SILEN-C2: sustained virological response (SVR) and safety of BI 201335 combined with

peginterferon alfa 2a and ribavirin (PegIFN/RBV) in chronic HCV genotype-1

patients with nonresponse to PegIFN/RBV

M.S. Sulkowski,1 M. Bourlière,2 J.-P. Bronowicki,3 A. Streinu-Cercel,4 L. Preotescu,4

T. Asselah,5 J.-M. Pawlotsky,6 S. Shafran,7 S. Pol,8 F.A. Caruntu,4 S. Mauss,9 D. Larrey,10

C. Häfner,11 Y. Datsenko,11 J.O. Stern,12 R. Kubiak,11 W. Böcher,11 G. Steinmann11

On behalf of the SILEN-C2 study group

1Johns Hopkins University, Baltimore, MD, USA; 2Hôpital Saint Joseph, Marseille, France; 3Hôpital de

Brabois, Vandoeuvre Cedex, France; 4“Prof. Dr. Matei Bals” Institute of Infectious Diseases,

Bucharest, Romania; 5Hôpital Beaujon, Clichy Cedex, France; 6Hôpital Henri Mondor, Créteil, France;7University of Alberta, Edmonton, AB, Canada; 8Hôpital Cochin, Paris, France; 9Center for HIV

and Hepatogastroenterology, Düsseldorf, Germany; 10Hôpital Saint-Eloi, Montpellier Cedex,

France; 11Boehringer Ingelheim Pharma, Biberach, Germany; 12Boehringer Ingelheim

Pharmaceuticals, Ridgefield, CT, USA

Speaker declaration

I have financial relationships within the last 12 monthsrelevant to my presentation with Boehringer IngelheimPharmaceuticals.

The terms of this arrangement are being managed by the

Johns Hopkins University in accordance with its conflictof interest policies and my presentation includesdiscussion of off-label or investigational use of:

• BI 201335• Peginterferon alfa 2a• Ribavirin

SILEN-C2 trial

Double-blind, placebo-controlled, phase IIb study in HCV genotype-1 (GT-1) patients with nonresponse to previous PegIFN/RBV

*3-day lead-in period (LI) of PegIFN alfa 2a (180 μg/week) plus ribavirin (1,000 mg or 1,200 mg/day); Re-randomisation 1:1 of patients with eRVR (extended rapid virological response) to 24 versus 48 weeksof PegIFN/RBVQD, once daily; BID, twice daily

n = 142

n = 76

n = 70 PegIFN/RBV240 mg BID LI BI 201335 + PegIFN/RBV*

PegIFN/RBV240 mg QD BI 201335 + PegIFN/RBV

D1 D4 Week 24 Week 48

* PegIFN/RBV240 mg QD LI BI 201335 + PegIFN/RBV

Main inclusion criteria

• Age 18 to 65 years

• Chronic hepatitis C GT-1 infection

• Confirmed nonresponse during previous PegIFN/RBV treatment– ≥ 12 weeks of an approved dose of PegIFN/RBV

– Null response: < 1 log10 maximum HCV RNA reduction any time during treatment

– Partial response: > 1 log10 maximum HCV RNA reduction, but never undetectable (with a sensitive assay)

– Relapsers were excluded

• HCV RNA ≥ 100,000 IU/mL at screening

• Liver biopsy within 2 years without evidence of cirrhosis

Baseline characteristics240 mg QD LI

n = 142240 mg QD

n = 76240 mg BID LI

n = 70

Mean age (years) 48.7 49.6 50.1

Male gender (%)71.1 65.8 58.6

Ethnicity (%)WhiteBlackAsian

92.33.54.2

84.29.26.6

92.94.32.9

Mean HCV RNA (log10) 6.60 6.56 6.55

Genotypea (%)1a1b1, other subtypesb

54.943.02.1

55.343.41.3

38.6 60.01.4

Prior response to PegIFN/RBV (%)

Null responsePartial responseNonresponseOthers

40.138.09.2

12.7

52.634.23.99.2

54.334.37.14.3

aBased on NS3/4A sequencing; bOther genotypes were 1C (n=1), 1D (n=1) and 1G (n=1). 1 patient was GT-1 but subgenotype could not be determined

Virological response

43

27

4541

47

31

0

5

10

15

20

25

30

35

40

45

50

eRVR SVR

Pro

po

rtio

n o

f p

ati

en

ts (

%)

240 mg QD LI 240 mg QD 240 mg BID LI

61/142 34/76 33/70 31/7639/142 22/70

eRVR: HCV RNA < 25 IU/mL at Week 4 and undetected at Weeks 8 to 20

Pro

po

rtio

n o

f p

atie

nts

(%

)

SVR in partial- and null-responders

30

21

50

3542

29

0

20

40

60

80

100

Partial-responders Null-responders

Pro

po

rtio

n o

f p

ati

en

ts (

%)

240 mg QD LI 240 mg QD 240 mg BID LI

16/54 13/26 10/24 14/4012/57 11/38

Null response, <1 log10 maximum HCV RNA reduction any time during treatment;Partial response, > 1 log10 maximum HCV RNA reduction, but never undetectable (with a sensitive assay)

100

80

60

40

20

0

Pro

po

rtio

n o

f p

atie

nts

(%

)

SVR and relapse in eRVR patients by duration of PegIFN/RBV

40

60

72

21

0

20

40

60

80

100

SVR Relapse

Pro

po

rtio

n o

f p

ati

en

ts (

%)

240 mg QD LI 24 weeks 240 mg QD LI 48 weeks

Relapse: rebound from undetectable at end of all treatment

12/30 21/29 18/30 6/29

P = 0.018100

80

60

40

20

0

Pro

po

rtio

n o

f p

atie

nts

(%

)

Virological failures

a≥ 1 log10 rebound from nadir, or rebound to ≥ 100 IU/mL if nadir < lower limit of detection (LLOD) on treatment, confirmed in a second sample; bRebound after end of all treatment from nadir < LLOD after end of treatment

100

80

60

40

20

0

Pro

po

rtio

n o

f p

atie

nts

(%

)

25

5

2528

7 917

6

19

Breakthrougha onBI 201335

Breakthrougha onPegIFN/RBV

Relapseb

240 mg QD LI 240 mg QD 240 mg BID LI

Adverse eventsa

240 mg QD LI(%)

240 mg QD(%)

240 mg BID LI(%)

All patients (nb) 141 76 69

Rashc

Mild

Moderate

Severe

34.0

27.7

5.7

0.7

27.6

23.7

2.6

1.3

42.0

15.9

20.3

5.8

Jaundice

Severe

19.0

0

21.1

0

41.4

0

Nausea 48.2 52.6 63.8

Diarrhoea 31.9 31.6 39.1

Vomiting 17.0 22.4 31.9

aAdverse events > 10% compared with PegIFN/RBV; bNumber quoted is according to given treatment; cNo cases of Stevens-Johnson syndrome, erythema multiforme or drug rash with eosinophilia and systemic symptoms

Adverse events: overall summary

240 mg QD LI(%)

240 mg QD(%)

240 mg BID LI (%)

All patients (na) 141 76 69With severe adverse events

14.2 14.5 27.5

Fatalities 0 0 0

Discontinuations for adverse events

5.7 3.9 23.2

Discontinuations for

Rash

Photosensitivity

Jaundice

Othersb

0

0

0.7

5.0

1.3

0

0

2.6

14.5

1.4

1.4

5.8

aNumber quoted is according to given treatment; bOther discontinuations mainly due to general disorders and administration site conditions, gastrointestinal and others

0

1

2

3

4

To

tal b

iliru

bin

mg

/dL

(n

orm

al r

an

ge

0.1–

1)

BL Day 4 Week 1 Week 2 Week 4 Week 8 Week10

Week12

Week16

Week20

Week24

Week28

Mean total bilirubin (mg/dL)

Effect of BI 201335 on bilirubin and haemoglobin

10

12

14

16

18

20

BL Day 4 Week 1 Week 2 Week 4 Week 8 Week10

Week12

Week16

Week20

Week24

Week28

Me

an

he

mo

glo

bin

(g

/dL

) Mean haemoglobin (g/dL)

240 mg QD LI 240 mg QD 240 mg BID LI

BL, baseline

Discussion and conclusion

• Virological response– robust SVR rates up to 41% at 240 mg QD

• dose selected for phase III– response-guided therapy was not effective for nonresponsive

patients achieving eRVR– 3-day PegIFN/RBV lead-in did not increase SVR

• Safety and tolerability– most adverse events were those commonly related to PegIFN/RBV

therapy• no excess effect on haemoglobin

– mild-to-moderate jaundice and rash are the main BI 201335-related adverse events and are dose-dependent • jaundice is due to isolated indirect hyperbilirubinaemia

• In treatment-experienced patients, BI 201335 240 mg QD appears to offer the best safety/efficacy balance– phase III trial in preparation

Acknowledgements

• Patients and study investigators at study centres in the following countries:AustraliaJacob GeorgeWilliam SievertBarbara LeggettGraeme MacDonaldStephen RiordanSally BellAmany Zekry

AustriaPeter FerenciMichael GschwantlerAndreas Maieron

CanadaJenny HeathcoteStephen ShafranBernard WillemsBrian Conway

NetherlandsHenk ReesinkBart van Hoek

PortugalArmando CarvalhoFernando RamalhoFilipe CalinasJosé SarmentoRui Sarmento e Castro

Republic of KoreaJeong HeoDoYoung KimYoung Oh KweonSeungWoon PaikYounJae LeeMong Cho

RomaniaAdrian Streinu-Cercel Liliana Preotescu Florin Alexandru Caruntu Ceasu Emanoil

SpainJose Luis CallejaJavier García-SamaniegoMaría Luisa Gracía BueyJaime EnriquezVicente Soriano

SwitzerlandEnos BernasconiJürg Reichen

FranceTarik AsselahYves BenhamouStanislas PolMarc BourlièreJean-Pierre BronowickiDominique LarreyJean-Michel PawlotskyChristophe HezodeChristian Trepo

GermanyThomas BergDieter HäussingerAnsgar LohseMarcus SchuchmannJohannes WiegandStefan MaussUlrich SpenglerWolfgang E. SchmidtElmar Zehnter

United KingdomJanice MainWilliam RosenbergMark WrightFiona GordonGraham FosterStephen RyderKosh AgarwalMark Nelson

United StatesMaurizio BonaciniDouglas DieterichIra JacobsonDavid WrightDonald JensenRajender ReddyJacob LalezariIra SteinLawrence Wruble

• Boehringer Ingelheim for sponsoring the study and their clinical and statistical teams for study monitoring, data collection and analysis

• Editorial support provided by StemScientific