Are (exogenous) interferons really necessary?

1
Are (exogenous) interferons really necessary?

• Peter Ferenci
• Medical University of Vienna

2
Effect of interferon on experimental vaccinia and
herpes-simplex virus infections in rabbits'
eyes. CANTELL K, TOMMILA V. Lancet. 1960 Sep
242(7152)682-4
3
Role of interferon-alfa in treatment of hepatitis?

• Mode of action
• immune-modulatory (dose dependent!)
• antiviral
• antiproliferative
• IFN-sensitivity
• IL28B
• Nullresponse.

4
Time Course of Virological Response to IFN
Therapy in Patients With CHC
100
Inhibition of viral replication
HCV RNA
Immune system elimination of infected cells
Induction phase
Maintenance phase
Detection limit
0
1428 Days
?
Ferenci P 1999
1st dose
5
NK cells and response to IFN therapy in patients
with CHC
Ahlenstiehl et al, Gastroenterology 2011
6
HCV Life Cycle and DAA Targets
Receptor bindingand endocytosis
Transportand release
Fusion and uncoating
ER lumen
Virionassembly
() RNA
LD
Translation andpolyprotein processing
Membranousweb
RNA replication
ER lumen
Adapted from Manns MP, et al. Nat Rev Drug
Discov. 20076991-1000.
7
INFORM-1 study proof of concept study,
combination of a PI (danoprevir, DNV) with the
polymerase inhibitor mericitabine (MCB)
48w
1d
4d
7d
14d
Active/placebo
TF IFN-treatment failures
Gane EJ et al. Lancet 2010
8
Median change from baseline by treatment
groupCohorts BG
Median Log10 HCV RNA Change from Baseline (IU/mL)
Days
Gane EJ et al. Lancet 2010
9
Naive and Null Responders with a BID Oral Regimen
of RG7128 and RG7227
88
RG7128 1000 mg BID RG7227 900 mg BID
63
Median Log10 HCV RNA (IU/mL)
50
TF - Nulls
Naives
25
Naives
Naives
Nulls
Nulls
Limit of Detection
1
3
5
7
9
11
13
Days
Gane et al, Lancet 2010
10
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
PR (n 16)
GS-9256 75 mg BID Tegobuvir 40 mg BID (n
16)
Treatment-naive patients with GT1 HCV
Part A
GS-9256 75 mg BID Tegobuvir 40 mg BID RBV
(n 15)
PR (n 15)
Part B(nonrandomized)
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.
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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.
12
ZENITH telaprevir (PI) VX-222 (NNI)
Peg-IFN/RBV in treatment-naive G1 patients
Week
0
12
A N18
B N29
RVR2-guided
Week 36
C N29
D N30
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.
DDI drug-drug interaction NNI non-nucleoside
inhibitor Peg-IFN peginterferon alfa PI
protease inhibitor RBV ribavirin
Nelson D, et al. AASLD 2011. Abstract LB-14.
13
ZENITH telaprevir (PI) VX-222 (NNI)
Peg-IFN/RBV in treatment-naive G1 patients
Week
0
12
A N18

• DUAL regimens terminated

B N29
RVR2-guided
Week 36
C N29
D N30
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.
14
ZENITH telaprevir (PI) VX-222 (NNI)
Peg-IFN/RBV in treatment-naive G1 patients
Week
0
12
A N18

• DUAL regimens terminated

B N29
RVR2-guided
Week 36
C N29
D N30
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.
E/F (E G1b N23 F G1a N23)
Enrolment complete
Nelson D, et al. AASLD 2011. Abstract LB-14.
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ZENITH telaprevir VX-222 Peg-IFN/RBV SVR12
data
SVR12,
24 29
27 30
9 11
14 15
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.
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MATTERHORN study design
N 420 (70 pts/arm)
IFN free MCB 1000mg DNVr 100/100mg R
A1
F/U

• Stratification by
• IL28B (CC, CT, TT)
• G1a/1b

Cohort APartialResponders
Triple DNVr 100/100mg P/R
A2
F/U
Quad MCB 1000mg DNVr 100/100mg P/R
A3
F/U
IFN free MCB 1000mg DNVr 100/100mg R
B1
F/U
Cohort B Null Responders
Quad MCB 1000mg DNVr 100/100mg P/R
B2
F/U
Quad MCB 1000mg DNVr 100/100mg P/R
P/R
B3
F/U
weeks
Phase 2, randomized within cohort, open-label,
parallel study of 2 cohorts
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MATTERHORN study design
N 420 (70 pts/arm)
GT1a
IFN free MCB 1000mg DNVr 100/100mg R
A1
F/U

• Stratification by
• IL28B (CC, CT, TT)
• G1a/1b

Cohort APartialResponders
Triple DNVr 100/100mg P/R
A2
F/U
Quad MCB 1000mg DNVr 100/100mg P/R
A3
F/U
GT1a
IFN free MCB 1000mg DNVr 100/100mg R
B1
F/U
Cohort B Null Responders
Quad MCB 1000mg DNVr 100/100mg P/R
B2
F/U
Quad MCB 1000mg DNVr 100/100mg P/R
P/R
B3
F/U
weeks
Phase 2, randomized within cohort, open-label,
parallel study of 2 cohorts
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Phase 2b SOUND-C2 BI201335 (PI) BI207127
(NNI) RBV in treatment naive G1 patients
Naive, CHC, G1 N362

• 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
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SOUND-C2 preliminary SVR in treatment Arm A (16
week treatment duration, BI201335 BI207127
RBV in treatment naive G1 patients) (n81)
Proportion of patients ()
Zeuzem S, et al. AASLD 2011. Abstract LB-15
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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 72
Wk 24
BMS-790052 60 mg QD BMS-650032 600 mg BID(n
11)
Follow-up
Prior null responders with GT1 HCV (N 21)
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.
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HCV RNA Levels in Groups A and B.
Lok AS et al. N Engl J Med 2012366216-224
22
0
23
BMS-790052/BMS-650032 in Japanese G1bnull
responders virological response
Patients ()

• 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
DOI10.1002/hep.24724.
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PSI-7977 ELECTRON PSI-7977 RBV study design
for treatment-naive G2/3

• Treatment-naive, non-cirrhotic, age 18 years
• HCV RNA gt50,000 IU/mL
• Allowed concurrent methadone use
• Stratified by HCV genotype and IL28B genotype
• Randomized 1111 into IFN sparing or IFN-free

PSI-7977 RBV Peg-IFN
N10
PSI-7977 RBV Peg-IFN
PSI-7977 RBV
N10
SVR12
PSI-7977 RBV Peg-IFN
PSI-7977 RBV
N10
PSI-7977 RBV
N10
Weeks
Gane EJ, et al. AASLD 2011. Abstract 34
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PSI-7977 ELECTRON IFN-free PSI-7977 RBV
achieves 100 SVR12
PSI-7977 RBV 12 weeks PEG PSI-7977 RBV 12 weeks PEG PSI-7977 RBV 8 weeks PEG PSI-7977 RBV 8 weeks PEG PSI-7977 RBV 4 weeks PEG PSI-7977 RBV 4 weeks PEG PSI-7977 RBV NO PEG PSI-7977 RBV NO PEG
Time, week N ltLOD N ltLOD N ltLOD N ltLOD
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
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CYCLOPHILIN A IS ESSENTIAL FOR HCV REPLICATION
AND IS INHIBITED BY ALISPORIVIR
Inhibition of replication
Replication of new viral RNA
ALISPORIVIR
Gallay PA. Clin Liver Dis 200913403417
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Phase 2b VITAL-1 alisporivir IFN-free therapy in
G2/3 treatment-naive patients
Viral response defined by HCV RNA lt 25 IU/mL sc
subcutaneous injection
Pawlotsky JM, et al. AASLD 2011. Abstract LB-11
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Phase 2b VITAL-1 ALV IFN-free treatment
maintains HCV RNA negative response to week 12
RCR patients On IFN-free treatment
Non-RCR patients with Add-on IFN from week 6
100
98
92
IFN-free week 12 results ALV1000 26 ALV800R
37 ALV600R 41
Add-on IFN to non-RVR patients shows rapid
response
Viral response by ltLOQ Analysis for patients who
had Week 12 HCV RNAassessment
Pawlotsky JM, et al. AASLD 2011. Abstract LB-11
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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?

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Outlook IFN-free therapy

• If no new safety signals are detected IFN-free
  therapy of hepatitis C may became reality in 2015

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Outlook IFN-free therapy

• If no new safety signals are detected IFN-free
  therapy of hepatitis C may became reality in 2015

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(No Transcript)
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NK cells in HCV infection and response to IFN
therapy in patients with CHC
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NK cells and response to IFN therapy in patients
with CHC
Ahlenstiehl et al, Gastroenterology 2011
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cellular response to HCV infection
IFN production
HCV
IFN receptor
virus activated kinase
IRF-3 IRF-7
IFN responding genes
antiviral proteins