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

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

3. U.S. 2704Belgium232 Switzerl.65 Canada2064Germany 224 Mexico60 Israel784Poland218 Italy52 Netherl.674U.K.202 Denmark32 Spain568 Australia168 Norway22 Czech R.532 France163 Austria21 Argentina316 Chile145 Finland19 Brazil277S Africa130 N Zealand16 Russia266 Ireland99 Portugal14 Hungary235 Patients Randomized = 10,288 Cannon CP et al. Circulation 2000;102:149-156

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

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

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

7. Baseline Characteristics

8. Day 30 Outcomes Plac.Orbo 50/30 Orbo 50/50 Orbo (All) P value Death1.42.31.62.00.02 MI2.92.8 0.89 Urg Rev4.42.43.02.7<0.0001 Isch-rehosp2.83.22.73.00.71 ICH Non-ICH 0.1 0.4 0.1 0.5 0.1 0.7 0.1 0.6 0.79 0.28 Composite10.810.09.9 0.12 Death /MI3.94.64.24.4 0.31 Cannon CP et al. Circulation 2000;102:149-156

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

10. TIMI Classification - Underlying Event Leading to Death 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 Orbo 50/50PlaceboOrbo 50/30 * * *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. Thrombocytopenia by Study Drug 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 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 0.009 / 0.0004 NS / 0.08 0.003 / 0.002 0.06 / 0.006 NS / 0.05 0.01 / 0.01 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. Plac Orbo Int. P 0.86 0.87 2.26 3.91 0.12 1.34 1.61 1.40 2.89 0.14 1.34 1.78 1.73 5.45 0.005 1.90 2.18 0.67 1.72 0.04 1.15 1.52 3.40 6.68 0.31 Age< 65 Age > 65 Men Women No prior CHF Prior CHF Acute MI UA Killiip I Killip II-IV Relative Risk 0.1 1 10 Subgroups: 30 Day Mortality Orbo better Orbo Worse Circulation 2000;102:149-156

17. Subgroups: 30 Day Mortality 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 30 Day Mortality Plac Orbo Int P. CC > 100 CC < 100 No Heparin Heparin PCI pre-R No PCI PCI pre/post No PCI OrboBetter Orbo Worse Relative Risk 0.1 1 10 Cannon CP et al. Circulation 2000;102:149-156

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

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

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

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