SStudy program to tudy program to EEvaluate the valuate the PPrevention revention of of IIschemia with direct schemia with direct AAnti-Xa inhibition:nti-Xa inhibition:

SEPIA-ACS1 – TIMI 42SEPIA-ACS1 – TIMI 42A randomized, double-blind, triple-dummy, dose-ranging study to

evaluate the clinical efficacy and safety of OTAMIXABAN in patients with NSTEACS and planned early invasive strategy

1

Marc S. Sabatine, MD, MPH

on behalf of the SEPIA-ACS1 TIMI 42 Investigators

M Sabatine has received honoraria and consulting fees from sanofi-aventis and honoraria from Bristol-Myers Squibb.

SEPIA-ACS1 TIMI 42 was supported by a research grant from sanofi-aventis

2

Extrinsic PathwayTissue factor, FVII

Thrombin(F IIa)

Fibrin FormationPlatelet Aggregation

Intrinsic PathwayFXII, FXI, FIX, FVIII, PL, Ca2+

Prothrombin(F II)

Factor V

OTAMIXABAN• Specific, Direct, IV, Factor Xa Inhib

– Proximal inhib of coag cascade

• Small molecule– Inhibits clot-bound factor Xa,

which is inaccessible tolarge molecule & indirect inhibitors

• Favorable PK/PD profile– Short-acting (half-life 30 min)– Wt-based bolus & infusion– No need for monitoring– No significant renal elimination

Common PathwayFactor X Factor Xa

Coagulation Cascade

Clinical Efficacy CompositeClinical Efficacy Composite

5.8

3.8

2.5

5.15.6

7.1

0

1

2

3

4

5

6

7

8

OTAM0.035

OTAM0.065

OTAM0.120

OTAM0.160

OTAM0.200

UFH

Dea

th,

MI,

or

Urg

Rev

asc(

%)

Cohen M et al. Circulation 2007:115:26423

947 patients undergoing non-urgent PCIGreater reduction in thrombin generation w/ OTAM vs. UFH

mg/kg/hr

Study Design:Study Design:Phase II, Dose-RangingPhase II, Dose-Ranging

Mod-to-High Risk NSTE ACS (ST deviation or biomarker)w/ Planned Early Invasive Strategy

OTAM0.035

(n=125)

OTAM0.035

(n=125)

RAspirin +

Clopidogrel

Blinded bail-out eptifibatide if

rec. ischemia or thrombotic

complic. during PCI

OTAM / UFH until end of PCI (or longer if indic)

Eptifibatide until 18-24 h after end of PCI

1° EP: Death, MI, Urgent Revasc, Bail-out IIb/IIIa thru 7 d1° EP: Death, MI, Urgent Revasc, Bail-out IIb/IIIa thru 7 d

Coronary angiography PCI within 3 daysCoronary angiography PCI within 3 days

OTAM0.070

(n=676)

OTAM0.070

(n=676)

OTAM0.140

(n=658)

OTAM0.140

(n=658)

OTAM0.175

(n=671)

OTAM0.175

(n=671)

OTAM0.105

(n=662)

OTAM0.105

(n=662)

UFH + Eptifi.(n=449)

UFH + Eptifi.(n=449)

at or before randomization

Follow-up at Day 30, Day 90, Day 180Follow-up at Day 30, Day 90, Day 1804

double-blind

Major Exclusion CriteriaMajor Exclusion Criteria

• Treatment with anticoagulant during index presentation for >24 h prior to randomization

• Requirement for treatment with an oral anticoagulant

• Contraindications to eptifibatide:– bleeding w/in previous 30 days or known bleeding diathesis

– severe hypertension (SBP >200 mmHg or DBP >110 mmHg)

– major surgery or trauma in the past 6 wks

– history of stroke in the past 30 d or any history of hemorrhagic stroke

– creatinine clearance <30 ml/min or dependence on renal dialysis

• Platelet count <100,000/ul; INR 2

• Prior PCI within 30 days of randomization

• Cardiogenic shock5

Trial OrganizationTrial Organization

6

TIMI Study GroupBrigham and Women’s HospitalHarvard Medical School

E Braunwald, MD (Chair)MS Sabatine, MD, MPH (PI)EM Antman, MD (Co-PI)CH McCabe (Director)S Crugnale (Project Manager)CF Contant (Director of Biostats)

Clinical Events Cmte SD Wiviott, MD (Chair)

Data Monitoring Cmte P Theroux, MD (Chair)JP BassandS Kelsey

SponsorSanofi-Aventis

A Moryusef, M Brynildsen, S Hitier, T Colineau, S Ribadeau-Dumas,P Taistra, C Mahdi

Steering CommitteeSteering Committee

7

Argentina JL Navaro Estrada Israel H Hod

Brazil JC Nicolau Italy G DeFerrari

Canada S Goodman Mexico F Petersen

Chile R Corbalan Netherlands F Verheugt

Croatia M Bergovec Poland W Ruzyllo

Czech Republic P Widimsky Portugal R Ferreira

Denmark P Clemmensen Russia M Ruda

Estonia J Voitk South Africa IO Ebrahim

Finland I Tierala South Korea M Jeong

France G Montalescot Southeast Asia R Zambahari

Germany C Bode Spain J Ruiz-Nodar

Greece D Alexopoulos Turkey Z Ongen

Hungary RG Kiss United States MS Sabatine

India BS Raju

Worldwide ParticipationWorldwide Participation

8

151

69

115

64

3

1128

8

391

5

15

35

43

157

19

220

88

17173

252

93

10

24

161 9871

91

25

129

125

19

102

112

65169

196 Sites36 countries

3241 Patients Randomized

Baseline CharacteristicsBaseline Characteristics

Variable ValueAge, yrs 61 ± 12

Male, % 69

Hypertension, % 70

Dyslipidemia, % 50

Current smoker, % 32

Diabetes mellitus, % 29

Prior MI, % 21

Creatinine clearance, ml/min 95 ± 36

ST segment deviation ≥ 0.1 mV, % 57

Elevated cardiac biomarker of necrosis, % 77

9No clinically relevant imbalances between treatment arms

MedicationsMedications

Treatment ValueStudy Med Duration, median (IQR) hr

OTAM / placebo & UFH / placebo 5 (4-19) hrs

Eptifibatide / placebo 21 (8-26) hrs

Aspirin, % 98

Clopidogrel, % 98

Dosed before angiography 95

Open label anticoag before study med*, % 65

UFH 34

LMWH 35

-blocker, % 83

Statin, % 8710*Patients could have received more than 1 type of anticoagulant prior to study med

Cardiac ProceduresCardiac Procedures

11

66

51

28

0

10

20

30

40

50

60

70

1 2 3 or 4 Never

Co

ron

ary

An

gio

gra

ph

y (

%)

Hospital Day

99%

PCI(63%)

Med Rx(34%)

CABG(3.6%)

Coronary Treatment

Primary Efficacy EndpointPrimary Efficacy EndpointDeath, MI, Urg Revasc, or Bailout GP IIb/IIIaDeath, MI, Urg Revasc, or Bailout GP IIb/IIIa

7.2

3.8 3.64.3

6.2

4.6

0

1

2

3

4

5

6

7

8

OTAM0.035

OTAM0.070

OTAM0.105

OTAM0.140

OTAM0.175

UFH +eptifi

De

ath

, M

I, U

rg R

ev

, B

ail

ou

t th

ru 7

d (

%)

1.16(0.56-2.38)

0.74(0.45-1.21)

0.61(0.36-1.02)

0.58(0.34-0.996)

0.69(0.42-1.15)

P=0.34 for trend across OTAM Dose Arms

RR vs UFH(95% CI)

12

n=125 n=676 n=662 n=658 n=671 n=449

RR 0.60 (95% CI 0.38-0.94)P=0.02

mg/kg/hr

Primary Endpoint over 180 DaysPrimary Endpoint over 180 Days

13

Cum

ulat

ive

inci

denc

e

OTAM 0.035

OTAM 0.070OTAM 0.175

OTAM 0.140OTAM 0.105

UFH+Eptifi

Death or MIDeath or MI

4.8

2.6 2.7 2.8

4.9

2.8

0

1

2

3

4

5

6

OTAM0.035

OTAM0.070

OTAM0.105

OTAM0.140

OTAM0.175

UFH +eptifi

De

ath

or

MI

thru

7 d

(%

)

0.98(0.41-2.36)

0.57(0.31-1.05)

0.52(0.28-0.98)

0.56(0.30-1.03)

0.58(0.32-1.06)

RR vs UFH(95% CI)

14

n=125 n=676 n=662 n=658 n=671 n=449

RR 0.54 (95% CI 0.32-0.91)P=0.02

mg/kg/hr

Urgent RevascularizationUrgent Revascularization

0.8 0.80.3

0.6 0.70.3

0

1

2

3

4

5

6

OTAM0.035

OTAM0.070

OTAM0.105

OTAM0.140

OTAM0.175

UFH +eptifi

Urg

en

t R

ev

as

cu

lari

zati

on

th

ru 7

d (

%)

15

n=125 n=676 n=662 n=658 n=671 n=449

mg/kg/hr

Bailout GP IIb/IIIa InhibitorBailout GP IIb/IIIa Inhibitor

3.2

1.40.8

1.2 1.1

2.2

0

1

2

3

4

5

6

OTAM0.035

OTAM0.070

OTAM0.105

OTAM0.140

OTAM0.175

UFH +eptifi

Ba

ilo

ut

GP

IIb

/III

a t

hru

7 d

(%

)

16

n=125 n=676 n=662 n=658 n=671 n=449

mg/kg/hr

2.87(0.78-5.44)

1.99(0.73-5.44)

RR vs UFH(95% CI)

Thrombotic ComplicationsThrombotic Complications

6.2

2.93.5 3.2

2.4

5.0

0

1

2

3

4

5

6

7

8

OTAM0.035

OTAM0.070

OTAM0.105

OTAM0.140

OTAM0.175

UFH +eptifi

Th

rom

bo

tic

Co

mp

lic

ati

on

(%

)

17

n=81 n=417 n=419 n=396 n=433 n=286

mg/kg/hr

2.52(0.82-7.74)

2.06(0.89-4.78)

RR vs UFH(95% CI)

PCI Subset, PCI Subset, n=2032 (63%)n=2032 (63%)

Defined as: abrupt or side branch closure, distal embolization or no/slow reflow, or new thrombus

Primary Safety EndpointPrimary Safety EndpointTIMI Major or Minor Bleed unrelated to CABGTIMI Major or Minor Bleed unrelated to CABG(defined as (defined as bleed with in Hgb of 3 g/dL or ICH)

1.6

3.13.4

5.4

2.7

1.6

0

1

2

3

4

5

6

OTAM0.035

OTAM0.070

OTAM0.105

OTAM0.140

OTAM0.175

UFH +eptifi

Pri

ma

ry S

afe

ty E

nd

po

int

thru

7 d

(%

)

0.61(0.14-2.70)

0.61(0.27-1.38)

1.15(0.57-2.32)

1.26(0.63-2.52)

2.02(1.07-3.85)

P=0.0001 for trendacross OTAM Dose Arms

RR vs UFH(95% CI)

18

n=122 n=669 n=651 n=651 n=664 n=448

mg/kg/hr

TIMI Minimal BleedingTIMI Minimal Bleeding (defined as any overt (defined as any overt bleed with in Hgb of <3 g/dL)

4.1

10.9 11.8

15.8

5.66.7

0

5

10

15

20

OTAM0.035

OTAM0.070

OTAM0.105

OTAM0.140

OTAM0.175

UFH +eptifi

TIM

I M

inim

al

Ble

ed

ing

th

ru 7

d (

%)

19

n=122 n=669 n=651 n=651 n=664 n=448

mg/kg/hr

RBC TransfusionRBC Transfusion

6.66.1

7.78.3

9.2

6.2

0

2

4

6

8

10

OTAM0.035

OTAM0.070

OTAM0.105

OTAM0.140

OTAM0.175

UFH +eptifi

Tra

ns

fus

ion

th

rou

gh

7 d

(%

)

20

n=122 n=669 n=651 n=651 n=664 n=448

mg/kg/hr

ConclusionsConclusions

We achieved our goal of defining the optimaldose range of otamixaban for future study

OTAM0.035

OTAM0.035

OTAM0.070

OTAM0.070

Inadequate anticoagulation

OTAM0.175

OTAM0.175

Excessive bleeding

OTAM0.140

OTAM0.140

OTAM0.105

OTAM0.105

Decreased risk of death or ischemic events,

with comparable risk of maj/min bleeding c/w UFH + eptifi

Otamixaban 0.105-0.140 mg/kg/h appears to be best range for further study as a replacement for UFH + GP IIb/IIIa

21

22

THE LANCET

Available at www.thelancet.com

Presentation slides available at www.timi.org