(and circ.ahajournals r23-r35).

1. A Phase 3 International, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Efficacy and Safety Of Orbofiban in Patients with Unstable Coronary Syndromes (and www.circ.ahajournals.org r23-r35). Cannon CP et al. Circulation 2000;102:149-156

2. Need for Long-Term Antiplatelet Therapy • Markers of platelet activation persist 1 month post ACS • Ault K, et al. P selectin in TIMI 12 trial. JACC 1999;33:634-639. • Angioscopy: Thrombus persists 1 month post ACS • Van Belle, et al. Circulation 1998;97:26-33 • Events persist beyond acute period: In the TIMI 3 Registry, Death/MI/Rec Ischemia • In-hospital = 10.5% • One year = 28.3% • Benefit of IIb/IIIa inhibition achieved only during IV infusion period (PURSUIT, PRISM-PLUS)

3. Patients Randomized = 10,288 U.S. 2704 Belgium 232 Switzerl. 65 Canada 2064 Germany 224 Mexico 60 Israel 784 Poland 218 Italy 52 Netherl. 674 U.K. 202 Denmark 32 Spain 568 Australia 168 Norway 22 Czech R. 532 France 163 Austria 21 Argentina 316 Chile 145 Finland 19 Brazil 277 S Africa 130 N Zealand 16 Russia 266 Ireland 99 Portugal 14 Hungary 235 Cannon CP et al. Circulation 2000;102:149-156

4. TIMI Study Chairman’s Office Eugene Braunwald, MD Christopher Cannon, MD Carolyn McCabe, BS Nottingham Clinical Trial Allan Skene, PhD Data Centre Robert Wilcox, MD Andrew Foxley Andrew Charlesworth Sponsor - G.D. Searle: John Alexander, MD Robert Anders, PharmD Daniel Burns Central Units Cannon CP et al. Circulation 2000;102:149-156

5. Eligibility Criteria • Inclusion Criteria: • Rest ischemic pain > 5 mins within 72 hrs with any 1: • ECG changes, Positive enzymes, (Hx coronary, peripheral or cerebrovasc disease, diabetes) • Major Exclusion Criteria: • Age < 18 years • Renal insufficiency (creatinine >1.6 mg/dl or a estimated creatinine clearance of <40 cc/min) • Increased bleeding risk (Hx. Plts, GI bleed) • Need for warfarin, chronic NSAIDs • ReoPro/IIb/IIIa inhibitor Rx for index event

6. Study Design Patient with Unstable Coronary Syndrome <72 hours N=10,288 ASA 150-162 mg daily Randomize 1:1:1 Orbofiban 50 mg BID Placebo BID Orbo 50 mg BID x 30 days then Orbo 30 mg BID Other Meds, Cath/Revasc per MD Primary endpoint to 30 days + follow-up Death, MI Urgent Revasc, Ischemia -> Rehosp, or Stroke 30 days: orbofiban vs. placebo p=0.01 F/U: each dose vs. placebo p=0.02 F/U Day 14, Day 30 Follow-up visit every 3 months

7. Baseline Characteristics

8. Plac. Orbo Orbo Orbo P value 50/30 50/50 (All) Death 1.4 2.3 1.6 2.0 0.02 MI 2.9 2.8 2.8 2.8 0.89 Urg Rev 4.4 2.4 3.0 2.7 <0.0001 Isch- rehosp 2.8 3.2 2.7 3.0 0.71 ICH 0.1 0.1 0.1 0.1 0.79 Non-ICH 0.4 0.5 0.7 0.6 0.28 Composite 10.8 10.0 9.9 9.9 0.12 Death /MI 3.9 4.6 4.2 4.4 0.31 Day 30 Outcomes Cannon CP et al. Circulation 2000;102:149-156

9. 10 Month Outcomes Cannon CP et al. Circulation 2000;102:149-156

10. Placebo Orbo 50/30 Orbo 50/50 No. Deaths Progressive Sudden Non-Ischemic Bleeding New Thrombotic Event Unclassified 98 10 28 19 4 24 13 144 22 30 21 9 43 19 118 11 25 20 4 40 18 TIMI Classification - Underlying Event Leading to Death * * *p=0.03 Cannon CP et al. Circulation 2000;102:149-156

11. Bleeding - Day 30 Cannon CP et al. Circulation 2000;102:149-156

12. Bleeding - 10 Months Cannon CP et al. Circulation 2000;102:149-156

13. Orbo 50/30 0.2 0 0.3 0.4 0 0.3 Orbo 50/50 0.4 0.2 0.3 0.5 0.2 0.3 P value 30 Day 50-80,000 (%) 20-50,000 (%) <20,000 (%) 10 Months 50-80,000 (%) 20-50,000 (%) <20,000 (%) Placebo 0 0.1 0 0.1 0.1 0 0.009 / 0.0004 NS / 0.08 0.003 / 0.002 0.06 / 0.006 NS / 0.05 0.01 / 0.01 Thrombocytopenia by Study Drug Cannon CP et al. Circulation 2000;102:149-156

14. Day 2 Results Cannon CP et al. Circulation 2000;102:149-156

15. Day 2 Results Cannon CP et al. Circulation 2000;102:149-156

16. Relative Risk 10 0.1 1 Int Plac Orbo . P Age < 65 0.86 0.87 Age > 65 2.26 3.91 0.12 Men 1.34 1.61 Women 1.40 2.89 0.14 No prior CHF 1.34 1.78 Prior CHF 1.73 5.45 0.005 Acute MI 1.90 2.18 UA 0.67 1.72 0.04 Killiip I 1.15 1.52 Killip II-IV 3.40 6.68 0.31 Subgroups: 30 Day Mortality Orbo better Orbo Worse Circulation 2000;102:149-156

17. Relative Risk 0.1 10 1 CC > 100 CC < 100 No Heparin Heparin PCI pre-R No PCI PCI pre/post No PCI Orbo Orbo Better Worse Subgroups: 30 Day Mortality 30 Day Mortality Plac Orbo Int P . 0.84 0.69 1.92 3.13 0.09 1.22 1.23 1.42 2.31 0.22 2.07 0.30 1.27 2.13 0.003 1.53 0.91 1.28 2.37 0.005 Cannon CP et al. Circulation 2000;102:149-156

18. Relative Risk 1 Plac Orbo Int . P 2 0 20.9 19.6 Age < 65 26.7 28.9 0.07 Age > 65 21.6 22.1 Men 26.4 25.2 0.52 Women 22.2 21.9 No prior CHF 34.8 41.7 0.09 Prior CHF 21.2 21.1 Acute MI 24.9 24.8 0.92 UA 22.5 21.8 Killiip I 27.7 34.7 0.03 Killip II-IV Orbo better Orbo Worse Subgroups: 10 Month Composite Cannon CP et al. Circulation 2000;102:149-156

19. Relative Risk 1 2 Plac Orbo Int . P 0 20.8 19.4 CC > 100 25.1 26.9 0.38 CC < 100 19.6 19.6 No Heparin 24.4 24.5 0.43 Heparin 21.4 19.1 PCI pre-R 23.0 23.3 0.36 No PCI 27.5 22.9 PCI pre/post 21.0 23.0 0.006 No PCI Orbo Orbo Better Worse Subgroups: 10 Month Composite Cannon CP et al. Circulation 2000;102:149-156

20. Summary • Orbofiban: • Minimal efficacy benefit overall in ACS • Greater benefit in PCI • Substudies:  P-selectin, FGN binding •  mortality, • Small absolute % •  thrombotic events • -> ? Prothrombotic, ?Unstable patients • Major bleeding, thrombocytopenia higher, but in acceptable range Cannon CP et al. Circulation 2000;102:149-156

21. Potential Explanations - Future Directions • PK/PD variability, peak trough - • Longer T1/2, ? Adjust with platelet monitoring • Only modest benefit in non-PCI ACS patients • Recurrent events not platelet -mediated?- unlikely • Concomitant Rx beyond ASA? • ? Clopidogrel to  Platelet Activation, • ? Antithrombin to inhibit clotting cascade • ? Prothrombotic effects: • Need drugs with tight binding Cannon CP et al. Circulation 2000;102:149-156