Sunil V. Rao MD

for the EMINENCE Investigators

Evaluation of a novel, rationally Evaluation of a novel, rationally designed, low-molecular-weight designed, low-molecular-weight

heparin during elective PCI: heparin during elective PCI: Results of the Phase 2 Results of the Phase 2

EMINENCE TrialEMINENCE Trial

EMINENCE Trial: Disclosures

Presenter disclosures Research funding: Cordis Corporation,

Momenta Pharmaceuticals, Portola Pharmaceuticals

Off-label uses: Enoxaparin for PCI, fondaparinux for PCI

The EMINENCE Trial was funded by Momenta Pharmaceuticals

Available Anticoagulant OptionsAvailable Anticoagulant Options

Unfractionated heparinUnfractionated heparin Advantages: measurable, Advantages: measurable,

reversible, experiencereversible, experience Disadvantages: platelet Disadvantages: platelet

activation, HIT (TS), activation, HIT (TS), unreliable degree of unreliable degree of antithrombin activityantithrombin activity

LMWHLMWH Advantages: more reliable Advantages: more reliable

anticoagulationanticoagulation Disadvantages: not Disadvantages: not

measurable, platelet measurable, platelet activation, some degree of activation, some degree of discomfort during PCIdiscomfort during PCI

FondaparinuxFondaparinux Advantages: similar Advantages: similar

efficacy to LMWH with efficacy to LMWH with less bleedingless bleeding

Disadvantages: not Disadvantages: not demonstrated to be safe demonstrated to be safe during PCI, not easily during PCI, not easily reversiblereversible

BivalirudinBivalirudin Advantages: less Advantages: less

bleeding, measurable, bleeding, measurable, short half-lifeshort half-life

Disadvantages: not more Disadvantages: not more efficacious than UFH, efficacious than UFH, trends toward slightly trends toward slightly more ischemic eventsmore ischemic events

Undesired Sequences Eliminated and Active Binding Sites Positioned on Opposite Ends of Chain

M118 Structure and PropertiesM118 Structure and Properties

Low-molecular-weight heparin Increased anti-factor II activity compared with other LMWHs Constant Xa/IIa ratio over time Predictable PK/PD Effects are reversible or neutralized with protamine sulfate High bioavailability: IV and SC administration

EMINENCE Study Design

Randomized, open-label, active-controlled, dose-ranging design Patients undergoing elective PCI Pre-PCI antiplatelet (ASA, clopidogrel) therapy

Planned GP IIb/IIIa not allowed Vascular sheaths removed 4 hours after last M118 dose or when

ACT < 160 sec if assigned to UFH Closure devices allowed; transfemoral encouraged

Phase A: 3 arms – 70 U/kg UFH, 75 IU/kg M118, 100 IU/kg M118 Qualitative review by DSMB after 5% of patients enrolled in 75

IU/kg M118 & UFH arms Phase B: 4 arms – 70 U/kg UFH, 50 IU/kg M118, 75 IU/kg M118,

100 IU/kg M118

Low-risk patients with stable CAD undergoing elective PCIPre-treat with ASA (325 mg) and clopidogrel 300 mg prior to PCI

Baseline ACT measurement

UFH 70 U/kg IV bolus

M118 75 anti-Xa IU/kg

M118 100 anti-Xa IU/kg

Cardiac catheterization

Randomization; ASA + clopidogrel

7-day telephone interview

14-day follow-up

30-day follow-up

M118 50 anti-Xa IU/kg

EMINENCE Study Design

EMINENCE Primary End Point Composite of 30-day death, MI, repeat revascularization,

catheter thrombus, stroke, thrombocytopenia, bailout use of glycoprotein IIb/IIIa inhibitors, or all bleeding (REPLACE-2 scale*)

*Major bleeding Transfusion of > 2 units whole blood or packed red blood

cells, or Intracranial hemorrhage, or Retroperitoneal hemorrhage, or A fall in hemoglobin (Hgb) > 4 g/dL (or 12.5% of hematocrit)

with no bleeding site identified despite attempts to do so, or Spontaneous or non-spontaneous blood loss associated with

a Hgb drop > 3 g/dL (or 10% of hematocrit)

*Minor bleeding: Any observed bleeding that does not meet major bleeding criteria

EMINENCE Primary Statistical Analysis

Primary end point analyzed on an intent-to-treat basis

Main comparison: subjects randomized to UFH vs. subjects randomized to experimental therapy (all M118 doses combined)

Primary analysis: non-inferiority analysis of UFH vs. pooled M118 doses

Assume control (UFH) rate of 8% Goal to reject an absolute 8% increase in the primary

outcome Non-inferiority will be achieved if the upper limit of the 95%

CI is less than 0.08

A sample size of 600 patients (150/arm) provides 93% power at a one-sided alpha of 0.05

EMINENCE: Secondary Comparisons

Prespecified Primary end point Primary end point minus major bleeding 30-day death or MI 30-day death/MI/repeat revascularization Primary end point and bleeding comparisons

between UFH and combined M118 without 50 IU/kg dose

Post-hoc Composite of 30-day death/MI/repeat

revascularization/24-hr major bleeding TIMI major and minor bleeding

EMINENCE Trial Results: Demographics

Background characteristics equally balanced across groups

Mean age: 63.8 yrs Sex: 72.4% male, 27.6% female Race:

91.7% White (8.0% Hispanic) 5.8% Black 1.2% Asian 0.8% Other 0.6% Native American

Median weight: 90.1 kg Mean 1.5 lesions treated across all groups

EMINENCE: Concomitant Procedural Treatments

UFH 70N=151

M118 50N=44

M118 75N=152

M118 100N=156

M118 AllN=352

DES 83.3% 80.5% 84.1% 83.8% 83.5%

Closure device

53.0% 43.2% 55.3% 55.2% 53.7%

Clopidogrel < 300 mg

6.8% 7.0% 8.6% 5.3% 6.9%

Clopidogrel ≥ 300 mg

93.2% 93.0% 91.4% 94.7% 93.1%

Coagulation Parameters: Median ACTs

UFH 70N=151

M118 50N=44

M118 75N=152

M118 100N=156

No closure device* 155 158 160 169

With closure device 251 206 237 271

*Protocol recommended sheath removal if ACT < 160 sec if randomized to UFH or at 4 hours postPCI if randomized to M118; “Per Protocol population

Median ACTs at Time of Sheath Pull

ACT is primarily influenced by anti-IIa (thrombin) activity.

M118 exhibits a greater degree of anti-Xa activity relative to anti-IIa than UFH (Xa:IIa ratio of 1.4:1 vs. 1:1 for UFH).

M118 would be expected to have greater anticoagulant activity at lower ACT values than UFH because the additional anti-Xa activity is not reflected in the measurement of ACT.

EMINENCE Results: Primary End Point, ITT

Primary End Point

31.1

22.7

28.330.1

28.4

0

5

10

15

20

25

30

35

UFH 70 M118 50 M118 75 M118 100 M118 Combined

%

M118 Group for Comparison w/ UFH

M118 Event Rate

UFH Event Rate

Upper 95% Confidence Limit

in Event Rates

Is M118 Event Rate <UFH +

Delta?

Primary - M118 combined

28.4% 31.1% 4.6% Yes

M118 50 IU 22.7% 31.1% 3.7% Yes

M118 75 IU 28.3% 31.1% 5.8% Yes

M118 100 IU 30.1% 31.1% 7.7% Yes

*Assumes missing end points were not end points per protocol and statistical analysis plan.

Primary and Secondary Efficacy Comparison*

EMINENCE Results: Prespecified Secondary End PointsPrimary End Point Excluding Minor Bleeding

Primary End Points (Excluding Minor Bleeds)

17.9

11.4

12.5

14.1

13.1

0

2

4

6

8

10

12

14

16

18

UFH 70 M118 50 M118 75 M118 100 M118 Combined

%

EMINENCE Results: Prespecified Secondary End PointsDeath, MI, or Repeat Revascularization

Death, MI, Revascularization

8.6

11.4

7.9

6.4

7.7

0

2

4

6

8

10

12

UFH 70 M118 50 M118 75 M118 100 M118 Combined

%

EMINENCE Results: Prespecified Secondary End PointsDeath or MI

Key Procedural End Point: Bailout GPIIb/IIIa Use

EMINENCE: Protocol-defined Major BleedingREPLACE-2 Scale

Bleeding Complications: Major Bleeds

1.3

2.3

0.7

1.3

0

0.5

1

1.5

2

2.5

UFH 70 M118 50 M118 75 M118 100

%

EMINENCE: Protocol-defined Minor BleedingREPLACE-2 Scale

Bleeding Complications: Minor Bleeds

15.9

11.4

17.1

19.9

0

2

4

6

8

10

12

14

16

18

20

UFH 70 M118 50 M118 75 M118 100

%

EMINENCE Bleeding: TIMI Scale (Post Hoc)

EMINENCE Bleeding: Transfusions

0.0 0.0

EMINENCE: Conclusions (1)

M118 is a safe and feasible anticoagulant to administer during elective PCI

M118 is comparable to weight-adjusted UFH at preventing a range of PCI-related complications

The 75 IU/kg and 100 IU/kg M118 doses appear promising

Lower rates of ischemic complications, similar rates of bleeding

EMINENCE: Conclusions (2)

Dose-related increase in ACT

Similar rates of protocol-defined major bleeding but higher rates of minor bleeding (dose-dependent)

The EMINENCE Phase 2 results form the basis for further evaluation of M118 for the treatment of ischemic heart disease

EMINENCE Trial Steering CommitteeEMINENCE Trial Steering Committee

Chiara Melloni MD MHS, Chiara Melloni MD MHS, Shelley Myles-DiMauro BSc RN, Samuel Shelley Myles-DiMauro BSc RN, Samuel

Broderick MS, Kristina Sigmon MS, Andrzej Broderick MS, Kristina Sigmon MS, Andrzej Kosinski PhD, Neal S. Kleiman MD, Kosinski PhD, Neal S. Kleiman MD,

Vladimir Dzavik MD, Jean Francois Tanguay Vladimir Dzavik MD, Jean Francois Tanguay MD, Ian Fier MBA, James Roach MD, and MD, Ian Fier MBA, James Roach MD, and

Richard C. Becker MD Richard C. Becker MD

THANK YOU TO THE EMINENCE THANK YOU TO THE EMINENCE INVESTIGATORS AND THE INVESTIGATORS AND THE

PATIENTS WHO PARTICIPATED IN PATIENTS WHO PARTICIPATED IN THE TRIALTHE TRIAL