Hadziyannis SJ et al. EASL Peginterferon alfa-2a (40KD) (PEGASYS ® ) in combination with ribavirin (RBV): efficacy and safety results from a phase III, randomized, double-blind, multicentre study examining effect of duration of treatment and RBV dose Professor Stephanos J. Hadziyannis Department of Medicine and Hepatology Henry Dunant Hospital Athens, Greece

Hadziyannis SJ et al. EASL Previous clinical studies with pegylated IFNs only investigated 48 weeks No prospective studies of the efficacy and safety of ribavirin doses have been conducted Therefore no evidence-based recommendation could be made Background

Hadziyannis SJ et al. EASL Study Aims To compare the efficacy and safety of the combination of PEGASYS ® and ribavirin given for 24 weeks vs. 48 weeks To compare the efficacy and safety of two different daily doses of ribavirin (low dose 800 mg vs. ‘standard’ dose of 1000/1200 mg) taken with PEGASYS ®

Hadziyannis SJ et al. EASL Study Design (1) Treatment-free follow-up of 24 weeks for all patients PEGASYS ® 180 µg sc qw + ribavirin 800 mg qd, 24 weeks PEGASYS ® 180 µg sc qw + ribavirin 1000/1200 mg qd, 24 weeks PEGASYS ® 180 µg sc qw + ribavirin 1000/1200 mg qd, 48 weeks PEGASYS ® 180 µg sc qw + ribavirin 800 mg qd, 48 weeks A : B : D : C : Total 1284 patients randomized and treated

Hadziyannis SJ et al. EASL Study Design (2) Randomization stratified by HCV genotype (1 vs. non-1) and viral titre (low vs. high, defined as  or >2 million copies/mL, respectively) and by geographic region Pre-planned distribution of genotypes – Genotype non 1 and 1 LVT 1:1:1:1 – Genotype 1 HVT1:1:4:4 Treatment duration blinded until week 24 Ribavirin dose blinded throughout study

Hadziyannis SJ et al. EASL Undetectable serum HCV RNA at the end of a 24-week treatment-free follow-up period (COBAS AMPLICOR ® HCV Test v2.0, sensitivity 50 IU/mL) Primary Endpoint

Hadziyannis SJ et al. EASL Main Inclusion Criteria Quantifiable HCV RNA in serum (AMPLICOR HCV MONITOR ® Test, v2.0) Elevated serum ALT levels Liver biopsy consistent with chronic HCV infection No previous interferon or ribavirin treatment

Hadziyannis SJ et al. EASL Main Exclusion Criteria Decompensated liver disease Coinfection with HIV or HBV Anaemia or expected inability to tolerate anaemia Significant co-morbid medical conditions

Hadziyannis SJ et al. EASL Patient Characteristics / / 1200 Male (%) Age (mean, y) Weight (mean, kg) weeks 48 weeks HCV RNA titre (mean, x10 6 copies/mL) Genotype 1 (%) Cirrhosis/ bridging fibrosis (%)

Hadziyannis SJ et al. EASL Results: SVR Genotype 1 24 weeks48 weeks SVR (%) 29% 41% 40% 51% n=101n=118n=250n=271 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200

Hadziyannis SJ et al. EASL Results: SVR Genotype 1 Low Viral Titre 24 weeks48 weeks SVR (%) 41% 51% 53% 61% n=51n=71n=60n=85 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200

Hadziyannis SJ et al. EASL Results: SVR Genotype 1 High Viral Titre 24 weeks48 weeks SVR (%) 16% 26% 35% 46% n=50n=47n=190n=186 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200

Hadziyannis SJ et al. EASL Results: SVR Genotype Non-1 SVR (%) 24 weeks48 weeks 78% 73% 77% n=106n=162n=111n=165 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200

Hadziyannis SJ et al. EASL Sustained Virologic Response: Effect of Cirrhosis SVR (%) 61% 65% 50% n=436n=321n=115 All patientsNon-cirrhoticsCirrhotics Treatment: PEGASYS ® + RBV 1000/1200 mg for 48 weeks

Hadziyannis SJ et al. EASL % Due to Adverse EventDue to Lab Abnormality 3.7% 0.9% 1.0% 12.4% 2.7% Rate of Withdrawal From Treatment 3.5% 14.2% 1.9% PEGASYS ® + RBV 800 mg, 24 weeks PEGASYS ® + RBV 1000/1200 mg, 24 weeks PEGASYS ® + RBV 800 mg, 48 weeks PEGASYS ® + RBV 1000/1200 mg, 48 weeks

Hadziyannis SJ et al. EASL Ribavirin Discontinuations for Adverse Events / Lab Abnormalities 24 weeks48 weeks Discontinuations (%) 7% 6% 18% 19% PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200

Hadziyannis SJ et al. EASL weeks48 weeks PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 PEGASYS ® RBV 800 PEGASYS ® RBV 1000/1200 3% 7% 9% 10% % Serious Adverse Events 3%4%3% Treatment-related SAEs 1%

Hadziyannis SJ et al. EASL Summary (1) Overall SVR of 61% in patients treated for 48 weeks with PEGASYS ® and RBV 1000/1200 mg Overall safety profile similar to previous studies

Hadziyannis SJ et al. EASL Summary (2) Genotype 1 – 51% SVR achieved with 48 weeks treatment, 1000/1200 mg RBV – Shorter duration and/or lower RBV dose leads to reduction in efficacy

Hadziyannis SJ et al. EASL Summary (3) Genotype non-1 – SVR 78% 24 weeks with 800 mg RBV – Increasing duration and/or dose of RBV gave no increase in efficacy Shorter treatment associated with fewer SAEs and withdrawals for safety Lower dose RBV associated with fewer – SAEs (24 weeks) – RBV dose modifications – Large decreases in haemoglobin

Hadziyannis SJ et al. EASL Study Countries Norway UK Sweden Canada Ireland Denmark Belgium Finland USA Netherlands France Mexico GermanyTaiwan Brazil Portugal Spain Australia Italy New Zealand Greece 21 Countries