Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09.

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Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 1 Reduced Dose and Duration of Peginterferon alfa-2b and Weight-Based Ribavirin in European and Asian Genotype 2 and 3 Chronic Hepatitis C Patients (REDD 2/3 Trial) Final Analysis M Manns 1, S Zeuzem 2, A Sood 3, Y Lurie 4, M Cornberg 1, H Klinker 5, I Merican 6, Y Ilan 7, T Mueller 8, R Chen 9, X Yu 9, R Faruqi 9, and H Wedemeyer 1 44th European Association for Study of the Liver Copenhagen Sunday, April 26, Medical School of Hannover, Hanover, Germany; 2 J.W. Goethe University Hospital, Frankfurt. Germany 3 Dayanand Medical College & Hospital, Ludhiana, India 4 Tel-Aviv Sorasky Medical Center, Tel-Aviv, Israel 5 University of Würzburg Medical Center, Würzburg, Germany 6 Selayang Hospital, Selangor, Malaysia 7 Hadassah Hebrew University Medical Center, Jerusalem, Israel 8 University of Munich, Munich, Germany 9 Schering Plough Corp., NJ, USA

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 2 International Recruitment Germany Poland Israel India Thailand Indonesia Malaysia Singapore International Cohort (SP sponsored, ) HepNet Cohort (investigator-initiated, )

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 3 Acknowledgments HEPNET INVESTIGATORSINTERNATIONAL INVESTIGATORS JC ArnoldS MaussS Abu-MauchY Lurie P BuggischU MeyerD AmarapurkarV Mahachai H CordesJ OckengaZ Ben-AriI Merican W FleigJ PauschC ChoudhuryT Piratvisuth W GicklerT PohleA ChutaputtiD Reddy J GottbergJ RiemannM GoenkaS Sachithanandan K GrungrieffM RössleW HalotaT Safadi A HeerA SchoberA HorbanS Sarin H HinrichsenH SteffensY IlanO Segol D Hüppe T Käser A TreinE Janczewska-KazekPB Setiawan H KlinkerK WiedmannA KonarA Sood MP MannsK WiegandL LesmanaT Tanwandee R MarkusS ZeuzemS Lim

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 4 Background   What is the optimum dose of PEG-IFN alfa-2b?   Reduced PEG-IFN dose? 1,2   What is the optimum treatment duration?   24 weeks for all patients?   Reduced treatment duration for selected patients (<24 weeks 2-6 )?   Are separate treatment regimens required for G2 and G3 patients?   Higher SVR with G2, higher relapse with G3   Do global/ethnic aspects influence treatment outcomes?   Asian vs white?   Prolonged infection leads to high rates of cirrhosis among Asian patients 7   What is the efficacy of standard antiviral treatment in a “real-life” setting 1. Manns et al. Lancet. 2001;358: Mangia et al. N Engl J Med. 2005;352: Shiffman et al. N Engl J Med. 2005;357; Lagging et al. Hepatology. 2008;47: PEG-IFN alfa-2b (1.5 µg/kg/wk) + weight-based RBV for 24 weeks is a recommended treatment for patients with genotype 2/3 hepatitis C, but many important clinical questions remain unanswered: 5. Dalgard et al. Hepatology. 2008;47: von Wagner et al. Gastroenterology. 2005;129: D’Souza et al. Clin Gastroenterol Hepatol. 2005;3:

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 5 Study Design and Aim   Study Design   Open-label, multicenter, randomized, parallel-group study   Treatment-naive genotypes 2 and 3   Combination of “real-life” and industry-sponsored study   Large Asian population   Aim   To evaluate the effect of reduced treatment duration or reduced PEG-IFN alfa-2b dosing on SVR and relapse rates among treatment-naive G2/3 patients

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 6 Methods   Treatment Arms   A: PEG-IFN alfa-2b (1.5 µg/kg/wk) + RBV ( mg/d) for 24 weeks   B: PEG-IFN alfa-2b (1.0 µg/kg/wk) + RBV ( mg/d) for 24 weeks   C: PEG-IFN alfa-2b (1.5 µg/kg/wk) + RBV ( mg/d) for 16 weeks   Co-primary End Points   Compare standard regimen of PEG-IFN alfa-2b (1.5 µg/kg/wk) + RBV with a lower dose PEG-IFN alfa-2b (1.0 µg/kg/wk) + RBV regimen (A vs B)   Compare 24-week vs 16-week regimen of PEG-IFN alfa-2b (1.5 µg/kg/wk) + RBV (A vs C)   Noninferiority criteria (p<0.025 required)   Period of Enrollment   HepNet cohort: July 2003 to March 2006   International cohort: January 2005 to March 2007   No Interim Analysis per Protocol   First presentation of results from REDD 2/3

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 7 Patient Population   Key Inclusion Criteria   Adult patients with chronic hepatitis C and compensated liver disease (Child-Pugh score <7)   Genotype 2 or 3   Treatment-naive   At least 1 abnormal ALT level in previous 12 months   Key Exclusion Criteria   HIV or hepatitis B coinfection   Causes of liver disease other than hepatitis C   Evidence of advanced liver disease   Preexisting psychiatric condition   Alcohol/substance abuse

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 8 Patient Demographics Group A PEG 1.5/R (24 wk) n = 230 Group B PEG 1.0/R (24 wk) n = 224 Group C PEG1.5/R (16 wk) n = 228 Total n = 682 Age, y, mean (SD)38.8 (10.2)39.9 (11.2)39.7 (11.1)39.5 (10.9) Male, n (%)139 (60.4)146 (65.2)148 (64.9)433 (63.5) Body weight, kg (SD)73.7 (15.2)72.8 (13.7)72.5 (15.0)73.0 (14.6) Time since infection, y (SD)7.3 (7.04)7.6 (7.49)7.3 (8.02)7.4 (7.52) Genotype, n (%) (16.5) 192 (83.5) 49 (21.9) 175 (78.1) 48 (21.1) 180 (78.9) 135 (19.8) 547 (80.2) Baseline HCV RNA, n (%) ≥600,000 IU/mL <600,000 IU/mL 119 (51.7) 109 (47.4) 120 (53.6) 103 (46.0) 123 (53.9) 103 (45.2) 362 (53.1) 315 (46.2)

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 9 HepNet vs International Cohort Patient Demographics HepNet Cohort n = 347 International Cohort n = 335 Age, y, mean (SD)38.8 (10.9)40.2 (10.8) Male, n (%)207 (59.7)226 (67.5) Body weight, kg (SD)74.4 (14.6)71.6 (14.6) Years since HCV exposure, y (SD)4.7 (5.01)11.4 (8.71) HCV genotype, n (%) (24.2) 263 (75.8) 51 (15.2) 284 (84.8) Baseline HCV-RNA, n (%) ≥600,000 IU/mL <600,000 IU/mL 171 (49.3) 191 (57.0) 144 (43.0)

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 10 SVR by Treatment Regimen Treatment differences (one-sided 95% CI): a Grp A – Grp B: (-0.10); P =.041. b Grp A – Grp C: (-0.17); P =.495. Noninferiority not achieved for all patients and individual cohorts. All Randomized and Treated Patients 153/230144/224129/228 68/11669/11555/11685/11475/10974/ a 56.6 b SVR, % All Patients (n = 682) HepNet Cohort (n = 347) International Cohort (n = 335) A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks)

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 11 SVR by Treatment Regimen Treatment differences (one-sided 95% CI): a Grp A – Grp B: (-0.10); P =.041. b Grp A – Grp C: (-0.17); P =.495. Noninferiority not achieved for all patients and individual cohorts. All Randomized and Treated Patients 153/230144/224129/228 68/11669/11555/11685/11475/10974/ a 56.6 b SVR, % All Patients (n = 682) HepNet Cohort (n = 347) International Cohort (n = 335) A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks) Real-life setting 67.1% completers vs. 85.7% in clinical setting

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 12 SVR: Completers Analysis Treatment differences (one-sided 95% CI): a Grp A – Grp B: (-0.09); P =.024. b Grp A – Grp C: (-0.21); P =.798. Noninferiority not achieved for all patients and individual cohorts. Completers 136/167139/174121/179 56/7066/8248/8180/9773/92 73/ a 67.6 b SVR, % All Patients (N = 520) HepNet Cohort (n = 233) International Cohort (n = 287) A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks)

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/ HepNet Cohort (n = 84) International Cohort (n = 51) HepNet Cohort (n = 263) International Cohort (n = 284) SVR by Genotype SVR, % Genotype 2Genotype 3 21/2719/3114/26 8/11 12/1816/2247/8950/8441/90 77/103 63/9158/90 A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks)

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/ International Cohort (n = 177) HepNet Cohort (n = 347) International Cohort (n = 158) SVR According to Race AsianWhite SVR, % 43/5741/5940/61 69/11568/11655/116 42/5734/5034/51 A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks)

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 15 Lower Relapse Rates With 24 Weeks of Therapy Rate d (two-sided 95% CI): a 0.18 (0.12, 0.24) b 0.16 (0.11, 0.22) c 0.29 (0.22, 0.36) All Randomized and Treated Patients 29/16327/16649/167 13/6911/7725/7316/9419/89 24/ a 16.3 b 29.3 c SVR, % All Patients (N = 496) HepNet Cohort (n = 219) International Cohort (n = 277) A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks)

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 16 Most Common Treatment-Emergent Adverse Events a Adverse Event, % Group A: PEG 1.5/R (24 wk) N = 230 Group B: PEG 1.0/R (24 wk) N = 224 Group C: PEG1.5/R (16 wk) N = 228 Pyrexia Fatigue Headache Alopecia Asthenia Myalgia Influenza-like illness Pruritus Weight decrease Anorexia Nausea Injection-site erythema Depressed mood Arthralgia Anemia Diarrhea Dry skin a Occurring at a frequency >10% in any treatment arm

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 17 Serious Adverse Events and Discontinuations Group A PEG 1.5/R (24 weeks) n = 230 Group B PEG 1.0/R (24 weeks) n = 224 Group C PEG1.5/R (16 weeks) n = 228 Treatment-emergent SAE, n (%)14 (6.1)11 (4.9)7 (3.1) Treatment-emergent severe/life- threatening AEs, n (%) 16 (7.0)10 (4.5)12 (5.3) Deaths, a n (%)2 (<1)1 (<1)0 (0) AE causing discontinuation of treatment, n (%) 3 (1.3) 5 (2.2) a All 3 deaths were considered unlikely to be related to study medication AE, adverse event; SAE, serious adverse event.

Manns M, et al. Presented at the 44 th Annual Meeting of the European Association for the Study of the Liver (EASL), April 26, 2009, Copenhagen, Denmark.04/28/09 18 Conclusions   Statistically unable to demonstrate that lower dose PEG-IFN alfa- 2b (1.0 ug/kg/wk) regimen is noninferior to standard dose PEG-IFN alfa-2b (1.5 ug/kg/wk) regimen.   PEG-IFN alfa-2b 1.5 µg/kg/wk and 1.0 µg/kg/wk in combination with weight-based ribavirin have similar tolerability profiles   24 weeks of therapy is the appropriate treatment duration for G2/3   Higher relapse rate with shorter duration treatment   SVR rates were similar in Asian and white patients   This is the largest study to date in Asian G3 patients   Results from REDD 2/3 are similar to those reported in other large prospective clinical trials of PEG-IFN alfa plus RBV Manns et al. Lancet. 2001;358: Fried et al. N Engl J Med. 2002;347: Shiffman et al. N Engl J Med. 2007;357: Mangia et al. N Engl J Med. 2005;352: