are (exogenous) interferons really necessary? peter ferenci medical university of vienna

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

http://content.nejm.org/content/vol315/issue25/index.dtl



http://www.ncbi.nlm.nih.gov/pubmed/13690501




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


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


An=8/0

n=8/0

Active/placebo



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*


VX-222 100 mg bid*

RBV

Peg-IFN alfa-2a


VX-222 400 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




• DUAL regimens terminated

Week 0 12


VX-222 100 mg bid*


VX-222 100 mg bid*

RBV

Peg-IFN alfa-2a


VX-222 400 mg bid*


VX-222 400 mg bid*

RBV


RBV

Peg-IFN alfa-2a

RVR2-guided Week 36

AN=18

BN=29

CN=29


VX-222 400 mg bid*

RBV

E/F(E G1b N=23; F G1a N=23)

Enrolment complete




• DUAL regimens terminated

Week 0 12


VX-222 100 mg bid*


VX-222 100 mg bid*

RBV

Peg-IFN alfa-2a


VX-222 400 mg bid*


VX-222 400 mg bid*

RBV


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%)


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



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)


F/UB3

482412 72

P/R

Stratification by:

» IL28B (CC, CT, TT)

» G1a/1b

MATTERHORN: study design

weeks

F/U


F/U

Cohort B: Null Responders

A2

A3


A1

Triple: 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)


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


Follow-up

BI207127 600 mg tid BI201335 120 mg qd

Follow-up

BI207127 600 mg bid BI201335 120 mg qd RBV

Follow-up


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

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




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 1000 mg(n=22)



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

are (exogenous) interferons really necessary? peter ferenci medical university of vienna

Documents

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