Biologics License Application: Recombinant Human Activated Protein C (rhAPC) [drotrecogin alfa (activated)] Xigris ™ f

1. Biologics License Application: Recombinant Human Activated Protein C (rhAPC)[drotrecogin alfa (activated)] Xigris™ for Severe Sepsis Anti-Infective Advisory Committee October 16, 2001 FDA/CBER

2. Sponsor’s Proposed Indication rhAPC is indicated for the treatment of pediatric and adult patients with sepsis associated with acute organ dysfunction (severe sepsis). Treatment with rhAPC reduces mortality in patients with severe sepsis.

3. Overview of Drotrecogin Product Development • 13 phase 1 studies: • 8 studies healthy volunteers (110 patients) • 3 studies end-stage renal disease (30 patients) • 1 study heterozygous Protein C deficiency (9 patients) • 1 study Purpura fulminans (42 patients)

4. Overview of Drotrecogin Product Development • 1 study, phase 2, randomized, double-blind, placebo-controlled study of 131 patients with severe sepsis • 1 study, phase 3, randomized, double-blind, placebo-controlled study of 1690 patients with severe sepsis • Pediatric study in 83 patients with severe sepsis • Ongoing, uncontrolled trials in > 500 patients

5. Study Design:Phase 2 Study • Randomized, placebo-controlled, dose-ranging, multicenter • 131 patients with severe sepsis • rhAPC: 12, 18, 24 or 30 ug/kg/hr continuous iv infusion 48 or 96 hours • Outcome measures • Pharmacodynamic & pharmacokinetic • Safety

6. Results:Phase 2 Study Phase 3 dose chosen based on PD effects on D-dimers in phase 2

7. Study Design:Phase 3 Study • Randomized, double-blind, single dose, placebo-controlled, multicenter study • rhAPC: 24 ug/kg/hr iv infusion for 96 hours • 2280 patients planned for enrollment • Inclusion: Severe sepsis • 3 of 4 SIRS criteria • 1 organ failure • Suspected or proven infection • Exclusion: patients at high risk for bleeding

8. Study Design:Final Statistical Analysis Plan • Primary efficacy endpoint: 28 day all cause mortality • Primary efficacy analysis: Cochran-Mantel-Haenszel test stratified by preinfusion: • APACHE II quartile • Age class • Protein C activity class • 2 interim analyses: • 760 patients (alpha level=0.0002), October 1999 • 1520 patients (alpha level=0.0118), June 2000

9. Study Design: Prospectively Defined Secondary Analyses • Mortality treatment effect by: • Protein C levels • APACHE II • Age • Gender, origin • SOFA, SIRS • Organ Failure • Shock, ARDS, DIC • AT III levels

10. Results: Demographics Age, Gender, Origin

11. Results:Demographics Disease Severity

12. Results: Demographics Disease Severity

13. Results:Demographics Disease Severity

14. Results:Demographics Disease Severity *Time from 1st OF to start drug 18 hours 17 hours

15. Results:Phase 3 StudyPrimary Efficacy Endpoint

16. Results:Primary Efficacy Endpoint ITT Population 100 80 60 SURVIVAL (%) 40 20 0 0 4 8 12 16 20 24 28 TIME (Days) Placebo rhAPC

17. Review of Mortality Effect by Patient Subgroups • Patient age • Disease severity • APACHE II • Organ failure • Shock • Hematologic parameters • Protein C • DIC • Use of heparin

18. Results: Mortality as a Function of Age

19. Results:Mortality as a Function of Age

20. Review of Mortality Effect by Patient Subgroups • Patient age • Disease severity • APACHE II • Organ failure • Shock • Hematologic parameters • Protein C • DIC • Use of heparin

21. APACHE II: Disease severity • Acute physiology and chronic health evaluation (Knaus 1985) • Index used to predict mortality in ICU setting • Uses physiologic measurements, age and chronic health status

22. Results:Mortality as a Function of APACHE II at Study Entry interaction p = 0.09

23. Results:Mortality as a Function of APACHE II

24. Results: Mortality as a Function of APACHE II Quartiles

25. Results:Mortality as a Function of Organ Failure

26. Results:Mortality as a Function Disease Severity (Organ Failure)

27. Mortality as a Function of Shock

28. Results:Summary of Treatment Effect by APACHE II & Organ Failure & Shock ALL PATIENTS APACHE - Q1 APACHE - Q2 APACHE - Q3 APACHE - Q4 OF - 1 OF - 2 OF - 3 OF - 4 OF - 5 SHOCK - Absent SHOCK - Present 0.1 1 10 rhAPC Better Placebo Better

29. Review of Mortality Effect by Patient Subgroups • Patient age • Disease severity • APACHE II • Organ failure • Shock • Hematologic parameters • Protein C • DIC • Use of heparin

30. Results:Mortality as a Function of Protein C Levels

31. Results: Mortality in Patients with Laboratory Evidence of DIC

32. Review of Mortality Effect by Patient Subgroups • Patient age • Disease severity • APACHE II • Organ failure • Shock • Hematologic parameters • Protein C • DIC • Use of heparin

33. Results:Mortality as a Function of Heparin Use

34. Morbidity Outcomes

35. Results:Functional Status at Day 28 100% 24.7 30.8 80% 12.2 DIED 9.8 60% ICU 23.5 Hosp 20.9 NursHome 40% 7.2 7.9 Home 20% 32.3 30.6 0% rhAPC PLACEBO

36. Protocol Amendment • June 1999-after trial initiated • Sponsor blinded • Before 1st interim analysis • Primary Analytic Plan • Elimination of PC deficiency status and septic shock as covariates from the CMH analysis • Inclusion and Exclusion Criteria • Esophageal varices • Cirrhosis • Transplant patients • Moribund patients • Pancreatitis • Malignancy • Definition of OF

37. Effect of Protocol Change: Original vs. Amended Protocol • ↓malignancy (21% vs 16%) • ↓ immunosuppressed (11% vs. 8%) • ↓ withdrawal of life support (17% vs. 13%) • ↓ APACHE II chronic health points (25% vs. 17%) • ↓ non-sepsis related death (5% vs. 4%) • ↓ at nursing home facilities (8% vs. 6%)

38. Effect of Protocol Change:Original vs. Amended Protocol • Higher Il-6 median levels in amended (566 ug/ml vs. 389 ug/ml ) • Mean APACHE II scores same at baseline (25) • Acidosis more common under original protocol than amended (46% vs. 26%)

39. rhAPC N (%) Placebo N (%) Original 57 (16) 64 (18) Amendment A 50 (10) 79 (16) Effect of Protocol Change: DNR Orders

40. Mortality:Original vs. Amended Protocol

41. Cumulative 28 Day Mortality Over Time

42. Sensitivity Analysis: Patients on Pre-Amendment Not Eligible Under Post-Amendment

43. Summary of Efficacy • 28 day all cause mortality 24.7% rhAPC vs. 30.8% placebo (p=0.005)

44. Summary of Efficacy • Additional analyses suggest treatment benefit predominant: • 3rd and 4th APACHE II quartile • laboratory evidence DIC • not on heparin • > 50 years of age • ≥ 2 OF • shock

45. Outline of Presentation • Pediatrics • Adult safety phase 2 • Adult safety phase 3 • Immunogenicity • Summary

46. Pediatric Database No controlled efficacy trials Total Pediatric data base - 121 pts • Safety PK/PD sepsis study - 83 pts. • Purpura Fulminans - 14 pts. • Additional uncontrolled trials - 24 pts.

47. Pediatric Sepsis Study vs. Adult Phase 3 Type of Organ Failure (% of Patients)

48. Pediatric Sepsis Study vs. Adult Phase 3 # of Organ Failures (% of Patients)

49. Pediatric Sepsis Study vs. Adult Phase 3 Primary Site of Infection (% of Patients)

50. Pediatric Sepsis Study vs. Adult Phase 3 Type of Pathogen (% of Patients)