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

Treatment Patients

Total (N)

28-Day Mortality

N (%)

rhAPC

(all doses)

90 26 (29%)

Placebo 41 14 (34%)

Total 131 P=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 PARAMETERS rhAPC (850)

(%)

Placebo (840)

(%)

AGE

<60 years 44 44

≥60 years 56 56

GENDER

Female 44 42

Male 56 58

ETHNIC ORIGIN

Caucasian 82 82

African descent 8 7

Hispanic 4 5

Other 6 6

Results: Demographics Disease Severity

rhAPC (850)

(%)

Placebo (840)

(%)

PREEXISTING CONDITIONS

Hypertension 38 35

Myocardial infarction 12 14

Congestive cardiomyopathy 6 9

Diabetes 21 22

Pancreatitis 3 4

Liver disease 2 3

COPD 22 26

Cancer 17 19

Recent Trauma 3 5

Results:

Demographics Disease Severity

RECENT SURGICAL HISTORY

rhAPC (850)

(%)

Placebo (840)

(%)

Elective surgery 6 6

Emergency Surgery

21 21

No history of surgery

74 73

Results: Demographics Disease Severity

MEASURE OF DISEASE SEVERITY

rhAPC (850) Placebo (840)

APACHE II score mean 25 25

Mechanical ventilation (%) 73 78

Shock (%) 70 72

Use of any vasopressor (%) 72 76

Use of dobutamine (%) 14 14

Results: Demographics Disease Severity

# of ORGAN FAILURES (OF)

rhAPC (850)

(%)

Placebo (840)

(%)

1 25 24

2 32 33

3 25 26

4 14 14

5 4 4

*Time from 1st OF to start drug 18 hours 17 hours

Results:

Phase 3 StudyPrimary Efficacy Endpoint

Treatment Patients

(N)

28-Day Mortality

N (%)

rhAPC 850 210 (24.7%)

Placebo 840 259 (30.8%)

Total 1690 Stratified, CMH p=0.005

Results: Primary Efficacy Endpoint

ITT Population

0 4 8 12 16 20 24 28

TIME (Days)

0

20

40

60

80

100

SU

RV

IVA

L (

%)

Placebo rhAPC

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

(%)

RR 95% CI

<60 59 /375

(16)

75 /366

(21)

-5 0.77 0.56, 1.05

≥60 151 /475

(32)

184 /474

(39)

-7 0.82 0.69, 0.97

Results: Mortality as a Function of Age

0102030405060

18-20n= (16)

21-30(86)

31-40(136)

41-50(217)

51-60(286)

61-70(356)

71-80(451)

81-90(129)

91-100(13)

Age (years)

Mo

rtal

ity

(%)

Placebo rhAPC

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 (%)

RR 95% CI

1st

(3-19)

33 /218

(15)

26 /215

(12)

+3 1.25 0.78, 2.02

2nd

(20-24)

49 /218

(22)

57 /222

(26)

-4 0.88 0.63, 1.22

3rd

(25-29)

48 /204

(24)

58 /162

(36)

-12 0.66 0.48, 0.91

4th

(30-53)

80 /210

(38)

118 /241

(49)

-11 0.78 0.63, 0.96

interaction p = 0.09

Results:

Mortality as a Function of APACHE II

0

10

20

30

40

50

60

70

80

5-10n=(24)

10-15(152)

15-20(330)

20-25(456)

25-30(345)

30-35(227)

35-40(102)

40-45(37)

45-50(13)

APACHE II

Mor

tali

ty (

%)

Placebo rhAPC

Results:

Mortality as a Function of APACHE II Quartiles

APACHE II Quartiles

(score)

rhAPC (850)

Mortality (%)

Placebo (840)

Mortality

(%)

Mort Diff

(%)

RR 95% CI

Q1+Q2

(<25)

82/436

(19)

83/437

(19)

0 0.99 0.75,

1.30

Q3+Q4

(≥25)

128/414

(31)

176/403

(44)

-13 0.71 0.59,

0.85

Results:

Mortality as a Function of Organ Failure

# OF rhAPC (850)

Mortality (%)

Placebo (840)

Mortality (%)

Mort Diff (%)

RR 95% CI

1 42 /215

(20)

43 /203

(21)

-1 0.92 0.63,

1.35

2 56 /270

(21)

71/273

(26)

-5 0.80 0.59, 1.08

3 56 /214

(26)

75 /218

(34)

-8 0.76 0.57, 1.02

4 46 /119

(39)

54 /116

(47)

-8 0.83 0.62, 1.12

5 10 /31

(32)

16 /30

(53)

-21 0.60 0.33, 1.11

Results: Mortality as a Function Disease

Severity (Organ Failure)

0

10

20

30

40

50

60

1 2 3 4 5

Number of Organ Dysfunctions

Mor

tali

ty (

%)

PlaceborhAPC

Mortality as a Function of Shock

Shock rhAPC

Mortality (%)

Placebo

Mortality (%)

Mort Diff

(%)

RR 95% CI RR

No 53 /252

(21)

53 /238

(22)

-1 0.94 0.67, 1.32

Yes 157 /598

(26)

206 /602

(34)

-8 0.77 0.64, 0.91

Results: Summary of Treatment Effect by

APACHE II & Organ Failure & ShockALL PATIENTS

APACHE - Q1APACHE - Q2APACHE - Q3APACHE - Q4

OF - 1OF - 2OF - 3OF - 4OF - 5

SHOCK - AbsentSHOCK - Present

0.1 1 10rhAPC Better Placebo 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

(%)

RR 95% CI

Deficient

(≤80%)

182 /709

(26)

215 /670

(32)

-6 0.80 0.68, 0.95

Not deficient

(>80%)

14 /90

(16)

28 /105

(27)

-11 0.58 0.33, 1.04

Unknown or Absent

14 /51

(28)

16 /65

(25)

+3 1.12 0.60, 2.07

Results:

Mortality in Patients with Laboratory Evidence of DIC

DIC rhAPC

Mortality (%)

Placebo

Mortality (%)

Mort Diff

(%)

RR 95% CI

DIC 196 /800

(25)

243 /774

(31)

-6 0.78 0.67, 0.92

Unknown or Absent

14 /49

(29)

16 /66

(24)

+5 1.18 0.65, 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

(%)

HeparinAt

baseline532 138 (26) 559 170 (30) 4

During infusion

634 158 (25) 637 179 (28) 3

Not on HeparinAt

baseline318 72 (23) 281 89 (32) 9

During infusion

216 52 (24) 203 80 (39) 15

Morbidity Outcomes

Results: Functional Status at Day 28

32.3 30.6

7.2 7.9

23.5 20.9

12.29.8

24.730.8

rhAPC PLACEBO0%

20%

40%

60%

80%

100%

Home

Nurs Home

Hosp

ICU

DIED

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

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

Strata Total Therapy Died by Day 28

Original 360 rhAPC 102 (28)

360 Placebo 109 (30)

720 P=0.5665

Amended 490 rhAPC 108 (22)

480 Placebo 150 (31)

970 P=0.0012

1690

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 (%)

RR 95% CI

No 41 14 (34) 40 17 (43) 0.80 0.46, 1.40

Yes 319 88 (28) 320 92 (29) 0.96 0.75, 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: – 3rd and 4th 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 DatabaseNo 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.

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

0%

20%

40%

60%

80%

100%

Cardiovascular Respiratory Hematologic Renal

Pediatric (N=32) Adult (N=1690)

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

0%

10%

20%

30%

40%

50%

60%

One Two Three Four

Pediatric (N=32) Adult (N=1690)

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

0%

10%

20%

30%

40%

50%

60%

Blood CNS Lung Intra-Abd UTI

Pediatric (N=83) Adult (N=1690)

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

0%

5%

10%

15%

20%

25%

30%

35%

Gram Positive Gram Negative Mixed Gram

Pediatric (N=83) Adult (N=1690)

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

0%

5%

10%

15%

20%

25%

Pediatric Index ofMortality

APACHE II Score

Pediatric (N=83) Adult (N=1690)

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

0%

5%

10%

15%

20%

14 Day Mortality 14 Day Mortality

Pediatric (N=83) Adult (N=1690)

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

0%

20%

40%

60%

80%

100%

SeriousBleedingEvents

BleedingAE

SAE AE

Pediatric (N=83) Adult (N=850)

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 2Patient Deaths by Treatment Group

Treatment group 48 hr infusion

96 hr infusion

12 ug/kg/hr 3/11 (27%) 5/14 (36%)

18 ug/kg/hr 3/11 (27%) 7/15 (47%)

24 ug/kg/hr 0/12 (0%) 5/15 (33%)

30 ug/kg/hr 3/12 (25%) Not Studied

All Placebo 14/41 (34%)

Safety Phase 2

• SAE during infusion period by treatment group– 48 hr rhAPC 7/46 (15%)– 96 hr rhAPC 12/44 (27%)– All Placebo 10/41 (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 TrialsNew 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 8/520 1.5% 95% CI (.67, 3.01)

Serious Bleeding EventsProtocol 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 EventsInfusion Period

Site rhAPC (n=850) Placebo (n=840)Total 20 8Gastrointestinal 5 4Intra-abdominal 2 3Intra-thoracic 4 0Retroperitoneal 3 0Intracranial hemorrhage 2 0Undefined hemorrhage 1 1Genitourinary 2 0Skin/soft tissue 1 0

Safety During the Infusion Period

2% 1%

19%11% 7% 7%

69% 65%

0%

10%

20%

30%

40%

50%

60%

70%

SeriousBleeding

Event

BleedingAE

SAE AE

rhAPC (N=850) Placebo (N=840)

First APACHE II QuartileEvents During Drug Infusion

Event (%)rhAPC Placebo Treatment

differenceBleedingAE

38/218 (17%) 17/210 (8%) 9%

SeriousBleedingEvent

9/218 (4%) 0 4%

Subjects Requiring Transfusion During 28 Day Study Period

rhAPCN (%)

PlaceboN (%)

PRBC 533/850 (63) 490/840 (58)

FFP 200/850 (24) 162/840 (19)

Platelets 114/850 (13) 96/840 (11)

Serious Bleeding Events in Patients Laboratory Evidence of

DIC

rhAPCN (%)

PlaceboN (%)

Subjects in DIC 28/800 (4) 16/774 (2)

Subjects withunknown DIC

2/49 (4) 1/66 (2)

Bleeding Events and Baseline Coagulation Factors

• Pooled phase 2 and phase 3 data

• rhAPC = 940 Placebo = 881

Baseline APTT and Adverse Bleeding Events

ActivatedPartialThromboplastinTime

rhAPCN (%)

PlaceboN (%)

APTT< 2x ULN 147/825 (18) 80/761 (11)

APTT> 2x ULN 9/44 (20) 5/37 (14)

Baseline PT and Adverse Bleeding Events

ProthrombinTime

rhAPCN (%)

PlaceboN (%)

PT < 1.2x ULN 49/354 (14) 29/311 (9)

PT > 1.2x ULN 108/516 (21) 55/484 (11)

Baseline Platelet Count and Adverse Bleeding Events

Platelet Count rhAPCN (%)

PlaceboN (%)

Platelet > 50,000/mm3 133/771 (17) 71/709 (10)

Platelet < 50,000/mm3 5/19 (26) 7/24 (29)

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

Treatment rhAPCEvents (%)

PlaceboEvents (%)

ReceivedHeparin

15/634 (2) 5/637 (1)

No Heparin 5/216 (2) 3/203 (1)

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

Treatment rhAPCEvents (%)

PlaceboEvents (%)

ReceivedHeparin

111/634 (18) 67/637 (11)

No Heparin 49/216 (23) 24/203 (12)

Subgroups

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

Baseline Surgical StatusPhase 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)

0%

5%

10%

15%

20%

25%

30%

Mortality >=1 SAE >=1 SAEinfusion

BE-SAE BE-SAEinfusion

Median and Below 14-45 ng/ml Above Median 45.1-390 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 EvaluationOutstanding issues regarding sensitivity,

specificity and quantificationDifficult to assess true incidence of Anti-APC

antibodies

Immunogenicity

• Patients tested: Phase 2 and 3– 942 subjects - 370 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