Biologics License Application: Recombinant Human Activated Protein C rhAPC drotrecogin alfa activate

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
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.

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 gt 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
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 level0.0002), October 1999
• 1520 patients (alpha level0.0118), 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
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Results Demographics Disease Severity
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Results Demographics Disease Severity
13
Results Demographics Disease Severity
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Results Demographics Disease Severity
Time from 1st OF to start drug 18
hours 17 hours
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Results Phase 3 StudyPrimary Efficacy Endpoint
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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
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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
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Results Mortality as a Function of Age
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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
interaction p 0.09
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Results Mortality as a Function of APACHE II
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Results Mortality as a Function of APACHE II
Quartiles
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ResultsMortality as a Function of Organ Failure
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Results Mortality as a Function Disease
Severity (Organ Failure)
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Mortality as a Function of Shock
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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
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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
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Results Mortality in Patients with Laboratory
Evidence of DIC
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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
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Morbidity Outcomes
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Results Functional Status at Day 28
100
24.7
30.8
80
12.2
DIED
9.8
60
ICU
23.5
Hosp
20.9
Nurs Home
40
7.2
7.9
Home
20
32.3
30.6
0
rhAPC
PLACEBO
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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
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MortalityOriginal vs. Amended Protocol
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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
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Summary of Efficacy

• 28 day all cause mortality
• 24.7 rhAPC vs. 30.8 placebo (p0.005)

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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
• gt 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 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.

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Pediatric Sepsis Study vs. Adult Phase 3 Type of
Organ Failure ( of Patients)
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Pediatric Sepsis Study vs. Adult Phase 3 of
Organ Failures ( of Patients)
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Pediatric Sepsis Study vs. Adult Phase 3 Primary
Site of Infection ( of Patients)
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Pediatric Sepsis Study vs. Adult Phase 3 Type of
Pathogen ( of Patients)
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Pediatric Sepsis Study vs. Adult Phase 3
Predicted Mortality ( of Patients)
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Pediatric Sepsis Study vs. Adult Phase 3 Actual
Mortality ( of Patients)
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Pediatric Sepsis Study vs. Adult Phase 3 Safety
Parameters ( of Patients)
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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
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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 gt 2 units (phase 2) or gt 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 (n850) Placebo (n840)
• Total 20 8
• Gastrointestinal 5 4
• Intra-abdominal 2 3
• Intra-thoracic 4 0
• Retroperitoneal 3 0
• Intracranial hemorrhage 2 0
• Undefined hemorrhage 1 1
• Genitourinary 2 0
• Skin/soft tissue 1 0

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Safety During the Infusion Period
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First APACHE II QuartileEvents During Drug
Infusion
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Subjects Requiring Transfusion During 28 Day
Study Period
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Serious Bleeding Events in Patients Laboratory
Evidence of DIC
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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
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Baseline PT and Adverse Bleeding Events
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Baseline Platelet Count and Adverse Bleeding
Events
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Serious Bleeding Events in Subjects who Received
Heparin(Received DVT prophylactic dose at
baseline up to day 5)
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Bleeding Adverse Events in Subjects who Received
Heparin(Received DVT prophylactic dose at
baseline up to day 5)
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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 (N326, median 45 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 Evaluation
• Outstanding issues regarding sensitivity,
  specificity and quantification
• Difficult 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

84
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

85
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 (N520)
• 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