are (exogenous) interferons really necessary? peter ferenci medical university of vienna
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Are (exogenous) interferons really necessary?
Peter Ferenci
Medical University of Vienna
Treatment of chronic non-A,non-B hepatitis with recombinant human alpha interferon. A preliminary reportJH 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
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
Role of interferon-alfa in treatment of hepatitis?
Mode of action• immune-modulatory (dose dependent!)• antiviral• antiproliferative
IFN-sensitivity• IL28B• Nullresponse….
100%
0%
1st dose14–28 Days
HC
V R
NA
Maintenance phaseDetection limit
Time Course of Virological Response to IFN Therapy in Patients With CHC
Inhibition of
viral replication Immune system eliminationof infected cells
?
Induction phase
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
Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Receptor bindingand endocytosis
Fusion and
uncoating
Transportand release
(+) RNA
Translation andpolyprotein processing
RNA replication
Virionassembly
Membranousweb
ER lumen
LD
LDER lumen
LD
NS3/4 protease inhibitors
NS5B polymerase inhibitors
Nucleoside/nucleotideNonnucleoside
*Role in HCV life cycle not well defined
NS5A* inhibitors
INFORM-1 study: proof of concept study, combination of a PI (danoprevir, DNV) with the polymerase inhibitor mericitabine (MCB)
48w1d 4d 7d 14d
500 mg BID MCB100 mg TID DNV
Bn=8/2
1000 mg BID MCB200 mg TID DNV
Dn=8/4
TF(non-null)
1000 mg BID MCB600 mg BID DNV
En=8/2
TF(null)
1000 mg BID MCB900 mg BID DNV
Fn=8/2
Naive1000 mg BID MCB900 mg BID DNV
Gn=8/2
Naive
P/R (Peg-IFN + RBV)100 mg TID DNV
500 mg BID MCB
500 mg BID MCB100 mg TID DNV
An=8/0
n=8/0
Active/placebo
500 mg BID MCB200 mg TID DNV
1000 mg BID MCB100 mg TID DNV
Cn=16/2
TF = IFN-treatment failures Gane EJ et al. Lancet 2010
Media
n L
og
10 H
CV
RN
AC
hange f
rom
Base
line (
IU/m
L)
Days
–6
–5
–4
–3
–2
–1
0
1
0 2 4 6 8 10 12 14
MCB (mg BID) / DNV (mg) 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)
Gane EJ et al. Lancet 2010
Median change from baseline by treatment groupCohorts B–G
Naive and Null Responders with a BID Oral Regimen of RG7128 and RG7227
Med
ian
Log
10 H
CV
RN
A (
IU/m
L)
1
2
3
4
5
6
7
Days1 3 5 7 9 11 13
Limit of Detection
TF - Nulls
Naives
RG7128 1000 mg BID + RG7227 900 mg BID
Gane et al, Lancet 2010
0
10
20
30
40
50
60
70
80
90
100
<LLOQ<LLOD
50
25
88
Nu
lls
Nai
ves
Nu
lls
Nai
ves
63
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
Zeuzem S, et al. AASLD 2010. Abstract LB-1.
GS-9256 75 mg BID + Tegobuvir 40 mg BID
(n = 16)†
Wk 48Wk 4
GS-9256 75 mg BID + Tegobuvir 40 mg BID +
RBV*†
(n = 15)
PR* (n = 16)
PR* (n = 15)
GS-9256 75 mg BID + Tegobuvir 40 mg BID +
PR* (n = 15)
PR* (n = 15)
Part A
Part B(nonrandomized)
Treatment-naive patients with GT1 HCV
*PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day. †PegIFN/RBV started early if virologic breakthrough.
GS-9256 + Tegobuvir Alone, With RBV, or With PegIFN/RBV: Virologic Response
Zeuzem S, et al. AASLD 2010. Abstract LB-1.
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 RBVprogram terminated due to safety issues
ZENITH: telaprevir (PI) + VX-222 (NNI) ± Peg-IFN/RBV in treatment-naive G1 patients
* 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.
Week 0 12
Telaprevir 1125 mg bid
VX-222 100 mg bid*
Telaprevir 1125 mg bid
VX-222 100 mg bid*
RBV
Peg-IFN alfa-2a
Telaprevir 1125 mg bid
VX-222 400 mg bid*
Telaprevir 1125 mg bid
VX-222 400 mg bid*
RBV
Peg-IFN alfa-2aDN=30
RBV
Peg-IFN alfa-2a
RVR2-guided Week 36
AN=18
BN=29
CN=29
DDI = drug-drug interaction; NNI = non-nucleoside inhibitor; Peg-IFN = peginterferon alfa; PI = protease inhibitor; RBV = ribavirin
ZENITH: telaprevir (PI) + VX-222 (NNI) ± Peg-IFN/RBV in treatment-naive G1 patients
* 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.
• DUAL regimens terminated
Week 0 12
Telaprevir 1125 mg bid
VX-222 100 mg bid*
Telaprevir 1125 mg bid
VX-222 100 mg bid*
RBV
Peg-IFN alfa-2a
Telaprevir 1125 mg bid
VX-222 400 mg bid*
Telaprevir 1125 mg bid
VX-222 400 mg bid*
RBV
Peg-IFN alfa-2aDN=30
RBV
Peg-IFN alfa-2a
RVR2-guided Week 36
AN=18
BN=29
CN=29
Telaprevir 1125 mg bid
VX-222 400 mg bid*
RBV
E/F(E G1b N=23; F G1a N=23)
Enrolment complete
ZENITH: telaprevir (PI) + VX-222 (NNI) ± Peg-IFN/RBV in treatment-naive G1 patients
* 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.
• DUAL regimens terminated
Week 0 12
Telaprevir 1125 mg bid
VX-222 100 mg bid*
Telaprevir 1125 mg bid
VX-222 100 mg bid*
RBV
Peg-IFN alfa-2a
Telaprevir 1125 mg bid
VX-222 400 mg bid*
Telaprevir 1125 mg bid
VX-222 400 mg bid*
RBV
Peg-IFN alfa-2aDN=30
RBV
Peg-IFN alfa-2a
RVR2-guided Week 36
AN=18
BN=29
CN=29
ZENITH: telaprevir + VX-222 ± Peg-IFN/RBV SVR12 data
Overall Patients eligible for 12 weeks treatment
Patients eligible for 24 weeks treatment
0
20
40
60
80
100
83 82 8390 93 90
Arm C 100 mg VX-222Arm D 400 mg VX-222
SV
R12
, %
2429
2730
911
1415
15 13
– 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
weeks
F/U
Quad: MCB 1000mg + DNVr 100/100mg + P/R
F/U
Cohort B: Null Responders
A2
A3
IFN free: MCB 1000mg + DNVr 100/100mg + R
A1
Triple: DNVr 100/100mg + P/R
IFN free: MCB 1000mg + DNVr 100/100mg + R
Quad: MCB 1000mg + DNVr 100/100mg + P/R
B1
B2
F/U
F/U
F/U
Cohort A:PartialResponders
Phase 2, randomized within cohort, open-label, parallel study of 2 cohorts
N= 420 (70 pts/arm)
Quad: MCB 1000mg + DNVr 100/100mg + P/R
F/UB3
482412 72
P/R
Stratification by:
» IL28B (CC, CT, TT)
» G1a/1b
MATTERHORN: study design
weeks
F/U
Quad: MCB 1000mg + DNVr 100/100mg + P/R
F/U
Cohort B: Null Responders
A2
A3
IFN free: MCB 1000mg + DNVr 100/100mg + R
A1
Triple: DNVr 100/100mg + P/R
IFN free: MCB 1000mg + DNVr 100/100mg + R
Quad: MCB 1000mg + DNVr 100/100mg + P/R
B1
B2
F/U
F/U
F/U
Cohort A:PartialResponders
Phase 2, randomized within cohort, open-label, parallel study of 2 cohorts
N= 420 (70 pts/arm)
Quad: MCB 1000mg + DNVr 100/100mg + P/R
F/UB3
482412 72
P/R
Stratification by:
» IL28B (CC, CT, TT)
» G1a/1b
GT1a
GT1a
Zeuzem S, et al. AASLD 2011. Abstract LB-15
Phase 2b SOUND-C2: BI201335 (PI) + BI207127 (NNI) ± RBV in treatment naive G1 patients
– 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
Randomization
Na
ive
, C
HC
, G
1N
=3
62
Weeks16 400 28
BI207127 600 mg tid BI201335 120 mg qd RBV
BI207127 600 mg tid BI201335 120 mg qd RBV
Follow-up
BI207127 600 mg tid BI201335 120 mg qd
Follow-up
BI207127 600 mg bid BI201335 120 mg qd RBV
Follow-up
BI207127 600 mg tid BI201335 120 mg qd RBV
Follow-up
SOUND-C2: preliminary SVR in treatment Arm A (16 week treatment duration, BI201335 + BI207127 + RBV in treatment naive G1 patients) (n=81)
Pro
po
rtio
n o
f p
ati
ents
(%
)
Zeuzem S, et al. AASLD 2011. Abstract LB-15
ETR SVR12 Relapse0
20
40
60
80
100
70
43
23
86
69
10
G1a G1b
BMS-790052 + BMS-650032 Alone or With PegIFN/RBV in GT1 Null Responders
Lok A, et al. NEJM 2012.
Prior null responders
with GT1 HCV(N = 21)
BMS-790052 60 mg QD + BMS-650032 600 mg BID
(n = 11)
Wk 72Wk 24
Follow-up
BMS-790052 60 mg QD + BMS-650032 600 mg BID
+ PR*(n = 10)
Open-label, randomized, placebo-controlled phase IIa trial
BMS-790052: NS5A polymerase inhibitor
Follow-up
*PegIFN alfa-2a 180 µg/wk; weight-based RBV 1000-1200 mg/day.
HCV RNA Levels in Groups A and B.
Lok AS et al. N Engl J Med 2012;366:216-224
Week 4 Week 8 Week 12 Week 24 Post-treatment week 12
Post-treatment week 24
0102030405060708090
100Below LLOQ Undetectable
BMS-790052/BMS-650032 in Japanese G1bnull responders: virological response
– 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
Pat
ien
ts (
%)
RVR cEVR EOTR SVR12 SVR24
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
Weeks
PSI-7977 + RBV
PSI-7977 + RBV + Peg-IFN
PSI-7977 + RBV + Peg-IFN
PSI-7977 + RBV + Peg-IFN
PSI-7977 + RBV
PSI-7977 + RBV
1284 24
SVR12
N=10
N=10
N=10
N=10
Gane EJ, et al. AASLD 2011. Abstract 34
PSI-7977 ELECTRON: IFN-free PSI-7977 + RBV achieves 100% SVR12
Gane EJ, et al. AASLD 2011. Abstract 34
PSI-7977 RBV
12 weeks PEG
PSI-7977 RBV
8 weeks PEG
PSI-7977 RBV
4 weeks PEG
PSI-7977 RBV
NO PEG
Time, week 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
26
NS5A
NS5B
NS2
NS3
NS4B
CYCLOPHILIN A IS ESSENTIAL FOR HCV REPLICATION AND IS INHIBITED BY ALISPORIVIR
Gallay PA. Clin Liver Dis 2009;13:403–417
ALISPORIVIR
Inhibition of replication
Replication of new viral RNA
NS5ANS5B
NS2
NS3
NS4B
CypACypA
Phase 2b VITAL-1: alisporivir IFN-free therapy in G2/3 treatment-naive patients
Pawlotsky JM, et al. AASLD 2011. Abstract LB-11Viral response defined by HCV RNA < 25 IU/mL; sc = subcutaneous injection
RandomizationScreening
ALV1000
ALV600R
ALV800R
ALV-P
PR
Loading1 week
RVR HCV EVR EOTR SVR12 SVR24RNA
BL 1 4 12 24 36 486Week
ALV 600 mg bid+ RBV 400 mg bid
ALV 600 mg bid
ALV 600 mg bid+ RBV 400 mg bid
ALV 600 mg bid+ Peg-IFN sc weekly
RBV 400 mg bid + Peg-IFN 180 mg sc weekly
ALV 1000 mg qd
ALV 600 mg qd + RBV 400 mg bid
ALV 800 mg qd + RBV 400 mg bid
ALV 600 mg qd + Peg-IFN 180 mg sc weekly
≥25 IU/mL
≥25 IU/mL
≥25 IU/mL
≥25 IU/mL
ALV 600 mg qd+ RBV400 mg bid + Peg-IFN sc weekly
ALV 600 mg qd+ RBV400 mg bid + Peg-IFN sc weekly
ALV 600 mg qd+ RBV400 mg bid + Peg-IFN sc weekly
ALV 600 mg qd+ RBV400 mg bid + Peg-IFN sc weekly
Phase 2b VITAL-1: ALV IFN-free treatment maintains HCV RNA negative response to week 12
Pawlotsky JM, et al. AASLD 2011. Abstract LB-11Viral response by <LOQ; Analysis for patients who had Week 12 HCV RNAassessment
RCR patientsOn IFN-free treatment
IFN-free week 12 results: ALV1000 26%; ALV800R 37%; ALV600R 41%
Non-RCR patients withAdd-on IFN from week 6
Add-on IFN to non-RVR patients shows rapid response
Week
Pro
po
rtio
n o
f p
atie
nts
(%
)
0 2 4 6 8 10 12
20
40
60
80
100
0
ALV 1000 mg(n=55)
ALV 600 mg + RBV(n=49)
ALV 800 mg + RBV(n=51)
ALV 1000 mg(n=22)
ALV 600 mg + RBV(n=30)
ALV 800 mg + RBV(n=37)
Week
Pro
po
rtio
n o
f p
atie
nts
(%
)
0 2 4 6 8 10 12
20
40
60
80
100
0
98%100%
92%
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?
– 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
Outlook IFN-free therapy
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
HCV
virus activatedkinase
IRF-3IRF-7
IFNproduction
IFNreceptor
IFNresponding
genesantiviralproteins
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