Are (exogenous) interferons really
necessary?
Peter Ferenci
Medical University of Vienna
Effect of interferon on experimental vaccinia and
herpes-simplex virus infections in rabbits' eyes.
CANTELL K, TOMMILA V.
Lancet. 1960 Sep 24;2(7152):682-4
Treatment of chronic non-A,non-B hepatitis with recombinant
human alpha interferon. A preliminary report
JH Hoofnagle, KD Mullen, DB Jones, V Rustgi, A Di Bisceglie, M
Peters, JG Waggoner, Y Park, and EA Jones Volume 315:1575-1578
December 18, 1986
Role of interferon-alfa in treatment of hepatitis?
 Mode of action
• immune-modulatory (dose dependent!)
• antiviral
• antiproliferative
 IFN-sensitivity
• IL28B
• Nullresponse….
Time Course of Virological Response to IFN
Therapy in Patients With CHC
HCV RNA
100%
Induction phase
0%
1st dose
Maintenance phase
Detection limit
14–28 Days
?
Ferenci P 1999
NK cells and response to IFN therapy in
patients with CHC
Ahlenstiehl et al, Gastroenterology 2011
HCV Life Cycle and DAA Targets
Receptor binding
and endocytosis
Transport
and release
Fusion
and
uncoating
(+) RNA
ER lumen
LD
LD
Translation
NS3/4 and
protease
polyprotein
inhibitors
processing
Virion
assembly
LD
Membranous
web
ER lumen
NS5A* inhibitors
*Role in HCV life cycle not well defined
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
NS5B polymerase
RNA
replication
inhibitors
Nucleoside/nucleotide
Nonnucleoside
INFORM-1 study: proof of concept study,
combination of a PI (danoprevir, DNV) with the
polymerase inhibitor mericitabine (MCB)
1d
4d
7d
14d 48w
Active/placebo
A
500 mg BID MCB
n=8/0
n=8/0
B
100 mg TID DNV
100 mg TID DNV
P/R (Peg-IFN + RBV)
500 mg BID MCB
n=8/2
500 mg BID MCB
100 mg TID DNV
C
500 mg BID MCB
200 mg TID DNV
Naive
n=16/2
1000 mg BID MCB
100 mg TID DNV
D
1000 mg BID MCB
200 mg TID DNV
n=8/4
TF
(non-null)
E
n=8/2
F
TF
(null)
n=8/2
Naive
n=8/2
G
TF = IFN-treatment failures
1000 mg BID MCB
600 mg BID DNV
1000 mg BID MCB
900 mg BID DNV
1000 mg BID MCB
900 mg BID DNV
Gane EJ et al. Lancet 2010
Median change from baseline by treatment group
Cohorts B–G
1
Median Log10 HCV RNA
Change from Baseline (IU/mL)
0
MCB (mg BID) / DNV (mg)
–1
Placebo
500 BID / 100 TID
1000 BID / 100 TID
500 BID / 200 TID
1000 BID / 200 TID
1000 BID / 600 BID (pEVR)
1000 BID / 900 BID (TF - Null)
1000 BID / 900 BID (Naive)
–2
–3
–4
–5
–6
0
2
4
6
Days
8
10
12
14
Gane EJ et al. Lancet 2010
Naive and Null Responders with a BID
Oral Regimen of RG7128 and RG7227
100
6
88
90
RG7128 1000 mg BID + RG7227 900 mg BID
80
5
70
63
60
4
50
50
TF - Nulls
40
20
2
10
Limit of Detection
1
0
1
3
5
7
Days
9
11
13
25
<LLOD
Gane et al, Lancet 2010
Naives
30
Nulls
Naives
Naives
3
Nulls
Median Log10 HCV RNA (IU/mL)
7
<LLOQ
GS-9256 + Tegobuvir Alone, With RBV, or
With PegIFN/RBV in GT1 Tx-Naive Patients
– Phase II study of tegobuvir (GS-9190), an NS5B nonnucleoside
polymerase inhibitor, and GS-9256, an NS3 protease inhibitor as part of
HCV therapy
Wk 48
Wk 4
Treatment-naive
patients with
GT1 HCV
Part A
Part B
(nonrandomized)
GS-9256 75 mg BID +
Tegobuvir 40 mg BID
(n = 16)†
PR*
(n = 16)
GS-9256 75 mg BID +
Tegobuvir 40 mg BID +
RBV*†
(n = 15)
PR*
(n = 15)
GS-9256 75 mg BID +
Tegobuvir 40 mg BID +
PR*
(n = 15)
PR*
(n = 15)
*PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. †PegIFN/RBV started early if virologic breakthrough.
Zeuzem S, et al. AASLD 2010. Abstract LB-1.
GS-9256 + Tegobuvir Alone, With RBV, or With
PegIFN/RBV: Virologic Response
HCV RNA Response
GS-9256 +
Tegobuvir
(n = 15)
GS-9256 +
Tegobuvir + RBV
(n = 13)
GS-9256 + Tegobuvir
+ PegIFN/RBV
(n = 14)
Median maximal
change from
baseline, log10 IU/mL
-4.1
-5.1
-5.7
Achieved nadir ≤ 25
IU/mL, %
13
62
100
Day 14 HCV RNA
≤ 25 IU/mL, %
7
46
71
Day 28 HCV RNA
≤ 25 IU/mL (RVR), %
7
38
100
Tegubovir requires both pegIFN and RBV
program terminated due to safety issues
Zeuzem S, et al. AASLD 2010. Abstract LB-1.
ZENITH: telaprevir (PI) + VX-222 (NNI) ±
Peg-IFN/RBV in treatment-naive G1 patients
Week 0
12
A
Telaprevir 1125 mg bid
N=18
VX-222 100 mg bid*
B
Telaprevir 1125 mg bid
N=29
VX-222 400 mg bid*
Telaprevir 1125 mg bid
RVR2-guided
C
VX-222 100 mg bid*
N=29
Peg-IFN alfa-2a
Peg-IFN alfa-2a
RBV
RBV
Week 36
Telaprevir 1125 mg bid
D
VX-222 400 mg bid*
N=30
Peg-IFN alfa-2a
RBV
DDI = drug-drug interaction; NNI = non-nucleoside inhibitor;
Peg-IFN = peginterferon alfa; PI = protease inhibitor; RBV = ribavirin
* Based on a 10 day healthy volunteer DDI study;
when combined with telaprevir,
VX-222 doses of 100 mg and 400 mg provide
VX-222 plasma exposures equivalent to 250 mg
and 750 mg bid.
Nelson D, et al. AASLD 2011. Abstract LB-14.
ZENITH: telaprevir (PI) + VX-222 (NNI) ±
Peg-IFN/RBV in treatment-naive G1 patients
Week 0
12
A
Telaprevir 1125 mg bid
N=18
VX-222 100 mg bid*
B
Telaprevir 1125 mg bid
N=29
VX-222 400 mg bid*
• DUAL regimens terminated
Telaprevir 1125 mg bid
RVR2-guided
C
VX-222 100 mg bid*
N=29
Peg-IFN alfa-2a
Peg-IFN alfa-2a
RBV
RBV
Week 36
Telaprevir 1125 mg bid
D
VX-222 400 mg bid*
N=30
Peg-IFN alfa-2a
RBV
* Based on a 10 day healthy volunteer DDI study;
when combined with telaprevir,
VX-222 doses of 100 mg and 400 mg provide
VX-222 plasma exposures equivalent to 250 mg
and 750 mg bid.
Nelson D, et al. AASLD 2011. Abstract LB-14.
ZENITH: telaprevir (PI) + VX-222 (NNI) ±
Peg-IFN/RBV in treatment-naive G1 patients
Week 0
12
A
Telaprevir 1125 mg bid
N=18
VX-222 100 mg bid*
B
Telaprevir 1125 mg bid
N=29
VX-222 400 mg bid*
• DUAL regimens terminated
Telaprevir 1125 mg bid
RVR2-guided
C
VX-222 100 mg bid*
N=29
Peg-IFN alfa-2a
Peg-IFN alfa-2a
RBV
RBV
Week 36
Telaprevir 1125 mg bid
D
VX-222 400 mg bid*
N=30
Peg-IFN alfa-2a
RBV
E/F
(E G1b
N=23;
F G1a
N=23)
Telaprevir 1125 mg bid
* Based on a 10 day healthy volunteer DDI study;
when combined with telaprevir,
VX-222 doses of 100 mg and 400 mg provide
VX-222 plasma exposures equivalent to 250 mg
and 750 mg bid.
VX-222 400 mg bid*
RBV
Enrolment complete
Nelson D, et al. AASLD 2011. Abstract LB-14.
ZENITH: telaprevir + VX-222 ± Peg-IFN/RBV SVR12 data
Arm C 100 mg VX-222
Arm D 400 mg VX-222
100
93
90
83
90
83
82
SVR12, %
80
60
40
20
24
29
27
30
9
11
14
15
15
13
0
Overall
–
Patients eligible for 12
weeks treatment
Patients eligible for 24
weeks treatment
No patient in either QUAD arm experienced viral breakthrough. However,
2 patients relapsed in Arm C (7%) and 2 patients (including 1 patient who
received only 1 week of treatment) in Arm D (7%)
Nelson D, et al. AASLD 2011. Abstract LB-14.
MATTERHORN: study design
N= 420 (70 pts/arm)
IFN free: MCB 1000mg
+ DNVr 100/100mg + R
F/U
Triple: DNVr 100/100mg + P/R
F/U
A3
Quad: MCB 1000mg
+ DNVr 100/100mg + P/R
F/U
B1
IFN free: MCB 1000mg
+ DNVr 100/100mg + R
F/U
Cohort B:
Null
B2
Responders
Quad: MCB 1000mg
+ DNVr 100/100mg + P/R
F/U
B3
Quad: MCB 1000mg
+ DNVr 100/100mg + P/R
A1
Cohort A:
Partial
A2
Responders
12
Stratification by:
» IL28B (CC, CT, TT)
» G1a/1b
P/R
24
weeks
Phase 2, randomized within cohort, open-label, parallel study of 2 cohorts
F/U
48
72
MATTERHORN: study design
N= 420 (70 pts/arm)
GT1a
IFN free: MCB 1000mg
+ DNVr 100/100mg + R
F/U
Triple: DNVr 100/100mg + P/R
F/U
A3
Quad: MCB 1000mg
+ DNVr 100/100mg + P/R
F/U
B1
IFN free: MCB 1000mg
+ DNVr 100/100mg + R
F/U
Cohort B:
Null
B2
Responders
Quad: MCB 1000mg
+ DNVr 100/100mg + P/R
F/U
B3
Quad: MCB 1000mg
+ DNVr 100/100mg + P/R
A1
Cohort A:
Partial
A2
Responders
Stratification by:
» IL28B (CC, CT, TT)
» G1a/1b
GT1a
12
P/R
24
weeks
Phase 2, randomized within cohort, open-label, parallel study of 2 cohorts
F/U
48
72
Phase 2b SOUND-C2: BI201335 (PI) + BI207127
(NNI) ± RBV in treatment naive G1 patients
BI207127 600 mg tid
BI201335 120 mg qd
RBV
Follow-up
Naive, CHC, G1
N=362
BI207127 600 mg tid
BI201335 120 mg qd
RBV
Follow-up
BI207127 600 mg tid
BI201335 120 mg qd
RBV
BI207127 600 mg bid
BI201335 120 mg qd
RBV
Follow-up
BI207127 600 mg tid
BI201335 120 mg qd
Follow-up
Randomization
0
16
Weeks
28
40
–
Randomization stratified by HCV subtype (G1a vs G1b) and IL28B genotype (rs12979860
CC vs non-CC)
–
52% of patients were male, 98% White, 38% G1a, 85% had baseline HCV RNA ≥800,000
IU/mL, 10% had compensated cirrhosis, and 25% had IL28B genotype CC
Zeuzem S, et al. AASLD 2011. Abstract LB-15
SOUND-C2: preliminary SVR in treatment
Arm A (16 week treatment duration, BI201335 +
BI207127 + RBV in treatment naive G1 patients) (n=81)
G1a
Proportion of patients (%)
100
G1b
86
80
70
69
60
43
40
23
20
10
0
ETR
SVR12
Relapse
Zeuzem S, et al. AASLD 2011. Abstract LB-15
BMS-790052 + BMS-650032 Alone or
With PegIFN/RBV in GT1 Null Responders

Open-label, randomized, placebo-controlled phase IIa trial

BMS-790052: NS5A polymerase inhibitor
Wk 24
Prior null
responders
with GT1 HCV
(N = 21)
BMS-790052 60 mg QD +
BMS-650032 600 mg BID
(n = 11)
Follow-up
BMS-790052 60 mg QD +
BMS-650032 600 mg BID
+ PR*
(n = 10)
Follow-up
*PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day.
Lok A, et al. NEJM 2012.
Wk 72
HCV RNA Levels in Groups A and B.
Lok AS et al. N Engl J Med
2012;366:216-224
BMS-790052/BMS-650032 in Japanese G1b
null responders: virological response
Patients (%)
Below LLOQ
Undetectable
100
90
80
70
60
50
40
30
20
10
0
Week 4
Week 8
RVR
Week 12
Week 24
Post-treatment
week 12
Post-treatment
week 24
cEVR
EOTR
SVR12
SVR24
–
1 subject discontinued at Week 2; HCV RNA was undetectable after 24 weeks’ follow-up
–
No apparent association between detection of baseline RAVs and virological outcome
LLOQ = lower limit of quantification (15 IU/mL);
RAV = resistance-associated variants
Chayama K, et al. Hepatology 2011; DOI:10.1002/hep.24724.
PSI-7977 ELECTRON: PSI-7977 + RBV study design for
treatment-naive G2/3
–
–
–
–
–
Treatment-naive, non-cirrhotic, age ≥18 years
HCV RNA >50,000 IU/mL
Allowed concurrent methadone use
Stratified by HCV genotype and IL28B genotype
Randomized 1:1:1:1 into IFN sparing or IFN-free
N=10
PSI-7977 + RBV + Peg-IFN
N=10
PSI-7977 + RBV + Peg-IFN
N=10
PSI-7977 +
RBV + Peg-IFN
N=10
PSI-7977 + RBV
PSI-7977 + RBV
SVR12
PSI-7977 + RBV
4
8
12
24
Weeks
Gane EJ, et al. AASLD 2011. Abstract 34
PSI-7977 ELECTRON: IFN-free PSI-7977 + RBV
achieves 100% SVR12
PSI-7977
RBV
12 weeks PEG
Time, week
PSI-7977
RBV
8 weeks PEG
PSI-7977
RBV
4 weeks PEG
PSI-7977
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
Gane EJ, et al. AASLD 2011. Abstract 34
CYCLOPHILIN A IS ESSENTIAL FOR HCV REPLICATION AND IS INHIBITED
BY ALISPORIVIR
Replication of
new viral RNA
Inhibition of
replication
CypA
CypA
ALISPORIVIR
NS3
NS5B
NS3
NS5B
NS5A
NS5A
NS4B
NS2
Gallay PA. Clin Liver Dis 2009;13:403–417
NS4B
NS2
26
Phase 2b VITAL-1: alisporivir IFN-free therapy in G2/3
treatment-naive patients
Screening
ALV1000
Randomization
Loading
RVR HCV RNA
1 week
ALV 600 mg bid
EVR
EOTR
SVR12
SVR24
36
48
ALV 1000 mg qd
ALV 600 mg qd+ RBV
400 mg bid + Peg-IFN sc weekly
ALV600R
ALV 600 mg bid
+ RBV 400 mg bid
ALV 600 mg qd + RBV 400 mg bid
ALV 600 mg qd+ RBV
400 mg bid + Peg-IFN sc weekly
ALV800R
ALV 600 mg bid
+ RBV 400 mg bid
ALV 800 mg qd + RBV 400 mg bid
ALV 600 mg qd+ RBV
400 mg bid + Peg-IFN sc weekly
ALV-P
ALV 600 mg bid
+ Peg-IFN sc weekly
ALV 600 mg qd + Peg-IFN 180 mg sc weekly
ALV 600 mg qd+ RBV
400 mg bid + Peg-IFN sc weekly
PR
RBV 400 mg bid + Peg-IFN 180 mg sc weekly
BL
1
Viral response defined by HCV RNA < 25 IU/mL;
sc = subcutaneous injection
4
6
Week
12
24
Pawlotsky JM, et al. AASLD 2011. Abstract LB-11
Phase 2b VITAL-1: ALV IFN-free treatment maintains
HCV RNA negative response to week 12
Non-RCR patients with
Add-on IFN from week 6
100
80
60
ALV 1000 mg
(n=22)
40
ALV 600 mg + RBV
(n=30)
20
ALV 800 mg + RBV
(n=37)
Proportion of patients (%)
Proportion of patients (%)
RCR patients
On IFN-free treatment
0
100%
98%
92%
100
80
60
ALV 1000 mg
(n=55)
40
ALV 600 mg + RBV
(n=49)
20
ALV 800 mg + RBV
(n=51)
0
0
2
4
6
8
10
12
0
2
4
6
8
10
12
Week
Week
IFN-free week 12 results:
ALV1000 26%; ALV800R 37%; ALV600R 41%
Add-on IFN to non-RVR patients
shows rapid response
Viral response by <LOQ; Analysis for patients who had Week 12 HCV RNA
assessment
Pawlotsky JM, et al. AASLD 2011. Abstract LB-11
Summary IFN-free therapy
– All combinations in early development
– SVR close to 100% in G1b
– SVR 100% Genotype 2/3 patients
– RBV required
– Shortening of treatment
– role of IL28B Polymorphisms?
Outlook IFN-free therapy
– If no new safety signals are detected IFN-free therapy of
hepatitis C may became reality in 2015
Outlook IFN-free therapy
– If no new safety signals are detected IFN-free therapy of
hepatitis C may became reality in 2015
and we have reached the
“holy grail” of hepatology
NK cells in HCV infection and response to IFN
therapy in patients with CHC
NK cells and response to IFN therapy in
patients with CHC
Ahlenstiehl et al, Gastroenterology 2011
cellular response to HCV infection
IFN
production
HCV
IFN
receptor
antiviral
proteins
IRF-3
IRF-7
IFN
responding
genes
virus activated
kinase