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Background and Aims

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 EPIC 3 Study Group.

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Background and Aims

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  1. 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 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 44th Annual Meeting of the European Association for the Study of the Liver Friday, April 24, 2009Copenhagen, 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;47:610-611 bAfdhal et al., J. Hepatol, 2008; 48, S2, A3 c DiBiesgelie et al., NEJM, 2008;359:2429-41

  3. METAVIR F4 CHC subjects DIRECT ENROLLERS EPIC3 Program Design Nonresponder Trial*: N = 2333 CHC with fibrosis (F2, F3, or F4 METAVIR) Evaluation of virological response at week 12 HCV-RNA Negative HCV RNA negative at week 12 Continue P/R for 48 wk HCV-RNA Positive F4 n = 454 F2/3 n = 172 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 Chronic Suppression for Noncirrhotics, n = 575 METAVIR F2 or F3 subjects PEG-Intron 0.5 g/kg/wk vs control Duration: 3 years * 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 Demographics

  7. 1.0 PEG 0.9 CONTROL 0.8 Censored 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Time to First Clinical Event* Liver decompensation (variceal bleed, >grade 2 enceph, ascites requiring Rx, CPT C); HCC; death; liver transplantation mean treatment duration = 32 months mean treatment duration = 31 months Probability of Failure CONTROL PEG Time At Risk PEG: CONTROL: 6 296 290 12 279 265 18 265 253 24 226 203 30 185 167 36 153 133 42 117 94 48 81 60 54 35 24 60 1 1 66 . . * All Randomized Subjects from sites not closed for noncompliance. *P = 0.144, HR = 1.452 vs observed controls

  8. Clinical Events by Treatment Arm 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. 1.0 PEG 0.9 CONTROL 0.8 Censored 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Time to Disease Progression*Primary events plus: Development of Child-Pugh B, Emergence of varices, Enlargement of pre-existing varices requiring additional therapy HR: 1.564 (95% CI 1.130, 2.166) P = 0.007 CONTROL Probability of Failure PEG Time At Risk PEG: CONTROL: 6 284 276 12 267 252 18 253 237 24 208 181 30 169 146 36 140 116 42 108 84 48 77 52 54 33 17 60 1 - 66 . . * All Randomized Subjects from sites not closed for noncompliance.

  10. Subgroup AnalysesAll Randomized Subjects Observation better PEG-IFN alfa-2b better AFP ≤40ng/mL No PTL HTN PTL HTN Albumin >4g/dL Albumin ≤4g/dL Child Pugh class >5 Child Pugh class ≤5 Platelet >100,000/mm3 Platelet ≤100,000/mm3 Nonresponder Relapser Body weight >105 kg Baseline/Disease Characteristic Category Body weight 85-105 kg Body weight 65-85 kg Body weight <65 kg VL >600,000 IU/mL VL ≤600,000 IU/mL Genotype 2/3 Genotype 1 Noncaucasian Caucasian Direct enroller From Retreatment phase Female Male Age >50 years Age ≤50 years All subjects 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 AFP, alfa fetoprotein; PTL HTN, portal hypertension; VL viral load

  11. 1.0 1.0 0.9 0.9 0.8 0.8 0.7 0.7 0.6 0.6 0.5 0.5 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0.0 0.0 Time to First Clinical Event Baseline Varices No Varices at Baseline Varices at Baseline PEG p=0.963 HR=1.014 p=0.016 HR=4.028 PEG CONTROL CONTROL Censored Censored CONTROL Probability of Failure Probability of Failure CONTROL PEG PEG Time At Risk PEG: CONTROL: 6 39 47 12 35 37 18 33 34 24 31 27 30 24 18 36 18 13 42 14 7 48 8 5 54 4 2 60 - - Time At Risk PEG: CONTROL: 6 257 249 12 244 228 18 232 219 24 195 176 30 161 149 36 135 120 42 103 87 48 73 55 54 31 22 60 1 1 66 . . • 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

  12. Clinical Events by Treatment ArmSubjects with Portal Hypertension at Baseline Subjects may have multiple events.

  13. Summary of Adverse Events Leading to Discontinuation

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

  15. Serious Adverse Events Infection/Infestation in Cirrhotic Subjects 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. EPIC3 Investigators Luis Colombato Jose Curciarello Hugo Fainboim Adrian Gadano Leonardo Pinchuk Marcelo Silva Hugo Tanno Ruben Terg Wendy Cheng Darrell Crawford Jacob George Gary Jeffrey Barbara Leggett Lindsay Mollison Meng Ngu Stuart Roberts Douglas Routley William Sievert Harald Brunner Andreas Maieron Jean Delwaide Yves Horsmans H. Van Vlierberghe Flair Carrilho Henrique S. M. Coelho Maria Lucia Gomes Ferraz Raymundo P.F. Filho Roberto Focaccia Fernando Lopes Goncales Luiz Lyra Angelo Mattos Marcos Mauad Carlos Brandao Mello Dominique Araujo Muzzillo Heitor Rosa Rosangela Teixeira Frank Anderson Kelly Warren Burak Robert Enns Victor Feinman Klaus Siegfried Gutfreund E. Jenny Heathcote Nir Hilzenrat Kelly Kaita Paul Marotta Kevork Peltekian Florence Wong Adriana Varon Karl Barange Marc Bourliere Jean-Pierre Bronowicki Xavier Causse Patrick Marcellin Raoul Poupon Thierry Poynard Albert Tran Christian Trepo Thomas Berg Peter Buggisch Wolfgang Caselmann Dieter Haussinger Holger Hinrichsen Michael Manns Claus Niederau Wolfgang Schmidt Ulrich Spengler Reinhart Zachoval Stefan Zeuzem Emanuel K. Manesis Alfredo Alberti Antonino Picciotto Mauro Podda Mario Rizzetto Maria Grazia Rumi Erica Villa Anna Linda Zignego Antonio Craxi Jorge-Luis Poo Armando Carvalho Ana Maria Vale Alvaro Reymunde Jose Sanchez-Tapias Doris Toro Esther Torres Ramon Perez Alvarez Jose Luis Calleja Miguel Angel Serra Desfilis Moises Diago Rafael Esteban-Mur Ricardo Moreno-Otero Mayra Ramos-Gomez G. Castellanos Tortajada Ramon Planas Vila Rolf Hultcrantz Beat Muellhaupt JurgReichen Ming-Yang Lai Geoffrey Dusheiko William Rosenberg Luis Balart Henry Bodenheimer Steven Flamm Stuart Gordon Ira Jacobson Paul King Paul Kwo Luis Marsano Arthur J. McCullough Thomas McGarrity John McHutchison Mary Pat Pauly Robert Perrillo Fred Poordad Robert Reindollar VinodRustgi Eugene Schiff Warren Schmidt Obaid S. Shaikh Kenneth Sherman Coleman Smith Mark Sulkowski Naoky Tsai Argentina Brazil Germany Sweden Switzerland Taiwan Canada UK Greece Italy USA Australia Mexico Columbia Portugal France Austria Puerto Rico Belgium Brazil Spain Germany

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