No difference in AEs between triple therapy and PR
Lawitz E, et al. EASL 2011, Berlin, P445
Phase IIB trial of Tegobuvir (GS9190, Non-
nucleoside) + PR vs PR for Genotype 1
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Emergence and Persistence of NS5B Mutations
Following Tegobuvir
N=148 in TGV arms with BL sequencing;
– Poor response or rebound (n=17)
– Relapse (n=15)
Main mutations in NS5B: C445, Y448, Y452, C316
C316N at BL did not affect response. Y448H most abundant mutation in G1a and G1b.
C445 only seen in G1b 4/6
Persistent Y448 mutations at 1-year follow-up
Hebner C, et al. EASL 2011, Berlin, P1211
NS5B TGV mutation
Mutation at rebound in arms 2+3, % (n)
G1a (n=11) G1b (n=6)
Y448H, H/Y or H/R 91 (10) 33 (2)
C316N(BL) + Y448H 17 (1)
C316N(BL) + C445C/F + Y448H/Y
17 (1)
C445F/Y452H 33 (2)
No relevant DRMs 9 (1)
Observed NS5B mutations associated
with poor response/viral rebound
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Inhibitors of Other Targets
16 Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
SVR12 with BMS-790052, an NS5A inhibitor, in
Treatment-naïve G1 patients
NS5A considered a replication complex inhibitor
BMS-790052 is an NS5A inhibitor with picomolar potency against HCV replicons
Resistance barrier similar to protease inhibitors (different mutations)
4 arms, all 48 weeks of triple therapy
– 1:1:1:1 ratio (n=12 each group)
Pol S, et al. EASL 2011, Berlin, P1373
PR
BMS-790052 3 mg QD/PR
BMS-790052 10 mg QD/PR
BMS-790052 60 mg QD/PR
48 weeks
Followup
24 weeks
SVR12
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
SVR12 with BMS-790052, an NS5A Inhibitor,
in Naive-G1 Patients
0
20
40
60
80
100
Placebo 3 mg 10 mg 60 mg
SVR12
RVR
eRVR
25
8 8
42
42
42 42
92 92
83
92 92 83 83 83
75
Pol S, et al. EASL 2011, Berlin, P1373
3 breakthroughs, 5 relapses with NS5A inhibitor
(2 of each in the 3 mg group)
%
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Safety Data: BMS-790052 SVR Study
No hematology signal
No ALT signal
4 discontinuations for AEs in the 60 mg group vs 1 discontinuation in the 3 and 10 mg groups
– Appeared related to PR
Pol S, et al. EASL 2011, Berlin, P1373
Alisporivir (DEB025) Plus PR in G1
Treatment-naive Patients
Cyclophilin inhibitor – Inhibits cyclophilins, which augment viral replication
– Potent pangenotypic activity
– Expected to have a high barrier to resistance
N=288
Four arms:
-Alisporivir + PR 48 wks
-Alisporivir + PR 24 wks
-Alisporivir + PR RGT by RVR (24 vs 48 wks)
-PEG IFN + RBV
Alisporivir = 600 mg BID first week, then 600 mg QD
Flisiak R, et al. EASL 2011, Berlin, O4
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Alisporivir (DEB025) plus PR in Genotype 1
Treatment-naive Patients (n=288)
0
20
40
60
80
100
Alisporivir
+ PR
48 wks
Alisporivir
+ PR
24 wks
Alisporivir
+ PR
RGT
PR
48 wks
SVR
(%)
Flisiak R, et al. EASL 2011, Berlin, O4
76
53
69
55
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
0
20
40
60
80
100
Alisporivir (DEB025) plus PR in Genotype 1
Treatment-naive Patients (n=288)
RVR
(<25 IU/ml)
%
44
53
42
15
Flisiak R, et al. EASL 2011, Berlin, O4
24* 28* 23* 8*
Alisporivir
+ PR
48 wks
Alisporivir
+ PR
24 wks
Alisporivir
+ PR
RGT
PR
48 wks
*HCV RNA neg
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
0
20
40
60
80
100
Relapse
%
15
39
16
24
Alisporivir
+ PR
48 wks
Alisporivir
+ PR
24 wks
Alisporivir
+ PR
RGT
PR
48 wks
Alisporivir (DEB025) plus PR in Genotype 1
Treatment-naive Patients (n=288)
Flisiak R, et al. EASL 2011, Berlin, O4
Alisporivir (DEB025) plus PR in G1
Treatment-naive Patients
No null responses with DEB025 for 12 wks (n=196)
Viral breakthrough in 4.7% with DEB025 vs 5.5% for PR
–2.8% had full dose of DEB025 at breakthrough
Hyperbilirubinemia ↑ with DEB025 vs PR (33% vs 1%)
Bilirubin ≥5 x ULN in 4.2% with DEB025, reversible, no ALT elevations
Jaundice in ~10% of pts
Bilirubin elevation attributed to transporter effect
Flisiak R, et al. EASL 2011, Berlin, O4
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
INFORM-1
The Study that Ushered in the Era
of Interferon-Free DAA Combinations
25 Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Gane EJ, et al. Lancet 2010;376:1467–75
INFORM-1: Danoprevir (Protease Inhibitor) +
Mericitabine (Nucleoside Polymerase Inhibitor)
Dose-ranging Phase I study of danoprevir (R7227/ITMN-191) plus mericitabine (R7128) for 14 days, followed by Peg-IFN/RBV up to Week 48, in HCV genotype-1 patients
Week 48 Day 14
Treatment-naïve
Mericitabine 500mg BID + Danoprevir 100mg Q8h
PR B n=8 active n=2 placebo
Mericitabine 500mg BID + Danoprevir 200mg Q8h
PR C1 n=8 active n=1 placebo
mericitabine 1,000mg BID + Danoprevir 100mg Q8h
PR C2 n=8 active n=1 placebo
Mericitabine 1,000mg BID + Danoprevir 200mg Q8h
PR D n=8 active n=4 placebo
Mericitabine 1,000mg BID + Danoprevir 900mg BID
PR G n=8 active n=2 placebo
Previous nonresponders (excluding null
responders)
Mericitabine 1,000mg BID + danoprevir 600mg BID
PR E n=8 active n=2 placebo
Previous null responders
Mericitabine 1,000mg BID + danoprevir 900mg BID
PR F n=8 active n=2 placebo
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Nucleoside (RG7128) + Protease Inhibitor(RG7227)
G1 Interferon-Naive and Null Responders
Gane EJ, et al. Lancet 2010;376:1467-75
RG7128 1000 mg BID + RG7227 900 mg BID
INFORM-1: HCV RNA Undetectability in
Different Treatment Arms
Nulls Non-
responders
Treatment naïve patients
HCV
RNA
neg
(%)
Gane EJ, et al. Lancet 2010;376:1467–75
MCB 1000 mg bid
+ Danoprevir 900 mg bid
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Effect of Host IL28B Genotype on Early Viral Kinetics
During IFN-free Treatment in Patients With CHC
INFORM-1 Cohorts C-G
0
1
2
3
4
5
CC Non-CC
Mean change in
HCV RNA after
13 days (log10 IU/ml)
5.01 4.59
n=12 n=33
0
20
40
60
80
100
CC Non-CC
50
27
Undetectable
HCV RNA at
day 14 (%)
n=12 n=33
Chu T, et al. EASL 2011, Berlin, P1323
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Two Proofs of Concept in One Study: NS3 Protease Inhibitor and
NS5A Replication Complex Inhibitor
30 Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
BMS-650032 (Protease Inhibitor)
+ BMS-790052 (NS5A Inhibitor + PR)
Phase IIa study of BMS-790052 plus BMS-650032, with or without Peg-IFN/RBV, for 24 weeks in HCV genotype-1 noncirrhotic null responders
Lok A, et al. J Hepatol 2011;54(Suppl. 1):S536
PR: peginterferon alfa-2a (180 µg/wk) + ribavirin (1000–1200 mg/day)
Cirrhotic patients excluded
BMS-790052 (60 mg QD) + BMS-650032 (600 mg BID)
(n=11)
BMS-790052 + BMS-650032 +
PEG IFN + RBV (n=10)
24-week treatment
Dual
Quad
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
BMS-650032 (PI) + BMS-790052 (NS5A) + PR
n/N (%)
DUAL
BMS-790052 + BMS-650032
n=11
QUAD
BMS-790052 + BMS-650032 + PR
n=10
SVR24 4/11 (36)
(2/2 G1b, 2/9 G1a) 9/10 (90)*
Breakthrough 6/11 (55)
(all GT-1a) 0/10 (0)
Lok A, et al. J Hepatol 2011;54(Suppl. 1):S536
McPhee F, et al. J Hepatol 2011;54(Suppl. 1):S28
*The 10th patient had detectable HCV RNA at f/u week 24
but was subsequently undetectable
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Quad therapy with BMS-790052, BMS-650032 and PR
gives 100% SVR24 in G1 null responders
Safety
– Dual: Diarrhea 73%, fatigue 55%,headache 46%
– Quad: Diarrhea 70%, fatigue 70%, headache 50%, nausea 50%
– LFTs: ALT elevations >3 x ULN in 6 pts (bilirubin<2x ULN)
-4 in dual group (2 on PR), 2 in quad group
1. Lok A, et al. EASL 2011, Berlin, O1356; 2. McPhee F, et al. EASL 2011, Berlin, P1223
Telaprevir (PI) + VX-222 (non-nuc): ZENITH
ZENITH: Phase II study of telaprevir (T) plus VX-222, with or without Peg-IFN/RBV,
for 12 weeks in treatment-naïve HCV genotype-1 patients
Week 12 12
Di Bisceglie AM, et al. J Hepatol 2011;54(Suppl. 1):S540
NS3/4A protease inhibitor plus NS5B non-nucleoside polymerase inhibitor
PR: peginterferon alfa-2a (180 µg/wk) + ribavirin (1000–1200 mg/day)
36
A n=18
DUAL
B n=29
VX-222 100mg BID + telaprevir 1125mg BID
VX-222 400mg BID + telaprevir 1125mg BID
Detectable at W2 or 8: PR up to W36
Undetectable W2 & 8: STOP treatment at W12
C n=29
D n=30
QUAD
VX-222 100mg BID + telaprevir 1125mg BID + PR
VX-222 400mg BID + telaprevir 1125mg BID + PR
Undetectable W2 & 8:
STOP treatment at W12
Detectable at W2 or 8:
PR up to W24
24
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
No virologic breakthrough in quad-therapy arms
Virologic breakthrough common in VX-222/TVR dual-therapy arms (17% to 31%)
Both dual regimens stopped early per protocol
HC
V R
NA
un
dete
cta
ble
(%
)
22 17
0 0
24
59
14
24
38
86
38
83
57
87
50
90
0
20
40
60
80
100
Week 2 Week 4 Weeks 2 & 8* Week 12
VX-222 100mg + telaprevir (n=18)
VX-222 400mg + telaprevir (n=29)
VX-222 100mg + telaprevir + PR (n=29)
VX-222 400mg + telaprevir + PR (n=30)
Telaprevir (PI) + VX-222 (non-nuc): ZENITH
*Indicates patients eligible to stop treatment at Week 12
Di Bisceglie AM, et al. J Hepatol 2011;54(Suppl. 1):S540
4 18
7 29
11 29
17 30
3 18
17 29
25 29
26 30
4 29
11 29
15 30
7 29
24 29
27 30
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Ribavirin: The Drug That Won’t Go Away
36 Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
GS-9256 (Protease Inhibitor) +
Tegobuvir (Non-nucleoside Polymerase Inhibitor)
Phase II study of tegobuvir plus GS-9256 for 4 weeks, with or without RBV or Peg-IFN/RBV, followed by PR up to Week 48, in treatment-naïve HCV genotype1 patients
48 Week
Part A
Part B PR
GS-9256 75mg BID + tegobuvir 40mg BID +
PR (n=15)
GS-9256 75mg BID + tegobuvir 40mg BID +
RBV* (n=15)
PR
GS-9256 75mg BID + tegobuvir 40mg BID*
(n=16) PR
4
Zeuzem S, et al. Hepatology 2010;52(Suppl.):400A
*Peg-IFN/RBV started early in the case of virologic breakthrough
PR: peginterferon alfa-2a (180 µg/wk) + ribavirin (1000–1200 mg/day)
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Day
Med
ian
HC
V R
NA
(IU
/ml)
Lo
g 1
0
0
1
3
2
4
7 14 21 28
6
5
7
GS-9256: protease inhibitor
GS-9190: polymerase inhibitor
GS-9256 + GS-9190 (n = 15)
GS-9256 + GS-9190 + RBV (n = 13)
GS-9256 + GS-9190 + PEG IFN/RBV (n = 3)
Breakthrough = resistance
GS-9256 (Protease Inhibitor)+ GS-9190 (Non-nuc
Polymerase) Inhibitor + Ribavirin vs Quad
Zeuzem S, et al. Hepatology. 2010;52:Abstract LB-1.
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
BI 201335 (PI) + BI 207127 (non-nuc): SOUND-C1
SOUND-C1: Phase Ib study of BI 201335 plus BI 207127, in combination with
RBV, for 28 days in treatment-naïve HCV genotype-1 patients
Zeuzem S, et al. Hepatology 2010;52(Suppl.):876A
24
120mg BI 201335 QD + PegIFN/RBV
400mg BI 207127 TID + 120mg BI 201335 QD +
RBV
Week
1 n=15
2 n=17
600mg BI 207127 TID + 120mg BI 201335 QD +
RBV
PR
4 48
PR
120mg BI 201335 QD + PegIFN/RBV
Cirrhotic patients excluded
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
BI 201335 (PI) + BI 207127 (non-nuc): SOUND-C1
Zeuzem S, et al. Hepatology 2010;52(Suppl.):876A
6/15 14/17 17/17 10/15 11/15 17/17
40
6773
82
100 100
0
20
40
60
80
100
Day 15 Day 22 Day 29
Pa
tie
nts
with
HC
V R
NA
<2
5 I
U/m
L (
%)
400 mg TID BI 207127 + BI 201335 + RBV
600 mg TID BI 207127 + BI 201335 + RBV
6/15 14/17 17/17 10/15 11/15 17/17
Conclusions (1)
DAA classes other than protease inhibitors will play a critical role in the evolution of HCV therapy
Extent to which DAA class should be studied with PR depends on the class and the specific drug
Non-nucleosides unlikely to be competitive with other classes in combination with PR alone; more likely to play an adjunctive role
Quad regimens have major potential for benefit in null responders and other refractory populations
– Dilemma for clinicians, especially investigators
– Tolerability and dosage schedules will be important given complexity imposed by number of drugs
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Presented at the 6th Int. workshop on Hepatitis C – Resistance & New Compounds, 23 – 24 June 2011, Cambridge, USA
Conclusions (2)
Proof of concept for curability of HCV without IFN now exists
– Many believe SVR rates will be very high
– Even if not, large population of IFN-incapable patients would benefit
A dual DAA combination MUST contain one drug with high resistance barrier; otherwise, a third drug is needed
Unknown if 3-drug regimen requires a high resistance barrier component (but it couldn‘t hurt)
Ribavirin has potential to remain an important adjunct
Final aim for a DAA combination regimen (adapted from Dr S Zeuzem)
– All oral
– QD or BID
– Safe and well tolerable
– Limited drug-drug interactions
– Pan-genotypic
– IL28-independent