1 Novel Antiplatelet Agents: AZD6140, Cangrelor, TRA

2 Meadows TA, Bhatt DL. Circ Res. 2007;100:1261

Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply van Giezen JJ, Humphries RG. Semin Thromb Hemost 2005;31: AZD6140 Characteristics n The first reversible oral adenosine diphosphate ( ADP) receptor antagonist 1 n New class of P2Y 12 inhibitors Cyclo-pentyl-triazolo-pyrimidine (CPTP) Not a thienopyridine or ATP analog Direct-acting (not a prodrug); does not require metabolic activation n Reversible binding; degree of inhibition reflects plasma concentration half-life of approximately 12 h More rapid reversal of effect—full recovery of platelet function n Rapid onset (within 2 hours); peak plasma levels within 2 to 3 hours n Greater and more consistent inhibition of ADP-induced platelet aggregation versus clopidogrel Cannon CP, et al. J Am Coll Cardiol 2007;50:

Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 4 Randomization V1 Day 1 V2V3V4Follow-up Week 4Week 8Week 12Final Visit +7 days AZD mg bid (n = 334) AZD mg bid (n = 323) Clopidogrel 75 mg qd (n = 327) ACS Patients; Onset of chest pain and 48 h maximum to randomization N = 990 *Of the 990 randomized patients, 984 who received ≥1 dose of study drug and were included in the safety analysis dataset. GP = glycoprotein; LMWH = low-molecular-weight heparin. DISPERSE2 Main Study Design n All patients received aspirin (≤325 mg first dose, then 75–100 mg qd) and heparin/LMWH and/or a GPIIb/IIIa antagonist 50% of AZD6140 patients in each arm received a 270-mg loading dose In the clopidogrel group, thienopyridine-naïve patients received a 300-mg loading dose Cannon CP, et al. J Am Coll Cardiol 2007;50:

Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 5 *p < 0.05 for AZD6140 versus clopidogrel. Mean ± SD. DISPERSE2 PK/PD Substudy: Inhibition of Platelet Aggregation After Initial Doses on Day 1 in Clopidogrel Naïve patients Time postdose (h) Mean % inhibition * * * * * * * * * * * * * * * * * * * * * * * * Time postdose (h) Mean % inhibition Maximum Aggregation ResponseFinal Aggregation Response AZD mgAZD mg Clopidogrel 300 mg AZD mg Storey R, et al. J Am Coll Cardiol 2007;50:

Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 6 *p < 0.05 for AZD6140 versus clopidogrel * * * * * * * * * * * * Time postdose (h) Mean % platelet aggregation DISPERSE2 PK/PD Substudy: Suppression of Platelet Aggregation in Clopidogrel-Pretreated Patients Clopidogrel 75 mg AZD mg AZD mg AZD mg Storey R, et al. J Am Coll Cardiol 2007;50:

Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 7 *Minor bleeding without major bleeding. Week 4 (Primary End Point) AZD mg bid AZD mg bid Clopidogrel 75 mg qd Total Bleeding Rate, % Overall AZD mg bid AZD mg bid Clopidogrel 75 mg qd Total Bleeding Rate, % Major Minor* DISPERSE2 Protocol-Defined Bleeding Rates (%) Week 4 and Overall (Week 12) n Protocol-defined total bleeding rates were similar for all groups n No evidence of dose-response pattern for major bleeds Cannon CP, et al. J Am Coll Cardiol 2007;50:

Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 8 20% 10% 5% % Cumulative Risk of an Event AZD mg bid AZD mg bid Clopidogrel 75 mg daily Study Day DISPERSE2 Cumulative Adjudicated Clinical End Point of CV Death/MI/Stroke Kaplan-Meier Estimates Cannon CP, et al. J Am Coll Cardiol 2007;50:

Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 9 n Discontinuation rates due to adverse events were low and similar among all groups 6%, 7%, and 6% discontinued in the AZD mg bid, AZD mg bid, and clopidogrel 75 mg qd groups, respectively *p < 0.05 vs. clopidogrel. All other values are not significant. DISPERSE2 Crude Incidence of Non-Bleeding Adverse Events (%) Preferred term AZD mg bid n = 334 AZD mg bid n = 323 Clopidogrel 75 mg qd n = 327 Dyspnea* *6.4 Chest pain Headache Nausea Dyspepsia Insomnia Diarrhea *3.4 Hypotension4.2 *3.7 *0.6 Dizziness Syncope Rash Cannon CP, et al. J Am Coll Cardiol 2007;50:

Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 10 ECG = electrocardiogram; NSVT = nonsustained ventricular tachycardia; VT = ventricular tachycardia. DISPERSE2 Arrhythmia Events Detected From Post-Hoc Analysis of ECG Monitoring (%) AZD mg bid n = 305 AZD mg bid n = 283 Clopidogrel 75 mg qd n = 297 Ventricular tachycardia Patients with sustained VT >30 s Patients with at least 1 NSVT Patients with at least 1 triplet Ventricular pauses Patients with at least 1 pause >2.5 s Patients with at least 1 pause >5 s n Ventricular pauses were mostly asymptomatic n Continuous ECG monitoring began at randomization for 885 patients (89.4% of patients enrolled) n There was no difference in rates of VT among the 3 groups Cannon CP, et al. J Am Coll Cardiol 2007;50:

Copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 11 DISPERSE2 Conclusions n AZD6140 had greater platelet inhibition than clopidogrel n AZD6140 shows similar safety and tolerability to clopidogrel n AZD6140, a reversible inhibitor of the P2Y 12 receptor, offers potential for flexibility by allowing rapid initiation of surgical procedures following discontinuation of drug n With lack of increased major bleeding and encouraging trends in efficacy, this agent is now being studied in the PLATlet inhibition and patient Outcomes (PLATO) outcomes study Cannon CP, et al. J Am Coll Cardiol 2007;50:

®* AZD mg bid Clopidogrel 300/600mg load: 75mg od V1V2V3V4V5V6 End of Treatment Follow- up Onset of chest pain <24h 1 mo 3 mo 6 mo 6 to 12 mo EOT + 1 mo * N=9000 per treatment arm Study Design 9 mo 12 mo

Cangrelor (AR-C69931MX) Parenteral ADP-P2Y12 receptor antagonist ATP analogue Molecular weight 800 Daltons Plasma half-life of 5-9 minutes 20 minutes for return to normal platelet function N N N N NH S CF 3 OH OH O O P O O P P O O O Cl O O O S 4Na +

Cangrelor Phase II Clinical Data: Compared with Abciximab in PCI Double-blind randomized trial performed in US Incidence of events up to 7 days 5.7% 5.4% 2.1% 1.0% Death, MI, revascularization Major bleed (TIMI criteria) Abciximab (N=94) Cangrelor (N=105) 0% 1% 2% 3% 4% 5% 6% P=NS Greenbaum, AB et al. Am Heart J. 2006;151;689.e1-689.e10.

CHAMPION Program  Phase III program underway 1 O Endpoint – superiority for ischemic events vs. clopidogrel 600 mg at the start of PCI vs. clopidogrel 600 mg at the end of PCI N = 9,000 ptsN = 6,300 pts

TRANSCENDENCE-PCI Subjects Undergoing Non-Urgent PCI or Cardiac Catheterization No PCI** Cardiac Catheterization Safety: TIMI Major plus Minor Bleeding Efficacy: Death/MACE CABG Medical Management Quantify Postoperative Chest- Tube Drainage, Transfusions, and Re-exploration Safety: TIMI Major plus Minor Bleeding No** 0.5 mg n~100 1 mg n~ mg n~100 Placebo n~100 PCI - Subjects Receive Clopidogrel and Antithrombin Randomization #2 Randomization #1  3:1 SCH : Placebo Single Loading Dose Prior to Catheterization TRANSCENDENCE-PCI, Thrombin Receptor Antagonist for Clinical Event Reduction Over Standard Concominant therapies in Percutaneous Coronary Intervention.

Prior MI, Ischemic CVA, or PAD SCH Placebo RANDOMIZE 1:1 DOUBLE BLIND Stratify by CAD, CVD or PAD and intent to use thienopyridine Follow up Visits Day 30, Mo 4, Mo 8, Mo 12 Q6 months Standard care, including oral antiplt rx Final Visit Primary EP CV Death, MI, Stroke, Urgent Coronary Revascularization Major Secondary EP: CV death, non-fatal MI, non-fatal stroke Trial Features Global: 31 countries ~1000 sites ~19,500 subjects Double-blind Event-driven Trial Features Global: 31 countries ~1000 sites ~19,500 subjects Double-blind Event-driven Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50