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

Sponsors 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
rhAPC (all doses) Placebo Total

Patients Total (N) 90

41 131

28-Day Mortality N (%) 26 (29%)

14 (34%) 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-MantelHaenszel 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 AGE <60 years 44 44 rhAPC (850) (%) Placebo (840) (%)

60 years
GENDER Female

56
44

56
42

Male
ETHNIC ORIGIN Caucasian

56
82

58
82

African descent
Hispanic Other

8
4 6

7
5 6

Results:

Demographics Disease Severity

rhAPC (850) (%) Placebo (840) (%) 35 14 9 22 4 3

PREEXISTING CONDITIONS
Hypertension Myocardial infarction Congestive cardiomyopathy Diabetes Pancreatitis Liver disease 38 12 6 21 3 2

COPD
Cancer Recent Trauma

22
17 3

26
19 5

Results:

Demographics Disease Severity

RECENT SURGICAL HISTORY Elective surgery Emergency Surgery No history of surgery rhAPC (850) Placebo (840) (%) (%) 6 21 74 6 21 73

Results:

Demographics Disease Severity

MEASURE OF DISEASE SEVERITY APACHE II score mean Mechanical ventilation (%) Shock (%) Use of any vasopressor (%) rhAPC (850) 25 73 70 72 Placebo (840) 25 78 72 76

Use of dobutamine (%)

14

14

Results:

Demographics Disease Severity

# of ORGAN FAILURES (OF) 1 2 rhAPC (850) (%) 25 32 Placebo (840) (%) 24 33

3
4 5
*Time from 1st OF to start drug

25
14 4
18 hours

26
14 4
17 hours

Results:

Phase 3 Study
Primary Efficacy Endpoint
Treatment Patients (N) 850
840 1690

rhAPC
Placebo Total

28-Day Mortality N (%) 210 (24.7%)

259 (30.8%) Stratified, CMH p=0.005

Results:

Primary Efficacy Endpoint

ITT Population
100
80 SURVIVAL (%) 60 40

20
0 0 4 8 12 Placebo 16 rhAPC 20 24 28 TIME (Days)

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 (%) 59 /375 (16) 151 /475 (32) Placebo (840) Mortality (%) 75 /366 (21) 184 /474 (39) Mort Diff (%) -5 RR 95% CI

<60

0.77

0.56, 1.05 0.69, 0.97

60

-7

0.82

Results:

Mortality as a Function of Age

Placebo rhAPC

60 50 40 30 20 10 0
18-20 21-30 31-40 n= (16) (86) (136) 41-50 51-60 61-70 (217) (286) (356) 71-80 81-90 91-100 (451) (129) (13)

Mortality (%)

Age (years)

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 rhAPC (850) Quartile Mortality (score) (%) 1st (3-19) 2nd (20-24) 3rd (25-29) 4th (30-53) 33 /218 (15) 49 /218 (22) 48 /204 (24) 80 /210 (38) Placebo (840) Mortality (%) 26 /215 (12) 57 /222 (26) 58 /162 (36) 118 /241 (49) Mort Diff (%) +3 -4 -12 -11 RR 95% CI

1.25 0.88 0.66 0.78

0.78, 2.02 0.63, 1.22 0.48, 0.91 0.63, 0.96

interaction p = 0.09

Results:

Mortality as a Function of APACHE II

Placebo 80 70 60 50 40 30 20 10 0 5-10 10-15 n=(24) (152) 15-20 (330) 20-25 (456) 25-30 (345) 30-35 (227) 35-40 (102) 40-45 (37) 45-50 (13) rhAPC

Mortality (%)

APACHE II

Results:

Mortality as a Function of APACHE II Quartiles

APACHE II Quartiles (score) Q1+Q2 (<25) Q3+Q4 (25) rhAPC (850) Mortality (%) 82/436 (19) 128/414 (31) Placebo (840) Mortality (%) 83/437 (19) 176/403 (44) Mort Diff (%) 0 RR 95% CI

0.99

0.75, 1.30 0.59, 0.85

-13

0.71

Results:

Mortality as a Function of Organ Failure

# OF rhAPC (850) Placebo (840) Mortality (%) Mortality (%) 42 /215 (20) 56 /270 (21) 56 /214 (26) 46 /119 (39) 10 /31 (32) 43 /203 (21) 71/273 (26) 75 /218 (34) 54 /116 (47) 16 /30 (53) Mort Diff (%) -1 -5 -8 -8 -21 RR 95% CI

1 2 3 4 5

0.92 0.80 0.76 0.83 0.60

0.63, 1.35 0.59, 1.08 0.57, 1.02 0.62, 1.12 0.33, 1.11

Results:

Mortality as a Function Disease Severity (Organ Failure)

60 50

Mortality (%)

40 30 20 10 0 1 2 3 4 5 Number of Organ Dysfunctions Placebo rhAPC

Mortality as a Function of Shock

Shock rhAPC Mortality (%) 53 /252 (21) Placebo Mortality (%) 53 /238 (22) Mort Diff (%) -1 RR 95% CI RR 0.67, 1.32

No

0.94

Yes

157 /598 (26)

206 /602 (34)

-8

0.77

0.64, 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 0.1
rhAPC Better

Placebo Better

10

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 Deficient (80%) Not deficient (>80%) Unknown or Absent rhAPC Mortality (%) 182 /709 (26) 14 /90 (16) Placebo Mortality (%) 215 /670 (32) 28 /105 (27) Mort Diff (%) -6 RR 95% CI

0.80

0.68, 0.95 0.33, 1.04

-11

0.58

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 (%) 196 /800 (25) 14 /49 (29) Placebo Mortality (%) 243 /774 (31) 16 /66 (24) Mort Diff (%) -6 +5 RR 95% CI 0.67, 0.92 0.65, 2.16

DIC
Unknown or Absent

0.78 1.18

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 (%) At baseline 532 138 (26) Placebo Total N (%) 559 170 (30) Mort Diff (%) 4

Heparin

During infusion At baseline

During infusion

634

158 (25)

637

179 (28)

Not on Heparin
318
216

72 (23)
52 (24)

281
203

89 (32)
80 (39)

9
15

Morbidity Outcomes

Results:

Functional Status at Day 28

100% 24.7 80% 12.2 30.8

60%
23.5 40% 7.2

9.8 20.9 7.9

DIED ICU Hosp Nurs Home Home

20%

32.3

30.6

0% rhAPC PLACEBO

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

rhAPC N (%) Original 57 (16) Placebo N (%) 64 (18)

Amendment A

50 (10)

79 (16)

Mortality:
Original vs. Amended Protocol
Strata
Original

Total
360 360 720 490 480 970 1690

Therapy

Died by Day 28

Amended

rhAPC 102 (28) Placebo 109 (30) P=0.5665 rhAPC 108 (22) Placebo 150 (31) P=0.0012

Cumulative 28 Day Mortality Over Time

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

Meet rhAPC Placebo Mortality Mortality New Incl Total N N (%) Total N N (%) No Yes 41 319 14 (34) 88 (28) 40 320 RR 95% CI 0.46, 1.40 0.75, 1.23

17 (43) 0.80 92 (29) 0.96

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 Database
No controlled efficacy trials
Total Pediatric data base 121 pts

Safety PK/PD sepsis study Purpura Fulminans Additional uncontrolled trials -

83 pts. 14 pts.
24 pts.

Pediatric Sepsis Study vs. Adult Phase 3

Type of Organ Failure (% of Patients)
Pediatric (N=32) 100% 80% 60% 40% 20% 0%
Cardiovascular Respiratory Hematologic Renal

Adult (N=1690)

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

Pediatric (N=32) 60% 50% 40% 30% 20% 10% 0% One Two Three Four Adult (N=1690)

Pediatric Sepsis Study vs. Adult Phase 3 Primary Site of Infection (% of Patients)
Pediatric (N=83) 60% 50% 40% 30% 20% 10% 0% Blood CNS Lung Intra-Abd UTI Adult (N=1690)

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

Pediatric (N=83) 35% 30% 25% 20% 15% 10% 5% 0% Gram Positive Gram Negative Mixed Gram Adult (N=1690)

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

Pediatric (N=83) 25% 20% 15% 10% 5% 0% Pediatric Index of Mortality APACHE II Score Adult (N=1690)

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

Pediatric (N=83) 20% 15% 10% 5% 0% 14 Day Mortality 14 Day Mortality Adult (N=1690)

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

Pediatric (N=83) 100% 80% 60% 40% 20% 0% Serious Bleeding Bleeding AE Events SAE AE 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 2
Patient Deaths by Treatment Group
Treatment group 12 ug/kg/hr 18 ug/kg/hr 24 ug/kg/hr 30 ug/kg/hr All Placebo 48 hr infusion 3/11 (27%) 3/11 (27%) 0/12 (0%) 3/12 (25%) 96 hr infusion 5/14 (36%) 7/15 (47%) 5/15 (33%)
Not Studied

14/41 (34%)

Safety Phase 2
SAE during infusion period by treatment group
48 hr rhAPC 96 hr rhAPC All Placebo 7/46 (15%) 12/44 (27%) 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 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 8/520 1.5% 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

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

Safety During the Infusion Period

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

70% 60% 50% 40% 30% 20% 10% 0%

69%

65%

2% 1%

19% 11% 7% 7% SAE AE

Serious Bleeding Bleeding AE Event

First APACHE II Quartile

Events During Drug Infusion

Treatment difference Bleeding 38/218 (17%) 17/210 (8%) 9% AE Serious 9/218 (4%) 0 4% Bleeding Event

Event rhAPC

(%) Placebo

Subjects Requiring Transfusion During 28 Day Study Period

rhAPC Placebo N (%) N (%) 533/850 (63) 490/840 (58) 200/850 (24) 162/840 (19) 114/850 (13) 96/840 (11)

PRBC FFP Platelets

Serious Bleeding Events in Patients Laboratory Evidence of DIC

rhAPC Placebo N (%) N (%) Subjects in DIC 28/800 (4) 16/774 (2) Subjects with unknown 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

Activated rhAPC Partial N (%) Thromboplastin Time APTT< 2x ULN 147/825 (18) APTT> 2x ULN 9/44 (20) Placebo N (%)

80/761 (11) 5/37 (14)

Baseline PT and Adverse Bleeding Events

Prothrombin Time PT < 1.2x ULN PT > 1.2x ULN rhAPC N (%) 49/354 (14) 108/516 Placebo N (%) 29/311 (9) (11)

(21) 55/484

Baseline Platelet Count and Adverse Bleeding Events

Platelet Count rhAPC N (%) Placebo N (%)

Platelet > 50,000/mm3 133/771 (17) 71/709 (10) Platelet < 50,000/mm
3

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 Received Heparin No Heparin

rhAPC Placebo Events (%) Events (%) 15/634 (2) 5/637 (1) 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 Received Heparin No Heparin

rhAPC Placebo Events (%) Events (%) 111/634 (18) 67/637 (11) 49/216 (23) 24/203 (12)

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%) rhAPC 20/63 (32%) placebo 49/187 (26%)

Elective post-op patient with sepsis

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)
Median and Below 14-45 ng/ml Above Median 45.1-390 ng/ml 30% 25% 20% 15% 10% 5% 0% Mortality >=1 SAE >=1 SAE BE-SAE BE-SAE infusion infusion

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 - 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 multiorgan 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