1 Definitions, Epidemiology, Pathophysiology and Treatment of Severe Sepsis

1

Definitions, Epidemiology, Definitions, Epidemiology, Pathophysiology and Pathophysiology and

Treatment of Severe SepsisTreatment of Severe Sepsis

2

* Based on data for septicemia * Based on data for septicemia ††Reflects hospital-wide cases of severe sepsis as defined by infection in the presence of organ dysfunction Reflects hospital-wide cases of severe sepsis as defined by infection in the presence of organ dysfunction

11Sands KE, et al. Sands KE, et al. JAMAJAMA 1997;278:234-40. 1997;278:234-40.22Murphy SL. National Vital Statistics Reports. 1998.Murphy SL. National Vital Statistics Reports. 1998.33Angus DC, et al. Angus DC, et al. Crit Care MedCrit Care Med 2001;29:1303-10. 2001;29:1303-10.

Severe Sepsis:Severe Sepsis:A Significant Healthcare ChallengeA Significant Healthcare Challenge

• Major cause of morbidity and mortality worldwideMajor cause of morbidity and mortality worldwide— Leading cause of death in noncoronary ICU (US)Leading cause of death in noncoronary ICU (US)11

— 1111thth leading cause of death overall (US) leading cause of death overall (US)22**

• More than 750,000 cases of severe sepsis More than 750,000 cases of severe sepsis in the US annuallyin the US annually33

• In the US, more than 500 patients dieIn the US, more than 500 patients dieof severe sepsis dailyof severe sepsis daily33††

3Bone RC, et al. Chest 1992;101:1644-55.

Sepsis: Sepsis: ACCP/SCCM DefinitionsACCP/SCCM Definitions

• InfectionInfection— Inflammatory response to microorganisms, orInflammatory response to microorganisms, or

— Invasion of normally sterile tissuesInvasion of normally sterile tissues

• Systemic Inflammatory Response Syndrome (SIRS)Systemic Inflammatory Response Syndrome (SIRS)— Core temperature >38Core temperature >38C or <36C or <36C (>100.4C (>100.4F or <96.8F or <96.8F)F)

— Elevated heart rate (>90 beats/min)Elevated heart rate (>90 beats/min)

— Respiratory rate >20 breaths/min or PaCORespiratory rate >20 breaths/min or PaCO22 <32 mm Hg or <32 mm Hg or

mechanical ventilation for acute respiratory processmechanical ventilation for acute respiratory process

— WBC count >12,000 cells/mmWBC count >12,000 cells/mm33 or <4,000 cells/mm or <4,000 cells/mm33 or >10% or >10% immature neutrophilsimmature neutrophils

4Bone RC, et al. Chest 1992;101:1644-55.

Sepsis: Sepsis: ACCP/SCCM Definitions (cont)ACCP/SCCM Definitions (cont)

• SepsisSepsis— Known or suspected infection, Known or suspected infection, plusplus 2 SIRS criteria2 SIRS criteria

• Severe SepsisSevere Sepsis— Sepsis Sepsis plusplus 1 organ dysfunction1 organ dysfunction— Multiple Organ Dysfunction Syndrome (MODS)Multiple Organ Dysfunction Syndrome (MODS)

Altered function of more than one organ in an acutely ill patientAltered function of more than one organ in an acutely ill patient Homeostasis cannot be maintained without interventionHomeostasis cannot be maintained without intervention

— Septic ShockSeptic Shock SepsisSepsis Hypotension despite fluid resuscitationHypotension despite fluid resuscitation Perfusion abnormalitiesPerfusion abnormalities

5

Burns

Trauma

Pancreatitis

Other

SIRSINFECTION

Adapted from: Bone RC, et al. Chest 1992;101:1644-55.Opal SM, et al. Crit Care Med 2000;28:S81-2.

Relationship of Infection, SIRS, Sepsis and Relationship of Infection, SIRS, Sepsis and Severe SepsisSevere Sepsis

SEVERESEPSIS

6

0

50

100

150

200

250

300

Severe Sepsis Stroke Breast Cancer Lung Cancer

IncidenceMortality

*Calculated data based on information compiled from the American Heart Association, American Cancer Society, National Center for Health Statistics and the US Census Bureau (1995-1999)

†Severe sepsis mortality rates range from 28%-50% (79/100,000 to 141/100,000 population).

Severe Sepsis is CommonSevere Sepsis is Common**

Rat

e pe

r 10

0,00

0 P

opul

atio

n

†

7

1Sands KE, et al. JAMA 1997;278:234-40.2Zeni F, et al. Crit Care Med 1997;1095-100.3Angus DC, et al. Crit Care Med 2001;29:1303-10.

Severe Sepsis is DeadlySevere Sepsis is Deadly

28%3

50%2

0

20

40

60

Sands KE, et al Zeni F, et al Angus DC, et al

34%1

Mo

rta

lity

(%)

8

800

1,000

1,200

1,400

1,600

1,800

2001 2025 2050

Year

300

400

500

600

Sep

sis

Cas

es (

x103 )

Tot

al U

S P

opul

atio

n (m

illio

n)

Angus DC, et al. JAMA 2000;284:2762-70.Angus DC, et al. Crit Care Med 2001;29:1303-10.

Severe Sepsis is Increasing in IncidenceSevere Sepsis is Increasing in Incidence

Severe Sepsis CasesUS Population

91Pittet D, et al. JAMA 1994;271:1598-601.2Angus DC, et al. Crit Care Med 2001;29:1303-10.

Severe Sepsis is a Significant Severe Sepsis is a Significant Healthcare BurdenHealthcare Burden

• Sepsis consumes significant healthcare resourcesSepsis consumes significant healthcare resources• In a study of patients who contract nosocomial infections, In a study of patients who contract nosocomial infections,

develop sepsis and survivedevelop sepsis and survive11::— ICU stay was prolonged by an additional 8 daysICU stay was prolonged by an additional 8 days

— Additional costs incurred were $40,890/patientAdditional costs incurred were $40,890/patient

• Estimated annual direct and indirect healthcare costs due Estimated annual direct and indirect healthcare costs due to severe sepsis in the United States exceed $16 billionto severe sepsis in the United States exceed $16 billion22

10Angus DC, et al. Crit Care Med 2001;29:1303-10.Wheeler AP, et al. N Engl J Med 1999;340:207-14.

Systemic Inflammation

Impaired Fibrinolysis

Coagulation

Severe Sepsis is a Complex and Severe Sepsis is a Complex and Unpredictable Clinical SyndromeUnpredictable Clinical Syndrome

• High mortality rate High mortality rate • Heterogeneous Heterogeneous

patient populationpatient population• Unpredictable disease Unpredictable disease

progressionprogression• Studies indicate that Studies indicate that

severe sepsis has severe sepsis has inflammatory, inflammatory, prothrombotic and prothrombotic and impaired fibrinolytic impaired fibrinolytic componentscomponents

Severe Severe SepsisSepsis

11Chart adapted from: van Deventer SJ, et al. Blood 1990;76:2520-6.

Inflammation is Activated in SepsisInflammation is Activated in Sepsis

14

12

10

8

6

4

2

0

0 60 120 180 240 300 360

Minutes after LPS Infusion

End

otox

in (

ng/L

)

TN

F (

ng/L

)

IL

-6 (

U/m

L)

12Data from: Yan SB, et al. Chest 2001;120:915-22.

0

20

40

60

80

100

Platelets PTT PT Any One Any Two All Three Protein C D-dimers

Per

cent

of

Pat

ient

s

Spectrum of Coagulopathy in Severe SepsisSpectrum of Coagulopathy in Severe Sepsis

13

0.0

0.2

0.4

0.6

0.8

1.0

1.2

**

*** *

1 4 7

Pla

smin

ogen

/ant

ipla

smin

Rat

io

Time after Hospital Admission (day)

*P<.05 vs normal values†P<.05 vs first day

**

* *

0

10

20

30

40

50

60

1 4 7P

AI-

1 (n

g/m

L)

Time after Hospital Admission (day)

*P<.05 vs normal values

Survivors (n=23) Nonsurvivors (n=25) Normal Values

Data from: Lorente JA, et al. Chest 1993;103:1536-42.

†

Fibrinolysis is Impaired in Severe SepsisFibrinolysis is Impaired in Severe Sepsis

14

Carvalho AC, Freeman NJ. J Crit Illness 1994;9:51-75.Kidokoro A, et al. Shock 1996;5:223-8.Vervloet MG, et al. Semin Thromb Hemost 1998;24:33-44.

Homeostasis

Homeostasis is Unbalanced in Severe SepsisHomeostasis is Unbalanced in Severe Sepsis

COAGULATIONCOAGULATIONINFLAMMATIONINFLAMMATION

FIBRINOLYSISFIBRINOLYSIS

Endothelial Dysfunction and Microvascular Thrombosis

Hypoperfusion/Ischemia

Acute Organ Dysfunction (Severe Sepsis)

Death

16Balk RA. Crit Care Clin 2000;16:337-52.

Identifying Acute Organ Dysfunction as a Identifying Acute Organ Dysfunction as a Marker of Severe SepsisMarker of Severe Sepsis

TachycardiaTachycardiaHypotensionHypotensionAltered CVPAltered CVP

Altered PAOPAltered PAOP

OliguriaOliguriaAnuriaAnuria

CreatinineCreatinine

PlateletsPlatelets PT/APTTPT/APTT Protein CProtein C D-dimerD-dimer

JaundiceJaundice EnzymesEnzymes AlbuminAlbumin

PT PT

Altered Altered ConsciousnessConsciousness

ConfusionConfusionPsychosisPsychosis

TachypneaTachypnea

PaOPaO22 <70 mm Hg <70 mm Hg

SaOSaO22 <90% <90%

PaOPaO22/FiO/FiO22 300 300

17Wheeler AP, Bernard GR. N Engl J Med 1999;340:207-14.

Severe Sepsis Therapy: Severe Sepsis Therapy: Conventional CareConventional Care

• Source controlSource control

• AntibioticsAntibiotics

• Hemodynamic supportHemodynamic support

• Mechanical ventilationMechanical ventilation

• Renal replacement therapyRenal replacement therapy

• Sedation/analgesiaSedation/analgesia

• Adequate nutritionAdequate nutrition

• Hematological supportHematological support

• Other supportive measuresOther supportive measures

18

Severe Sepsis Therapy:Severe Sepsis Therapy: Numerous Investigational ApproachesNumerous Investigational Approaches

• Bacterial product modulatorsBacterial product modulators— Antiendotoxin, bactericidal/permeability-increasing protein Antiendotoxin, bactericidal/permeability-increasing protein

• AnticytokinesAnticytokines— IL-1ra, anti-TNF, sTNF-rIL-1ra, anti-TNF, sTNF-r

• Antiinflammatory agentsAntiinflammatory agents— Glucocorticoids, leukocyte adhesion molecule inhibitorsGlucocorticoids, leukocyte adhesion molecule inhibitors

• Hemostatic agentsHemostatic agents— ATIII, TFPIATIII, TFPI

• Other mechanismsOther mechanisms— iNOS inhibition, antioxidants, thromboxane antagonists, iNOS inhibition, antioxidants, thromboxane antagonists,

bradykinin receptor antagonistsbradykinin receptor antagonists

Wheeler AP, Bernard GR. N Engl J Med 1999;340:207-14.

19

Conclusions:Conclusions:Epidemiology, Pathophysiology and Conventional TherapyEpidemiology, Pathophysiology and Conventional Therapy

Sepsis + acute organ dysfunction = severe sepsisSepsis + acute organ dysfunction = severe sepsis Severe sepsis is common, deadly and consumes Severe sepsis is common, deadly and consumes

significant healthcare resourcessignificant healthcare resources— >750,000 cases/year in the United States>750,000 cases/year in the United States— Mortality of 28% to 50% despite conventional careMortality of 28% to 50% despite conventional care— In the United States, the costs of severe sepsis exceed In the United States, the costs of severe sepsis exceed

$16 billion$16 billion Severe sepsis is more than just inflammationSevere sepsis is more than just inflammation

— Coagulopathy, evidenced by increased D-dimers and Coagulopathy, evidenced by increased D-dimers and decreased Protein C levels, is almost universaldecreased Protein C levels, is almost universal

— Patients have impaired fibrinolysisPatients have impaired fibrinolysis

20

Conclusions:Conclusions:Epidemiology, Pathophysiology and Conventional Therapy (cont)Epidemiology, Pathophysiology and Conventional Therapy (cont)

The origin of multiple organ dysfunction syndrome The origin of multiple organ dysfunction syndrome (MODS) in severe sepsis is multifactorial in origin (MODS) in severe sepsis is multifactorial in origin but includes disordered hemostasis and endothelial but includes disordered hemostasis and endothelial dysfunctiondysfunction

The development of interventions to reduce mortality in The development of interventions to reduce mortality in life-threatening severe sepsis has remained an unmet life-threatening severe sepsis has remained an unmet need until recentlyneed until recently

21

The Role of Endogenous The Role of Endogenous Activated Protein C in Activated Protein C in

Severe Sepsis Severe Sepsis

22

The Protein C SystemThe Protein C System

• The Protein C system is essential in restoring homeostasis The Protein C system is essential in restoring homeostasis in patients with severe sepsis. Components include:in patients with severe sepsis. Components include:

— Protein C: An inactive precursor of Activated Protein CProtein C: An inactive precursor of Activated Protein C

— Activated Protein C: An endogenous modulator with antithrombotic, Activated Protein C: An endogenous modulator with antithrombotic, antiinflammatory and profibrinolytic propertiesantiinflammatory and profibrinolytic properties

— Thrombomodulin: An endothelial cell protein. The thrombomodulin/thrombin Thrombomodulin: An endothelial cell protein. The thrombomodulin/thrombin complex is required for activation of Protein Ccomplex is required for activation of Protein C

— Protein S: A cofactor for endogenous Activated Protein C activityProtein S: A cofactor for endogenous Activated Protein C activity

23

Endothelium

Neutrophil

Monocyte

IL-6IL-1TNF-

IL-6

Activated Protein C

Inactivation

Inactivation

Inactivation

Prev

entio

n of

act

ivat

ion

Activated Protein C

Inflammatory Responseto Infection

Thrombotic Responseto Infection

Fibrinolytic Responseto Infection

TAFI

PAI-1

Suppressedfibrinolysis

Factor VIIIaTissue Factor

COAGULATION CASCADE

Factor Va

THROMBIN

Fibrin

Fibrin clotTissue Factor

The Role of Endogenous Activated Protein C The Role of Endogenous Activated Protein C in Patients with Severe Sepsisin Patients with Severe Sepsis

ActivatedProtein C

Reduction

of Rolling

Inhi

bitio

nIn

hibi

tion

Activated Protein C

24

Carvalho AC, et al. J Crit Illness 1994;9:51-75.Kidokoro A, et al. Shock 1996;5:223-8.Vervloet MG, et al. Semin Thromb Hemost 1998;24:33-44.

Homeostasis

Endogenous Activated Protein C Restores Endogenous Activated Protein C Restores Homeostasis in Patients with Severe SepsisHomeostasis in Patients with Severe Sepsis

Activated Protein C

FIBRINOLYSISFIBRINOLYSIS COAGULATIONCOAGULATION INFLAMMATIONINFLAMMATION

25

Conclusions:Conclusions: The Role of Endogenous Activated Protein C in Severe SepsisThe Role of Endogenous Activated Protein C in Severe Sepsis

Endogenous Activated Protein C is a key element in the body’s Endogenous Activated Protein C is a key element in the body’s response to severe sepsisresponse to severe sepsis

Endogenous Activated Protein C has the following properties:Endogenous Activated Protein C has the following properties:— AntiinflammatoryAntiinflammatory

— AntithromboticAntithrombotic

— ProfibrinolyticProfibrinolytic In the presence of sepsis-associated endothelial dysfunction, the In the presence of sepsis-associated endothelial dysfunction, the

body may be unable to convert significant amounts of body may be unable to convert significant amounts of endogenous Protein C to Activated Protein C; consequently, endogenous Protein C to Activated Protein C; consequently, patients are unable to benefit from the properties of endogenous patients are unable to benefit from the properties of endogenous Activated Protein CActivated Protein C

26

The Development of The Development of Drotrecogin Alfa (Activated)Drotrecogin Alfa (Activated)

27

Drotrecogin Alfa (Activated):Drotrecogin Alfa (Activated):IndicationsIndications

• Drotrecogin alfa (activated) is indicated for the reduction of Drotrecogin alfa (activated) is indicated for the reduction of mortality in adult patients with severe sepsis (sepsis mortality in adult patients with severe sepsis (sepsis associated with acute organ dysfunction) who have a high associated with acute organ dysfunction) who have a high risk of death (eg, as determined by APACHE II*) risk of death (eg, as determined by APACHE II*)

• Efficacy has not been established in adult patients with Efficacy has not been established in adult patients with severe sepsis and lower risk of death. Safety and efficacy severe sepsis and lower risk of death. Safety and efficacy have not been established in pediatric patients with have not been established in pediatric patients with severe sepsissevere sepsis

* APACHE (Acute Physiology and Chronic Health Evaluation). For more information * APACHE (Acute Physiology and Chronic Health Evaluation). For more information on using the APACHE II scoring system, please see on using the APACHE II scoring system, please see http://www.sfar.org/scores2/scores2.htmlhttp://www.sfar.org/scores2/scores2.html

See important safety information in this presentation.See important safety information in this presentation.

28

Scientific Basis for the Development of Scientific Basis for the Development of Recombinant Human Activated Protein C Recombinant Human Activated Protein C

• Severe sepsis is an inflammatory and prothrombotic Severe sepsis is an inflammatory and prothrombotic state with impaired fibrinolysisstate with impaired fibrinolysis

• Endogenous Activated Protein C is a regulator of Endogenous Activated Protein C is a regulator of inflammation, coagulation and fibrinolysisinflammation, coagulation and fibrinolysis

• Levels of endogenous Protein C are low in patients Levels of endogenous Protein C are low in patients with severe sepsis and are associated with an with severe sepsis and are associated with an adverse outcomeadverse outcome

• Sepsis is a complex syndrome that can lead toSepsis is a complex syndrome that can lead toacute organ dysfunction and deathacute organ dysfunction and death

• Sepsis exerts a significant clinical and economic burdenSepsis exerts a significant clinical and economic burden

29

The Development of Drotrecogin The Development of Drotrecogin Alfa (Activated)Alfa (Activated)

1960s:1960s:Antithrombotic activity of Activated Protein C identifiedAntithrombotic activity of Activated Protein C identified

1980s:1980s:Human Protein C purifiedHuman Protein C purified

1980s:1980s:Lilly commits to the development of recombinant human Lilly commits to the development of recombinant human Activated Protein CActivated Protein C

1994: 1994: Phase 1 studies beginPhase 1 studies begin

1996-1998:1996-1998:Phase 2 trialPhase 2 trial

1998-2000:1998-2000:PROWESS trialPROWESS trial

2000:2000:Drotrecogin alfa (activated) designated as the generic nameDrotrecogin alfa (activated) designated as the generic name

2001:2001: Xigris accepted as the proprietary name for drotrecogin alfa Xigris accepted as the proprietary name for drotrecogin alfa (activated)(activated)

2001:2001:Xigris approved for marketing by the US FDAXigris approved for marketing by the US FDA

Xigris is a trademark of Eli Lilly and Company.

30

Drotrecogin Alfa (Activated): Drotrecogin Alfa (Activated): PropertiesProperties

• Recombinant form of human Activated Protein CRecombinant form of human Activated Protein C• Produced by an established human cell line Produced by an established human cell line

possessing the complementary DNA for the inactive possessing the complementary DNA for the inactive human Protein C zymogenhuman Protein C zymogen

• May variably prolong the APTTMay variably prolong the APTT

31

Conclusions:Conclusions:The Development of Drotrecogin Alfa (Activated)The Development of Drotrecogin Alfa (Activated)

• Drotrecogin alfa (activated) is a recombinant form of Drotrecogin alfa (activated) is a recombinant form of human Activated Protein Chuman Activated Protein C

• Derivation of the name:Derivation of the name:— Cogin = family of coagulation inhibitors Cogin = family of coagulation inhibitors — Alfa = first form of the recombinant moleculeAlfa = first form of the recombinant molecule— Activated = the molecule is the activated form of Activated = the molecule is the activated form of

recombinant human Protein Crecombinant human Protein C

32

The PROWESS The PROWESS (Recombinant Human (Recombinant Human

Activated Activated ProProtein C tein C WWorldwide orldwide EEvaluation in valuation in

SSevere evere SSepsis) Trial: epsis) Trial: OverviewOverview

33

PROWESS Study DescriptionPROWESS Study Description

DesignDesign– Randomized, double-blind, placebo-controlled trial of drotrecogin Randomized, double-blind, placebo-controlled trial of drotrecogin

alfa (activated)alfa (activated)

– 164 sites in 11 countries164 sites in 11 countries

– 1690 patients (age 18-96 years)1690 patients (age 18-96 years)

PopulationPopulation——Severe SepsisSevere Sepsis– Presence of a known or suspected infectionPresence of a known or suspected infection

– Evidence of a systemic response to the infection (3 or more SIRS criteria)Evidence of a systemic response to the infection (3 or more SIRS criteria)

– At least one sepsis-associated organ dysfunction of no longerAt least one sepsis-associated organ dysfunction of no longerthan 24 hours durationthan 24 hours duration

Treatment ArmsTreatment Arms– All patients received conventional care (1:1 randomization)All patients received conventional care (1:1 randomization)

– 1:1 randomization to drotrecogin alfa (activated) 24 µg/kg/hr or1:1 randomization to drotrecogin alfa (activated) 24 µg/kg/hr orplacebo for 96 hoursplacebo for 96 hours

Bernard GR, et al. N Engl J Med 2001;344:699-709.

34

Respiratory

Cardiovascular

PaO2/FiO2 250 in the presence of otherdysfunctional organs/systems or 200 if lung dysfunction alone

Arterial systolic BP 90 mm Hg orMAP 70 mm Hg for 1 hour despiteadequate fluid resuscitation, adequateintravascular volume status or use ofvasopressors


Renal

Hematologic

Unexplained metabolic acidosis

Platelets <80,000/mm3 or decreased by 50%in preceding 3 days

pH 7.3 or base deficit 5.0 mmol/Lassociated with plasma lactate level>1.5 times the upper limit of normal

Urine output <.5 mL/kg/hrdespite adequate fluid resuscitation

Organ Dysfunction in the PROWESS Organ Dysfunction in the PROWESS Clinical TrialClinical Trial

35

Conventional Patient Care

Start of study agent Start of study agent infusioninfusion

Assessment of Assessment of 28-day all-cause 28-day all-cause mortalitymortality


24 hrs to meet inclusion 24 hrs to meet inclusion criteria and obtain consentcriteria and obtain consent

24 hrs from meeting 24 hrs from meeting inclusion criteria to inclusion criteria to start of study agentstart of study agent

PROWESS Study DesignPROWESS Study Design

End of 96-hr infusion of study agentEnd of 96-hr infusion of study agent

Average time from first Average time from first acute organ acute organ

dysfunction to start of dysfunction to start of drug was 17 hrsdrug was 17 hrs

36

Summary of PROWESS MainSummary of PROWESS MainExclusion Criteria*Exclusion Criteria*

• Platelet count <30,000/mmPlatelet count <30,000/mm33

• Certain medications associated with increased bleeding riskCertain medications associated with increased bleeding risk(eg, therapeutic heparin, warfarin, thrombolytics, glycoprotein(eg, therapeutic heparin, warfarin, thrombolytics, glycoproteinIIb/IIIa inhibitors)IIb/IIIa inhibitors)

• Increased risk of bleeding (eg, surgery within 12 hours, GI bleedIncreased risk of bleeding (eg, surgery within 12 hours, GI bleedwithin 6 weeks, risk of CNS bleed, trauma patients at risk ofwithin 6 weeks, risk of CNS bleed, trauma patients at risk ofbleeding [significant contusion or injury to vascular organ], bleeding [significant contusion or injury to vascular organ], portosystemic hypertension)portosystemic hypertension)

• Moribund patients expected to die within 24 hoursMoribund patients expected to die within 24 hours• Patients expected to die from comorbidities within 28 daysPatients expected to die from comorbidities within 28 days• Pregnancy or breastfeedingPregnancy or breastfeeding

• HIV positive, with most recent CDHIV positive, with most recent CD44 count count ≤50/mm≤50/mm33

• Chronic dialysisChronic dialysis• Bone marrow, lung, liver, pancreas or small-bowel transplantBone marrow, lung, liver, pancreas or small-bowel transplant

* Details of additional exclusion criteria not presented on the slide are specified in the reference article.Bernard GR, et al. N Engl J Med 2001;344:699-709.

37

n=380

n=380

Placebo

Drotrecogin alfa(activated)

Stage 1 Stage 2

n=380

n=380

n=760 N=1728

Interim 1October 1999

n=1520

P≤.0002 July 26, 2000last patient visit

P≤.0118

Number of patients

Efficacy stopping rules

Bernard GR, et al. New Engl J Med 2001;344:699-709.

Interim 2June 2000

PROWESS Study Stopped for Efficacy by PROWESS Study Stopped for Efficacy by Independent DSMB at 2Independent DSMB at 2ndnd Interim Analysis Interim Analysis

38Bernard GR, et al. N Engl J Med 2001;344:699-709.

Drotrecogin alfa (activated)

n=840 completedn=840 completedprotocolprotocol

n=840 completedn=840 completedprotocolprotocol

n=850 completedprotocol

n=850 completedprotocol

n=850 treatedn=850 treatedn=840 treatedn=840 treatedn=840 treatedn=840 treated

n=17n=17not treatednot treated

n=17n=17not treatednot treated

n=21not treated

n=21not treated

n=857n=857randomizedrandomized

n=857n=857randomizedrandomized

n=871randomized

n=871randomized

N=1728N=1728patients enrolledpatients enrolled

N=1728N=1728patients enrolledpatients enrolled

Placebo

Patient Disposition in PROWESSPatient Disposition in PROWESS

39

GenderMaleFemale

Racial originCaucasianNon-Caucasian

Placebo n=840 (%)

Drotrecogin alfa (activated)n=850 (%)

Mean age (years) 60.6 60.5 60.5

Total N=1690 (%)

353 (42.0)487 (58.0)

689 (82.0)151 (18.0)

Mean weight (kg) 75.0 74.8 74.9

373 (43.9) 477 (56.1)

695 (81.8)155 (18.2)

726 (43.0) 964 (57.0)


PROWESS Demographics Were PROWESS Demographics Were Well BalancedWell Balanced

1384 (81.9) 306 (18.1)


*Includes blood, skin, central nervous system, cardiovascular system,*Includes blood, skin, central nervous system, cardiovascular system,reproductive system, bones and joints, etc.reproductive system, bones and joints, etc.

Common Sources of Infection in PROWESSCommon Sources of Infection in PROWESS

Urinary tract

Other*

Placebo n=840 (%)

Drotrecogin alfa (activated)n=850 (%)

Lung 450 (53.6) 456 (53.6) 906 (53.6)

Total N=1690 (%)

86 (10.2)

137 (16.3)

Intra-abdominal 167 (19.9) 170 (20.0) 337 (19.9)

85 (10.0)

139 (16.4)

171 (10.1)

276 (16.3)

411Data on file, Eli Lilly and Company2Bernard GR, et al. N Engl J Med 2001;344:699-709.

**Includes unconfirmed, culture negative or not obtainedIncludes unconfirmed, culture negative or not obtained

Type of Infection and Gram Stain Class Type of Infection and Gram Stain Class in PROWESSin PROWESS

Type of Gram Stain Class of Bacterial PathogenType of Gram Stain Class of Bacterial Pathogen22

Placebo Placebo n=840 (%)n=840 (%)

Drotrecogin alfa Drotrecogin alfa (activated)(activated)n=850 (%)n=850 (%)

At least one positive At least one positive bacterial culturebacterial culture11

567 (67.5)567 (67.5) 562 (66.1)562 (66.1) 1129 (66.8)1129 (66.8)

Total Total N=1690 (%)N=1690 (%)

At least one positive At least one positive blood cultureblood culture22

273 (32.5)273 (32.5) 278 (32.7)278 (32.7) 551 (32.6)551 (32.6)

Pure Gram +Pure Gram + 211 (25.1)211 (25.1) 430 (25.4)430 (25.4)219 (25.8)219 (25.8)

Pure Gram -Pure Gram - 196 (23.3)196 (23.3) 185 (21.8)185 (21.8) 381 (22.5)381 (22.5)

Mixed GramMixed Gram 117 (13.9)117 (13.9) 133 (15.6)133 (15.6) 250 (14.8)250 (14.8)

Other*Other* 316 (37.6)316 (37.6) 313 (36.8)313 (36.8) 629 (37.2)629 (37.2)

Fungal (+ culture)Fungal (+ culture)11 64 (7.6)64 (7.6) 72 (8.5)72 (8.5) 136 (8.0)136 (8.0)

421Bernard GR, et al. N Engl J Med 2001;344:699-709.2Data on file, Eli Lilly and Company

PROWESS Patients Were Evenly Distributed PROWESS Patients Were Evenly Distributed by APACHE II Score at Study Entryby APACHE II Score at Study Entry

Preinfusion APACHE II ScorePreinfusion APACHE II Score11

MeanMean

RangeRange

Preinfusion APACHE II QuartilePreinfusion APACHE II Quartile22

11stst



Total Total N=1690 (%)N=1690 (%)

24.9524.95 24.5824.58 24.7724.77

3 - 503 - 50 5 - 535 - 53 3 - 533 - 53

215 (25.6)215 (25.6) 218 (25.6)218 (25.6) 433 (25.6)433 (25.6)

22ndnd 222 (26.4)222 (26.4) 218 (25.6)218 (25.6) 440 (26.0)440 (26.0)

33rdrd 162 (19.3)162 (19.3) 204 (24.0)204 (24.0) 366 (21.7)366 (21.7)

44thth 241 (28.7)241 (28.7) 210 (24.7)210 (24.7) 451 (26.7)451 (26.7)

43

PROWESS Patients Were Evenly Distributed PROWESS Patients Were Evenly Distributed by Number of Dysfunctional Organ Systemsby Number of Dysfunctional Organ Systems

Number of Organ Failure Entry Criteria MetNumber of Organ Failure Entry Criteria Met

00

11

22



Total Total N=1690 (%)N=1690 (%)

0 (0)0 (0) 1 (0.1)1 (0.1) 1 (0.1)1 (0.1)

203 (24.2)203 (24.2) 215 (25.3)215 (25.3) 418 (24.7)418 (24.7)

273 (32.5)273 (32.5) 270 (31.8)270 (31.8) 543 (32.1)543 (32.1)

33 218 (26.0)218 (26.0) 214 (25.2)214 (25.2) 432 (25.6)432 (25.6)

44 116 (13.8)116 (13.8) 119 (14.0)119 (14.0) 235 (13.9)235 (13.9)

55 30 (3.6)30 (3.6) 31 (3.6)31 (3.6) 61 (3.6)61 (3.6)


44Data on file, Eli Lilly and Company

Most PROWESS Subjects Had Most PROWESS Subjects Had Sepsis-Induced CoagulopathySepsis-Induced Coagulopathy

Procoagulant Activity

BiomarkersBiomarkers Normal RangeNormal Range % Patients Abnormal% Patients Abnormal

D-dimer (mg/L)D-dimer (mg/L) 0 - .390 - .39 99.799.7‡‡

TAT* (µg/L)TAT* (µg/L) 1.0 - 4.11.0 - 4.1 95.595.5‡‡

FI.2FI.2† † (nmol/L)(nmol/L) .44 - 1.10.44 - 1.10 77.577.5‡‡

Anticoagulant Activity

Protein C activityProtein C activity 81 - 173%81 - 173% 87.687.6§§

Protein S activityProtein S activity 60 - 155%60 - 155% 77.877.8§§

AT-III activityAT-III activity 80 - 120%80 - 120% 81.781.7§§

** TAT = Thrombin-antithrombin complexTAT = Thrombin-antithrombin complex††F1.2 = Prothrombin fragment 1.2F1.2 = Prothrombin fragment 1.2‡‡Percentage of patients with values higher than the upper limit of normalPercentage of patients with values higher than the upper limit of normal§§Percentage of patients with values lower than the lower limit of normalPercentage of patients with values lower than the lower limit of normal

45

* Percentage of patients with values higher than the upper limit of normal* Percentage of patients with values higher than the upper limit of normal†† Percentage of patients with values lower than the lower limit of normalPercentage of patients with values lower than the lower limit of normal

Data on file, Eli Lilly and CompanyData on file, Eli Lilly and Company

BiomarkersBiomarkers Normal RangeNormal Range % Patients % Patients AbnormalAbnormal

Global Coagulation TestsGlobal Coagulation TestsPlatelet count (mmPlatelet count (mm33)) 140 - 400 x10140 - 400 x1033 30.630.6††

PT (s)PT (s) 10.6 - 14.5 10.6 - 14.5 93.4*93.4*APTT (s) APTT (s) 21 - 39 21 - 39 63.1*63.1*Proinflammatory MarkerProinflammatory MarkerIL-6 (pg/mL) IL-6 (pg/mL) .38 - 10.1 .38 - 10.1 98.5*98.5*Endothelial DysfunctionEndothelial DysfunctionsTM (ng/mL)sTM (ng/mL) 18 - 53 18 - 53 72.0*72.0*Antifibrinolytic ActivityAntifibrinolytic ActivityPAI-1 activity (AU/mL) PAI-1 activity (AU/mL) 4 - 37.8 4 - 37.8 44.0*44.0*

Inflammation and Microvascular Dysfunction Inflammation and Microvascular Dysfunction Were Very Common in PROWESSWere Very Common in PROWESS


Summary of Baseline Characteristics Summary of Baseline Characteristics in PROWESSin PROWESS

• Baseline characteristics for the two treatment groups Baseline characteristics for the two treatment groups were similarwere similar

• In the overall PROWESS population:In the overall PROWESS population:— Pulmonary and intra-abdominal sources were the most common Pulmonary and intra-abdominal sources were the most common

sites of infectionsites of infection— The types of infection were similar in both groupsThe types of infection were similar in both groups— The population was homogenous with respect to evidence of The population was homogenous with respect to evidence of

systemic inflammation and coagulopathysystemic inflammation and coagulopathy

47

The PROWESSThe PROWESS(Recombinant Human (Recombinant Human

Activated Activated ProProtein C tein C WWorldwide orldwide EEvaluation in valuation in

SSevere evere SSepsis) Trial: epsis) Trial: ResultsResults

48

Placebo(n=840)

Drotrecoginalfa

(activated)(n=850)

35

Mo

rta

lity

(%)

30

25

20

15

10

5

Bernard GR, et al. N Engl J Med 2001; 344:699-709.

Drotrecogin Alfa (Activated) Significantly Drotrecogin Alfa (Activated) Significantly Reduced Mortality in PROWESSReduced Mortality in PROWESS

Primary Analysis Results

.00519%

2-sided P-valueAdjusted relative risk reduction

6% Absolutereduction inmortality

25%

31%



00 77 1414 2121 2828

70 70

80 80

90 90

100 100

Days from Start of Infusion to DeathDays from Start of Infusion to Death

Per

cent

Sur

vivo

rsP

erce

nt S

urvi

vors

P=.006 (stratified log-rank test)00

Placebo(n=840)

Drotrecogin alfa (activated) (n=850)

Drotrecogin Alfa (Activated) Significantly Drotrecogin Alfa (Activated) Significantly Reduced Mortality in PROWESS (cont)Reduced Mortality in PROWESS (cont)

6% Absolute 6% Absolute mortality mortality differencedifference



Overall

Gender

Male

Female

Origin

Caucasian

Non-Caucasian

964 24.3%31.0%

726 25.2%30.6%

1384 24.5%31.1%

306 25.8%29.8%

Drotrecogin alfan (activated)

Placebo

| | | | | | | |

Relative Risk (%)

Mortality Reduction by Gender and Mortality Reduction by Gender and Ethnic Origin in PROWESSEthnic Origin in PROWESS

-50 -40 -30 -20 -10 0 10 20


51

Relative Risk (%)

| | | | | | | | |

Overall

Pure Gram +

Pure Gram -

MixedGram +/-

No bacteriaisolated

430 22.8%32.7%

381 24.3%28.6%

250 21.8% 26.5%

556 25.6%32.5%

Drotrecogin alfan (activated)

Placebo

Mortality Reduction by Infectious Agent Mortality Reduction by Infectious Agent in PROWESSin PROWESS

-50 -40 -30 -20 -10 0 10 20 30

Data on file, Eli Lilly and Company


52

Mortality Reduction by Baseline APACHE II Mortality Reduction by Baseline APACHE II Scores in PROWESSScores in PROWESS

Absolute Reduction in Mortality

6%

13%

Overall Population N=1690

Quartiles 3 & 4

Relative Risk Reduction in Mortality

19% (P=.005)

29%

0%Quartiles 1 & 2 1%

Baseline APACHE II Score*

Overall PopulationOverall Population

* Of measures used, the APACHE II score was most * Of measures used, the APACHE II score was most effective in classifying patients by risk of death and by effective in classifying patients by risk of death and by likelihood of benefit from drotrecogin alfa (activated). likelihood of benefit from drotrecogin alfa (activated).


53

Mortality Reduction by Number of Mortality Reduction by Number of Dysfunctional Organs in PROWESSDysfunctional Organs in PROWESS

Absolute Reduction in Mortality

11%

8%

5%

Number of Dysfunctional Organ Systems at Baseline

4

3

2

Relative Risk Reduction in Mortality1

22%

24%

20%

2% 1 8%


Other important indicators of risk or severity also supported an Other important indicators of risk or severity also supported an association between likelihood of drotrecogin alfa (activated) association between likelihood of drotrecogin alfa (activated) benefit and risk of death.benefit and risk of death.



Mortality Reduction Regardless of Protein C Mortality Reduction Regardless of Protein C Level in PROWESSLevel in PROWESS

Relative Risk (%)

| | | | | | | | |

-50-40 -30 -20 -10 0 10 20 30

OverallProtein C

Low levels

Normal levels

1379 25.7% 32.1%

195 15.6% 26.7%

Drotrecogin alfan (activated) Placebo

• Mortality reductions were observed in patients with and without normal Protein C levels

• There is no scientific basis to assay Protein C levels to determine candidates for drotrecogin alfa (activated) therapy


55

Serious Bleeding Events in PROWESS by Serious Bleeding Events in PROWESS by Site of Hemorrhage: Site of Hemorrhage: Study Drug Infusion PeriodStudy Drug Infusion Period

1Other source*

20 (2.4%)Total

1Skin/soft tissue

2Genitourinary

2Cerebral hemorrhage

3Retroperitoneal

4Intra-thoracic

2Intra-abdominal

5Gastrointestinal

Site of Hemorrhage Total Events

1

8 (1.0%)

0

0

0

0

0

3

4

Total Events

Drotrecogin alfa (activated) n=850

Placebo n=840

*Event requiring 3 U packed RBCs/d for 2 consecutive days, but a site of bleeding could not be identified


56Data on File, Eli Lilly and Company

Procedure-Related Bleeding Events in Procedure-Related Bleeding Events in PROWESS:PROWESS: 28-Day Study Period28-Day Study Period

*Event requiring *Event requiring 3 U packed RBCs/d for 2 consecutive days, but a site of bleeding could not be identified3 U packed RBCs/d for 2 consecutive days, but a site of bleeding could not be identified

Drotrecogin alfa (activated) Drotrecogin alfa (activated) (n=850) (n=850)

22 22 22Other source*Other source*

15153030 33TotalTotal

11 22 00Skin/soft tissueSkin/soft tissue

11 22 00GenitourinaryGenitourinary

00 22 00Cerebral hemorrhageCerebral hemorrhage

44 44 00RetroperitonealRetroperitoneal

33 66 11Intra-thoracicIntra-thoracic

33 33 00Intra-abdominalIntra-abdominal

11 99 00GastrointestinalGastrointestinal

Site of HemorrhageSite of Hemorrhage Procedure-RelatedProcedure-RelatedTotal EventsTotal Events Procedure-RelatedProcedure-Related

22

1717

00

0 0

11

00

11

44

99

Total Events Total Events

Placebo Placebo (n=840)(n=840)



Safety Evaluations in PROWESSSafety Evaluations in PROWESS

• Incidence of serious bleeding events defined as:Incidence of serious bleeding events defined as:— Any intracranial hemorrhageAny intracranial hemorrhage— Any life-threatening bleed Any life-threatening bleed — Bleeds that required Bleeds that required 3 units of PRBC per day for3 units of PRBC per day for

2 consecutive days2 consecutive days— Any bleeding event classified as serious by the investigatorAny bleeding event classified as serious by the investigator

• Incidence of thrombotic eventsIncidence of thrombotic events• Incidence of new infectionsIncidence of new infections• ImmunogenicityImmunogenicity: : Anti-APC antibody formationAnti-APC antibody formation• OtherOther: : Serious adverse events, organ function,Serious adverse events, organ function,

hematology and chemistry data, vital signshematology and chemistry data, vital signs



Serious Bleeding Events in PROWESSSerious Bleeding Events in PROWESS

• Bleeding is the most common adverse reaction associated with drotrecogin Bleeding is the most common adverse reaction associated with drotrecogin alfa (activated) therapyalfa (activated) therapy

• In the Phase 3 study, serious bleeding events were observed during the In the Phase 3 study, serious bleeding events were observed during the 28-day study period in 3.5% of drotrecogin alfa (activated)-treated and 2.0% 28-day study period in 3.5% of drotrecogin alfa (activated)-treated and 2.0% of placebo-treated patients (of placebo-treated patients (PP=.06)=.06)

• The difference in serious bleeding occurred primarily during infusion The difference in serious bleeding occurred primarily during infusion

• Serious bleeding events were primarily related toSerious bleeding events were primarily related to11::— Trauma or instrumentation of blood vessel or a highly vascular organTrauma or instrumentation of blood vessel or a highly vascular organ

— Ulceration of gastrointestinal tractUlceration of gastrointestinal tract

• NonNon––procedure-related serious bleeding events were similar in both the placebo procedure-related serious bleeding events were similar in both the placebo and drotrecogin alfa (activated) groupsand drotrecogin alfa (activated) groups11

• The incidence of intracranial hemorrhage (ICH) was .2% for The incidence of intracranial hemorrhage (ICH) was .2% for drotrecogin alfa (activated)-treated and .1% for placebo-treated patientsdrotrecogin alfa (activated)-treated and .1% for placebo-treated patients



Safety Results in PROWESSSafety Results in PROWESS

• Similar incidence of thrombotic eventsSimilar incidence of thrombotic events— Placebo 3.0% Placebo 3.0% — Drotrecogin alfa (activated)Drotrecogin alfa (activated) 2.0% 2.0%— ((PP=.20)=.20)

• Similar incidence of new infectionsSimilar incidence of new infections— Placebo 25.1% Placebo 25.1% — Drotrecogin alfa (activated)Drotrecogin alfa (activated) 25.5% 25.5%— ((PP=.85)=.85)

• No other safety concerns identified based onNo other safety concerns identified based on— Serious adverse eventsSerious adverse events— Organ functionOrgan function— Hematology and chemistry dataHematology and chemistry data


60

Drotrecogin Alfa (Activated):Drotrecogin Alfa (Activated): Potential Mechanisms of Action in PROWESS*Potential Mechanisms of Action in PROWESS*

• AntiinflammatoryAntiinflammatory— Decrease IL-6 levelsDecrease IL-6 levels

• AntithromboticAntithrombotic— Decrease D-dimersDecrease D-dimers

• ProfibrinolyticProfibrinolytic— Decrease PAI-1 activityDecrease PAI-1 activity

*The specific mechanisms by which drotrecogin alfa (activated) exerts its effect on survival in patients with severe sepsis are not completely understood.



PRE 1 2 3 4 5 6 7

Me

dia

n IL

-6, p

g/m

LM

ed

ian

IL-6

, pg

/mL

0

100

200

300

400

500

600Drotrecogin alfa (activated)

Placebo

Infusion Period

Drotrecogin Alfa (Activated) is Drotrecogin Alfa (Activated) is Antiinflammatory:Antiinflammatory: Effects on IL-6 in PROWESSEffects on IL-6 in PROWESS

The specific mechanisms by which drotrecogin alfa (activated) exerts its effect on survival in patients with severe sepsis are not completely understood.


62

Ch

ang

e fr

om

Ba

selin

eC

ha

nge

fro

m B

ase

line

Drotrecogin alfa (activated)

Placebo 0

-100

-200

-300

-400

-500

PRE 1 2 3 4 5 6 7

** **P<.05P<.05

Infusion Period

Drotrecogin Alfa (Activated) is Drotrecogin Alfa (Activated) is Antiinflammatory:Antiinflammatory: Effects on IL-6 in PROWESS (cont)Effects on IL-6 in PROWESS (cont)




****

** **

63

PRE 1 2 3 4 5 6 7

Med

ian

D-d

imer

µg/

mL

2

3

4

5Drotrecogin alfa (activated)Placebo

*

** *

*

*P<.05

Infusion Period

Drotrecogin Alfa (Activated) is Antithrombotic: Drotrecogin Alfa (Activated) is Antithrombotic: Effects on D-dimer in PROWESSEffects on D-dimer in PROWESS




* *


PROWESS ConclusionsPROWESS Conclusions

• The study groups at baseline were well matched and The study groups at baseline were well matched and representative of a diverse severe sepsis populationrepresentative of a diverse severe sepsis population

• Drotrecogin alfa (activated) produced a highly significant Drotrecogin alfa (activated) produced a highly significant reduction in mortality vs placebo (25% vs 31%, reduction in mortality vs placebo (25% vs 31%, PP=.006) =.006)

• No substantial differences in drotrecogin alfa (activated) No substantial differences in drotrecogin alfa (activated) treatment effect were observed in sub-groups defined by treatment effect were observed in sub-groups defined by gender, ethnic origin, infectious agent or Protein C levelgender, ethnic origin, infectious agent or Protein C level

• Adverse events associated with drotrecogin alfa (activated) Adverse events associated with drotrecogin alfa (activated) treatment were limited to bleeding and the majority of them treatment were limited to bleeding and the majority of them were manageablewere manageable


65

Drotrecogin Alfa (Activated)Drotrecogin Alfa (Activated)Administration Guidelines Administration Guidelines

and Safetyand Safety

66

Drotrecogin Alfa (Activated):Drotrecogin Alfa (Activated):AdministrationAdministration

• Supplied as a sterile, lyophilized powder in 5 mg and 20 mg vialsSupplied as a sterile, lyophilized powder in 5 mg and 20 mg vials• Administer intravenously at the infusion rate of 24 Administer intravenously at the infusion rate of 24 µµg/kg of actual g/kg of actual

body weight/hr for a total duration of 96 hoursbody weight/hr for a total duration of 96 hours• Administer through a dedicated line or a single lumen of a Administer through a dedicated line or a single lumen of a

multilumen cathetermultilumen catheter• The ONLY other solutions that can be administered through the The ONLY other solutions that can be administered through the

same line are 0.9% Sodium Chlorine Injection, Lactated Ringer’s same line are 0.9% Sodium Chlorine Injection, Lactated Ringer’s Injection, Dextrose, or Dextrose and Saline mixturesInjection, Dextrose, or Dextrose and Saline mixtures

• Dose escalation or bolus doses are not recommendedDose escalation or bolus doses are not recommended

67

Drotrecogin Alfa (Activated): Drotrecogin Alfa (Activated): ContraindicationsContraindications

• Drotrecogin alfa (activated) increases the risk of bleeding. Drotrecogin Drotrecogin alfa (activated) increases the risk of bleeding. Drotrecogin alfa (activated) is contraindicated in patients with the following clinical alfa (activated) is contraindicated in patients with the following clinical situations in which bleeding could be associated with a high risk of situations in which bleeding could be associated with a high risk of death or significant morbidity:death or significant morbidity:

— Active internal bleedingActive internal bleeding— Recent (within 3 months) hemorrhagic strokeRecent (within 3 months) hemorrhagic stroke— Recent (within 2 months) intracranial or intraspinal surgery, or severe head traumaRecent (within 2 months) intracranial or intraspinal surgery, or severe head trauma— Trauma with increased risk of life-threatening bleedingTrauma with increased risk of life-threatening bleeding— Presence of an epidural catheterPresence of an epidural catheter— Intracranial neoplasm or mass lesion or evidence of cerebral herniationIntracranial neoplasm or mass lesion or evidence of cerebral herniation

• Drotrecogin alfa (activated) is contraindicated in patients with known Drotrecogin alfa (activated) is contraindicated in patients with known hypersensitivity to drotrecogin alfa (activated) or any component of hypersensitivity to drotrecogin alfa (activated) or any component of this productthis product

Please refer to complete prescribing information available at presentation.

68

Drotrecogin Alfa (Activated): Drotrecogin Alfa (Activated): WarningsWarnings

• Bleeding is the most common serious adverse effect associated with Bleeding is the most common serious adverse effect associated with drotrecogin alfa (activated) therapy. Each patient being considered drotrecogin alfa (activated) therapy. Each patient being considered for therapy with drotrecogin alfa (activated) should be carefully for therapy with drotrecogin alfa (activated) should be carefully evaluated and anticipated benefits weighed against potential risks evaluated and anticipated benefits weighed against potential risks associated with therapyassociated with therapy

• Certain conditions, many of which led to exclusion from the Phase 3 Certain conditions, many of which led to exclusion from the Phase 3 trial, are likely to increase the risk of bleeding with drotrecogin alfa trial, are likely to increase the risk of bleeding with drotrecogin alfa (activated) therapy (activated) therapy


69

Drotrecogin Alfa (Activated): Drotrecogin Alfa (Activated): Warnings (cont)Warnings (cont)

• For patients with severe sepsis who have one or more of the For patients with severe sepsis who have one or more of the following conditions, the increased risk of bleeding should be following conditions, the increased risk of bleeding should be carefully considered when deciding whether to use drotrecogin carefully considered when deciding whether to use drotrecogin alfa (activated) therapy: alfa (activated) therapy:

— Concurrent therapeutic heparin (Concurrent therapeutic heparin (15 units/kg/hr)15 units/kg/hr)— Platelet count Platelet count 30,000 x 1030,000 x 1066/L, even if the platelet count is /L, even if the platelet count is

increased after transfusionsincreased after transfusions— Prothrombin time-INR Prothrombin time-INR 3.03.0— Recent (within 6 weeks) gastrointestinal bleedingRecent (within 6 weeks) gastrointestinal bleeding— Recent administration (within 3 days) of thrombolytic therapyRecent administration (within 3 days) of thrombolytic therapy— Recent administration (within 7 days) of oral anticoagulants or Recent administration (within 7 days) of oral anticoagulants or

glycoprotein IIb/IIIa inhibitorsglycoprotein IIb/IIIa inhibitors


70


— Recent administration (within 7 days) of aspirin >650 mg/d or Recent administration (within 7 days) of aspirin >650 mg/d or other platelet inhibitorsother platelet inhibitors

— Recent (within 3 months) ischemic strokeRecent (within 3 months) ischemic stroke— Intracranial arteriovenous malformation or aneurysmIntracranial arteriovenous malformation or aneurysm— Known bleeding diathesisKnown bleeding diathesis— Chronic severe hepatic diseaseChronic severe hepatic disease— Any other condition in which bleeding constitutes a significant Any other condition in which bleeding constitutes a significant

hazard or would be particularly difficult to manage because of hazard or would be particularly difficult to manage because of its locationits location


71


• Bleeding is the most common adverse event associated Bleeding is the most common adverse event associated with drotrecogin alfa (activated) therapywith drotrecogin alfa (activated) therapy

• During the 28-day Phase 3 studyDuring the 28-day Phase 3 study— Serious bleeding events were observed during the study Serious bleeding events were observed during the study

period in 3.5% of drotrecogin alfa (activated)-treated patients period in 3.5% of drotrecogin alfa (activated)-treated patients and 2.0% of placebo-treated patientsand 2.0% of placebo-treated patients

— The difference in serious bleeding occurred primarily during The difference in serious bleeding occurred primarily during infusioninfusion

— The incidence of intracranial hemorrhage (ICH) was .2% for The incidence of intracranial hemorrhage (ICH) was .2% for drotrecogin alfa (activated)-treated and .1% for placebo-drotrecogin alfa (activated)-treated and .1% for placebo-treated patientstreated patients


72


• ICH has been reported in drotrecogin alfa (activated)-ICH has been reported in drotrecogin alfa (activated)-treated patients in nontreated patients in non–placebo-controlled trials with an –placebo-controlled trials with an incidence of approximately 1% during infusionincidence of approximately 1% during infusion

• The risk of ICH may be increased in patients with risk The risk of ICH may be increased in patients with risk factors for bleeding such as severe coagulopathy and factors for bleeding such as severe coagulopathy and severe thrombocytopeniasevere thrombocytopenia

• Should clinically important bleeding occur, immediately stop Should clinically important bleeding occur, immediately stop the drotrecogin alfa (activated) infusionthe drotrecogin alfa (activated) infusion


73

Management of Bleeding Risks Associated with Management of Bleeding Risks Associated with Drotrecogin Alfa (Activated)Drotrecogin Alfa (Activated)

• In the event of clinically important bleeding:In the event of clinically important bleeding:— Immediately stop infusion of drotrecogin alfa (activated)— Continued use of other agents affecting the coagulation system should

be carefully assessed— Once adequate hemostasis has been achieved, continued use of

drotrecogin alfa (activated) may be reconsidered

• Discontinue drotrecogin alfa (activated) 2 hours prior to Discontinue drotrecogin alfa (activated) 2 hours prior to undergoing an invasive surgical procedure or procedures undergoing an invasive surgical procedure or procedures with an inherent risk of bleedingwith an inherent risk of bleeding

• Once adequate hemostasis has been achieved, initiation Once adequate hemostasis has been achieved, initiation of drotrecogin alfa (activated) may be:of drotrecogin alfa (activated) may be:

— Reconsidered 12 hours after major invasive procedures or surgery— Restarted immediately after uncomplicated, less invasive procedures


74

Reimbursement Issues in Reimbursement Issues in the Patient with the Patient with

Severe SepsisSevere Sepsis

75Linde-Zwirble WT, et al. Linde-Zwirble WT, et al. Value in HealthValue in Health 2001;4:2:61. 2001;4:2:61.Jones MK. Jones MK. Illustrated ICD-9-CM Code Book.Illustrated ICD-9-CM Code Book.

Septicemia: Septicemia: DefinitionDefinition

• A systemic disease associated with the presence and A systemic disease associated with the presence and persistence of pathogenic microorganisms or their toxinspersistence of pathogenic microorganisms or their toxinsin the bloodin the blood

• Includes symptoms such as increased or decreased Includes symptoms such as increased or decreased temperature, tachypnea, tachycardia and impaired temperature, tachypnea, tachycardia and impaired organ perfusionorgan perfusion

76

Confusion Between Septicemia and Confusion Between Septicemia and Severe SepsisSevere Sepsis

Problem:Problem: Use of septicemia codes as identifiers of Use of septicemia codes as identifiers of severe sepsissevere sepsis

Linde-Zwirble WT, et al. Linde-Zwirble WT, et al. Value in HealthValue in Health 2001;2:61. 2001;2:61.

Septicemia withoutSepticemia withoutsevere sepsissevere sepsis 7927 14.4% $ 18,381

Severe sepsisSevere sepsiswithout septicemiawithout septicemia 21,655 23.1% $ 24,396

Severe sepsisSevere sepsiswith septicemiawith septicemia 9970 42.1% $ 33,470

OverallOverall 39,552 26.1% $ 25,478

Number of Cases Number of Cases Mortality Mortality Cost Cost

77

Septicemia/Severe Sepsis Sensitivity AnalysisSepticemia/Severe Sepsis Sensitivity Analysis

• Sensitivity of septicemia as a predictor of severe sepsisSensitivity of septicemia as a predictor of severe sepsis

— 29.6%29.6%

• Positive predictive value of septicemia as a predictor of Positive predictive value of septicemia as a predictor of severe sepsissevere sepsis

— 30.0%30.0%

• Conclusion: Conclusion: Septicemia codes are not accurate for Septicemia codes are not accurate for identifying patients with severe sepsisidentifying patients with severe sepsis

Linde-Zwirble WT, et al. Linde-Zwirble WT, et al. Value in HealthValue in Health 2001;2:61. 2001;2:61.

78

Severe Sepsis ReimbursementSevere Sepsis Reimbursement

• DRGDRG - Diagnosis Related Groups (DRGs) are used by - Diagnosis Related Groups (DRGs) are used by Medicare and some private insurers. Each DRG represents Medicare and some private insurers. Each DRG represents clinically similar patients based on average resource clinically similar patients based on average resource intensity during acute inpatient hospitalization intensity during acute inpatient hospitalization

• ICD-9-CMICD-9-CM - International Classification of Diseases, 9 - International Classification of Diseases, 9thth edition, includes codes for both diagnoses and certain edition, includes codes for both diagnoses and certain procedures procedures

• Severe sepsis occurs in 392 of the possible 511 DRGsSevere sepsis occurs in 392 of the possible 511 DRGs

Data on file, Eli Lilly and CompanyData on file, Eli Lilly and Company

79

ConclusionsConclusions

80

ConclusionsConclusions

• Sepsis + acute organ dysfunction = severe sepsisSepsis + acute organ dysfunction = severe sepsis• Severe sepsis is a common, deadly disorder that Severe sepsis is a common, deadly disorder that

consumes significant healthcare resources and is increasing consumes significant healthcare resources and is increasing in incidencein incidence

• Severe sepsis is a complex syndrome with inflammatory, Severe sepsis is a complex syndrome with inflammatory, prothrombotic and impaired fibrinolytic componentsprothrombotic and impaired fibrinolytic components

• Until recently, development of interventions to reduce mortality Until recently, development of interventions to reduce mortality in life-threatening severe sepsis has been an unmet needin life-threatening severe sepsis has been an unmet need

• Endogenous Activated Protein C has multiple mechanisms of Endogenous Activated Protein C has multiple mechanisms of action including:action including:

— Modulation of the inflammatory responseModulation of the inflammatory response— AntithrombosisAntithrombosis— ProfibrinolysisProfibrinolysis

81

Conclusions (cont)Conclusions (cont)

• Drotrecogin alfa (activated) = Xigris = recombinant human Activated Drotrecogin alfa (activated) = Xigris = recombinant human Activated Protein CProtein C

• The results of a Phase 3 trial of drotrecogin alfa (activated) The results of a Phase 3 trial of drotrecogin alfa (activated) (PROWESS) indicated the following:(PROWESS) indicated the following:

— No substantial differences in drotrecogin alfa (activated) treatment effect No substantial differences in drotrecogin alfa (activated) treatment effect were observed in subgroups defined by gender, ethnic origin, infectious were observed in subgroups defined by gender, ethnic origin, infectious agent or Protein C levelagent or Protein C level

— Drotrecogin alfa (activated) significantly reduced mortality as compared to Drotrecogin alfa (activated) significantly reduced mortality as compared to placebo (25% vs 31%, placebo (25% vs 31%, PP=.006)=.006)

— Adverse events associated with drotrecogin alfa activated therapy were Adverse events associated with drotrecogin alfa activated therapy were limited to bleeding and the majority of them were manageablelimited to bleeding and the majority of them were manageable

— Conditions and therapies associated with hemorrhagic complications Conditions and therapies associated with hemorrhagic complications increase the risk of drotrecogin alfa (activated)-related bleedingincrease the risk of drotrecogin alfa (activated)-related bleeding


Xigris is a trademark of Eli Lilly and CompanyDR. 22250 3000000500 01021Copyright © 2002, Eli Lilly and Company. All rights reserved.

Documents

1 Definitions, Epidemiology, Pathophysiology and Treatment of Severe Sepsis