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M Manns 1 , S Zeuzem 2 , A Sood 3 , Y Lurie 4 , M Cornberg 1 , H Klinker 5 ,

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 12.00-13.30 Sunday, April 26, 2009. .

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M Manns 1 , S Zeuzem 2 , A Sood 3 , Y Lurie 4 , M Cornberg 1 , H Klinker 5 ,

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  1. M Manns1, S Zeuzem2, A Sood3, Y Lurie4, M Cornberg1, H Klinker5, I Merican6, Y Ilan7, T Mueller8, R Chen9, X Yu9, R Faruqi9, and H Wedemeyer1 44th European Association for Study of the Liver Copenhagen 12.00-13.30 Sunday, April 26, 2009. 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 1Medical School of Hannover, Hanover, Germany; 2J.W. Goethe University Hospital, Frankfurt. Germany 3Dayanand Medical College & Hospital, Ludhiana, India 4Tel-Aviv Sorasky Medical Center, Tel-Aviv, Israel 5University of Würzburg Medical Center, Würzburg, Germany 6Selayang Hospital, Selangor, Malaysia 7Hadassah Hebrew University Medical Center, Jerusalem, Israel 8University of Munich, Munich, Germany 9Schering Plough Corp., NJ, USA

  2. Poland Germany Thailand Malaysia Israel Singapore India Indonesia HepNet Cohort (investigator-initiated, 2003-2006) International Cohort (SP sponsored, 2005-2007) International Recruitment

  3. Acknowledgments

  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 weeks2-6)? 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 patients7 What is the efficacy of standard antiviral treatment in a “real-life” setting 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: 1. Manns et al. Lancet. 2001;358:958-965 2. Mangia et al. N Engl J Med. 2005;352:2609-2617 3. Shiffman et al. N Engl J Med. 2005;357;124-134 4. Lagging et al. Hepatology. 2008;47:1837-1845 5. Dalgard et al. Hepatology. 2008;47:35-42 6. von Wagner et al. Gastroenterology. 2005;129:522-527 7. D’Souza et al. Clin Gastroenterol Hepatol. 2005;3:910-917.

  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

  6. Methods • Treatment Arms • A: PEG-IFN alfa-2b (1.5 µg/kg/wk) + RBV (800-1200 mg/d) for 24 weeks • B: PEG-IFN alfa-2b (1.0 µg/kg/wk) + RBV (800-1200 mg/d) for 24 weeks • C: PEG-IFN alfa-2b (1.5 µg/kg/wk) + RBV (800-1200 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

  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

  8. Patient Demographics

  9. HepNet vs International Cohort Patient Demographics

  10. SVR by Treatment Regimen A: PEG 1.5/R (24 weeks) 100 B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks) 74.6 68.8 66.5 66.1 75 64.3a 60.0 58.6 56.6b 47.4 50 SVR, % 25 153/230 144/224 129/228 68/116 69/115 55/116 85/114 75/109 74/112 0 All Patients(n = 682) HepNet Cohort(n = 347) InternationalCohort (n = 335) All Randomized and Treated Patients Treatment differences (one-sided 95% CI): aGrp A – Grp B: -0.02 (-0.10); P = .041. bGrp A – Grp C: -0.10 (-0.17); P = .495. Noninferiority not achieved for all patients and individual cohorts.

  11. SVR by Treatment Regimen Real-life setting 67.1% completers vs. 85.7% in clinical setting A: PEG 1.5/R (24 weeks) 100 B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks) 74.6 68.8 66.5 66.1 75 64.3a 60.0 58.6 56.6b 47.4 50 SVR, % 25 153/230 144/224 129/228 68/116 69/115 55/116 85/114 75/109 74/112 0 All Patients(n = 682) HepNet Cohort(n = 347) InternationalCohort (n = 335) All Randomized and Treated Patients Treatment differences(one-sided 95% CI): aGrp A – Grp B: -0.02 (-0.10); P = .041. bGrp A – Grp C: -0.10 (-0.17); P = .495. Noninferiority not achieved for all patients and individual cohorts.

  12. SVR: Completers Analysis A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks) 100 81.5 82.5 79.9a 80.5 80.0 79.4 74.5 67.6b 75 59.3 50 SVR, % 25 136/167 139/174 121/179 56/70 66/82 48/81 80/97 73/92 73/98 0 All Patients (N = 520) HepNet Cohort (n = 233) International Cohort (n = 287) Completers Treatment differences (one-sided 95% CI): aGrp A – Grp B: -0.02 (-0.09); P = .024. bGrp A – Grp C: -0.14 (-0.21); P = .798. Noninferiority not achieved for all patients and individual cohorts.

  13. SVR by Genotype A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks) 100 77.8 74.8 72.7 72.7 69.2 66.7 64.4 75 61.3 59.5 53.8 52.8 45.6 50 SVR, % 25 77/103 21/27 19/31 14/26 12/18 16/22 47/89 50/84 41/90 63/91 58/90 8/11 0 HepNet Cohort(n = 84) InternationalCohort (n = 51) HepNet Cohort(n = 263) InternationalCohort (n = 284) Genotype 2 Genotype 3

  14. SVR According to Race A: PEG 1.5/R (24 weeks) B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks) 100 75.4 73.7 69.5 68.0 66.7 65.6 75 60.0 58.6 47.4 50 SVR, % 25 68/116 69/115 55/116 43/57 41/59 40/61 42/57 34/50 34/51 0 InternationalCohort (n = 177) HepNet Cohort(n = 347) InternationalCohort (n = 158) Asian White

  15. Lower Relapse Rates With 24 Weeks of Therapy A: PEG 1.5/R (24 weeks) 50 B: PEG 1.0/R (24 weeks) C: PEG 1.5/R (16 weeks) 34.2 29.3c 25.5 25 SVR, % 18.8 17.8a 17.0 18.0 16.3b 14.3 29/163 27/166 49/167 13/69 11/77 25/73 16/94 19/89 24/94 0 All Patients (N = 496) HepNet Cohort (n = 219) InternationalCohort (n = 277) All Randomized and Treated Patients Rated (two-sided 95% CI): a0.18 (0.12, 0.24) b0.16 (0.11, 0.22) c0.29 (0.22, 0.36)

  16. Most Common Treatment-Emergent Adverse Eventsa a Occurring at a frequency >10% in any treatment arm

  17. Serious Adverse Events and Discontinuations aAll 3 deaths were considered unlikely to be related to study medication AE, adverse event; SAE, serious adverse event.

  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 RBV1-4 1. Manns et al. Lancet. 2001;358:958-965. 2. Fried et al. N Engl J Med. 2002;347:975-982. 3. Shiffman et al. N Engl J Med. 2007;357:124-134. 4. Mangia et al. N Engl J Med. 2005;352:2609-2617.

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