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1 Anti-Infective Drugs Advisory Committee Meeting Xigris™ Drotrecogin Alfa (Activated) October 16, 2001 Eli Lilly and Company 6058.01.

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Presentation on theme: "1 Anti-Infective Drugs Advisory Committee Meeting Xigris™ Drotrecogin Alfa (Activated) October 16, 2001 Eli Lilly and Company 6058.01."— Presentation transcript:

1 1 Anti-Infective Drugs Advisory Committee Meeting Xigris™ Drotrecogin Alfa (Activated) October 16, 2001 Eli Lilly and Company

2 2 Xigris Drotrecogin Alfa (Activated) Holger K. Schilske, MD, PhD Executive Director and Xigris TM Product Team Leader Eli Lilly and Company

3 33 Proposed Indication Statement Drotrecogin alfa (activated) is indicated for the treatment of adult and pediatric patients with sepsis associated with acute organ dysfunction (severe sepsis)Drotrecogin alfa (activated) is indicated for the treatment of adult and pediatric patients with sepsis associated with acute organ dysfunction (severe sepsis) Treatment with drotrecogin alfa (activated) reduces mortality in patients with severe sepsisTreatment with drotrecogin alfa (activated) reduces mortality in patients with severe sepsis

4 44 Burden of Severe Sepsis Annual incidence: ~750,000 cases in US 1Annual incidence: ~750,000 cases in US 1 Case fatality rate: 28% to 50% 2Case fatality rate: 28% to 50% 2 Direct costs – National costs: ~$16.7 billion 1Direct costs – National costs: ~$16.7 billion 1 Incidence on the rise:Incidence on the rise: –Aging population –Incidence projected to rise to 1.0 million cases annually in US during the next decade 1 1 Angus DC et al Crit Care Med 29: Natanson Crit Care Med 26:

5 55 Reference Diseases Incidence in US (cases per 100,000)Incidence in US (cases per 100,000) –AIDS 1 17 –Colon and rectal cancer 2 48 –Breast cancer –Congestive heart failure 3 ~196 –Severe sepsis 4 ~300 Number of deaths in US each yearNumber of deaths in US each year –Acute myocardial infarction 5 218,000 –Severe sepsis 4 215, Centers for Disease Control and Prevention Incidence rate for American Cancer Society Incidence rate for American Heart Association Angus DC et al Crit Care Med 29: National Center for Health Statistics

6 6 600 Patients with Severe Sepsis Die Each Day in the United States 600 Patients with Severe Sepsis Die Each Day in the United States Xigris Reduces the Relative Risk of 28-Day All-Cause Mortality by 19.4% 28-Day All-Cause Mortality by 19.4%

7 Drotrecogin Alfa (Activated) Recombinant Human Activated Protein C

8 88 Agenda Lilly Advisory Committee Presentation IntroductionIntroduction –Holger K. Schilske, MD, PhD – Eli Lilly and Company Pathophysiology of Severe Sepsis, Rationale for Drotrecogin Alfa (Activated) for the Treatment of Severe SepsisPathophysiology of Severe Sepsis, Rationale for Drotrecogin Alfa (Activated) for the Treatment of Severe Sepsis –Steven M. Opal, MD – Professor of Medicine, Brown University School of Medicine Efficacy and Safety of Drotrecogin Alfa (Activated) in the Treatment of Severe SepsisEfficacy and Safety of Drotrecogin Alfa (Activated) in the Treatment of Severe Sepsis –William Macias, MD, PhD – Eli Lilly and Company Formal Benefit-Risk Assessment of Drotrecogin Alfa (Activated) in the Treatment of Severe SepsisFormal Benefit-Risk Assessment of Drotrecogin Alfa (Activated) in the Treatment of Severe Sepsis –Jeffrey Helterbrand, PhD – Eli Lilly and Company Clinical Experience in Pediatric Patients with Severe Sepsis and Overall ConclusionsClinical Experience in Pediatric Patients with Severe Sepsis and Overall Conclusions –William Macias, MD, PhD – Eli Lilly and Company

9 99 External Consultants Gordon Bernard, MD Professor of Medicine Pulmonary Medicine Division Vanderbilt University Medical Center Brett Giroir, MD Chief Medical Officer Children's Medical Center, Dallas Associate Dean for Clinical Affairs UT Southwestern Medical Center Mitchell Levy, M.D. Associate Professor of Medicine Brown University School of Medicine Medical Director Medical Intensive Care Unit Rhode Island Hospital Steven M. Opal, MD Professor of Medicine Brown University School of Medicine Chief Infectious Disease Division Memorial Hospital of Rhode Island Michael Seneff, M.D. Medical Director Intensive Care Unit George Washington University Medical Center

10 10 Pathophysiology of Severe Sepsis Rationale for Drotrecogin Alfa (Activated) for the Treatment of Severe Sepsis Steven M. Opal, MD Professor of Medicine, Brown University School of Medicine Chief, Infectious Disease Division Memorial Hospital of Rhode Island

11 11 Sepsis and Severe Sepsis Sepsis is a syndrome characterized by host systemic inflammatory and procoagulant responses (SIRS) to pathogensSepsis is a syndrome characterized by host systemic inflammatory and procoagulant responses (SIRS) to pathogens An intense host response may lead to organ dysfunction; this is designated severe sepsisAn intense host response may lead to organ dysfunction; this is designated severe sepsis The mortality rate in severe sepsis remains high despite appropriate antibiotic and supportive therapyThe mortality rate in severe sepsis remains high despite appropriate antibiotic and supportive therapy

12 12 Infection Microbial Products (exotoxin/endotoxin) Cellular Responses Oxidases PlateletActivation KininsComplement Coagulopathy/DIC Vascular/Organ System Injury Multi-Organ Failure Death Endothelial damage Coagulation Activation Cytokines TNF, IL-1, IL Pathogenesis of Severe Sepsis: Inflammation/Coagulation as Intervention Target

13 13 The Perils of Subgroup Analysis in Sepsis Trials Compound Post-hoc Subgroup with Potential Efficacy Outcome of Follow-up Study HA-1A Gm– Bacteremia 49% vs. 30% (p=0.014) Gm– Bacteremia 32% vs. 33% (p=0.86) E5 Gm– Sepsis w/o Shock 49% vs. 30% (p=0.01) Gm– Sepsis w/o Shock 30% vs. 26% (p=0.21) p55 TNF Severe Sepsis w/ Early Septic Shock 36% vs. 37% vs. 23% (p=0.07) Severe Sepsis w/ Early Septic Shock 28% vs. 27% (p=0.14) IL-1ra Predicted Risk of Mortality Greater than 24% 45% vs. 38% vs. 35% (p=0.005) Severe Sepsis 36% vs. 33% (p=0.36)

14 14 Activation of Inflammation and Coagulation in Severe Sepsis Activation of coagulation occurs early in severe sepsis and is associated with:Activation of coagulation occurs early in severe sepsis and is associated with: –Increased thrombin generation and fibrin formation –Impaired fibrinolysis –Depletion of key regulatory proteins (eg, Protein C and antithrombin) –Decreased capacity to activate Protein C –Systemic inflammation resulting from activation of monocytes, neutrophils, and endothelium

15 15 Systemic Host Response to Infection–Similar Across Causative Microorganism Class Causative microorganism classification–CEC adjudicated Baseline biomarker data from Study F1K-MC-EVAD Percent of Patients with Abnormal Values Suspected - No Organism Identified Pure Fungal Pure Gram Positive Pure Gram Negative IL-6Prothrombin Time Protein CD-Dimer

16 16 TAFI EPCR ? X X X X X Activated Protein C – Mechanisms of Activity Monocyte Activation Increased Fibrinolysis Prothrombin Coagulation Cascade Neutrophil Adhesion Thrombin Va VIIIa Cell Activation Via PARs Fibrin/Platelets aPC Receptor PAI-1 PC Thrombomodulin Thrombin aPC Tr PSPS CD1/ MHC

17 17 Baboon Sepsis Model: Effect of Activated Protein C on Survival Lethal E coli Model Infusing exogenous Activated Protein C reduces mortality Sub-lethal E coli Model Administration of anti-APC antibodies converts a sub-lethal dose to lethal dose Administration of exogenous Activated Protein C with anti-APC antibodies prevents increase in lethality Administration of exogenous Activated Protein C with anti-APC antibodies prevents increase in lethality Taylor FB et al J Clin Invest 79:

18 18 Plasma Human Activated Protein C Versus Heparin: Double-Blind Trial in Disseminated Intravascular Coagulation Okajima et al Blood 96:50a Abstract

19 19 Rationale for Use of Activated Protein C in Patients with Severe Sepsis Pathophysiology of sepsis–infection, inflammation, and coagulation activation are tightly linkedPathophysiology of sepsis–infection, inflammation, and coagulation activation are tightly linked Multiple mechanisms of action of Activated Protein C may disrupt the linkage between inflammation and coagulation resulting in improved survivalMultiple mechanisms of action of Activated Protein C may disrupt the linkage between inflammation and coagulation resulting in improved survival Baboon E coli sepsis model suggests critical role of Activated Protein C for survivalBaboon E coli sepsis model suggests critical role of Activated Protein C for survival Activated Protein C is preferred because the patient's ability to convert Protein C in vivo may be impairedActivated Protein C is preferred because the patient's ability to convert Protein C in vivo may be impaired

20 20 Efficacy and Safety of Drotrecogin Alfa (Activated) in the Treatment of Severe Sepsis William Macias, MD, PhD Medical Director Xigris Product Team Eli Lilly and Company

21 21 Objectives Provide rationale for proposed indication statementProvide rationale for proposed indication statement Review data supporting recommended dose and dose duration for drotrecogin alfa (activated)Review data supporting recommended dose and dose duration for drotrecogin alfa (activated) –24  g/kg/hr dose for 96 hours Review primary efficacy and safety data from pivotal Phase 3 study F1K-MC-EVADReview primary efficacy and safety data from pivotal Phase 3 study F1K-MC-EVAD –Favorable benefit-risk profile in severe sepsis Provide clinical update on ongoing studiesProvide clinical update on ongoing studies Review clinical experience in pediatric patients with severe sepsisReview clinical experience in pediatric patients with severe sepsis

22 22 Proposed Indication Statement Drotrecogin alfa (activated) is indicated for the treatment of adult and pediatric patients with sepsis associated with acute organ dysfunction (severe sepsis)Drotrecogin alfa (activated) is indicated for the treatment of adult and pediatric patients with sepsis associated with acute organ dysfunction (severe sepsis) Treatment with drotrecogin alfa (activated) reduces mortality in patients with severe sepsisTreatment with drotrecogin alfa (activated) reduces mortality in patients with severe sepsis Drotrecogin alfa (activated) is recommended for use as adjunctive therapy to best standard care

23 23 Rationale for Indication Statement Definitions of sepsis and severe sepsisDefinitions of sepsis and severe sepsis –Based on 1991 SCCM/ACCP consensus conference Efficacy in adults with severe sepsisEfficacy in adults with severe sepsis –Based on data from one pivotal Phase 3 study with supporting data from one Phase 2 study Use in pediatric patients with severe sepsisUse in pediatric patients with severe sepsis –Supported by open-label, safety, and pharmacokinetic studies in patients aged 38 weeks gestation to 18 years –Efficacy requires extrapolation from adult studies Inclusion of mortality reductionInclusion of mortality reduction –Primary benefit is improved survival –For use in patients at risk of death from severe sepsis

24 24 Phase 2 Study F1K-MC-EVAA

25 25 Phase 2 Study F1K-MC-EVAA Randomized, double-blind, placebo-controlled study of drotrecogin alfa (activated) in patients with severe sepsisRandomized, double-blind, placebo-controlled study of drotrecogin alfa (activated) in patients with severe sepsis Primary objectivesPrimary objectives –Assess safety of drotrecogin alfa (activated) as a function of infusion rate and infusion duration –Assess impact of drotrecogin alfa (activated) on coagulation abnormalities as a function of infusion rate and infusion duration –Assess pharmacokinetics of drotrecogin alfa (activated) –Determine dose for Phase 3 testing (based on change in D-dimer)

26 26 Study F1K-MC-EVAA Treatment Assignments (N=131) Stage 2 Stage 1 96 Hrs Day hrs Day 028 Dosing Groups 12  g/kg/hr N=11 Placebo N=26 18  g/kg/hr N=11 24  g/kg/hr N=12 30  g/kg/hr N=12 2:1 Randomization Drotrecogin Alfa (activated):Placebo Dosing Groups 12  g/kg/hr N=14 Placebo N=15 18  g/kg/hr N=15 24  g/kg/hr N=15 3:1 Randomization Drotrecogin Alfa (activated):Placebo

27 27 D-dimer: Median Percent Change from Baseline to End of Infusion Analysis based on ranked response data.

28 28 IL-6: Median Percent Change from Baseline to End of Infusion Percent Change (%) Placebo Monotonic Dose Response p-Value = Median with IQR Displayed Drotrecogin Alfa (activated)  g/kg/hr Analysis based on ranked response data.

29 29 Dose Selection for Phase 3 No safety concerns notedNo safety concerns noted Linear pharmacokineticsLinear pharmacokinetics Decline in D-dimer and IL-6 most evident at >18  g/kg/hrDecline in D-dimer and IL-6 most evident at >18  g/kg/hr Largest decrease in D-dimer most evident at the end of 96-hour infusionLargest decrease in D-dimer most evident at the end of 96-hour infusion 24  g/kg/hr for 96 hours recommended for future Phase 3 studies

30 30 Pivotal Phase 3 Study F1K-MC-EVAD

31 31 Phase 3 Study F1K-MC-EVAD Randomized, double-blind, placebo-controlled study in adult patients with severe sepsisRandomized, double-blind, placebo-controlled study in adult patients with severe sepsis –164 sites in 11 countries Single-dose studySingle-dose study –24  g/kg/hr drotrecogin alfa (activated) or placebo for 96 hours Primary objectivePrimary objective –Effect on 28-day all-cause mortality Secondary objectivesSecondary objectives –Safety –Effect on organ function –Pharmacokinetics and pharmacodynamics

32 32 Patient Population (EVAD) Severe SepsisSevere Sepsis –Known or suspected infection –Evidence of a systemic response to infection Three or four of the criteria defining SIRSThree or four of the criteria defining SIRS –One or more sepsis-induced organ dysfunctions CardiovascularCardiovascular RespiratoryRespiratory RenalRenal HematologicHematologic Metabolic acidosisMetabolic acidosis

33 33 Study Design (EVAD) Start of study drug infusion 24 hr to meet entry criteria End of 96-hour infusion of study drug 28-day all-cause mortality assessed Routine Patient Care 24 hr from meeting entry criteria to start of drug

34 34 Timeline of Study (EVAD)

35 35 Patient Disposition (EVAD) N=1728 Patients Enrolled N=857RandomizedN=871Randomized N=17 Not Treated N=840 Treated N=850 Completed Protocol N=840 Completed Protocol N=21 Not Treated Drotrecogin Alfa (activated) Placebo N=850 Treated

36 36 Investigator Assessment of Primary Site of Infection (EVAD) Percent of Patients Placebo N=840 Drotrecogin Alfa (activated) N=850 OtherSkinBloodUrinary Tract Intra- Abdominal Lung Site of Infection

37 37 Baseline Microbiology Data (EVAD) Percent of Patients Placebo (N=840) Drotrecogin Alfa (activated) (N=850) No Identifiable Microorganism* Pure Fungal Gram Mixed Gram Negative Gram Positive *No bacterial, fungal, or viral pathogen identified.

38 38 All Patients Had Laboratory Evidence of Coagulopathy D-dimerTATcF1.2 Protein CProtein SAnti- thrombin Percent of patients with abnormally high values Percent of patients with abnormally low values Drotrecogin Alfa (activated) Placebo

39 39 Most Patients Had Evidence of Impaired Fibrinolysis and Systemic Inflammation (EVAD) PAI-1 IL-6 PT APTT Platelet Count Percent of patients with abnormally high values Percent of patients with abnormally low values Drotrecogin Alfa (activated) Placebo

40 40 Majority of patients with documented infectionMajority of patients with documented infection Evidence of a systemic response characterized by:Evidence of a systemic response characterized by: –Systemic inflammation –Thrombin generation –Fibrin deposition –Impaired fibrinolysis Systemic response similar despite different types of infecting organismsSystemic response similar despite different types of infecting organisms Majority of patients had respiratory and/or cardiovascular dysfunctionMajority of patients had respiratory and/or cardiovascular dysfunction Severe Sepsis Population (EVAD) % with laboratory 99.9% with laboratory evidence of DIC evidence of DIC

41 41 Drotrecogin Alfa (Activated) Reduced 28-Day All-Cause Mortality % 24.7% Primary Analysis Results 2-Sided p-Value Relative Risk Reduction19.4% Increase in Odds of Survival38.1% Placebo (N=840) Drotrecogin Alfa (activated) (N=850)

42 42 Drotrecogin Alfa (Activated) Improves Survival Days from Start of Infusion to Death Percent Survivors p=0.006 (stratified log-rank test) 0 Placebo (N=840) Drotrecogin Alfa (activated) (N=850)

43 43 28-Day All-Cause Mortality Sensitivity Analyses

44 44 Cumulative Mortality for Sites Enrolling Under Both Original and Amended Protocol Aug Nov Feb May Aug Feb May Jul 2000 Over Time (by Covance Randomization Date) Number of Sites = 99 Number of Patients = Nov 1999 Placebo Drotrecogin Alfa (activated) Last patient enrolled - original protocol First patient enrolled - amended protocol 28-Day Mortality Rate

45 45 Mortality by Patient Demographics (EVAD) Drotrecogin Alfa N (activated) Placebo Gender Overall Male Female Age <65 >65 Origin Caucasian Noncaucasian Relative Risk of Death (Point Estimate and 95% CI) <50 >

46 46 Mortality by Region (EVAD) Drotrecogin Alfa N (activated) Placebo Overall United States Relative Risk of Death (Point Estimate and 95% CI) Europe North America Other* *Other = Brazil, South Africa, Australia, New Zealand.

47 47 Drotrecogin Alfa (Activated) Improves Cardiovascular and Respiratory Function Improvement in cardiovascular functionImprovement in cardiovascular function –Reduction in time-averaged CV SOFA scores –Increase in vasopressor-free days –Fewer deaths from septic shock Improvement in respiratory functionImprovement in respiratory function –Reduction in time-averaged respiratory SOFA scores –Increase in ventilator-free days –Fewer deaths from respiratory failure Comparison of 28-day survivorsComparison of 28-day survivors –Similar patient location and functional status

48 48 Safety Assessment

49 49 Bleeding Events Reported as Serious Adverse Events (EVAD) Placebo N=840 Drotrecogin Alfa (activated) N= Day Study Period Study Drug Infusion Period p=0.024p=0.060 Percent of Patients 2.4% (n=20) 1.0% (n=8) 3.5% (n=30) 2.0% (n=17) n=number of patients

50 50 Procedure and Non-Procedure Related Serious Bleeding Events: 28-Day Study Period

51 51 No Other Safety Concerns Similar incidence of serious thrombotic eventsSimilar incidence of serious thrombotic events – Drotrecogin alfa (activated) 2.0% – Placebo 3.0% Similar incidence of postbaseline infectionsSimilar incidence of postbaseline infections – Drotrecogin alfa (activated) 25.5% – Placebo 25.1% <0.5% Incidence of anti-APC antibody formation<0.5% Incidence of anti-APC antibody formation – Low level and non-neutralizing No other safety concerns identified based on:No other safety concerns identified based on: – Other adverse events and serious adverse events – Organ function – Hematology and chemistry data

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

53 53 Intracranial Hemorrhage Summary (as of 30 September 2001) H. Infarct = Hemorrhagic infarction SAH = Subarachanoid hemorrhage Cerebral H. = Cerebral Hemorrhage *Event occurred on Study Day 14 while receiving heparin for dialysis

54 54 Mortality by Platelet Count (EVAD)

55 55 Conclusions from Adult Studies Drotrecogin alfa (activated) in adult patients with severe sepsis: Substantially reduces 28-day all-cause mortalitySubstantially reduces 28-day all-cause mortality –6.1% absolute, 19.4% relative risk reduction (2-sided p-value = 0.005) Improves cardiovascular and respiratory functionImproves cardiovascular and respiratory function Increased risk of serious bleeding eventsIncreased risk of serious bleeding events –Infrequent serious bleeding events –Increased risk with vessel trauma or severe coagulopathy Very favorable benefit-risk profileVery favorable benefit-risk profile

56 56 Formal Benefit-Risk Assessment of Drotrecogin Alfa (Activated) in the Treatment of Severe Sepsis Jeffrey Helterbrand, PhD Senior Statistical Scientist Xigris Product Team Eli Lilly and Company

57 57 Benefit-Risk Objectives Assess benefit-risk for overall populationAssess benefit-risk for overall population Explore potential differential effects across subgroups (70 subgroups)Explore potential differential effects across subgroups (70 subgroups) – Bleeding risk – Survival Benefit Benefit-Risk Conclusion: Drotrecogin alfa (activated) is associated with a positive benefit-risk profile across the diverse population of patients enrolled in the studyBenefit-Risk Conclusion: Drotrecogin alfa (activated) is associated with a positive benefit-risk profile across the diverse population of patients enrolled in the study Address Advisory Committee Subgroup QuestionsAddress Advisory Committee Subgroup Questions –Patients without laboratory evidence of DIC –Low-dose heparin exposure –Less severe disease patients

58 58 Patient Classification by Survival and Serious Bleeding 0259 (30.8%)210 (24.7%)Died 0 to 1*8 (1.0%) 18 (2.1%)Survived, bleed 1573 (68.2%)622 (73.2%)Survived, no bleed Value to the Patient Placebo (N=840) Drotrecogin Alfa (activated) (N=850) * Value subjectively chosen by the decision maker

59 59 Benefit-Risk for Entire Patient Population Net Benefit for Drotrecogin Alfa (Activated) Number of additional serious bleeding events in survivors one would accept to save an additional life * Based on 1000 bootstrap samples from Study F1K-MC-EVAD results. Median with IQR* Net Benefit Negative Positive

60 60 Explorations of Potential Differential Effects with Drotrecogin Alfa (Activated) Across Subgroups

61 61 Caveats Associated with Interpreting Subgroup Analyses Trial sized to detect treatment benefit for entire population onlyTrial sized to detect treatment benefit for entire population only No trial can ensure definitive statistical evidence of a benefit in all subgroupsNo trial can ensure definitive statistical evidence of a benefit in all subgroups No adjustments for multiplicityNo adjustments for multiplicity

62 62 † Agresti: "The generally accepted [scale] " † † FDA Clinical Studies Section of Labeling for Prescription Drugs and Biologics - Content and Format Draft Guidance † † † The Revised CONSORT Statement A. Agresti, Categorical Data Analysis, 1990, page 149 D. Altman et al., Ann Intern Med. 2001; 134: Lilly Analyses Measures: Relative Risks Odds Ratios † Methods: Confidence Intervals †† Interaction Tests † † † Assessing Consistency Across Subgroups

63 63 Subgroups: Bleeding Risk Summary Serious bleeding events:Serious bleeding events: –Few events to assess differential risk –No clinically relevant differential effects observed Treatment emergent bleeding events:Treatment emergent bleeding events: –More events to assess differential risk –No clinically relevant differential effects observed Conclusion: Based on trial results, relative risk of bleeding consistent across subgroups

64 64 Mortality Subgroup Analyses

65 65 Subgroups – Demographic Characteristics

66 66 Subgroups – Disease Severity Measures

67 67 Subgroups – Disease Severity Measures

68 68 Subgroups – Disease Severity Measures

69 69 Benefit: Mortality by Subgroups Consistency Assessment Lower mortality observed for 68 of 70 subgroupsLower mortality observed for 68 of 70 subgroups –Exceptions: 1st APACHE II Quartile and Urinary Tract Infection Consistent treatment effect for 69 of 70 subgroupsConsistent treatment effect for 69 of 70 subgroups –Overall RR Point Estimate = –Lower RR estimate for 1st IL-6 Quartile patients Point estimate = 0.47, 95% RR CI: 0.29 to 0.77Point estimate = 0.47, 95% RR CI: 0.29 to

70 70 Favorable Benefit-Risk Associated with Drotrecogin Alfa (Activated) Drotrecogin alfa (activated) is associated with a positive benefit risk profile across the diverse population of patients enrolled in the pivotal Phase 3 study

71 71 Advisory Committee Questions based on Subgroup Explorations: Treatment effect in patients without laboratory evidence of Disseminated Intravascular Coagulation (DIC)Treatment effect in patients without laboratory evidence of Disseminated Intravascular Coagulation (DIC) Treatment effect and concomitant low-dose heparin exposureTreatment effect and concomitant low-dose heparin exposure Treatment effect in less severe disease patientsTreatment effect in less severe disease patients

72 72 Clinical Trial Definition of DIC Patient classified with (non-overt) DIC if at least 2 of the following 4 criteria met:Patient classified with (non-overt) DIC if at least 2 of the following 4 criteria met: –Platelet < 100k or 50% decrease in past 3 days –PT or APTT > 1.2x ULN –D-dimer > ULN –Protein C, Protein S or Antithromibin < LLN No biochemical data for 113 of 115 patientsNo biochemical data for 113 of 115 patients 99.9% of patients with laboratory data met clinical trial definition of (non-overt) DIC99.9% of patients with laboratory data met clinical trial definition of (non-overt) DIC –Other severe sepsis studies confirm this observation The inclusion criteria employed in study essentially defines a population with sepsis-associated coagulopathy

73 73 Summary of Drotrecogin Alfa (Activated) Treatment Effect and Low-Dose Heparin Use Similar bleeding rates in drotrecogin alfa (activated) patients receiving and not receiving heparin - no treatment by heparin interactionSimilar bleeding rates in drotrecogin alfa (activated) patients receiving and not receiving heparin - no treatment by heparin interaction Lower mortality with drotrecogin alfa (activated) in all subgroups defined by either baseline or concomitant heparin exposure (all RR <0.90)Lower mortality with drotrecogin alfa (activated) in all subgroups defined by either baseline or concomitant heparin exposure (all RR <0.90) Concomitant heparin analyses are biasedConcomitant heparin analyses are biased –Reason: Many patients move from "no heparin" group to "heparin" group with post-baseline exposure

74 74 Summary of Drotrecogin Alfa (Activated) Treatment Effect and Low-Dose Heparin Use Valid analyses of low-dose heparin exposure: Baseline (BL)Baseline (BL) –Treatment-by-heparin interaction p=0.30 –Placebo group p= 0.71 –Drotrecogin alfa (activated) group p=0.28 Incorporating post-BL exposure (time-dependent covariate)*Incorporating post-BL exposure (time-dependent covariate)* –Treatment-by-heparin interaction p=0.16 (p=0.29**) –Placebo group p=0.69 (p=0.57**) –Drotrecogin alfa (activated) group p=0.11 (p=0.26**) * Therneau and Grambsch, Modeling Survival Data: Extending the Cox Model (2000) **Analysis adjusted by baseline APACHE II score

75 75 Drotrecogin Alfa (Activated) Survival Benefit in Patients with Less Disease Severity Observed variation in relative risk estimates across subgroups consistent with random chance if treatment uniformly beneficialObserved variation in relative risk estimates across subgroups consistent with random chance if treatment uniformly beneficial –Higher mortality for effective treatment Expected for 5 of 70 subgroupsExpected for 5 of 70 subgroups Observed for 2 subgroupsObserved for 2 subgroups Survival benefit evident in less severe patients almost uniformly across the totality of measures of disease severitySurvival benefit evident in less severe patients almost uniformly across the totality of measures of disease severity Survival benefit evident in patients with less disease severity within the 1st APACHE II QuartileSurvival benefit evident in patients with less disease severity within the 1st APACHE II Quartile

76 Relative Risk of Death (95% Confidence Interval) Overall APACHE II 1st Quartile No Shock within 6 hr 1 Organ Failure Platelet Count >LLN No Metabolic OF No Cardiovascular OF Hematologic SOFA 0 or 1 Any Shock–No No Hematologic OF No Renal OF Renal SOFA 0 or 1 No Respiratory OF No Mechanical Ventilation Antithrombin Not Deficient Hepatic SOFA 0 or 1 Cardiovascular SOFA 0 or 1 APTT < 37 sec PT < 14.5 sec Protein C Not Deficient Respiratory SOFA 0 or 1 IL-6 1st Quartile Survival Benefit Evident in Patients with Less Disease Severity

77 /58 (12.1%)17/53 (32.1%)>3 OF (N=111) /157 (12.1%)16/165 (9.7%)<3 OF (N=322) Relative RiskPlacebo Drotrecogin Alfa (activated) 28-Day All-Cause Mortality Results By Number of Organ Failures (OF) Conclusion: Survival benefit evident in less severe disease patients enrolled in pivotal study Similar benefit evident in patients with low IL-6, normal PT, normal APTT levels within the 1st Quartile Survival Benefit Evident in Less Severe Patients within 1st APACHE II Quartile

78 78 Clinical Perspective of Treatment-by- Disease Severity Analyses

79 79 Treatment-by-Severity Analyses APACHE II observation does not reconcile with other treatment-by-disease severity analyses APACHE II data not collected and score not calculated according to published method –Not used in EVAD to predict mortality APACHE II score rarely used to make individual patient treatment decisions

80 80 Study F1K-MC-EVAD: Mortality by Number of Organ Failures/Single Organ Failures Relative Risk of Death (Point Estimate and 95% CI) Drotrecogin Alfa N (activated) Placebo No. of Organ Failures Overall Single Organ Failure Cardiovascular Respiratory Breslow-Day interaction p=0.93

81 81 Study F1K-MC-EVAD: Mortality by Cardiovascular Disease Severity Measures Drotrecogin Alfa N (activated) Placebo Overall Shock within 48 hrs Yes No Cardiovascular SOFA Shock within 6 hrs Yes No Any Shock Yes No Relative Risk of Death (Point Estimate and 95% CI) or to

82 82 Study F1K-MC-EVAD: Mortality by Baseline Cardiovascular SOFA Score Relative Risk of Death (Point Estimate and 95% CI) Drotrecogin Alfa N (activated) Placebo Cardiovascular SOFA Overall Breslow-Day interaction p=0.65 Logistic interaction p=

83 83 Study F1K-MC-EVAD: Mortality by Baseline Respiratory SOFA Score Relative Risk of Death (Point Estimate and 95% CI) Drotrecogin Alfa N (activated) Placebo Respiratory SOFA Overall Breslow-Day interaction p=0.27 Logistic interaction p=0.55

84 84 1st Apache II Quartile Baseline Characteristics (N=433) 2 or more organ failures61.2%2 or more organ failures61.2% Respiratory failure69.1%Respiratory failure69.1% Mechanical ventilation59.4%Mechanical ventilation59.4% Shock55.7%Shock55.7% High-dose vasopressors 46.7%High-dose vasopressors 46.7% Severe Protein C deficiency65.1%Severe Protein C deficiency65.1% % of patients had 2 or more organ failures and/or required high dose vasopressor support

85 85 Subgroup Conclusions F1K-MC-EVAD tested one primary hypothesis - results show that drotrecogin alfa (activated) significantly reduces mortality in population of patients defined by inclusion/exclusion criteria Caution should be exercised in interpreting individual exploratory subgroup results (multiplicity, natural variability, supportive evidence) No clear evidence to support a differential effect of drotrecogin alfa (activated) by disease severity

86 86 Clinical Experience in Pediatric Patients with Severe Sepsis

87 87 Rationale for Pediatric Development Program Provide guidance to pediatric intensivists –If approved, drotrecogin alfa (activated) will be used in pediatric patients with severe sepsis Development program based on: –ICH guidelines –Code of Federal Regulations –Collaboration with FDA Majority of drugs used by pediatric intensivists are not approved for use in pediatric patients Majority of drugs used by pediatric intensivists are not approved for use in pediatric patients

88 88 Where the course of the disease and the effects of the drug are sufficiently similar in adult and pediatric patients, FDA may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults usually supplemented with other information obtained in pediatric patients such as pharmacokinetic studies. 21 CFR (a) CPMP/ICH/2711/ Extrapolation of Efficacy

89 Overview of Pediatric Experience (as of 30 September 2001)

90 90 Pediatric Phase 1B Study F1K-MC-EVAO

91 91 Baseline Characteristics of Pediatric and Adult Patients

92 Adult Patients N = Pediatric Patients N=78-79 Protein CD-dimerAntithrombin Percent of patients with abnormally high values Percent of patients with abnormally low values Pediatric Baseline Biomarkers of Disease Severity are Similar to Adults

93 93 Clearance Versus Age in Adult and Pediatric Patients With Severe Sepsis

94 94 Median Pediatric Biomarker Change from Baseline to End of Infusion are Similar to Adult Protein C Activity % Increase No. of patients D-dimer Level % Decrease No. of patients Antithrombin Activity % Increase No. of patients 43% % % % % % 734 Pediatric Patients F1K-MC-EVAO Part 2 0 to <18 yr Adult Patients F1K-MC-EVAD Drotrecogin Alfa (activated) Placebo % 57 26% 56 24% 56

95 95 Serious Bleeding Events – Pediatric and Adult Patients

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

97 97 Conclusions from Pediatric Studies Pediatric patients are similar to adults based upon –Similar inclusion criteria –Presence of coagulopathy Effect of drotrecogin alfa (activated) is similar in adult and pediatric patients –PK of drotrecogin alfa (activated) –PD effect of drotrecogin alfa (activated) on D-dimer –Safety profile Results of the pediatric study support drotrecogin alfa (activated) use in pediatric patients with severe sepsis – Extrapolation of efficacy results from Phase 3 study F1K-MC- EVAD in adult patients with severe sepsis

98 98 Overall Conclusions Drotrecogin alfa (activated) reduces mortality in patients with severe sepsis and is associated with a favorable benefit-risk profile in patients with severe sepsis

99 99 Observed Number Needed to Treat (NNT) Compared to Thrombolytic Trials 1 ISIS Lancet 2: Activase® USPI

100 100 Proposed Indication Statement Drotrecogin alfa (activated) is indicated for the treatment of adult and pediatric patients with sepsis associated with acute organ dysfunction (severe sepsis)Drotrecogin alfa (activated) is indicated for the treatment of adult and pediatric patients with sepsis associated with acute organ dysfunction (severe sepsis) Treatment with drotrecogin alfa (activated) reduces mortality in patients with severe sepsisTreatment with drotrecogin alfa (activated) reduces mortality in patients with severe sepsis


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