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

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.

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)

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

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

Results: Phase 2 Study TreatmentPatients Total (N) 28-Day Mortality N (%) rhAPC (all doses) 9026 (29%) Placebo4114 (34%) Total131P=0.55 Chi-square test Phase 3 dose chosen based on PD effects on D-dimers in phase 2

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

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

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

Results: Demographics Age, Gender, Origin DEMOGRAPHIC PARAMETERSrhAPC (850) (%) Placebo (840) (%) AGE <60 years44 ≥60 years56 GENDER Female4442 Male5658 ETHNIC ORIGIN Caucasian82 African descent87 Hispanic45 Other66

Results: Demographics Disease Severity rhAPC (850) (%) Placebo (840) (%) PREEXISTING CONDITIONS Hypertension3835 Myocardial infarction1214 Congestive cardiomyopathy69 Diabetes2122 Pancreatitis34 Liver disease23 COPD2226 Cancer1719 Recent Trauma35

Results: Demographics Disease Severity RECENT SURGICAL HISTORY rhAPC (850) (%) Placebo (840) (%) Elective surgery66 Emergency Surgery 21 No history of surgery 7473

Results: Demographics Disease Severity MEASURE OF DISEASE SEVERITY rhAPC (850)Placebo (840) APACHE II score mean25 Mechanical ventilation (%)7378 Shock (%)7072 Use of any vasopressor (%)7276 Use of dobutamine (%)14

Results: Demographics Disease Severity # of ORGAN FAILURES (OF) rhAPC (850) (%) Placebo (840) (%) *Time from 1 st OF to start drug 18 hours 17 hours

Results: Phase 3 Study Primary Efficacy Endpoint TreatmentPatients (N) 28-Day Mortality N (%) rhAPC (24.7%) Placebo (30.8%) Total1690Stratified, CMH p=0.005

Results: Primary Efficacy Endpoint ITT Population TIME (Days) SURVIVAL (%) PlaceborhAPC

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

Results: Mortality as a Function of Age Age (years) rhAPC (850) Mortality (%) Placebo (840) Mortality (%) Mort Diff (%) RR95% CI <6059 /375 (16) 75 /366 (21) , 1.05 ≥60151 /475 (32) 184 /474 (39) , 0.97

Results: Mortality as a Function of Age

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

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

Results: Mortality as a Function of APACHE II at Study Entry Apache Quartile (score) rhAPC (850) Mortality (%) Placebo (840) Mortality (%) Mort Diff (%) RR95% CI 1 st (3-19) 33 /218 (15) 26 /215 (12) , nd (20-24) 49 /218 (22) 57 /222 (26) , rd (25-29) 48 /204 (24) 58 /162 (36) , th (30-53) 80 /210 (38) 118 /241 (49) , 0.96 interaction p = 0.09

Results: Mortality as a Function of APACHE II

Results: Mortality as a Function of APACHE II Quartiles APACHE II Quartiles (score) rhAPC (850) Mortality (%) Placebo (840) Mortality (%) Mort Diff (%) RR95% CI Q1+Q2 (<25) 82/436 (19) 83/437 (19) , 1.30 Q3+Q4 (≥25) 128/414 (31) 176/403 (44) , 0.85

Results: Mortality as a Function of Organ Failure # OFrhAPC (850) Mortality (%) Placebo (840) Mortality (%) Mort Diff (%) RR95% CI 142 /215 (20) 43 /203 (21) , /270 (21) 71/273 (26) , /214 (26) 75 /218 (34) , /119 (39) 54 /116 (47) , /31 (32) 16 /30 (53) , 1.11

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

Mortality as a Function of Shock ShockrhAPC Mortality (%) Placebo Mortality (%) Mort Diff (%) RR95% CI RR No53 /252 (21) 53 /238 (22) , 1.32 Yes157 /598 (26) 206 /602 (34) , 0.91

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 rhAPC BetterPlacebo Better

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

Results: Mortality as a Function of Protein C Levels Protein C Def rhAPC Mortality (%) Placebo Mortality (%) Mort Diff (%) RR95% CI Deficient (≤80%) 182 /709 (26) 215 /670 (32) , 0.95 Not deficient (>80%) 14 /90 (16) 28 /105 (27) , 1.04 Unknown or Absent 14 /51 (28) 16 /65 (25) , 2.07

Results: Mortality in Patients with Laboratory Evidence of DIC DICrhAPC Mortality (%) Placebo Mortality (%) Mort Diff (%) RR95% CI DIC196 /800 (25) 243 /774 (31) , 0.92 Unknown or Absent 14 /49 (29) 16 /66 (24) , 2.16

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

Results: Mortality as a Function of Heparin Use rhAPC Total N (%) Placebo Total N (%) Mort Diff (%) Heparin At baseline (26) (30)4 During infusion (25) (28)3 Not on Heparin At baseline (23)28189 (32)9 During infusion (24)20380 (39)15

Morbidity Outcomes

Results: Functional Status at Day rhAPCPLACEBO 0% 20% 40% 60% 80% 100% Home Nurs Home Hosp ICU DIED

Protocol Amendment June 1999-after trial initiated –Sponsor blinded –Before 1 st 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

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%)

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%)

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

Mortality: Original vs. Amended Protocol StrataTotalTherapyDied by Day 28 Original360rhAPC102 (28) 360Placebo109 (30) 720P= Amended490rhAPC108 (22) 480Placebo150 (31) 970P=

Cumulative 28 Day Mortality Over Time

Sensitivity Analysis: Patients on Pre-Amendment Not Eligible Under Post-Amendment Meet New Incl rhAPC Mortality Total N N (%) Placebo Mortality Total N N (%) RR95% CI No4114 (34)4017 (43) , 1.40 Yes31988 (28)32092 (29) , 1.23

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

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

Outline of Presentation Pediatrics Adult safety phase 2 Adult safety phase 3 Immunogenicity Summary

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

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

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

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

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

Pediatric Sepsis Study vs. Adult Phase 3 Predicted Mortality (% of Patients)

Pediatric Sepsis Study vs. Adult Phase 3 Actual Mortality (% of Patients)

Pediatric Sepsis Study vs. Adult Phase 3 Safety Parameters (% of Patients)

Pediatric Safety 1 death due to intracranial hemorrhage 3 Bleeding SAE –6y/o nasopharyngeal hemorrhage –5 month/old with petechial cerebral hemorrhage –15 y/o with UGI hemorrhage

Pediatric Summary Limited uncontrolled database Similar –PK/PD data –Serious bleeding events Different –Organ failure - CV –Primarily one organ failure –Site of infection - blood, lung, CNS –Type of pathogen - gram negative –10% 14 day mortality

Outline of Presentation Pediatrics Adult safety phase 2 Adult safety phase 3 Immunogenicity Summary

Safety Phase 2 Patient Population Exclusion of patients with: – high risk of bleeding –on medications affecting coagulation Specific criteria to start and stop the infusion –related to procedures –related to coagulation parameters

Safety Phase 2 Patient Deaths by Treatment Group

Safety Phase 2 SAE during infusion period by treatment group –48 hr rhAPC7/46 (15%) –96 hr rhAPC12/44 (27%) –All Placebo10/41 (24%) Bleeding events reported as significant 3/90 (3%) No intracranial hemorrhages

Outline of Presentation Pediatrics Adult safety phase 2 Adult safety phase 3 Immunogenicity Summary

Safety Phase 3 Deaths Attributable to Hemorrhage During the Infusion Period 850 patients in the rhAPC treatment arm –2 intracranial hemorrhage (ICH) –1 pulmonary hemorrhage –1 thoracic hemorrhage 840 patients in the placebo arm –No Deaths attributable to hemorrhage

Ongoing Open-Label Trials New Intracranial Hemorrhages During the Infusion Period 13 new ICH in 520 patients enrolled in ongoing safety studies 8 of these occurred during the infusion period Infusion period event rate 8/ % 95% CI (.67, 3.01)

Serious Bleeding Events Protocol Definition Intracranial hemorrhage Life-threatening bleed Transfusion of > 2 units (phase 2) or > 3 units (phase 3) PRBC on 2 consecutive days Met other criteria for a SAE

Serious Bleeding Events Infusion Period SiterhAPC (n=850)Placebo (n=840) Total208 Gastrointestinal54 Intra-abdominal23 Intra-thoracic40 Retroperitoneal30 Intracranial hemorrhage20 Undefined hemorrhage11 Genitourinary20 Skin/soft tissue10

Safety During the Infusion Period

First APACHE II Quartile Events During Drug Infusion

Subjects Requiring Transfusion During 28 Day Study Period

Serious Bleeding Events in Patients Laboratory Evidence of DIC

Bleeding Events and Baseline Coagulation Factors Pooled phase 2 and phase 3 data rhAPC = 940 Placebo = 881

Baseline APTT and Adverse Bleeding Events

Baseline PT and Adverse Bleeding Events

Baseline Platelet Count and Adverse Bleeding Events

Serious Bleeding Events in Subjects who Received Heparin (Received DVT prophylactic dose at baseline up to day 5)

Bleeding Adverse Events in Subjects who Received Heparin (Received DVT prophylactic dose at baseline up to day 5)

Subgroups No differences in safety profile were observed in the following sub-groups –Gender –Origin –Age

Baseline Surgical Status Phase 2 and 3 Data Mortality –Emergency post-op patient with sepsis rhAPC 56/186 (30%) placebo 49/187 (26%) –Elective post-op patient with sepsis rhAPC 20/63 (32%) placebo 22/59 (37%) Bleeding Rate –Similar bleeding adverse event rate between post-op and non operative patients

rhAPC Steady State Concentration and Adverse Events (N=326, median 45 ng/ml)

Outline of Presentation Pediatrics Adult safety phase 2 Adult safety phase 3 Immunogenicity Summary

Immunogenicity 3 tier testing 1 Chemiluminescent Binding Assay (CBA) 2 Inhibition Chemiluminescent Binding Assay 3 Neutralizing antibody assay (APTT) Assay Evaluation Outstanding issues regarding sensitivity, specificity and quantification Difficult to assess true incidence of Anti-APC antibodies

Immunogenicity Patients tested: Phase 2 and 3 – 942 subjects tested 5 positive patients by tier 1 test (Binding assay) 2 positive patients by tier 2 tests (Inhibition assay) 0 positive patient by tier 3 tests (Neutralizing)

Patients Positive for Specific anti-APC Ab (Inhibition Assay) Phase 2 Patient – no clinical sequalae Phase 3 Patient –Superficial and deep venous thrombosis –alive at day 28 study end –follow-up revealed subject died at day 36 of multi- organ failure

Outline of Presentation Pediatrics Adult safety phase 2 Adult safety phase 3 Immunogenicity Summary

Pediatric Summary No controlled studies to support efficacy Limited patient population Compared to adults –similar drug effects –different disease characteristics –low mortality rate/similar adverse event rate

Summary of Safety - Adults Subjects enrolled in the phase 2 and 3 trials were carefully selected to minimize bleeding risk Increased rate during infusion in rhAPC treated subjects compared to placebo of: –bleeding adverse events 19% vs.11% respectively –serious bleeding events 2% vs. 1% respectively

Summary of Safety - Adults Phase 3 trial –4 deaths attributed to bleeding during infusion of rhAPC (2 ICH) - none in placebo –rate of ICH during infusion of rhAPC - 0.2% Subsequent open label trials (N=520) –13 new intracranial hemorrhages –8 during the infusion period –Rate of ICH during infusion (8/520) -1.5%

Summary of Safety - Adults One subject with anti-APC Ab developed DVT No other pattern of adverse events noted comparing rhAPC to placebo

Safety Conclusion Difficult disease process to detect adverse events Trend in intracranial hemorrhage True risk uncertain