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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
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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.
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Review of Mortality Effect by Patient Subgroups
• Patient age• Disease severity
– APACHE II– Organ failure– Shock
• Hematologic parameters– Protein C– DIC
• Use of heparin
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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
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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
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Review of Mortality Effect by Patient Subgroups
• Patient age
• Disease severity– APACHE II– Organ failure– Shock
• Hematologic parameters– Protein C– DIC
• Use of heparin
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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
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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
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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
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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
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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
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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
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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
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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
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Review of Mortality Effect by Patient Subgroups
• Patient age
• Disease severity– APACHE II– Organ failure– Shock
• Hematologic parameters– Protein C– DIC
• Use of heparin
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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
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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
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Review of Mortality Effect by Patient Subgroups
• Patient age
• Disease severity– APACHE II– Organ failure– Shock
• Hematologic parameters– Protein C– DIC
• Use of heparin
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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
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Morbidity Outcomes
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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
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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
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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%)
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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%)
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Effect of Protocol Change: DNR Orders
79 (16)50 (10)Amendment A
64 (18)57 (16)Original
Placebo
N (%)
rhAPC
N (%)
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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
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Cumulative 28 Day Mortality Over Time
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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
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Summary of Efficacy
• 28 day all cause mortality
24.7% rhAPC vs. 30.8% placebo (p=0.005)
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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
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Outline of Presentation
• Pediatrics
• Adult safety phase 2
• Adult safety phase 3
• Immunogenicity
• Summary
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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.
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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)
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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)
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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)
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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)
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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)
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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)
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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)
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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
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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
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Outline of Presentation
• Pediatrics
• Adult safety phase 2
• Adult safety phase 3
• Immunogenicity
• Summary
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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
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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%)
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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
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Outline of Presentation
• Pediatrics
• Adult safety phase 2
• Adult safety phase 3
• Immunogenicity
• Summary
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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
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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)
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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
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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
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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)
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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%
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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)
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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)
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Bleeding Events and Baseline Coagulation Factors
• Pooled phase 2 and phase 3 data
• rhAPC = 940 Placebo = 881
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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)
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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)
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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)
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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)
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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)
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Subgroups
• No differences in safety profile were observed in the following sub-groups– Gender– Origin– Age
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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
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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
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Outline of Presentation
• Pediatrics
• Adult safety phase 2
• Adult safety phase 3
• Immunogenicity
• Summary
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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
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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)
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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
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Outline of Presentation
• Pediatrics
• Adult safety phase 2
• Adult safety phase 3
• Immunogenicity
• Summary
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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
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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
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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%
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Summary of Safety - Adults
• One subject with anti-APC Ab developed DVT
• No other pattern of adverse events noted comparing rhAPC to placebo
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Safety Conclusion
• Difficult disease process to detect adverse events
• Trend in intracranial hemorrhage
• True risk uncertain