Anti-Infective Drugs Advisory Committee Meeting

10/17/01


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Table of Contents

Anti-Infective Drugs Advisory Committee Meeting

Xigris Drotrecogin Alfa (Activated)

Proposed Indication Statement

Burden of Severe Sepsis

Reference Diseases

600 Patients with Severe Sepsis Die Each Day in the United States

Drotrecogin Alfa (Activated) Recombinant Human Activated Protein C

Agenda Lilly Advisory Committee Presentation

External Consultants

Pathophysiology of Severe Sepsis Rationale for Drotrecogin Alfa (Activated) for the Treatment of Severe Sepsis

Sepsis and Severe Sepsis

Pathogenesis of Severe Sepsis: Inflammation/Coagulation as Intervention Target

The Perils of Subgroup Analysis in Sepsis Trials

Activation of Inflammation and Coagulation in Severe Sepsis

Systemic Host Response to Infection–Similar Across Causative Microorganism Class

Activated Protein C – Mechanisms of Activity

Baboon Sepsis Model: Effect of Activated Protein C on Survival

Plasma Human Activated Protein C Versus Heparin: Double-Blind Trial in Disseminated Intravascular Coagulation

Rationale for Use of Activated Protein C in Patients with Severe Sepsis

Efficacy and Safety of Drotrecogin Alfa (Activated) in the Treatment of Severe Sepsis

Objectives

Proposed Indication Statement

Rationale for Indication Statement

Phase 2 Study F1K-MC-EVAA

Phase 2 Study F1K-MC-EVAA

Study F1K-MC-EVAA Treatment Assignments (N=131)

D-dimer: Median Percent Change from Baseline to End of Infusion

IL-6: Median Percent Change from Baseline to End of Infusion

Dose Selection for Phase 3

Pivotal Phase 3 Study F1K-MC-EVAD

Phase 3 Study F1K-MC-EVAD

Patient Population (EVAD)

Study Design (EVAD)

Timeline of Study (EVAD)

Patient Disposition (EVAD)

Investigator Assessment of Primary Site of Infection (EVAD)

Baseline Microbiology Data (EVAD)

All Patients Had Laboratory Evidence of Coagulopathy

Most Patients Had Evidence of Impaired Fibrinolysis and Systemic Inflammation (EVAD)

Severe Sepsis Population (EVAD)

Drotrecogin Alfa (Activated) Reduced 28-Day All-Cause Mortality

Drotrecogin Alfa (Activated) Improves Survival

28-Day All-Cause Mortality Sensitivity Analyses

Cumulative Mortality for Sites Enrolling Under Both Original and Amended Protocol

Mortality by Patient Demographics (EVAD)

Mortality by Region (EVAD)

Drotrecogin Alfa (Activated) Improves Cardiovascular and Respiratory Function

Safety Assessment

Bleeding Events Reported as Serious Adverse Events (EVAD)

Procedure and Non-Procedure Related Serious Bleeding Events: 28-Day Study Period

No Other Safety Concerns

Overview of Ongoing Severe Sepsis Studies Clinical Update (as of 30 September 2001)

Intracranial Hemorrhage Summary (as of 30 September 2001)

Mortality by Platelet Count (EVAD)

Conclusions from Adult Studies

Formal Benefit-Risk Assessment of Drotrecogin Alfa (Activated) in the Treatment of Severe Sepsis

Benefit-Risk Objectives

Patient Classification by Survival and Serious Bleeding

Benefit-Risk for Entire Patient Population Net Benefit for Drotrecogin Alfa (Activated)

Explorations of Potential Differential Effects with Drotrecogin Alfa (Activated) Across Subgroups

Caveats Associated with Interpreting Subgroup Analyses

Assessing Consistency Across Subgroups

Subgroups: Bleeding Risk Summary

Mortality Subgroup Analyses

Subgroups – Demographic Characteristics

Subgroups – Disease Severity Measures

Subgroups – Disease Severity Measures

Subgroups – Disease Severity Measures

Benefit: Mortality by Subgroups Consistency Assessment

Favorable Benefit-Risk Associated with Drotrecogin Alfa (Activated)

Advisory Committee Questions based on Subgroup Explorations:

Clinical Trial Definition of DIC

Summary of Drotrecogin Alfa (Activated) Treatment Effect and Low-Dose Heparin Use

Summary of Drotrecogin Alfa (Activated) Treatment Effect and Low-Dose Heparin Use

Drotrecogin Alfa (Activated) Survival Benefit in Patients with Less Disease Severity

Survival Benefit Evident in Patients with Less Disease Severity

Survival Benefit Evident in Less Severe Patients within 1st APACHE II Quartile

Clinical Perspective of Treatment-by-Disease Severity Analyses

Treatment-by-Severity Analyses

Study F1K-MC-EVAD: Mortality by Number of Organ Failures/Single Organ Failures

Study F1K-MC-EVAD: Mortality by Cardiovascular Disease Severity Measures

Study F1K-MC-EVAD: Mortality by Baseline Cardiovascular SOFA Score

Study F1K-MC-EVAD: Mortality by Baseline Respiratory SOFA Score

1st Apache II Quartile Baseline Characteristics (N=433)

Subgroup Conclusions

Clinical Experience in Pediatric Patients with Severe Sepsis

Rationale for Pediatric Development Program

PPT Slide

Overview of Pediatric Experience (as of 30 September 2001)

Pediatric Phase 1B Study F1K-MC-EVAO

Baseline Characteristics of Pediatric and Adult Patients

Pediatric Baseline Biomarkers of Disease Severity are Similar to Adults

Clearance Versus Age in Adult and Pediatric Patients With Severe Sepsis

Median Pediatric Biomarker Change from Baseline to End of Infusion are Similar to Adult

Serious Bleeding Events – Pediatric and Adult Patients

Safety Summary of All Pediatric Experience (as of 30 September 2001)

Conclusions from Pediatric Studies

Overall Conclusions

Observed Number Needed to Treat (NNT) Compared to Thrombolytic Trials

Proposed Indication Statement

Author: amos, jane