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Advances in the treatment of chronic hepatitis C: Update to the Committee

PEG-Intron/Rebetol. Advances in the treatment of chronic hepatitis C: Update to the Committee. 61%. 52%. 41%. 25%. 16%. 6%. Intron A. Intron A. PEG-Intron. Intron A +. PEG-Intron. PEG-Intron. 24 weeks. 48 weeks. Rebetol. + Rebetol. + Rebetol. >10.6 mg/kg.

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Advances in the treatment of chronic hepatitis C: Update to the Committee

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  1. PEG-Intron/Rebetol Advances in the treatment of chronic hepatitis C:Update to the Committee

  2. 61% 52% 41% 25% 16% 6% Intron A Intron A PEG-Intron Intron A + PEG-Intron PEG-Intron 24 weeks 48 weeks Rebetol + Rebetol + Rebetol >10.6 mg/kg PEG-Intron/Rebetol Treating chronic hepatitis C10 years of progress 100 80 60 % Sustained vriologic response 40 20 0 2001 1991

  3. PEG-Intron/Rebetol Advancements in the treatment of chronic hepatitis C Participant Introduction Dr. Penelope J. Giles Director, Regulatory Affairs Dr. Janice K. Albrecht Vice President, Clinical Research Schering-Plough Team Dr. J.J. Garaud Exec. V.P., Clinical Research Dr. Kenneth Koury Director, Biostatistics Dr. Mark Laughlin Director, Clinical Pharmacology Consultants Dr. J. McHutchison Medical Director, Liver Transplantation, Scripps Clinic Dr. L.J. Wei Professor, Biostatistics, Harvard School of Public Health

  4. Indication: Chronic Hepatitis C(Treatment Naïve Adults) Approved Dose PEG-Intron 1.5g/kg Once Weekly plus Rebetol 800mg/day 48 Weeks

  5. Treatment chronic hepatitis CInformation provided to the committee • Intron A + Rebetol • Treatment of Relapse Patients • NEJM 1998, Davis et al • Treatment of Naïve Patients • NEJM 1998, McHutchison et al • Lancet 1998, Poynard et al • PEG-Intron Monotherapy • Treatment of Naïve Patients • Hepatology 2001, Lindsay et al • PEG-Intron + Rebetol • Treatment of Naïve Patients • Lancet 2001, Manns et al

  6. PEG-Interferon alfa-2b 1.5 μg/kg Interferon alfa-2b 3MIU 1000 T½ 40 hours 100 pg/ml interferon α-2b 10 1 0 20 40 60 80 100 120 140 160 180 Hours The PEG-Intron molecule

  7. Intron A 3MU TIWSustained virologic response by patient weight 25% 19% 12% 9% IntronA 3 MU TIW 48 weeks

  8. PEG 0.5g/kg QW N= 315 • PEG 1.0g/kg QW N= 297 Screening • PEG 1.5g/kg QW N= 304 • Intron-A 3MIU TIW N= 303 Endpoint 48 weeks 24 weeks Follow-up PEG-Intron monotherapystudy design Primary Endpoint: Loss of serum HCV-RNA 24 weeks post-treatment

  9. PEG-Intron monotherapyvirologic response 49% 41% 33% 24% *HCV <100 copies/ml

  10. PEG-Intron monotherapyvirologic response 25% 23% 18% 12% *HCV <100 copies/ml

  11.    X PEG-Intron monotherapyFactors Associated withSustained Virologic Response* • HCV Genotype - Non-1* • HCV-RNA level -Lower* • Cirrhosis or bridging fibrosis - Absence** • Age - Younger *** • Body weight - Lighter (p=0.9336) * p0.0001 ** p<0.006 *** p<0.05 *Multivariate logistic regression, n=914

  12. PEG-Intron/Rebetol PEG-Intron dose selection • PEG-Intron doses selected for use in combination with Rebetol • 1.5 g/kg - had maximum antiviral activity particularly in HCV-1 • 0.5 g/kg - had similar antiviral activity to Intron A and was better tolerated

  13. Intron A + Rebetol 1000-1200mg/daily 3MIU TIW (48 wks) • N=505 Screening • PEG-Intron + Rebetol 1000-1200mg/daily • N=514 1.5 g/kg QW (4 wks) 0.5 g/kg QW (44 wks) • PEG-Intron + Rebetol 800mg/daily • N=511 1.5 g/kg QW (48 weeks) 48 weeks 24 weeks Endpoint Follow-up PEG-Intron/Rebetol PEG-Intron plus Rebetol Primary Endpoint: Loss of serum HCV-RNA 24 weeks post-treatment

  14. Intron A/R(n=505) PEG 0.5/R (n=514) PEG 1.5/R (n=511) Age Mean (yrs.) 43 44 43 Range 22-68 22-67 22-68 Gender Male 63% 67% 67% Race Caucasian 91% 88% 89% Weight (kg) Mean 82 83 82 Range 43-163 38-181 43-159 PEG-Intron/Rebetol Demographics

  15. PEG-Intron/Rebetol Disease Characteristics Intron A/R(n=505) PEG 0.5/R (n=514) PEG 1.5/R (n=511) HCV genotype Geno 1 68% 68% 68% Geno 2/3 29% 30% 29% Geno 4/5/6 3% 2% 3% HCV RNA copies/ml >2 million 69% 67% 68% Fibrosis/Cirrhosis* Present 28% 30% 29% * Knodell HAI F3/4

  16. PEG-Intron/Rebetol Sustained Virologic Response * 52% 46% 46% * PEG 1.5/800 vs. I/R p=0.03

  17. PEG-Intron/Rebetol Sustained Virologic Response * 54% 47% 47% * PEG 1.5/800 vs. I/R p=0.01

  18. Univariate • Genotype • non-1* • Baseline HCV level* • lower • Baseline Weight* • lighter • Bridging fibrosis/cirrhosis* • absence • Age* • Lower • Gender** • Female • Multivariate • Genotype • non-1* • Baseline HCV level* • lower • Baseline Weight** • lighter • Bridging fibrosis/cirrhosis* • Absence • Age** • Lower *p 0.001 **p=0.01 *p 0.001 **p<0.05 PEG-Intron/Rebetol Variables associated with sustained response logistic regression analysis

  19. Rebetol 10.6 mg/kg Intron-A 3MU TIW PEG-Intron/Rebetol Effect of Rebetol dose mg/kg on virologic response(Logistic regression analysis) PEG 1.5 g/kg Rebetol mg/kg

  20. * n=511 n=323 n=188 n=505 n=22 n=483  Rebetol dose/weight (mg/kg) PEG-Intron/Rebetol All genotypesSustained virologic response Controlling for Rebetol dose (mg/kg) *p=0.01

  21. * n=348 n=226 n=122 n=343 n=15 n=328  Rebetol dose/weight (mg/kg) PEG-Intron/Rebetol HCV-1Sustained virologic response Controlling for Rebetol dose (mg/kg) *p=0.02

  22. n=147 n=89 n=58 n=146 n=6 n=140  Rebetol dose/weight (mg/kg) PEG-Intron/Rebetol HCV-2/3Sustained virologic response Controlling for Rebetol dose (mg/kg)

  23. PEG-Intron/Rebetol Sustained virologic responseControlling for Rebetol dose (mg/kg) PEG-Intron 1.5 g/kg Rebetol 800mg PEG-Intron 1.5 g/kg Rebetol (mg/kg) Intron A Rebetol 10.6 >10.6 HCV-1  2 million 45% 73% 74% 71% > 2 million 29% 30% 27% 37% HCV-2/3  2 million 80% 91% 89% 94% > 2 million 77% 76% 74% 81%

  24. Intron/ PEG 1.5/ PEG 1.5/ PEG 1.5/ R1000-1200 R800 R 10.6 R >10.6 All patients 14% 18% 22% 12% Genotype 1 21% 24% 28% 17% Genotype 2/3 7% 11% 14% 7% PEG-Intron/Rebetol RelapseControlling for Rebetol dose and genotype

  25. PEG-Intron/Rebetol Efficacy summary • PEG-Intron 1.5 g/kg/Rebetol is significantly more effective than Intron A/Rebetol and PEG-Intron 0.5 g/kg /Rebetol • Approved Regimen: 48 weeks of treatment • PEG-Intron 1.5g/kg once weekly plus • Rebetol 800mg/day • Further analyses suggest that weight based dosing of ribavirin (mg/kg) results in improved sustained virologic response

  26. PEG-Intron/Rebetol PEG-Intron/Rebetol Safety

  27. Incidence  10% in any treatment group: Injection site inflammation, Injection site reaction , mouth dry, sweating,Asthenia, fatigue, fever, headache, flu-like symptoms, rigors, RUQ pain, weight decrease, dizziness, abdominal pain, anorexia, diarrhea, nausea, vomiting, arthralgia, musculoskeletal pain, myalgia, anxiety, concentration impaired, depression, emotional liability, insomnia, irritability, infection viral, coughing, dyspnea, pharyngitis, alopecia, pruritis, rash, dry skin PEG-Intron/Rebetol Adverse events Incidence >10% difference between groups Intron/R N=505 PEG 1.5/R 800 mg N=511 PEG 1.5/R <10.6 mg/kgN=323 PEG 1.5/R >10.6 mg/kgN=188 Application site Injection site inflammation 18% 25% 28% 20% Injection site reaction 36% 58% 61% 54% Body as a whole Fever 33% 46% 49% 41% Rigors 41% 48% 51% 43% Weight decrease 20% 29% 28% 30% GI side effects Nausea 33% 43% 44% 43% Skin Alopecia 32% 36% 31% 45%

  28. PEG-Intron/Rebetol Discontinuations and dose modificationsdue to adverse events Intron/R N=505 PEG 1.5/R 800 mg N=511 PEG 1.5/R <10.6 mg/kgN=323 PEG 1.5/R >10.6 mg/kgN=188 Discontinuations 13% 14% 15% 14% Dose Modifications 34% 42% 38% 49%

  29. PEG-Intron/Rebetol Dose modification>2% difference between groups Intron/R N=505 PEG 1.5/R 800 mg N=511 PEG 1.5/R <10.6 mg/kgN=323 PEG 1.5/R >10.6 mg/kgN=188 Neutropenia Anemia Platelet Body as a Whole Gastrointestinal 8% 18% 16% 21% 13% 9% 7% 12% 1% 3% 4% 2% 6% 9% 9% 10% 4% 7% 6% 9% Psychiatric Events 4% 5% 4% 6%

  30. Intron /R N=505 PEG 1.5/R 800 mg N=511 PEG 1.5/R <10.6 mg/kgN=323 PEG 1.5/R >10.6 mg/kgN=188 Neutrophils 109/L % Patients with <750 at any time 8% 18% 17% 21% 2% 4% 3% 7% 0.2% 1% 0.3% 2% (1)* (5) (1) (4) % Patients with <500 at any time Discontinued for Neutropenia PEG-Intron/Rebetol Adverse hematologic effects Neutrophils *Number of patients

  31. PEG-Intron/Rebetol Adverse hematologic effects Hemoglobin Intron /R N=505 PEG 1.5/R 800 mg N=511 PEG 1.5/R <10.6 mg/kgN=323 PEG 1.5/R >10.6 mg/kgN=188 Decrease below 10g Hemoglobin 12% 9% 6% 14% 0.2% 0.8% 0% 2% (1)* (4) (0) (4) Discontinued for Anemia *Number of patients

  32. Safety Summary • The types of adverse events observed in the I/R and PEG 1.5/R groups are similar, but there is a somewhat higher incidence with PEG1.5/R • Neutropenia (<750) was more frequent withPEG 1.5/R than with I/R for both the fixed-dose and weight-based dose analyses • With weight-based Rebetol >10.6 mg/kg there was an increased occurrence of anemia and neutropenia than with PEG 1.5/800 • Discontinuations due to adverse events were low and similar between the groups; dose modifications due to the adverse events were more frequent with PEG 1.5/R • The higher incidence of AE’s associated with PEG 1.5/R for either fixed-dose or weight-based Rebetol were adequately managed by dose modifications

  33. PEG-Intron/Rebetol Post-marketing studies • Study 1-(n~4000) PEG1.5g/kg QW • Rebetol 800mg vs. weight-based dosing (800 to 1400mg) • (n~1000) evaluate effect of duration (6 vs.12 months) for patients with favorable prognostic factors • Study 2-(n~1500) • PEG1.5g/kg vs. PEG1.0g/kg • Rebetol dose regimen determined from study 1 • Evaluate effect of therapy in African Americans (n~100) • PK food effect of ribavirin (fasted vs. low fat vs. high fat)

  34. Dr. J. McHutchison Medical Director, Liver Transplantation, Scripps Clinic, La Jolla, California

  35. The Decision to Treat Hepatitis C • Complex • Controversial • Host • Severity disease • Co-morbid conditions • Viral • Genotype • Therapy • Efficacy • Side effects • Cost

  36. Weighing the Risks and Benefits Likelihood of response • side effects • investments • Sustained response • ALT normal • HCV RNA neg • Histologic improvement • Improved HQOL • Durable

  37. Decision to Treat • Majority hepatitis C patients • Unfavorable profile • Genotype 1 • Significant investment and commitment • Time (48 weeks) • More “aggressive” therapy • Patient • Doctor • Other Staff

  38. Decision to Treat Hepatitis C • Practitioner and patients • “Do our best first time around”

  39. Provide best support/education available Prescribe most effective dose of peginterferon Provide most appropriate dose of ribavirin Manage side effects via dose reduction rather than discontinuation Discontinue treatment early in those unlikely to respond How can we achieve the greatest benefit whilst diminishing the risk?

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