1. Biologic License Supplement: Peginterferon α-2b and Ribavirin for Treatment of Chronic Hepatitis C Division of Clinical Trials Design and Analysis CBER, FDA

2. Objectives of Presentation 1.Review of Study Design –Rationale for selection of peginterferon and ribavirin doses studied in phase 3 Models for predicting sustained viral responses Power of dose ranging studies

3. Objectives of Presentation 2.Summary of Efficacy –Treatment effects –Virologic response in patient subgroups

4. Objectives of Presentation 3.Summary of Safety Safety profile of PEG/R compared to IFN/R

5. Objectives of Presentation 4.Summary of Post-marketing Commitments Optimal dosage of peginterferon and ribavirin Optimal duration of treatment in patient subgroups Treatment response in African Americans Effect of food on ribavirin absorption

6. Phase 3 Combination Study(N= 1530) Multi-center, randomized, open-label, active control, parallel group study with 48WK treatment and 24WK follow-up - PEG 1.5  g/kg QW, ribavirin 800 mg/day - PEG 1.5  0.5  g/kg QW, riba 1000-1200 mg/day - IFN 3x10 6 U TIW, ribavirin 1000-1200 mg/day Ribavirin absorption increased 70% in the presence of food. Protocol amended to require that ribavirin be taken with food.

7. Peg 0.5  g/kg QW (N=315) Peg 1.0  g/kg QW (N=297) Peg 1.5  g/kg QW (N=304) IFN 3x10 6 U TIW (N=303) In-Treatment Response 24W 42% 48% 57%32% Sustained Resp. 48W Treatment and 24W FU 18% 25%24%12% Selection of Peginterferon Dosage for Phase 3 Combination Study Phase 3 Peginterferon Monotherapy Study Virologic Response

8. Selection of Ribavirin Dosage for Phase 3 Combination Study Phase 1 dose-ranging study (N=72) - PEG 0.35  g/kg/w and riba 600, 800 mg/day - PEG 0.7 and riba 600, 800, 1000-1200 mg/day - PEG 1.4 and riba 600, 800, 1000-1200 mg/day Viral response at 24 weeks of treatment

9. Primary Efficacy Outcome: Sustained Virologic Response Treatment Groups HCV RNA Negative Treatment Difference 1 PEG 1.5/R264/511 (52%)6% (0.18, 11.6) PEG 0.5/R239/514 (46%)1% (- 4.7, 6.5) IFN/R231/505 (46%) 1 vs. IFN/R

10. Efficacy Outcomes According to Subgroup Analyses Pre-specified - Viral genotype (1 vs. Non-1) - Cirrhosis Post-hoc - Viral titers (>2 x10 6 /ml serum) - Age, gender, ethnicity - Geographic location - Body weight

11. Treatment Response in Patients with Genotype 1 High titerLow titer I/R70/247 (28)42/96 (44) PEG1.5/R75/256 (29)66/92 (72) Treatment difference 1% (-7, 8.8)28% (14, 42)

12. Treatment Response in Patients with Genotype 2-6 High titerLow titer I/R72/97 (74)47/65 (72) PEG1.5/R68/95 (72)55/68 (81) Treatment difference -3% (-15,10)9% (-6, 22)

13. Treatment Response by Geographic Location TREATMENT GROUP Study Center PEG 1.5/RI/R US 169/346 (49%) 131/337 (39%) Non-US 95/165 (57%) 100/168 (59%)

14. SUBGROUP ANALYSES Efficacy and Safety of Weight- adjusted Ribavirin Dosage

15. Treatment Response Based on Ribavirin Weight-adjusted Dose Analysis is post-hoc True variable: body weight Hypothesis: BW is surrogate for ribavirin dosage (mg/kg)

16. PEG 1.5 a Riba 800 c PEG 0.5 a Riba 1000- 1200 c IFN 9x10 6 b Riba 1000- 1200 c PEG or IFN Weight adjusted No weight adjustment Riba “Lower” dose No weight adjustment “Higher” dose Crude weight adjustment Treatment Response by Ribavirin Weight-adjusted Dose Differences in dosages across study arms a mcg/kg/week/SC; b IU/week/SC; c mg/day/PO.

17. Treatment Response by Ribavirin Weight-adjusted Dose Non-randomized subgroups differ in: –Numbers, body weights, ?other unknown factors Within-arm comparison suggestive –Data too few and inconsistent Across-arm comparisons not appropriate

18. Treatment Response by Ribavirin Dose Ribavirin Dose PEG 1.5 Riba PEG 0.5 Riba IFN Riba <14.7 a 13/21 76/17199/184 >13.3 <14.7 25/3891/17475/170 >10.7 <13.3 70/12658/13450/126 <10.7 156/32614/357/25 Median (range) 9.8(5-19) 14(7-26)14(7-23) a dose quartiles, mg/kg/day

19. Treatment Response by Ribavirin Weight-adjusted Dose Body Weight Treatment Groups I/RPEG1.5/R < 75 kg94/178 (53)108/185 (58) > 75 kg 137/327 (42)156/326 (48) Difference 11%10%

20. Population PK and PD analysis Modeling for: –Clearance –Virologic response –Safety (anemia) Remaining Issues –Simulation of Safety and Efficacy did not follow proposed dosing –No data at 1400 mg/kg for BW >105 kg –Ideal body weight –Separation by gender

21. SAFETY DATA SUMMARY Peginterferon and Ribavirin vs. Interferon and Ribavirin

22. Summary of Safety PEG/R compared to IFN/R associated with higher incidence of: dose-modifications serious and severe adverse events (e.g neutropenia, infections) certain AEs (fever, headache, application site reactions)

23. Summary of Safety: Analyses by Ribavirin Weight-Adjusted Dose IFN and/or ribavirin dose-reduction due to adverse events Adverse events (both ribavirin- and interferon-associated) Dose threshold with steeper increase in ribavirin toxicity?

24. Serious Infectious Adverse Events PEG1.5/RPEG0.5/RI/R Abscess310 Cellulitis511 Infection300 Sepsis010 Appendicitis411 Bronchitis010 Pneumonia111 Prostatitis100 UTI011 TOTAL1773

25. Modification of Dose (IFN or Ribavirin) in PEG1.5/R Arm Body Wt Ribavirin Dose All Causes Anemia Neutropenia kgmg/kg%% 54>14.7471224 60-54 >13.3 <14.7 611620 60-75 >10.7 <13.3 451022 75<10.738716

26. Incidence of Anemia and Neutro- penia in PEG 1.5/R Arm Body Wt Riba Dose Anemia All Severe/LT Neutropenia All Severe/LT kgmg/kg % % <54>14.7 18 0 47 24 60-54>13.3 <14.7 31 2 29 12 60-75>10.7 <13.3 13 0 31 12 >75<10.7 8 0 23 9

27. Conclusions (1) Peg-IFN + ribavirin (1.5 mcg/kg + 800 mg) is more effective than IFN + ribavirin (3x10 6 U + 1000-1200 mg) for inducing sustained HC viral response Most responders (95%) to Peg-IFN + ribavirin did so by week 12

28. Conclusions (2)  Sustained response rates are higher in patients with genotypes 2 and 3, and lower with genotype 1  Patients with genotype 1 and high viral loads have poorest response of all

29. Conclusions (3)  Peg IFN + ribavirin is associated with a higher number of adverse events (eg infections, neutropenia and injection-site reactions) compared I/R  Few safety or efficacy data exist for African Americans, a group known to have poor response to IFN

30. Conclusions (4) Compared to patient with higher body weights, patients with lower body weight tended to have: – Higher response rates – Higher rates of toxicity

31. Conclusions (5) A number of factors could account for this apparent effect of body weight on treatment response and toxicity Definitive conclusions about the safety and efficacy of Peg IFN+ribavirin as a weight-based regimen cannot be drawn

32. Post-marketing Studies Safety and efficacy of Peg IFN + ribavirin as a weight-based regimen Safety and efficacy of shorter durations of Peg IFN + ribavirin in patients with high likelihood of response (genotypes 2-3, genotype-1 with low viral load)

33. Optimization of Ribavirin Dose and Treatment Duration Multi-center, randomized,open label trial in 4000 treatment-naïve patients with CHC Arm A: fixed dose ribavirin PEG1.5/Riba 800 mg for 24 or 48 wks Arm B: weight-adjusted ribavirin PEG1.5/Riba 13+2 mg/kg for 24 or 48 wks BW kg: 105 Riba mg: 800 1,000 1,200 1,400

34. Optimization of Peginterferon Dose Safety and efficacy of lower doses of Peg IFN when given with ribavirin Safety and efficacy of PEG/R in African Americans

35. Peginterferon Dose Optimization Multi-center randomized study comparing combination therapy with PEG1.5  g/kg vs. PEG1.0  g/kg plus ribavirin in 1,000 patients with CHC genotype 1 The dose regimen of ribavirin will be determined from in-treatment data in the ribavirin dose optimization study Evaluation of the effect of therapy in African Americans (n~100)

36. In-treatment vs. Post-treatment Response In-treatm wk24Follow-up wk24 <75 kg>75kg<75 kg>75 kg I/R 106/78 (60) 172/327 (53) 94/178 (53) 137/327 (42) PEG 0.5/R 114/187 (61) 176/327 (54) 91/187 (49) 148/327 (45) PEG 1.5/R 127/185 (69) 202/326 (62) 108/185 (59) 156/326 (48)

37. Effect of Food on Ribavirin Absorption Relative bioavailability of ribavirin compared to the fasted state after: –High fat meal –Non-fat meal