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

1

Anti-Infective Drugs Anti-Infective Drugs Advisory Committee MeetingAdvisory Committee Meeting

Xigris™Xigris™Drotrecogin Alfa (Activated)Drotrecogin Alfa (Activated)

October 16, 2001October 16, 2001Eli Lilly and CompanyEli Lilly and Company

6058.01

2

XigrisXigrisDrotrecogin Alfa (Activated)Drotrecogin Alfa (Activated)

Holger K. Schilske, MD, PhDHolger K. Schilske, MD, PhDExecutive Director and Executive Director and

XigrisXigrisTMTM Product Team Leader Product Team LeaderEli Lilly and CompanyEli Lilly and Company

6743.01

33

Proposed Indication StatementProposed Indication Statement

• Drotrecogin alfa (activated) is indicated for the Drotrecogin alfa (activated) is indicated for the treatment of adult and pediatric patients with treatment of adult and pediatric patients with sepsis associated with acute organ dysfunction sepsis associated with acute organ dysfunction (severe sepsis) (severe sepsis)

• Treatment with drotrecogin alfa (activated) Treatment with drotrecogin alfa (activated) reduces mortality in patients with severe sepsisreduces mortality in patients with severe sepsis

6105.01

44

Burden of Severe Sepsis Burden of Severe Sepsis

• Annual incidence: ~750,000 cases in USAnnual incidence: ~750,000 cases in US1 1

• Case fatality rate: 28% to 50%Case fatality rate: 28% to 50%22

• Direct costs – National costs: ~$16.7 billionDirect costs – National costs: ~$16.7 billion11

• Incidence on the rise:Incidence on the rise:– Aging populationAging population– Incidence projected to rise to 1.0 million cases Incidence projected to rise to 1.0 million cases

annually in US during the next decadeannually in US during the next decade11

1 Angus DC et al. 2001. Crit Care Med 29:1303-1310.

2 Natanson. 1998. Crit Care Med 26:1927-1931.

6747.02

55

Reference DiseasesReference Diseases• Incidence in US (cases per 100,000)Incidence in US (cases per 100,000)

– AIDSAIDS11 1717– Colon and rectal cancerColon and rectal cancer22 4848– Breast cancerBreast cancer22 112112– Congestive heart failureCongestive heart failure33 ~196 ~196– Severe sepsisSevere sepsis44 ~300~300

• Number of deaths in US each yearNumber of deaths in US each year– Acute myocardial infarctionAcute myocardial infarction55 218,000218,000– Severe sepsisSevere sepsis44 215,000 215,000

6748.01

1Centers for Disease Control and Prevention. 2000. Incidence rate for 1999.

2American Cancer Society. 2001. Incidence rate for 1993-1997.

3American Heart Association. 2000.

4Angus DC et al. 2001. Crit Care Med 29:1303-1310.

5National Center for Health Statistics. 2001.

6

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

Xigris Reduces the Relative Risk ofXigris Reduces the Relative Risk of 28-Day All-Cause Mortality by 19.4%28-Day All-Cause Mortality by 19.4%

9141.01

776287.01

Drotrecogin Alfa (Activated) Drotrecogin Alfa (Activated) Recombinant Human Activated Protein CRecombinant Human Activated Protein C

COOH

370Ser

CHO

320

CHO300

150

CHO

Asp

KR

AP

130

CHO

OH

40NH2

HIS

180

230

Thrombincleavage site

EGFDomain

Gla Domain

SerineProteaseDomain

88

Agenda Lilly Advisory Committee Agenda Lilly Advisory Committee Presentation Presentation

• IntroductionIntroduction– Holger K. Schilske, MD, PhD – Eli Lilly and CompanyHolger K. Schilske, MD, PhD – Eli Lilly and Company

• Pathophysiology of Severe Sepsis, Rationale for Drotrecogin Alfa Pathophysiology of Severe Sepsis, Rationale for Drotrecogin Alfa (Activated) for the Treatment of Severe Sepsis(Activated) for the Treatment of Severe Sepsis– Steven M. Opal, MD – Professor of Medicine, Brown University School Steven M. Opal, MD – Professor of Medicine, Brown University School

of Medicineof Medicine

• Efficacy and Safety of Drotrecogin Alfa (Activated)Efficacy and Safety of Drotrecogin Alfa (Activated)in the Treatment of Severe Sepsisin the Treatment of Severe Sepsis– William Macias, MD, PhD – Eli Lilly and CompanyWilliam Macias, MD, PhD – Eli Lilly and Company

• Formal Benefit-Risk Assessment of Drotrecogin Alfa (Activated) in Formal Benefit-Risk Assessment of Drotrecogin Alfa (Activated) in the Treatment of Severe Sepsisthe Treatment of Severe Sepsis– Jeffrey Helterbrand, PhD – Eli Lilly and CompanyJeffrey Helterbrand, PhD – Eli Lilly and Company

• Clinical Experience in Pediatric Patients with Severe SepsisClinical Experience in Pediatric Patients with Severe Sepsisand Overall Conclusionsand Overall Conclusions– William Macias, MD, PhD – Eli Lilly and CompanyWilliam Macias, MD, PhD – Eli Lilly and Company

6516.01

99

External ConsultantsExternal ConsultantsGordon Bernard, MDGordon Bernard, MD Professor of Medicine Professor of Medicine Pulmonary Medicine Division Pulmonary Medicine Division Vanderbilt University Vanderbilt University Medical CenterMedical Center

Brett Giroir, MDBrett Giroir, MD ChiefChief Medical OfficerMedical OfficerChildren's Medical Center, Dallas Children's Medical Center, Dallas Associate Dean for Clinical AffairsAssociate Dean for Clinical AffairsUT Southwestern Medical CenterUT Southwestern Medical Center

Mitchell Levy, M.D.Mitchell Levy, M.D.Associate Professor of Medicine Associate Professor of Medicine Brown University School of MedicineBrown University School of MedicineMedical DirectorMedical DirectorMedical Intensive Care UnitMedical Intensive Care UnitRhode Island HospitalRhode Island Hospital6744.02

Steven M. Opal, MDSteven M. Opal, MD Professor of Medicine Professor of Medicine Brown University School of Medicine Brown University School of Medicine Chief Infectious Disease DivisionChief Infectious Disease DivisionMemorial Hospital of Rhode IslandMemorial Hospital of Rhode Island

Michael Seneff, M.D.Michael Seneff, M.D.Medical DirectorMedical DirectorIntensive Care UnitIntensive Care UnitGeorge Washington UniversityGeorge Washington UniversityMedical CenterMedical Center

10

Pathophysiology of Severe SepsisPathophysiology of Severe SepsisRationale for Drotrecogin AlfaRationale for Drotrecogin Alfa

(Activated) for the Treatment of Severe Sepsis(Activated) for the Treatment of Severe Sepsis

Steven M. Opal, MDSteven M. Opal, MD

Professor of Medicine,Professor of Medicine,Brown University School of MedicineBrown University School of Medicine

Chief, Infectious Disease DivisionChief, Infectious Disease DivisionMemorial Hospital of Rhode IslandMemorial Hospital of Rhode Island

6254.01

1111

Sepsis and Severe SepsisSepsis and Severe Sepsis

• SepsisSepsis is a syndrome characterized by host is a syndrome characterized by host systemic inflammatory and procoagulant systemic inflammatory and procoagulant responses (SIRS) to pathogensresponses (SIRS) to pathogens

• An intense host response may lead to organ An intense host response may lead to organ dysfunction; this is designated dysfunction; this is designated severe sepsissevere sepsis

• The mortality rate in severe sepsis remains The mortality rate in severe sepsis remains high despite appropriate antibiotic and high despite appropriate antibiotic and supportive therapysupportive therapy

9142.02

1212

InfectionInfection

Microbial ProductsMicrobial Products(exotoxin/endotoxin)(exotoxin/endotoxin)

Cellular ResponsesCellular Responses

OxidasesOxidasesPlateletPlatelet

ActivationActivationKininsKinins

ComplementComplement

Coagulopathy/DICCoagulopathy/DICVascular/Organ System InjuryVascular/Organ System Injury

Multi-Organ FailureMulti-Organ Failure

DeathDeath

EndothelialEndothelial damagedamage Endothelial damageEndothelial damage

CoagulationCoagulationActivationActivation

CytokinesCytokinesTNF, IL-1, IL-6TNF, IL-1, IL-6

9143.01

Pathogenesis of Severe Sepsis: Pathogenesis of Severe Sepsis: Inflammation/Coagulation as Intervention Inflammation/Coagulation as Intervention TargetTarget

1313

The Perils of Subgroup Analysis in Sepsis The Perils of Subgroup Analysis in Sepsis TrialsTrials

Compound

Post-hoc Subgroup

with Potential Efficacy

Outcome of

Follow-up Study

HA-1A Gm– Bacteremia49% vs. 30% (p=0.014)

Gm– Bacteremia32% vs. 33% (p=0.86)

E5 Gm– Sepsis w/o Shock49% vs. 30% (p=0.01)

Gm– Sepsis w/o Shock30% 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)

9282.01

1414

Activation of Inflammation and Coagulation Activation of Inflammation and Coagulation in Severe Sepsisin Severe Sepsis

• Activation of coagulation occurs early in severe Activation of coagulation occurs early in severe sepsis and is associated with:sepsis and is associated with:– Increased thrombin generation and fibrin formationIncreased thrombin generation and fibrin formation– Impaired fibrinolysisImpaired fibrinolysis– Depletion of key regulatory proteins (eg, Protein C Depletion of key regulatory proteins (eg, Protein C

and antithrombin)and antithrombin)– Decreased capacity to activate Protein CDecreased capacity to activate Protein C– Systemic inflammation resulting from activation of Systemic inflammation resulting from activation of

monocytes, neutrophils, and endotheliummonocytes, neutrophils, and endothelium

9147.02

1515

Systemic Host Response to Infection–Similar Systemic Host Response to Infection–Similar Across Causative Microorganism ClassAcross Causative Microorganism Class

Causative microorganism classification–CEC adjudicated Baseline biomarker data from Study F1K-MC-EVAD

9145.01

Per

cen

t o

f P

atie

nts

wit

h A

bn

orm

al V

alu

es

0

20

40

60

80

100

Suspected - NoOrganism Identified

Pure Fungal

Pure Gram PositivePure Gram Negative

IL-6ProthrombinTime

Protein CD-Dimer

1616

TAFI

EPCR

?

X

X

X

XX

Activated Protein C – Mechanisms of ActivityActivated Protein C – Mechanisms of Activity

9146.02

MonocyteActivationIncreased Fibrinolysis

Prothrombin

CoagulationCascade

NeutrophilAdhesion

Thrombin

Va

VIIIa

Cell ActivationVia PARs

Fibrin/Platelets aPCReceptor

PAI-1

PC

Thrombomodulin

ThrombinaPC

Tr

PS CD1/

MHC

1717

Baboon Sepsis Model:Baboon Sepsis Model:Effect of Activated Protein C on SurvivalEffect of Activated Protein C on Survival

Lethal Lethal E coliE coli Model Model

Infusing exogenous Activated Protein C reduces Infusing exogenous Activated Protein C reduces mortalitymortality

Sub-lethal Sub-lethal E coliE coli Model Model

Administration of anti-APC antibodies converts a sub-Administration of anti-APC antibodies converts a sub-lethal dose to lethal dose lethal dose to lethal dose

Administration of exogenous Activated Protein C with Administration of exogenous Activated Protein C with anti-APC antibodies prevents increase in lethalityanti-APC antibodies prevents increase in lethality

Taylor FB et al. 1987. J Clin Invest 79:918-925.

9148.01

1818

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

Human APC(N=49)

Heparin(13,000 U/day*)

(N=55) p-Value

30-Day All-CauseMortality

20.4% 40.0% <0.05

* 192 U/kg/day

Okajima et al. 2000. Blood 96:50a Abstract 208.

9174.01

1919

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

• Pathophysiology of sepsis–infection, inflammation, Pathophysiology of sepsis–infection, inflammation, and coagulation activation are tightly linkedand coagulation activation are tightly linked

• Multiple mechanisms of action of Activated Protein C Multiple mechanisms of action of Activated Protein C may disrupt the linkage between inflammation and may disrupt the linkage between inflammation and coagulation resulting in improved survivalcoagulation resulting in improved survival

• Baboon Baboon E coli E coli sepsis model suggests critical role of sepsis model suggests critical role of Activated Protein C for survivalActivated Protein C for survival

• Activated Protein C is preferred because the patient's Activated Protein C is preferred because the patient's ability to convert Protein C in vivo may be impairedability to convert Protein C in vivo may be impaired

9149.01

20

Efficacy and Safety of Efficacy and Safety of Drotrecogin Alfa (Activated)Drotrecogin Alfa (Activated)

in the Treatment of Severe Sepsisin the Treatment of Severe Sepsis

William Macias, MD, PhDWilliam Macias, MD, PhD Medical Director Medical Director

Xigris Product TeamXigris Product TeamEli Lilly and CompanyEli Lilly and Company

6285.01

2121

ObjectivesObjectives

• Provide rationale for proposed indication statementProvide rationale for proposed indication statement

• Review data supporting recommended dose and dose Review data supporting recommended dose and dose duration for drotrecogin alfa (activated)duration for drotrecogin alfa (activated)– 24 24 g/kg/hr dose for 96 hours g/kg/hr dose for 96 hours

• Review primary efficacy and safety data from pivotal Review primary efficacy and safety data from pivotal Phase 3 study F1K-MC-EVADPhase 3 study F1K-MC-EVAD– Favorable benefit-risk profile in severe sepsisFavorable benefit-risk profile in severe sepsis

• Provide clinical update on ongoing studiesProvide clinical update on ongoing studies

• Review clinical experience in pediatric patients with Review clinical experience in pediatric patients with

severe sepsissevere sepsis

9009.01

2222




6105.01

Drotrecogin alfa (activated) is recommendedDrotrecogin alfa (activated) is recommendedfor use as adjunctive therapy for use as adjunctive therapy to best to best

standard carestandard care

2323

Rationale for Indication StatementRationale for Indication Statement• Definitions of sepsis and severe sepsisDefinitions of sepsis and severe sepsis

– Based on 1991 SCCM/ACCP consensus conference 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 Based on data from one pivotal Phase 3 study with

supporting data from one Phase 2 study 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 Supported by open-label, safety, and pharmacokinetic

studies in patients aged 38 weeks gestation to 18 yearsstudies in patients aged 38 weeks gestation to 18 years– Efficacy requires extrapolation from adult studiesEfficacy requires extrapolation from adult studies

• Inclusion of mortality reductionInclusion of mortality reduction– Primary benefit is improved survivalPrimary benefit is improved survival– For use in patients at risk of death from severe sepsisFor use in patients at risk of death from severe sepsis

9258.01

24

Phase 2 StudyPhase 2 Study

F1K-MC-EVAAF1K-MC-EVAA

6291.01

2525

Phase 2 Study F1K-MC-EVAAPhase 2 Study F1K-MC-EVAA

• Randomized, double-blind, placebo-controlled study Randomized, double-blind, placebo-controlled study of drotrecogin alfa (activated) in patients with severe of drotrecogin alfa (activated) in patients with severe sepsissepsis

• Primary objectivesPrimary objectives– Assess safety of drotrecogin alfa (activated) as a Assess safety of drotrecogin alfa (activated) as a

function of infusion rate and infusion durationfunction of infusion rate and infusion duration– Assess impact of drotrecogin alfa (activated) on Assess impact of drotrecogin alfa (activated) on

coagulation abnormalities as a function of infusion coagulation abnormalities as a function of infusion rate and infusion durationrate and infusion duration

– Assess pharmacokinetics of drotrecogin alfa Assess pharmacokinetics of drotrecogin alfa (activated)(activated)

– Determine dose for Phase 3 testing (based on Determine dose for Phase 3 testing (based on change in D-dimer)change in D-dimer)

6110.01

2626

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

6111.02

Stage 2

Stage 1

96 Hrs

Day 0 28

48 hrs

Day 0 28

Dosing Groups 12 g/kg/hr N=11 Placebo N=2618 g/kg/hr N=11 24 g/kg/hr N=1230 g/kg/hr N=12 2:1 Randomization Drotrecogin Alfa (activated):Placebo

Dosing Groups12 g/kg/hr N=14 Placebo N=1518 g/kg/hr N=15 24 g/kg/hr N=153:1 Randomization Drotrecogin Alfa (activated):Placebo

2727

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

6116.02 Analysis based on ranked response data.

Per

cen

t C

han

ge

(%)

Placebo 12 18 24 30

-80

-60

-40

-20

0

20

40

60

80Monotonic Dose Response p<0.001Median with IQR Displayed

Drotrecogin Alfa (activated) g/kg/hrg/kg/hr

2828

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

6293.02

Per

cen

t C

han

ge

(%)

Placebo 12 18 24 30

-100

-80

-60

-40

-20

0

20 Monotonic Dose Response p-Value = 0.021Median with IQR Displayed

Drotrecogin Alfa (activated) g/kg/hr

Analysis based on ranked response data.

2929

Dose Selection for Phase 3Dose 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 Decline in D-dimer and IL-6 most evident at >18 g/kg/hrg/kg/hr

• Largest decrease in D-dimer most evident at the Largest decrease in D-dimer most evident at the end of 96-hour infusionend of 96-hour infusion

24 24 g/kg/hr for 96 hours recommended for future g/kg/hr for 96 hours recommended for future Phase 3 studiesPhase 3 studies

6294.01

3030

Pivotal Phase 3 StudyPivotal Phase 3 Study

F1K-MC-EVADF1K-MC-EVAD

6295.01

3131

Phase 3 Study F1K-MC-EVADPhase 3 Study F1K-MC-EVAD

• Randomized, double-blind, placebo-controlled study Randomized, double-blind, placebo-controlled study in adult patients with severe sepsisin adult patients with severe sepsis– 164 sites in 11 countries164 sites in 11 countries

• Single-dose studySingle-dose study– 24 24 g/kg/hrg/kg/hr drotrecogin alfa (activated) or placebo drotrecogin alfa (activated) or placebo

for 96 hours for 96 hours

• Primary objectivePrimary objective– Effect on 28-day all-cause mortalityEffect on 28-day all-cause mortality

• Secondary objectivesSecondary objectives– SafetySafety– Effect on organ functionEffect on organ function– Pharmacokinetics and pharmacodynamicsPharmacokinetics and pharmacodynamics

6510.01

3232

Patient Population (EVAD)Patient Population (EVAD)

• Severe SepsisSevere Sepsis– Known or suspected infectionKnown or suspected infection– Evidence of a systemic response to infectionEvidence of a systemic response to infection

• Three or four of the criteria defining SIRS Three or four of the criteria defining SIRS – One or more sepsis-induced organ dysfunctionsOne or more sepsis-induced organ dysfunctions

• CardiovascularCardiovascular

• RespiratoryRespiratory

• RenalRenal

• HematologicHematologic

• Metabolic acidosisMetabolic acidosis

6760.01

3333

Study DesignStudy Design (EVAD) (EVAD)

6125.01

Start of study drug infusion24 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

3434

Date Event

7/28/1998 First patient enrolled

3/05/1999 Protocol amendment approved by Lilly

6/06/1999 First patient enrolled under amendment

10/08/1999 First interim analysis by independent DSMB (Efficacy stopping rules based on method of O’Brien-Fleming)

Recommendation: “Continue the trial”

6/28/2000 Second interim analysis by independent DSMB

Recommendation: “Stop trial for highly statistically significant results”

7/26/2000 Last patient enrolled completes study

Timeline of Study (EVAD)Timeline of Study (EVAD)

9150.02

3535

Patient Disposition (EVAD)Patient Disposition (EVAD)

N=1728N=1728Patients Patients EnrolledEnrolled

N=857N=857RandomizedRandomized

N=871N=871RandomizedRandomized

N=17N=17Not Treated Not Treated

N=840 TreatedN=840 Treated

N=850 Completed N=850 Completed ProtocolProtocol

N=840 Completed N=840 Completed ProtocolProtocol

N=21N=21Not Treated Not Treated

Drotrecogin Alfa (activated)

Placebo

N=850 TreatedN=850 Treated

6129.01

3636

Investigator Assessment of Primary Site of Investigator Assessment of Primary Site of Infection (EVAD)Infection (EVAD)

6075.02

Per

cen

t o

f P

atie

nts

0

10

20

30

40

50

60

Placebo N=840

Drotrecogin Alfa(activated) N=850

OtherSkinBloodUrinaryTract

Intra-Abdominal

Lung

Site of Infection

3737

Baseline Microbiology Data (EVAD)Baseline Microbiology Data (EVAD)

6076.01

Per

cen

t o

f P

atie

nts

0

5

10

15

20

25

30

35

Placebo (N=840)

Drotrecogin Alfa(activated) (N=850)

NoIdentifiable

Microorganism*

PureFungal

GramMixed

GramNegative

GramPositive

*No bacterial, fungal, or viral pathogen identified.

3838

All Patients Had Laboratory Evidence of All Patients Had Laboratory Evidence of CoagulopathyCoagulopathy

6077.01

100

80

60

40

20

0

20

40

60

80

100

D-dimer TATc F1.2

Protein C Protein S Anti-thrombin

Percent ofpatients withabnormallyhigh values

Percent ofpatients withabnormallylow values

Drotrecogin Alfa(activated)

Placebo

3939

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

6078.0140

20

0

20

40

60

80

100

PAI-1

IL-6 PT

APTT

PlateletCount




Placebo

4040

• 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 Systemic inflammation – Thrombin generationThrombin generation– Fibrin deposition Fibrin deposition – Impaired fibrinolysisImpaired fibrinolysis

• Systemic response similar despite different types of Systemic response similar despite different types of infecting organismsinfecting organisms

• Majority of patients had respiratory and/or Majority of patients had respiratory and/or cardiovascular dysfunctioncardiovascular dysfunction

Severe Sepsis Population (EVAD)Severe Sepsis Population (EVAD)

9151.01

99.9% with laboratory99.9% with laboratory evidence of DICevidence of DIC

4141

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

0

5

10

15

20

25

30

3530.8%

24.7%

Primary Analysis Results2-Sided p-Value 0.005Relative Risk Reduction 19.4%Increase in Odds of Survival 38.1%

Placebo(N=840)

DrotrecoginAlfa

(activated)(N=850)

6138.01

4242

Drotrecogin Alfa (Activated) Improves Drotrecogin Alfa (Activated) Improves SurvivalSurvival

0 7 14 21 28

70

80

90

100

Days from Start of Infusion to Death

Per

cen

t S

urv

ivo

rs

p=0.006 (stratified log-rank test)0

Placebo(N=840)

Drotrecogin Alfa (activated) (N=850)

6139.01

4343

28-Day All-Cause Mortality 28-Day All-Cause Mortality Sensitivity AnalysesSensitivity Analyses

Type of Analysis

ObservedRelative Risk

Reduction p-Value

Treated Patients (N=1690)As Randomly AssignedPrimary Stratified

19.4% 0.005

Treated Patients (N=1690)As Randomly AssignedNon-Stratified

19.9% 0.005

Treated Patients (N=1690)As TreatedNon-Stratified

20.8% 0.003

All Randomized Patients (N=1728)As Randomly AssignedNon-Stratified

20.7% 0.003

6140.01

4444

Cumulative Mortality for Sites Enrolling Cumulative Mortality for Sites Enrolling Under Both Original and Amended Protocol Under Both Original and Amended Protocol

6404.02

0.40

0.35

0.30

0.25

0.20

1 Aug1998

1 Nov1998

1 Feb1999

1 May1999

1 Aug1999

1 Feb2000

1 May2000

1 Jul2000

Over Time (by Covance Randomization Date)

Number of Sites = 99Number of Patients = 1463

1 Nov1999

Placebo


Last patient enrolled - original protocolFirst patient enrolled - amended protocol

28-D

ay M

ort

alit

y R

ate

4545

Mortality by Patient Demographics (EVAD)Mortality by Patient Demographics (EVAD)

Drotrecogin Alfa N (activated) Placebo

Gender

Overall

964 24.3 31.0

886 15.6 20.9

804 34.4 42.2

726 25.2 30.6MaleFemale

Age

<65>65

Origin

CaucasianNoncaucasian

1384 24.5 31.1306 25.8 29.8

0.5 0.6 0.7 0.8 1 1.25 1.67 20.9Relative Risk of Death (Point Estimate and 95% CI)

1690 24.7 30.8

<50>50 1235 29.1 36.5

455 13.0 15.2

6778.01

4646

Mortality by Region (EVAD)Mortality by Region (EVAD)

6312.02


Overall

705 24.4 32.9

259 22.0 26.8

United States

507 25.8 30.3

924 24.9 32.3


Europe

North America

Other*

1690 24.7 30.8

*Other = Brazil, South Africa, Australia, New Zealand.

4747

Drotrecogin Alfa (Activated) Improves Drotrecogin Alfa (Activated) Improves Cardiovascular and Respiratory FunctionCardiovascular and Respiratory Function

• Improvement in cardiovascular functionImprovement in cardiovascular function– Reduction in time-averaged CV SOFA scoresReduction in time-averaged CV SOFA scores– Increase in vasopressor-free daysIncrease in vasopressor-free days– Fewer deaths from septic shockFewer deaths from septic shock

• Improvement in respiratory functionImprovement in respiratory function– Reduction in time-averaged respiratory SOFA Reduction in time-averaged respiratory SOFA

scoresscores– Increase in ventilator-free daysIncrease in ventilator-free days– Fewer deaths from respiratory failureFewer deaths from respiratory failure

• Comparison of 28-day survivorsComparison of 28-day survivors– Similar patient location and functional statusSimilar patient location and functional status

9283.01

48

Safety AssessmentSafety Assessment

9152.01

4949

Bleeding Events Reported as Serious Bleeding Events Reported as Serious Adverse Events (EVAD)Adverse Events (EVAD)

6178.01

PlaceboN=840

Drotrecogin Alfa (activated)N=850

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

28-DayStudy Period

Study DrugInfusion Period

p=0.024 p=0.060

Per

cen

t o

f P

atie

nts 2.4%

(n=20)

1.0%(n=8)

3.5%(n=30)

2.0%(n=17)

n=number of patients

5050

Procedure Related EventsNon-Procedure Related

Events

Site of Hemorrhage

DrotrecoginAlfa

(activated) Placebo

DrotrecoginAlfa

(activated) Placebo

Gastrointestinal 1 0 8 9

Intra-Abdominal 3 0 0 4

Intrathoracic 3 1 3 0

Retroperitoneal 4 0 0 0

Intracranial 0 0 2 1

Genitourinary 1 0 1 0

Skin/Soft Tissue 1 0 1 0

Unidentified Source 2 2 0 0

Total 15 (1.8%) 3 (0.4%) 15 (1.8%) 14 (1.7%)

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

9154.01

5151

No Other Safety ConcernsNo Other Safety Concerns

• Similar incidence of serious thrombotic eventsSimilar incidence of serious thrombotic events– Drotrecogin alfa (activated) 2.0%Drotrecogin alfa (activated) 2.0%– Placebo 3.0% Placebo 3.0%

• Similar incidence of postbaseline infectionsSimilar incidence of postbaseline infections– Drotrecogin alfa (activated) 25.5%Drotrecogin alfa (activated) 25.5%– Placebo 25.1% Placebo 25.1%

• <0.5% Incidence of anti-APC antibody formation<0.5% Incidence of anti-APC antibody formation– Low level and non-neutralizingLow level and non-neutralizing

• No other safety concerns identified based on:No other safety concerns identified based on:– Other adverse events and serious adverse eventsOther adverse events and serious adverse events– Organ functionOrgan function– Hematology and chemistry dataHematology and chemistry data

6174.01

5252

StudyNo. of

Patients Mortality*

SeriousBleeding EventsDuring Infusion

PeriodTreatment Use ProtocolEVBC 185 21.0% 3.2%

Open Label StudiesEVBE

EVBF

EVBG580 19.0% 2.1%

*Not all patients have completed 28-day study period.

9284.02

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

5353

Fatal Non-Fatal

StudyDuring

InfusionAfter

Infusion During InfusionAfter

Infusion

Open Label

N=580

Cerebral H.

2 0

H. Infarct

1

H. Infarct

2

Treatment Use

N=185

Cerebral H.

1

H. Infarct*

1

SAH

1

SAH

2

Total (n=765) 3 (0.4%) 1 (0.1%) 2 (0.3%) 4 (0.5%)

Intracranial Hemorrhage SummaryIntracranial Hemorrhage Summary(as of 30 September 2001)(as of 30 September 2001)

9285.02

H. Infarct = Hemorrhagic infarction

SAH = Subarachanoid hemorrhage

Cerebral H. = Cerebral Hemorrhage

*Event occurred on Study Day 14 while receiving heparin for dialysis

5454

Mortality by Platelet Count (EVAD)Mortality by Platelet Count (EVAD)

Platelet Count

DrotrecoginAlfa

(activated) Placebo

<50,000 at baseline(n=40)

4/16 (25%) 15/24 (63%)

Minimum <50,000 baselineto Study Day 5(n=113)

12/50 (24%) 34/63 (54%)

Minimum <30,000 baselineto Study Day 5(n=34)

5/15 (33%) 16/19 (84%)

9015.01

5555

Conclusions from Adult StudiesConclusions from Adult Studies

Drotrecogin alfa (activated) in adult patients with severe Drotrecogin alfa (activated) in adult patients with severe sepsis:sepsis:

• SubstantiallySubstantially reduces 28-day all-cause mortality reduces 28-day all-cause mortality– 6.1% absolute, 19.4% relative risk reduction6.1% absolute, 19.4% relative risk reduction

((2-sided p-value = 0.005)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 Infrequent serious bleeding events – Increased risk with vessel trauma or severe Increased risk with vessel trauma or severe

coagulopathycoagulopathy

• Very favorable benefit-risk profileVery favorable benefit-risk profile

6777.01

56

Formal Benefit-Risk Assessment of Formal Benefit-Risk Assessment of Drotrecogin Alfa (Activated)Drotrecogin Alfa (Activated)

in the Treatment of Severe Sepsisin the Treatment of Severe Sepsis

Jeffrey Helterbrand, PhDJeffrey Helterbrand, PhDSenior Statistical ScientistSenior Statistical Scientist

Xigris Xigris Product Team Product Team Eli Lilly and CompanyEli Lilly and Company

6774.01

5757

Benefit-Risk ObjectivesBenefit-Risk Objectives• Assess benefit-risk for overall populationAssess benefit-risk for overall population

• Explore potential differential effects across subgroups (70 Explore potential differential effects across subgroups (70 subgroups)subgroups)

– Bleeding riskBleeding risk

– Survival BenefitSurvival Benefit

• Benefit-Risk Conclusion:Benefit-Risk Conclusion: Drotrecogin alfa (activated) is Drotrecogin alfa (activated) is associated with a positive benefit-risk profile across the associated with a positive benefit-risk profile across the diverse population of patients enrolled in the studydiverse population of patients enrolled in the study

• Address Advisory Committee Subgroup QuestionsAddress Advisory Committee Subgroup Questions– Patients without laboratory evidence of DICPatients without laboratory evidence of DIC– Low-dose heparin exposureLow-dose heparin exposure– Less severe disease patientsLess severe disease patients

9155.01

5858

Patient Classification by Survival and Patient Classification by Survival and Serious BleedingSerious 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)

DrotrecoginAlfa (activated)

(N=850)

9286.01

* Value subjectively chosen by the decision maker

5959

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

6781.01

10

5

0

-5

-10

100 10 5 4 3 2 1

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

Ben

efit

Neg

ativ

e

Po

siti

ve

60

Explorations of Potential Differential Explorations of Potential Differential Effects with Drotrecogin Alfa Effects with Drotrecogin Alfa

(Activated) Across Subgroups(Activated) Across Subgroups

6782.01

6161

Caveats Associated with Interpreting Caveats Associated with Interpreting Subgroup AnalysesSubgroup Analyses

• Trial sized to detect treatment benefit for entire Trial sized to detect treatment benefit for entire

population onlypopulation only

• No trial can ensure definitive statistical evidence of a No trial can ensure definitive statistical evidence of a

benefit in all subgroups benefit in all subgroups

• No adjustments for multiplicityNo adjustments for multiplicity

6512.01

6262

† 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 149D. Altman et al., Ann Intern Med. 2001; 134: 663-694

Lilly AnalysesLilly AnalysesMeasures:Measures:

Relative Risks Relative Risks Odds RatiosOdds Ratios††

Methods: Methods: Confidence Intervals Confidence Intervals ††††

Interaction Tests Interaction Tests † † †† † †

9287.02

Assessing Consistency Across Assessing Consistency Across SubgroupsSubgroups

6363

Subgroups: Bleeding Risk SummarySubgroups: Bleeding Risk Summary

• Serious bleeding events:Serious bleeding events: – Few events to assess differential riskFew events to assess differential risk– No clinically relevant differential effects observedNo clinically relevant differential effects observed

• Treatment emergent bleeding events:Treatment emergent bleeding events:– More events to assess differential riskMore events to assess differential risk– No clinically relevant differential effects observedNo clinically relevant differential effects observed

Conclusion: Based on trial results,Conclusion: Based on trial results,relative risk of bleeding consistent across subgroupsrelative risk of bleeding consistent across subgroups

9156.01

64

Mortality Subgroup AnalysesMortality Subgroup Analyses

9288.01

6565

Subgroups – Demographic CharacteristicsSubgroups – Demographic Characteristics

PrimaryAge >65 <65Gender Male FemaleRacial Origin Caucasian NoncaucasianRegion North America Europe OtherRecent Surgery Yes NoSite of Infection Lung Intra-Abdominal Urinary Tract OtherType of Infection Pure Gram Positive Pure Gram Negative No Bacteria Isolated Mixed Gram

1690

804886

964726

1384306

924507259

5021177

906337171276

430381556250

24.7

34.415.6

24.325.2

24.525.8

24.925.822.0

27.823.6

25.027.621.222.3

22.824.325.621.8

30.8

42.220.9

31.030.6

31.129.8

32.330.326.8

30.730.9

33.630.520.928.5

32.728.632.526.5


N Trt Plc

6763.01

6666

Subgroups – Disease Severity MeasuresSubgroups – Disease Severity Measures

PrimaryAPACHE II 1st Quartile 2nd Quartile 3rd Quartile 4th QuartileCardiovascular Organ Failure Yes NoCardiovascular SOFA 0 or 1 2 to 4Shock Within 6 Hours Yes NoAny Shock Yes NoRespiratory Organ Failure Yes NoRespiratory SOFA 0 or 1 2 to 4Mechanical Ventilation Yes No

1690

433440366451

1214476

4941196

1200490

1362328

1272418

1841479

1275415

24.7

15.122.523.538.1

25.123.8

19.127.3

26.321.0

26.019.7

25.622.0

12.926.4

27.317.6

30.8

12.125.735.849.0

32.027.6

26.632.4

34.222.3

32.523.3

31.628.5

26.431.7

33.122.9

N Trt Plc

0.5 0.6 0.7 0.8 1 1.25 1.67 20.9Relative Risk of Death (Point Estimate and 95% CI)6764.01

6767


PrimaryHematologic Organ Failure Yes NoHematologic SOFA 0 or 1 2 to 4Renal Organ Failure Yes NoRenal SOFA 0 or 1 2 to 4Metabolic Organ Failure Yes NoHepatic SOFA 0 or 1 2 to 4Organ Failures 1 2 3 4 5

1690

2681422

1317368

710980

1122564

5811109

1265275

418543432235

61

24.7

27.524.2

23.927.7

32.519.1

20.432.6

29.822.0

22.731.4

19.520.726.238.732.3

30.8

36.929.7

28.340.0

40.523.8

25.741.4

41.525.4

30.236.2

21.226.034.446.653.3

N Trt Plc

0.5 0.6 0.7 0.8 1 1.25 1.67 20.9Relative Risk of Death (Point Estimate and 95% CI)6765.01

6868


PrimaryProtein C Deficient Not DeficientProthrombin Time Class <14.5 sec >14.5 thru 17.4 sec >17.4 secAPTT Class <37 sec >37 thru 74 sec >74 secPlatelet Class >LLN <LLNAntithrombin Deficient Not DeficientIL-6 Quartile 1st 2nd 3rd 4th


1690

1379195

103463992

4411039

81

985434

1273285

408409409409

24.7

25.715.6

16.317.228.4

17.925.638.6

23.825.9

25.320.1

10.526.428.531.1

30.8

32.126.7

27.826.034.5

25.632.751.4

27.435.9

32.526.7

22.126.533.243.5

N Trt Plc

6766.01

6969

Benefit: Mortality by Subgroups Benefit: Mortality by Subgroups Consistency AssessmentConsistency Assessment

• Lower mortality observed for 68 of 70 subgroups Lower mortality observed for 68 of 70 subgroups – Exceptions: 1st APACHE II Quartile and Urinary Exceptions: 1st APACHE II Quartile and Urinary

Tract InfectionTract Infection

• Consistent treatment effect for 69 of 70 subgroupsConsistent treatment effect for 69 of 70 subgroups– Overall RR Point Estimate = 0.806Overall RR Point Estimate = 0.806– Lower RR estimate for 1st IL-6 Quartile patientsLower 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 0.77

6784.01

7070

Favorable Benefit-Risk Associated with Favorable Benefit-Risk Associated with Drotrecogin Alfa (Activated)Drotrecogin Alfa (Activated)

Drotrecogin alfa (activated) is associated with a positive Drotrecogin alfa (activated) is associated with a positive benefit risk profile across the diverse population of benefit risk profile across the diverse population of patients enrolled in the pivotal Phase 3 studypatients enrolled in the pivotal Phase 3 study

6768.01

7171

Advisory Committee Questions based on Advisory Committee Questions based on Subgroup Explorations:Subgroup Explorations:

• Treatment effect in patients without laboratory Treatment effect in patients without laboratory evidence of Disseminated Intravascular Coagulation evidence of Disseminated Intravascular Coagulation (DIC)(DIC)

• Treatment effect and concomitant low-dose heparin Treatment effect and concomitant low-dose heparin exposureexposure

• Treatment effect in less severe disease patientsTreatment effect in less severe disease patients

9289.01

7272

Clinical Trial Definition of DICClinical Trial Definition of DIC

• Patient classified with (non-overt) DIC if at least 2 of Patient classified with (non-overt) DIC if at least 2 of the following 4 criteria met:the following 4 criteria met:– Platelet < 100k or 50% decrease in past 3 daysPlatelet < 100k or 50% decrease in past 3 days– PT or APTT > 1.2x ULNPT or APTT > 1.2x ULN– D-dimer > ULND-dimer > ULN– Protein C, Protein S or Antithromibin < LLNProtein C, Protein S or Antithromibin < LLN

• No biochemical data for 113 of 115 patients No biochemical data for 113 of 115 patients

• 99.9% of patients with laboratory data met clinical 99.9% of patients with laboratory data met clinical trial definition of (non-overt) DIC trial definition of (non-overt) DIC – Other severe sepsis studies confirm this observationOther severe sepsis studies confirm this observation

9290.03

The inclusion criteria employed in study essentially The inclusion criteria employed in study essentially defines a population with sepsis-associated coagulopathydefines a population with sepsis-associated coagulopathy

7373

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

• Similar bleeding rates in drotrecogin alfa (activated) Similar bleeding rates in drotrecogin alfa (activated) patients receiving and not receiving heparin - no patients receiving and not receiving heparin - no treatment by heparin interaction treatment by heparin interaction

• Lower mortality with drotrecogin alfa (activated) in all Lower mortality with drotrecogin alfa (activated) in all subgroups defined by either baseline or concomitant subgroups defined by either baseline or concomitant heparin exposure (all RR <0.90)heparin exposure (all RR <0.90)

• Concomitant heparin analyses are biasedConcomitant heparin analyses are biased– Reason: Many patients move from "no heparin" group to Reason: Many patients move from "no heparin" group to

"heparin" group with post-baseline exposure"heparin" group with post-baseline exposure

9291.01

7474

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

Valid analyses of low-dose heparin exposure: Valid analyses of low-dose heparin exposure:

• Baseline (BL)Baseline (BL)– Treatment-by-heparin interaction p=0.30Treatment-by-heparin interaction p=0.30– Placebo group p= 0.71Placebo group p= 0.71– Drotrecogin alfa (activated) group p=0.28 Drotrecogin alfa (activated) group p=0.28

• Incorporating post-BL exposure (time-dependent Incorporating post-BL exposure (time-dependent covariate)*covariate)*– Treatment-by-heparin interaction p=0.16 (p=0.29**)Treatment-by-heparin interaction p=0.16 (p=0.29**)– Placebo group p=0.69 (p=0.57**)Placebo group p=0.69 (p=0.57**)– Drotrecogin alfa (activated) group p=0.11 (p=0.26**)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

9292.01

7575

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

• Observed variation in relative risk estimates across Observed variation in relative risk estimates across subgroups consistent with random chance if subgroups consistent with random chance if treatment uniformly beneficialtreatment uniformly beneficial– Higher mortality for effective treatment 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 Survival benefit evident in less severe patients almost uniformly across the totality of measures of disease uniformly across the totality of measures of disease severityseverity

• Survival benefit evident in patients with less disease Survival benefit evident in patients with less disease severity within the 1st APACHE II Quartileseverity within the 1st APACHE II Quartile

9157.01

76760.5 0.6 0.7 0.8 1 1.25 1.67 20.9

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

6787.01

Survival Benefit Evident in Patients with Survival Benefit Evident in Patients with Less Disease SeverityLess Disease Severity

7777

2.667/58 (12.1%)17/53 (32.1%)

>3 OF (N=111)

0.8019/157 (12.1%)16/165 (9.7%)<3 OF (N=322)

Relative RiskPlacebo

Drotrecogin Alfa (activated)

28-Day All-CauseMortality Results

By Number of Organ Failures (OF)By Number of Organ Failures (OF)

6788.01

Conclusion: Survival benefit evident in lesssevere 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 Survival Benefit Evident in Less Severe Patients within 1st APACHE II QuartilePatients within 1st APACHE II Quartile

78

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

9293.01

7979

Treatment-by-Severity AnalysesTreatment-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

9294.02

8080

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



No. of Organ Failures

Overall

1

2

3

4

5

418 19.5 21.2

61 32.3 53.3

432 26.2 34.4

235 38.7 46.6

543 20.7 26.0

1690 24.7 30.8

Single Organ Failure

Cardiovascular

Respiratory 231 18.6 24.6

124 13.6 15.5

9045.01

Breslow-Day interaction p=0.93

8181

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

Drotrecogin Alfa

N (activated) PlaceboOverall

Shock within 48 hrs

1214 25.1 32.0

1362 26.0 32.5

476 23.8 27.6

Yes

No

Cardiovascular SOFA

Shock within 6 hrs

Yes

NoAny Shock

Yes

No

1200 26.3 34.2

490 21.0 22.3

328 19.7 23.3


494 19.1 26.60 or 1

1196 27.3 32.42 to 4

1690 24.7 30.8

6314.03

8282

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



Cardiovascular SOFA

Overall

0

1

2

3

4

208 20.2 26.0

743 29.1 36.7

139 29.0 24.7

314 22.0 26.6

286 18.5 27.1

1690 24.7 30.8

Breslow-Day interaction p=0.65Logistic interaction p=0.956634.01

8383

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



Respiratory SOFA

Overall

0

1

2

3

4

65 14.8 23.7

409 30.2 40.6

516 22.5 28.0

554 27.8 28.5

119 12.1 28.3

1690 24.7 30.8

6635.01

Breslow-Day interaction p=0.27Logistic interaction p=0.55

8484

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

• 2 or more organ failures2 or more organ failures 61.2%61.2%

• Respiratory failureRespiratory failure 69.1%69.1%

• Mechanical ventilationMechanical ventilation 59.4%59.4%

• ShockShock 55.7%55.7%

• High-dose vasopressorsHigh-dose vasopressors 46.7% 46.7%

• Severe Protein C deficiencySevere Protein C deficiency 65.1%65.1%

6792.01

69.5% of patients had 2 or more organ failures69.5% of patients had 2 or more organ failuresand/or required high dose vasopressor supportand/or required high dose vasopressor support

8585

Subgroup ConclusionsSubgroup 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

9296.02

86

Clinical Experience in Pediatric Clinical Experience in Pediatric Patients with Severe SepsisPatients with Severe Sepsis

6775.01

8787

Rationale for Pediatric Development ProgramRationale 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

6340.03

Majority of drugs used by pediatric intensivistsMajority of drugs used by pediatric intensivists are not approved for use in pediatric patients are not approved for use in pediatric patients

8888

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 314.55(a) CPMP/ICH/2711/99

9306.01

Extrapolation of EfficacyExtrapolation of Efficacy

8989

TrialStudyDesign

Enrollment(0 to <18 yr)

EnrollmentStatus

F1K-MC-EVAO Open-label PK,PD, and Safety

83 Complete

F1K-MC-EVAS Compassionateuse for purpura

fulminans

14 Complete

F1K-MC-EVBC Treatment usefor severe

sepsis

31 Ongoing

F1K-MC-EVBE,EVBF, and EVBG

Open-labelsafety study forsevere sepsis

54 Ongoing

Total 182

6338.01

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

90

Pediatric Phase 1B StudyPediatric Phase 1B StudyF1K-MC-EVAOF1K-MC-EVAO

9297.01

9191

Baseline Characteristics of Pediatric and Baseline Characteristics of Pediatric and Adult PatientsAdult Patients

Pediatric PatientsF1K-MC-EVAOParts 1 and 2

(N=83)(% of patients)

Adult PatientsF1K-MC-EVAD

(N=1690)(% of patients)

Gender Male 50.6 57.0Racial Origin Caucasian African Hispanic

68.712.19.6

81.97.84.4

Site of Infection Blood Lung Central Nervous System Intra-Abdominal

34.920.516.97.2

5.153.62.3

19.9

6524.01

9292

100

80

60

40

20

0

20

40

60

80

100

Adult PatientsN =1550-1574

Pediatric Patients N=78-79

Protein C D-dimer Antithrombin



Pediatric Baseline Biomarkers of Disease Pediatric Baseline Biomarkers of Disease Severity are Similar to AdultsSeverity are Similar to Adults

6770.01

9393

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

6159.02

9494

Median Pediatric Biomarker Change from Median Pediatric Biomarker Change from Baseline to End of Infusion are Similar to AdultBaseline 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%777

27%770

17%772

18%746

-7%729

15%734

Pediatric Patients F1K-MC-EVAO

Part 2 0 to <18 yr

Adult Patients F1K-MC-EVAD

Drotrecogin Alfa

(activated) Placebo

6771.02

79%57

26%56

24%56

9595

Serious Bleeding Events – Pediatric and Serious Bleeding Events – Pediatric and Adult PatientsAdult Patients

Adult Patients (EVAD)

PediatricPatients(N=83)n (%)

DrotrecoginAlfa

(activated)(N=850)n (%)

Placebo(N=840)n (%)

Serious BleedingEvents During StudyDrug Infusion Period

2 (2.4%) 20 (2.4%) 8 (1.0%)

Serious BleedingEvents During EntireStudy Period

4 (4.8%) 30 (3.5%) 17 (2.0%)

6773.01

96966776.02

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

Trial

Current Enrollment (0 to <18 yr)

No. of Patients with at Least One Bleeding SAE

During Infusion n (%)

F1K-MC-EVAO 83 2 (2.4%)

F1K-MC-EVAS 14 0 (0)

F1K-MC-EVBC 31 0 (0)

F1K-MC-EVBE, EVBF, and EVBG

54 2 (3.7%)

Total 182 4 (2.2%)

9797

Conclusions from Pediatric StudiesConclusions 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

6538.01

9898

Overall ConclusionsOverall Conclusions

Drotrecogin alfa (activated) reduces Drotrecogin alfa (activated) reduces mortality in patients with severe sepsis mortality in patients with severe sepsis

and is associated with a favorable and is associated with a favorable benefit-risk profile in patients with benefit-risk profile in patients with

severe sepsis.severe sepsis.

9257.01

9999

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

Agents

Observed NNTto Save an

Additional Life

Drotrecogin Alfa (activated) inStudy F1K-MC-EVADSevere Sepsis28-Day Mortality

16

Streptokinase vs Placebo in ISIS-2Acute Myocardial Infarction35-Day Mortality1

36

TPA vs Streptokinase in GUSTOAcute Myocardial infarction30-Day Mortality2

100

1 ISIS-2. 1988. Lancet 2:349-360.2 Activase® USPI.

6762.01

100100




6105.01

Documents

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