1. The Opus Trial

2. Antithrombotic Therapy Stable Angina Unstable Angina ST Elevation MI Non-Q wave MI Thrombolysis Non-ST Elevation MI Q wave MI

3. Role of Platelets in Unstable Coronary Syndromes 1. Platelet Adhesion - GP Ib receptor 2. Platelet Activation Shape Change Degranulation IIb/IIIa receptors ex- pressed and activated 3. Platelet Aggregation At site of plaque rupture: Platelet IIb/IIIa Receptor Fibrinogen

4. Role of Platelets in Unstable Coronary Syndromes 1. Platelet Adhesion - GP Ib receptor 2. Platelet Activation Shape Change Degranulation IIb/IIIa receptors ex- pressed and activated 3. Platelet Aggregation At site of plaque rupture: Platelet IIb/IIIa Receptor Fibrinogen

5. Orbofiban: Oral IIb/IIIa Inhibitor Platelet IIb/IIIa Receptor Orbofiban

6. IIb/IIIa Inhibitors Platelet IIb/IIIa Receptor Inhibitor

7. Platelet Activation: Effects of ASA and Ticlopidine ADP Collagen Thrombin Epinephrine Tx A 2 Serotonin  Ca ++ PLA 2 PGG 2 -PGH 2 AA Release Tx A 2 CO Tx Syn ASA Tx A 2 Ticlopidine ?

8. Platelet Activation: Effects of ASA and Ticlopidine ADP Collagen Thrombin Epinephrine Tx A 2 Serotonin  Ca ++ PLA 2 PGG 2 -PGH 2 AA Release Tx A 2 CO Tx Syn ASA Tx A 2 Ticlopidine ?

9. IIb/IIIa Inhibition: Final Common Pathway of Platelet Aggregation ADP Collagen Thrombin Epinephrine Tx A 2 Serotonin GP IIb/IIIa ReceptorActivation IIb/IIIa Shear forces FGN Orbofiban

10. IIb/IIIa Inhibition: Final Common Pathway of Platelet Aggregation ADP Collagen Thrombin Epinephrine Tx A 2 Serotonin GP IIb/IIIa ReceptorActivation IIb/IIIa Shear forces FGN IIb/IIIaInhibitor

11. TIMI 12: P-Selectin In Patients with Unstable Coronary Syndromes AgonistBaseln.(%)Day 7(%)Day 28(%)Normals Spont.28 ± 19*17 ± 13**20 ± 1410.2 ± 4.3 0 uM ADP36 ± 17*24 ±17*25 ± 1517.7 ± 4.8 1 uM ADP48 ± 19**44 ± 20**40 ± 1760.4 ± 15.9 5 uM ADP65 ± 1968 ± 1864 ± 1875.5 ± 9.1 Cannon CP, et al. AHA 1997; TIMI 14 Platelet Substudy, prelim data *p<0.001**p<0.05

12. PURSUIT : IV IIb/IIIa Inhibitor (Integrilin TM ) for UA/NQWMI 10,948 Patients with UA/NQWMI: Angina at rest Rest pain <12 hours, with ECG ‘s or + enzymes

13. PRISM-PLUS: IV IIb/IIIa Inhibitor (Tirofiban) in UA/NQWMI Primary Endpoint (7 Days) TirofibanOdds Heparin + HeparinRatiop-value (N=797) (N=773) Composite Endpoint 17.9% 12.9%0.660 0.004 Refractory Isch. Condition 12.7% 9.3%0.685 0.022 MI (fatal/non-fatal) 7.0% 3.9%0.528 0.006 Death 1.9% 1.9%1.011 0.98 Death or MI 8.3% 4.9%0.565 0.007 1915 Patients with UA/NQWMI: Angina at rest Rest pain <12 hours, with ECG ‘s or +enzymes

14. Indications for IIb/IIIa Inhibition Current and Future Acute Treatment –PTCR –Acute Coronary Syndromes –Stroke Secondary Prevention –PTCR –Acute Coronary Syndromes –Stroke Both early treatment and secondary prevention Inhibition of atherosclerosis (atherothrombosis) - IV IIb/IIIa inhibitors - ?Oral IIb/IIIa - ? IV + oral ? Oral agents

15. Conclusions Platelets: central role in unstable coronary syndromes ASA dramatic benefit IIb/IIIa receptor - final common pathway of platelet aggregation Intravenous IIb/IIIa Inhibitors significant benefit in PTCR and UA/NQWMI Will long-term IIb/IIIa inhibition be beneficial?

16. Phase III Trials Oral IIb/IIIa Inhibitors OPUS-TIMI 16Symphony PatientsAcute Cor. SStabilized Time window<72 hours< 7 days No. Doses22 Level of inhibitionHigh High High->MediumMedium Duration of RxTo F/U (1 yr) 3 months 1 0 EndpointTo F/U (1 yr) 3 months Concomit. ASAYesNo No. Patients12,0006,000

17. 17 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 N= 10,302

18. Primary Endpoint - Through F/U (300 days) No. Pts Composite (%) Death MI Urg revasc Rehosp Stroke Placebo 20.3 3.1 5.5 8.0 11.3 0.9 Orbo 50/30* 20.2 4.4 5.1 6.1 12.1 1.1 Orbo 50/50 20.1 4.1 5.4 6.1 11.2 1.1 P values Each Dose vs. Placebo Data as of Jun 10 1999 NS 0.002 / 0.03 NS 0.001 / 0.003 NS *Orbofiban 50mg bid x 30 days, then 30mg bid

19. Cause of Deaths within 30 Days (Preliminary Review) Data as of Jun 10 1999 No. Deaths reviewed Progressive Sudden Non-Ischemic Bleeding New Thrombotic Event 35 7 11 7 2 8 69 19 15 5 25 43 9 1 3 21 Orbo 50/50PlaceboOrbo 50/30

20. Bleeding Events and Thrombocytopenia (F/U) No. Pts Severe ICH Major Major/Sev Platelets 50-80,000 20-50,000 <20,000 Placebo 0.4 0.1 1.7 1.9 0.1 0.0 Orbo 50/30 1.2 0.2 2.2 3.3 0.6 0.3 Orbo 50/50 0.7 0.1 3.1 3.7 0.6 0.3 P value Each Dose vs. Placebo Data as of Jun 10 1999 0.0001 / 0.04 NS NS / 0.0002 < 0.0001 0.0003 0.01 / 0.02 0.01/0.01

21. Primary Endpoint to F/U Patients-> PCI on study drug Time (days) 050100150200250300 0 5 10 15 20 25 30 % Patients placebo 50-30 mg 50-50 mg F/U pl v. 50-30: p=0.14 pl v. 50-50: p=0.02 30d pl v. 50-30: p=0.73 pl v. 50-50: p=0.08 Data as of Jun 10 1999

22. Summary l First large global trial in ACS of oral IIb/IIIa inhibitor l Orbofiban: minimal efficacy benefit with small excess in mortality l Major bleeding and thrombocytopenia rates were low but higher than placebo l Greater benefit and no harm was seen in subgroups with normal renal function and without heart failure. l 30% benefit in PCI patients on study drug

23. IV vs. Oral GP IIb/IIIa inhibition 0 25 50 75 100 06h12h24h % inhibition (ADP) 36h IV infusion: (Eptifibatide 180 ug/kg + 2.0 ug/kg/min) (mean +/- Std. Dev) N=48 IntravenousOral Data on File, COR/Key Ferguson et al JACC 1998;31:185A (abstract) 0 50100 0h6h 0h 6h 80 Oral : (Orbofiban 50 mg BID) = Mean = Mean

24. ADP-Inducted Activation of Platelets from Patients Treated with Orbofiban Platelet Degranulation/P Selectin 2.0 µM ADP Randomization1 Month P-selectin Expression (percentage of platelets) 0 20 40 60 80 100 p < 0.05 _ _ Fibrinogen Binding 0.2 µM ADP Randomization1 Month Fibrinogen Binding (percentage of platelets) 0 20 40 60 80 100 p < 0.01 _ _ Holmes et al. Am J Cardiol (in press)

25. Fibrinogen Binding and Platelet Aggregation with IIb/IIIa Inhibitor P=0.001 Fibrinogen BindingPlatelet Aggregation Peter et al, Blood 1998;92:3230-9.

26. Hypothesis: Intrinsic Activating Property of IIb/IIIa Inhibition GP IIb/IIIa Receptor IIb/IIIa inhibitor ActivatedUnactivated Platelet Adapted: Peter et al., Blood 1998;92:3230-9. Dissociation of competitive inhibitor FGN FGN Binding IIb/IIIa inhibitor Allows Binding of Fibrinogen + Plt Aggreg Activation of IIb/IIIa receptor “Outside-In Signaling  Platelet Activation FGN FGN

27. Exploratory Analyses: Lessons Learned Fixed-dosing with a competitive oral IIb/IIIa inhibitor: è Peaks/troughs in % inhibition and high inter-patient variability è Low blood levels at some time periods è Too low to prevent events è ? Proaggregatory effects (Peter et al, Blood 1998) è High blood levels in some patients (  creat.) è Potential for excess bleeding è ? Plaque hemorrhage -> increased events

28. Scorecard - Comparing Oral Agents Roxifiban Orbofiban SibrafibanXemilofiban Trial Rocket OPUS-TIMI16SymphonyEXCITE IIb/IIIa selective ++++++++++++ Binding Tightly CompetitiveCompetitive Competitive bound “Off rate” 7 mins secondssecondsseconds Peak of Onset 3-6h4-6h4-6h2-3h Half-life 24 h8-10h 11h 4-5h Excretion Plt. Dissoc.RenalRenalRenal Dosing QD BIDBIDTID Low Peak/trough +++ +++++ Intra-pt variability +++++++ Inter-pt variability ++++++++ Plts < 50,000 <0.5% 0.6%<0.5%0.5% Plts Pro-aggreg. NoYes- Yes 2nd Generation1st Generation Oral IIb/IIIa inhibitors

29. Conclusions - Oral Antiplatelet Therapy at the End of the Millennium l Future Directions - Oral IIb/IIIa inhibitors: 1. Need to optimize dosing è Mimic stable effect of IV drugs è Reduce inter- and intra-patient variability è ? Use bedside platelet test to adjust dose 2. Test “second generation” drugs (tight IIb/IIIa binding) l ASA and ADP antagonists l Proven benefit in large trials l Both decrease platelet activation l Combination ASA/Clopidogrel being tested