1. Sunil V. Rao MD for the EMINENCE Investigators Evaluation of a novel, rationally designed, low-molecular-weight heparin during elective PCI: Results of the Phase 2 EMINENCE Trial

2. EMINENCE Trial: Disclosures n n Presenter disclosures l l Research funding: Cordis Corporation, Momenta Pharmaceuticals, Portola Pharmaceuticals l l Off-label uses: Enoxaparin for PCI, fondaparinux for PCI n n The EMINENCE Trial was funded by Momenta Pharmaceuticals

3. Available Anticoagulant Options n Unfractionated heparin l Advantages: measurable, reversible, experience l Disadvantages: platelet activation, HIT (TS), unreliable degree of antithrombin activity n LMWH l Advantages: more reliable anticoagulation l Disadvantages: not measurable, platelet activation, some degree of discomfort during PCI n Fondaparinux l Advantages: similar efficacy to LMWH with less bleeding l Disadvantages: not demonstrated to be safe during PCI, not easily reversible n Bivalirudin l Advantages: less bleeding, measurable, short half-life l Disadvantages: not more efficacious than UFH, trends toward slightly more ischemic events

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

5. M118 Structure and Properties n n Low-molecular-weight heparin n n Increased anti-factor II activity compared with other LMWHs n n Constant Xa/IIa ratio over time n n Predictable PK/PD n n Effects are reversible or neutralized with protamine sulfate n n High bioavailability: IV and SC administration

6. EMINENCE Study Design n n Randomized, open-label, active-controlled, dose-ranging design n n Patients undergoing elective PCI n n Pre-PCI antiplatelet (ASA, clopidogrel) therapy l l Planned GP IIb/IIIa not allowed n n Vascular sheaths removed 4 hours after last M118 dose or when ACT < 160 sec if assigned to UFH l l Closure devices allowed; transfemoral encouraged n n Phase A: 3 arms – 70 U/kg UFH, 75 IU/kg M118, 100 IU/kg M118 l l Qualitative review by DSMB after 5% of patients enrolled in 75 IU/kg M118 & UFH arms n n Phase B: 4 arms – 70 U/kg UFH, 50 IU/kg M118, 75 IU/kg M118, 100 IU/kg M118

7. Low-risk patients with stable CAD undergoing elective PCI Pre-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

8. EMINENCE Primary End Point n n 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*) n n *Major bleeding l l Transfusion of > 2 units whole blood or packed red blood cells, or l l Intracranial hemorrhage, or l l Retroperitoneal hemorrhage, or l l A fall in hemoglobin (Hgb) > 4 g/dL (or 12.5% of hematocrit) with no bleeding site identified despite attempts to do so, or l l Spontaneous or non-spontaneous blood loss associated with a Hgb drop > 3 g/dL (or 10% of hematocrit) n n *Minor bleeding: Any observed bleeding that does not meet major bleeding criteria

9. EMINENCE Primary Statistical Analysis n n Primary end point analyzed on an intent-to-treat basis n n Main comparison: subjects randomized to UFH vs. subjects randomized to experimental therapy (all M118 doses combined) n n Primary analysis: non-inferiority analysis of UFH vs. pooled M118 doses l l Assume control (UFH) rate of 8% l l Goal to reject an absolute 8% increase in the primary outcome l l Non-inferiority will be achieved if the upper limit of the 95% CI is less than 0.08 n n A sample size of 600 patients (150/arm) provides 93% power at a one-sided alpha of 0.05

10. EMINENCE: Secondary Comparisons n n Prespecified l l Primary end point l l Primary end point minus major bleeding l l 30-day death or MI l l 30-day death/MI/repeat revascularization l l Primary end point and bleeding comparisons between UFH and combined M118 without 50 IU/kg dose n n Post-hoc l l Composite of 30-day death/MI/repeat revascularization/24-hr major bleeding l l TIMI major and minor bleeding

11. EMINENCE Trial Results: Demographics n n Background characteristics equally balanced across groups n n Mean age: 63.8 yrs n n Sex: 72.4% male, 27.6% female n n Race: l l 91.7% White (8.0% Hispanic) l l 5.8% Black l l 1.2% Asian l l 0.8% Other l l 0.6% Native American n n Median weight: 90.1 kg n n Mean 1.5 lesions treated across all groups

12. EMINENCE: Concomitant Procedural Treatments UFH 70 N=151 M118 50 N=44 M118 75 N=152 M118 100 N=156 M118 All N=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%

13. Coagulation Parameters: Median ACTs

14. UFH 70 N=151 M118 50 N=44 M118 75 N=152 M118 100 N=156 No closure device*155158160169 With closure device251206237271 *Protocol recommended sheath removal if ACT < 160 sec if randomized to UFH or at 4 hours post PCI if randomized to M118; “Per Protocol population Median ACTs at Time of Sheath Pull n n ACT is primarily influenced by anti-IIa (thrombin) activity. n n 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). n n 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.

15. EMINENCE Results: Primary End Point, ITT

16. 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 IU22.7%31.1%3.7%Yes M118 75 IU28.3%31.1%5.8%Yes M118 100 IU30.1%31.1%7.7%Yes *Assumes missing end points were not end points per protocol and statistical analysis plan. Primary and Secondary Efficacy Comparison*

17. EMINENCE Results: Prespecified Secondary End Points Primary End Point Excluding Minor Bleeding

18. EMINENCE Results: Prespecified Secondary End Points Death, MI, or Repeat Revascularization

19. EMINENCE Results: Prespecified Secondary End Points Death or MI

20. Key Procedural End Point: Bailout GPIIb/IIIa Use

21. EMINENCE: Protocol-defined Major Bleeding REPLACE-2 Scale

22. EMINENCE: Protocol-defined Minor Bleeding REPLACE-2 Scale

23. EMINENCE Bleeding: TIMI Scale (Post Hoc)

24. EMINENCE Bleeding: Transfusions 0.0

25. EMINENCE: Conclusions (1) n n M118 is a safe and feasible anticoagulant to administer during elective PCI n n M118 is comparable to weight-adjusted UFH at preventing a range of PCI-related complications n n The 75 IU/kg and 100 IU/kg M118 doses appear promising l l Lower rates of ischemic complications, similar rates of bleeding

26. EMINENCE: Conclusions (2) n n Dose-related increase in ACT n n Similar rates of protocol-defined major bleeding but higher rates of minor bleeding (dose-dependent) n n The EMINENCE Phase 2 results form the basis for further evaluation of M118 for the treatment of ischemic heart disease

27. EMINENCE Trial Steering Committee Chiara Melloni MD MHS, Shelley Myles-DiMauro BSc RN, Samuel Broderick MS, Kristina Sigmon MS, Andrzej Kosinski PhD, Neal S. Kleiman MD, Vladimir Dzavik MD, Jean Francois Tanguay MD, Ian Fier MBA, James Roach MD, and Richard C. Becker MD

28. THANK YOU TO THE EMINENCE INVESTIGATORS AND THE PATIENTS WHO PARTICIPATED IN THE TRIAL