Bruix J, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09

Bruix J, et al. Presented at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09

1

PegIntron Maintenance Therapy in Cirrhotic (METAVIR F4) HCV Patients Who Failed to

Respond to Interferon/Ribavirin (IR) Therapy: Final Results of the EPIC3 Cirrhosis

Maintenance Trial

J Bruix, T Poynard, M Colombo, E Schiff, J Reichen, K Burak, EJL Heathcote, T Berg, J-L Poo, C Brandao Mello, R Guenther,

C Niederau, R Terg, N Boparai, J Harvey, LH Griffel, M Burroughs, CA Brass, JK Albrecht for the EPIC3 Study Group

44th Annual Meeting of the European Association for the Study of the Liver Friday, April 24, 2009

Copenhagen, Denmark


2

Background and Aims A large proportion of HCV patients are nonresponders

to previous treatment HCV-related cirrhosis is associated with hepatocellular

carcinoma (HCC) and end-stage liver disease (ESLD) Interferon therapy has been associated with reduction

in rates of HCCa and ESLD-related eventsb

The aim of this study was to compare long-term, low-dose PEG-IFN alfa-2b with observed controls regarding the occurrence of HCC and ESLD-related events in cirrhotic patients (F4)

Similar trials COPILOT: 548 cirrhotics; primary end-point negativeb

HALT- C: included 428 cirrhotics; all endpoints negativec

a Yohsida et al., Gut 2000;47:610-611b Afdhal et al., J. Hepatol, 2008; 48, S2, A3 c DiBiesgelie et al., NEJM, 2008;359:2429-41


3

HCV RNA negative at week 12HCV RNA negative at week 12

Continue P/R for 48 wkContinue P/R for 48 wk

EPIC3 Program Design

Nonresponder Trial*Nonresponder Trial*: N = 2333: N = 2333CHC with fibrosis (F2, F3, or F4 METAVIR) CHC with fibrosis (F2, F3, or F4 METAVIR)

Evaluation of virological response at week 12Evaluation of virological response at week 12

Chronic Suppression for Chronic Suppression for NoncirrhoticsNoncirrhotics, n = 575, n = 575

METAVIR F2 or F3 subjects METAVIR F2 or F3 subjects PEG-Intron 0.5 PEG-Intron 0.5 g/kg/wk vs controlg/kg/wk vs control

Duration: 3 yearsDuration: 3 years

Chronic Suppression for Cirrhotics, n = 626

(Child-Pugh A, Compensated)

METAVIR F4 subjects PEG-Intron 0.5 g/kg/wk vs control

Max. duration: up to 5 years

METAVIR F4 CHC subjects

DIRECT ENROLLERS

n = 172n = 454

HCV-RNA

Negative

HCV-RNA

Positive

F2/3 F4

* Poynard et al., Gastro 2009:136:1618-1628


4

Methods Study duration

Up to 5 years from time first subject was randomized or occurrence of 98 clinical events

Statistical plan: 90% power for 98 events and hazard ratio of 2

Study completed based upon 5-year rule

Primary objective – time to first clinical event Liver decompensation (variceal bleed, >grade 2 enceph,

ascites requiring Rx, CPT C); HCC; death; liver transplantation.

Clinical evaluation/3 months, US every 6 months

Clinical events, with the exception of death and liver transplantation, were adjudicated by an external adjudication committee


5

Methods (cont) Secondary objective – time to disease progression

Includes all clinical events and

Development of Child-Pugh B

Emergence of varices

Enlargement of pre-existing varices requiring additional therapy

Additional prospective analyses in subjects with baseline portal hypertension Prospectively planned based upon results of COPILOT study

Defined as the existence of esophageal varices

Sensitivity analysis performed using definition of splenomegaly and platelet count <100K


6

Baseline DemographicsRoll-over Subjects

From Treatment Phase Direct Enrollers All Randomized

PEG (n = 224)

Control (n = 230)

PEG (n = 87)

Control (n = 85)

PEG (n = 311)

Control (n = 315)

Male, n (%) 155 (69) 156 (68) 51 (59) 59 (69) 206 (66) 216 (68)

Caucasian, n (%) 189 (84) 197 (86) 69 (79) 68 (80) 258 (83) 265 (84)

Age, years (SD) 52.2 (7.6) 51.7 (8.0) 52.3 (7.3) 53.0 (6.4) 52.3 (7.5) 52.0 (7.6)

Weight, kg (SD) 78.08 (14.35) 77.48 (14.36)

83.09 (17.62)

83.08 (16.26) 79.48 (15.47)

78.99 (15.08)

BMI, kg/m2 (SD) 26.72 (4.07) 26.78 (4.25) 28.55 (5.09)

28.13 (4.38) 27.24 (4.45) 27.13 (4.32)

Genotype 1, n (%) 207 (92) 217 (94) 71 (82) 68 (80) 278 (89) 285 (90)

Viral Load >600,000 IU/mL, n (%)

Baseline ALT U/L (SD)

155 (69)

116.5 (70.2)

161 (70)

116.8 (80.4)

58 (67)

102 (66.5)

59 (69)

108.3 (65.9)

213 (68)

112.4 (69.4)

220 (70)

114.7(77.0)


7

Time to First Clinical Event* Liver decompensation (variceal bleed, >grade 2 enceph,

ascites requiring Rx, CPT C); HCC; death; liver transplantation

* All Randomized Subjects from sites

not closed for noncompliance.*P = 0.144, HR = 1.452 vs observed controls

Pro

bab

ility

of

Fai

lure

1.00.9

0.80.7

0.60.50.40.3

0.20.1

0.0

TimeAt RiskPEG:

CONTROL:

6

296290

12

279265

18

265253

24

226203

30

185167

36

153133

42

11794

48

8160

54

3524

60

11

66

.

.

CONTROL

PEG

PEGCONTROLCensored

mean treatment duration = 32 months

mean treatment duration = 31 months


8

Clinical Events by Treatment Arm

Event, n (%)

Observed Controls

n = 315

PEG-IFN alfa-2b

n = 311

Subjects With Clinical Eventa 36 (11) 27 (9)*

Ascitesb 13 (4) 10 (3)

Childs Pugh Class Cb 1 (<1) 4 (1)

Variceal bleedingb 10 (3) 1 (<1)

HCCb 13 (4) 12 (4)

≥Grade 2 hepatic encephalopathyb 3 (1) 4 (1)

Liver transplantation 4 (1) 2 (<1)

Death 6 (2) 7 (2)aEarliest event counted in case of multiple events.

bEvents were adjudicated.cBased on Cox proportional Hazards model with age (≤50, >50 years)

and participation in retreatment phase (yes, no) as stratification factors.


9

Time to Disease Progression* Primary events plus: Development of Child-Pugh B, Emergence of

varices, Enlargement of pre-existing varices requiring additional therapy

* All Randomized Subjects from sites not closed for noncompliance.

Pro

bab

ility

of

Fai

lure

TimeAt RiskPEG:

CONTROL:

6

284276

12

267252

18

253237

24

208181

30

169146

36

140116

42

10884

48

7752

54

3317

60

1-

66

.

.

PEG

1.00.9

0.80.7

0.60.50.40.3

0.20.1

0.0

PEGCONTROLCensored

HR: 1.564 (95% CI 1.130, 2.166)P = 0.007 CONTROL


10

Subgroup AnalysesAll Randomized Subjects

AFP, alfa fetoprotein; PTL HTN, portal hypertension; VL viral load

Observation better

PEG-IFN alfa-2bbetter

Bas

elin

e/D

ise

ase

Ch

arac

teri

stic

Cat

ego

ry

AFP ≤40ng/mLNo PTL HTN

PTL HTNAlbumin >4g/dL

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Albumin ≤4g/dLChild Pugh class >5Child Pugh class ≤5

Platelet >100,000/mm3

Platelet ≤100,000/mm3

NonresponderRelapser

All subjects

Body weight >105 kgBody weight 85-105 kg

Body weight 65-85 kgBody weight <65 kg

VL >600,000 IU/mLVL ≤600,000 IU/mL

Genotype 2/3Genotype 1

NoncaucasianCaucasian

Direct enrollerFrom Retreatment phase

FemaleMale

Age >50 yearsAge ≤50 years


11

Time to First Clinical Event Baseline Varices

Portal hypertension defined as esophageal varices at baseline EGD performed at baseline, EOT and when clinically indicated Findings confirmed by exploratory analysis when portal hypertension defined

as platelet <100 and presence of splenomegaly

Pro

bab

ility

of

Fai

lure

TimeAt RiskPEG:

CONTROL:

6

3947

12

3537

18

3334

24

3127

30

2418

36

1813

42

147

48

85

54

42

60

--

CONTROL

PEG

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

PEG

CONTROLCensored

Pro

bab

ility

of

Fai

lure

TimeAt RiskPEG:

CONTROL:

6

257249

12

244228

18

232219

24

195176

30

161149

36

135120

42

10387

48

7355

54

3122

60

11

66

.

.

CONTROL

PEG

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

PEG

CONTROLCensored

Varices at Baseline No Varices at Baseline

p=0.963HR=1.014

p=0.016HR=4.028


12

Clinical Events by Treatment ArmSubjects with Portal Hypertension at Baseline

32.6

16.3

2.3

14.0

4.7 4.72.3 2.3

10.3

2.6 2.6

0.0

7.7

2.6

0.0 0.00

10

20

30

40

Any ClinicalEvent

Ascites Child-PughClass C

VaricealBleeding

HCC HE LiverTransplant

Death

Pa

tie

nts

, %

Observed Control (n = 43)

PEG-IFN alfa-2b (0.5 µg/kg/week) [n = 39]

Subjects may have multiple events.


13

Summary of Adverse Events Leading to Discontinuation

Event, n (%)PEG-IFN alfa-2b

n = 311Observed Controls

n = 315

Subjects Reporting any AE 53 (17) 12 (4)

Psychiatric disorders 8 (3) 1 (<1)

Investigations 8 (3) 0

Infections (all) 7 (2) 0

Blood and lymphatic disorders 5 (2) 0

Neoplasms 5 (2) 4 (1)

Nervous system disorders 4 (1) 1 (<1)

Gastrointestinal disorders 4 (1) 4 (1)

Respiratory disorders 3 (1) 0

Hepatobiliary disorders 2 (1) 0

General disorders 2 (1) 0

Cardiac disorders 1 (<1) 0

Endocrine disorders 1 (<1) 0

Eye disorders 1 (<1) 0

Musculoskeletal disorders 1 (<1) 1 (<1)

Renal and urinary disorders 1 (<1) 0

Vascular disorders 1 (<1) 0

Metabolism and nutrition disorders 0 1 (<1)


14

Adverse Events: More Serious Infections in PEG-IFN alfa-2b Group

Expert Review Conclusions from review by 2 infectious disease specialists

Predominance of events in PEG-IFN alfa-2b-treated patients

No pattern that suggests relationship to Rx in timing, type of infection, WBC count

Events seem random

Control Experimental

EPIC3

All patients 1% (3/315) 8% (25/311)

Baseline portal hypertension 0% (0/52) 7% (3/46)

HALT-C 8.5% (44/517) 8% (44/533)

COPILOT 6.3% (17/269) 2.8 % (8/286)


15

Serious Adverse Events Infection/Infestation in Cirrhotic Subjects

N Description

Treated Subjects (n = 25)

Bacterial 6

3

6

6

4

1

Pneumonia, bronchitis, bronchiectasis

Pyelonephritis/UTI

Abscess: lung, subQ, rectal, psoas, abdominal wall

Sepsis/bacteremia/endocarditis

Cellulitis/soft tissue infection

Discitis

Tuberculosis 1

Fungal 1 Esophageal candidiasis

Viral 3 Viral meningitis, gastroenteritis, febrile infection

Procedure 2 Appendicitis

Observed Subjects (n = 3)

Bacterial 3 Pneumonia, bronchitis, E. coli UTI

Treated subjects: 3 deaths (pneumonia, septic shock, sepsis).


16

Results Summary

Mean treatment duration PEG-IFN alfa-2b: 32 months, 14 subjects for 5 yrs

Observed controls: 31 months, 10 subjects for 5 yrs

Primary end point failed: Time to clinical event (adjudicated events + death/liver transplant) Treatment has no effect on occurrence of HCC

Significant treatment effect in Disease Progression

Portal hypertension Treatment benefit suggested in subjects with baseline portal

hypertension


17

Conclusions Long-term therapy with low-dose PEG-IFN

alfa-2b has no effect on incidence of HCC in HCV-infected cirrhotics

Long-term therapy with low-dose PEG-IFN alfa-2b may be beneficial for cirrhotic patients with chronic HCV and portal hypertension


18

SwitzerlandSwitzerland

EPICEPIC33 Investigators InvestigatorsMichael Manns Michael Manns Claus NiederauClaus NiederauWolfgang SchmidtWolfgang SchmidtUlrich SpenglerUlrich SpenglerReinhart Zachoval Reinhart Zachoval Stefan ZeuzemStefan Zeuzem

Emanuel K. Manesis Emanuel K. Manesis

Alfredo Alberti Alfredo Alberti Antonino Picciotto Antonino Picciotto Mauro PoddaMauro PoddaMario RizzettoMario RizzettoMaria Grazia Rumi Maria Grazia Rumi Erica Villa Erica Villa Anna Linda Zignego Anna Linda Zignego Antonio Craxi Antonio Craxi

Jorge-Luis Poo Jorge-Luis Poo

Armando Carvalho Armando Carvalho Ana Maria ValeAna Maria Vale

Alvaro ReymundeAlvaro ReymundeJose Sanchez-Tapias Jose Sanchez-Tapias Doris ToroDoris ToroEsther TorresEsther Torres

Ramon Perez Alvarez Ramon Perez Alvarez Jose Luis CallejaJose Luis CallejaMiguel Angel Serra Desfilis Miguel Angel Serra Desfilis Moises Diago Moises Diago Rafael Esteban-MurRafael Esteban-MurRicardo Moreno-OteroRicardo Moreno-OteroMayra Ramos-GomezMayra Ramos-GomezG. Castellanos TortajadaG. Castellanos TortajadaRamon Planas VilaRamon Planas Vila

Luis Colombato Luis Colombato Jose Curciarello Jose Curciarello Hugo Fainboim Hugo Fainboim Adrian GadanoAdrian GadanoLeonardo PinchukLeonardo PinchukMarcelo SilvaMarcelo SilvaHugo TannoHugo TannoRuben Terg Ruben Terg

Wendy Cheng Wendy Cheng Darrell Crawford Darrell Crawford Jacob GeorgeJacob GeorgeGary JeffreyGary JeffreyBarbara LeggettBarbara LeggettLindsay MollisonLindsay MollisonMeng NguMeng NguStuart Roberts Stuart Roberts Douglas Routley Douglas Routley William SievertWilliam Sievert

Harald BrunnerHarald BrunnerAndreas Maieron Andreas Maieron

Jean Delwaide Jean Delwaide Yves Horsmans Yves Horsmans H. Van VlierbergheH. Van Vlierberghe

Flair CarrilhoFlair CarrilhoHenrique S. M. CoelhoHenrique S. M. CoelhoMaria Lucia Gomes FerrazMaria Lucia Gomes FerrazRaymundo P.F. FilhoRaymundo P.F. FilhoRoberto FocacciaRoberto FocacciaFernando Lopes Goncales Fernando Lopes Goncales Luiz Lyra Luiz Lyra

Angelo MattosAngelo Mattos

Marcos MauadMarcos MauadCarlos Brandao MelloCarlos Brandao MelloDominique Araujo MuzzilloDominique Araujo MuzzilloHeitor RosaHeitor RosaRosangela Teixeira Rosangela Teixeira

Frank AndersonFrank AndersonKelly Warren Burak Kelly Warren Burak Robert Enns Robert Enns Victor Feinman Victor Feinman Klaus Siegfried Gutfreund Klaus Siegfried Gutfreund E. Jenny HeathcoteE. Jenny HeathcoteNir HilzenratNir HilzenratKelly KaitaKelly KaitaPaul MarottaPaul MarottaKevork PeltekianKevork PeltekianFlorence WongFlorence Wong

Adriana VaronAdriana Varon

Karl BarangeKarl BarangeMarc Bourliere Marc Bourliere Jean-Pierre Bronowicki Jean-Pierre Bronowicki Xavier CausseXavier CaussePatrick Marcellin Patrick Marcellin Raoul Poupon Raoul Poupon Thierry Poynard Thierry Poynard Albert Tran Albert Tran Christian Trepo Christian Trepo

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Rolf Hultcrantz Rolf Hultcrantz

Beat MuellhauptBeat MuellhauptJurg Reichen Jurg Reichen

Ming-Yang LaiMing-Yang Lai

Geoffrey Dusheiko Geoffrey Dusheiko William Rosenberg William Rosenberg

Luis BalartLuis BalartHenry BodenheimerHenry BodenheimerSteven FlammSteven FlammStuart GordonStuart GordonIra JacobsonIra JacobsonPaul KingPaul KingPaul KwoPaul KwoLuis MarsanoLuis MarsanoArthur J. McCulloughArthur J. McCulloughThomas McGarrityThomas McGarrityJohn McHutchisonJohn McHutchisonMary Pat PaulyMary Pat PaulyRobert PerrilloRobert PerrilloFred Poordad Fred Poordad Robert Reindollar Robert Reindollar Vinod Rustgi Vinod Rustgi Eugene Schiff Eugene Schiff Warren SchmidtWarren SchmidtObaid S. ShaikhObaid S. ShaikhKenneth ShermanKenneth ShermanColeman SmithColeman SmithMark SulkowskiMark SulkowskiNaoky TsaiNaoky Tsai

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Documents

Bruix J, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 24, 2009, Copenhagen, Denmark.04/28/09