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

2 Treating chronic hepatitis C 10 years of progress % Sustained vriologic response PEG-Intron + Rebetol >10.6 mg/kg 61% PEG-Intron + Rebetol 52% Intron A + Rebetol 41% PEG-Intron 25% Intron A 24 weeks Intron A 48 weeks 6% 16% PEG-Intron/RebetolPEG-Intron/Rebetol

3 Advancements in the treatment of chronic hepatitis C Participant Introduction Schering-Plough Team Dr. J.J. GaraudExec. V.P., Clinical Research Dr. Kenneth KouryDirector, Biostatistics Dr. Mark LaughlinDirector, Clinical Pharmacology Dr. Penelope J. Giles Director, Regulatory Affairs Dr. Janice K. Albrecht Vice President, Clinical Research Consultants Dr. J. McHutchisonMedical Director, Liver Transplantation, Scripps Clinic Dr. L.J. WeiProfessor, Biostatistics, Harvard School of Public Health PEG-Intron/RebetolPEG-Intron/Rebetol

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 C Information 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 The PEG-Intron molecule Hours pg/ml interferon α-2b Interferon alfa-2b 3MIU PEG-Interferon alfa-2b 1.5 μg/kg T½ 40 hours

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

8 PEG-Intron monotherapy study design Primary Endpoint: Loss of serum HCV-RNA 24 weeks post-treatment 48 weeks24 weeks Endpoint Follow-up Screening PEG 0.5  g/kg QW N= 315 PEG 1.0  g/kg QW N= 297 PEG 1.5  g/kg QW N= 304 Intron-A 3MIU TIW N= 303

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

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

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

12 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  g/kg - had similar antiviral activity to Intron A and was better tolerated PEG-Intron/RebetolPEG-Intron/Rebetol

13 PEG-Intron plus Rebetol PEG-Intron + Rebetol mg/daily 0.5  g/kg QW (44 wks)1.5  g/kg QW (4 wks) N=514 PEG-Intron + Rebetol 800mg/daily N=  g/kg QW (48 weeks) Screening Intron A + Rebetol mg/daily N=505 3MIU TIW (48 wks) Endpoint Follow-up 48 weeks24 weeks Primary Endpoint: Loss of serum HCV-RNA 24 weeks post-treatment PEG-Intron/RebetolPEG-Intron/Rebetol

14 Demographics Age Gender Race Weight (kg) Mean Mean (yrs.) 67% 63% Male 89%88%91% Caucasian Range Range Intron A/R (n=505) PEG 0.5/R (n=514) PEG 1.5/R (n=511)PEG-Intron/RebetolPEG-Intron/Rebetol

15 Disease Characteristics HCV RNA copies/ml HCV genotype Fibrosis/Cirrhosis* * Knodell HAI F3/4 29%30%29%Geno 2/3 68% Geno 1 68%67%69%>2 million 29%30%28%Present Geno 4/5/63%2%3% Intron A/R (n=505) PEG 0.5/R (n=514) PEG 1.5/R (n=511) PEG-Intron/RebetolPEG-Intron/Rebetol

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

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

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

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

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

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

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

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

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

25 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 PEG-Intron/RebetolPEG-Intron/Rebetol

26 PEG-Intron/Rebetol Safety PEG-Intron/RebetolPEG-Intron/Rebetol

27 Adverse events Incidence >10% difference between groups Application site Injection site inflammation18%25%28%20% Injection site reaction36%58%61%54% Body as a whole Fever33%46%49%41% Rigors41%48%51%43% Weight decrease20%29%28%30% GI side effects Nausea33%43%44%43% Skin Alopecia32%36%31%45% PEG 1.5/R <10.6 mg/kg N=323 PEG 1.5/R >10.6 mg/kg N=188 Intron/R N=505 PEG 1.5/R 800 mg N=511 PEG-Intron/RebetolPEG-Intron/Rebetol 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

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

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

30 Adverse hematologic effects Neutrophils Discontinued for Neutropenia % Patients with <500 at any time 8%18%17%21% 2%4%3% 7% 0.2%1%0.3% 2% (1)*(5)(1) (4) % Patients with <750 at any time Neutrophils 10 9 /L PEG 1.5/R <10.6 mg/kg N=323 PEG 1.5/R >10.6 mg/kg N=188 Intron /R N=505 PEG 1.5/R 800 mg N=511 *Number of patients PEG-Intron/RebetolPEG-Intron/Rebetol

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

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 with PEG 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  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) Post-marketing studies PEG-Intron/RebetolPEG-Intron/Rebetol

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

35 The Decision to Treat Hepatitis C Complex Complex Controversial Controversial Host Host Severity disease Severity disease Co-morbid conditions Co-morbid conditions Viral Viral Genotype Genotype Therapy Therapy Efficacy Efficacy Side effects Side effects Cost 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 Majority hepatitis C patients Unfavorable profile Unfavorable profile Genotype 1 Genotype 1 Significant investment and commitment Significant investment and commitment Time (48 weeks) Time (48 weeks) More “aggressive” therapy More “aggressive” therapy Patient Patient Doctor Doctor Other Staff Other Staff

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

39 How can we achieve the greatest benefit whilst diminishing the risk? 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