The DISPERSE2 Trial Safety, Tolerability, and Initial Efficacy of AZD6140, the First Reversible Oral Adenosine Diphosphate Receptor Antagonist, Compared With Clopidogrel, in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes Primary Results of the DISPERSE2 Trial and Inhibition of Platelet Aggregation by AZD6140, A Reversible Oral P2Y12 Receptor Antagonist, Compared With Clopidogrel in Patients With Acute Coronary Syndromes Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. Storey R, et al. J Am Coll Cardiol 2007;50:1852-6. DISPERSE2

Background: AZD6140 and DISPERSE

Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. AZD6140 Characteristics The first reversible oral adenosine diphosphate (ADP) receptor antagonist1 New class of P2Y12 inhibitors Cyclo-pentyl-triazolo-pyrimidine (CPTP) Not a thienopyridine or ATP analog Direct-acting (not a prodrug); does not require metabolic activation Reversible binding; degree of inhibition reflects plasma concentration half-life of approximately 12 h More rapid reversal of effect—full recovery of platelet function Rapid onset (within 2 hours); peak plasma levels within 2 to 3 hours Greater and more consistent inhibition of ADP-induced platelet aggregation versus clopidogrel 1. van Giezen JJ, Humphries RG. Semin Thromb Hemost 2005;31:195-204. Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

DISPERSE Study: Greater and More Consistent IPA With AZD6140 Than With Clopidogrel (Final Extent) Clopidogrel 75 mg qd Time, h 20 40 60 80 100 Day 1 Day 14 Mean % Inhibition 2 4 8 12 24 AZD6140 100 mg bid Husted S. Presented at ESC 2005. DISPERSE2

Safety, Tolerability, and Initial Efficacy of AZD6140, the First Reversible Oral Adenosine Diphosphate Receptor Antagonist, Compared with Clopidogrel, in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes Primary Results of the DISPERSE2 Trial Christopher P. Cannon, MD, FACC, Steen Husted, MD, Robert A. Harrington, MD, FACC, Benjamin M. Scirica, MD, Håkan Emanuelsson, MD, PhD, Gary Peters, MD, Robert F. Storey, MD, for the DISPERSE2 Investigators J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

DISPERSE2 Main Study Objectives Randomized, double-blind, double-dummy, phase IIb trial assessing safety, tolerability, and initial efficacy of different doses of AZD6140 (plus aspirin) versus clopidogrel (plus aspirin) in patients with NSTE-ACS Assessments included Protocol-defined total (major plus minor, excluding minimal) bleeding events within first 4 weeks Adjudicated by an Independent Clinical Adjudication Committee Clinical end points of MI (including silent MI), severe recurrent ischemia, stroke, and death MI = myocardial infarction; NSTE-ACS = non-ST-segment elevation acute coronary syndromes. Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

DISPERSE2 Main Study Design AZD6140 90 mg bid (n = 334) Onset of chest pain and 48 h maximum to randomization N = 990 AZD6140 180 mg bid (n = 323) Clopidogrel 75 mg qd (n = 327) Randomization V1 V2 V3 V4 Follow-up Day 1 Week 4 Week 8 Week 12 Final Visit +7 days 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 *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. Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

DISPERSE2 Patient Population Inclusion Criteria Hospitalized for NSTE-ACS within the previous 48 hours Ischemic symptoms of ≥10 minutes at rest with: Biochemical marker evidence of MI or Electrocardiographic evidence of ischemia Exclusion Criteria Persistent ST-segment elevation ≥20 minutes >48 hours from symptom onset to expected therapy initiation PCI within 48 hours prior to index event or randomization Increased risk of bleeding Concomitant treatment with oral anticoagulants, daily NSAIDs, or thrombolysis for STEMI NSAIDs = nonsteroidal anti-inflammatory drugs; STEMI = ST-segment elevation myocardial infarction. Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

DISPERSE2 Bleeding Definitions Major bleeding (life-threatening) Fatal, intracranial, pericardial with tamponade, hypovolemic shock, decrease in hemoglobin (Hgb) >50 g/L, or transfusion of 4 or more units for bleeding Major bleeding (other) Significantly disabling, decrease in Hgb of 30–50 g/L, or transfusion of 2–3 units for bleeding Minor bleeding Requires medical intervention to stop bleeding or transfusion of 1 unit for bleeding Patients with multiple bleeding events are counted only once in the respective category, and patients may have a major and a minor bleed Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

DISPERSE2 Baseline Patient Characteristics AZD6140 90 mg bid n = 334 180 mg bid n = 323 Clopidogrel 75 mg qd n = 327 Age, yr; mean (SD) 64 (± 12.1) 63 (± 11.4) 62 (± 11.0) Male, % 61 65 66 White race, % 95 94 Weight, kg; mean (SD) 81 (± 17.0) 81 (± 16.4) 83 (± 16.5) BMI, kg/m2; mean (SD) 28 (± 5.4) 29 (± 5.1) 29 (± 5.0) Prior clopidogrel, % 26 27 28 BMI = body mass index; SD = standard deviation. Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

DISPERSE2 Kaplan-Meier Bleeding Events Rates Through Week 4 AZD6140 90 mg bid n = 334 180 mg bid n = 323 Clopidogrel 75 mg qd n = 327 Total*, % (n) 9.8 (32) 8.0 (25) 8.1 (26) Major, % (n) 7.1 (23) 5.1 (16) 6.9 (22) Major―fatal/life-threatening 3.4 (11) 3.2 (10) 4.4 (14) Major―other 3.7 (12) 1.9 (6) 2.5 (8) Minor, % (n) 2.7 (9) 3.8 (12) 1.3 (4) *Total bleeding is defined as major and minor bleeding. The number of events to the time point is given with a Kaplan-Meier percent estimate of the event rate. Because follow-up ranged from 4 to 12 weeks, incidence rates and Kaplan-Meier event rates will differ. Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.

DISPERSE2 Kaplan-Meier Bleeding Events Rates Through Week 12 AZD6140 90 mg bid n = 334 180 mg bid n = 323 Clopidogrel 75 mg qd n = 327 Total*, % (n) 10.9 (34) 11.4 (33) 9.9 (30) Major, % (n) 8.6 (26) 6.3 (20) 8.7 (26) Major―fatal/life-threatening 4.5 (13) 4.3 (14) 5.4 (16) Major―other 4.2 (13) 1.9 (6) 3.3 (10) Minor, % (n) 2.7 (9) 6.1 (16) 1.3 (4) *Total bleeding is defined as major and minor bleeding. The number of events to the time point is given with a Kaplan-Meier percent estimate of the event rate. Because follow-up ranged from 4 to 12 weeks, incidence rates and Kaplan-Meier event rates will differ. Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.

Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2 Protocol-Defined Bleeding Rates (%) Week 4 and Overall (Week 12) Minor* Week 4 (Primary End Point) Overall Major 12 12 10.2 10.2 9.6 9.2 10 10 8.0 Total Bleeding Rate, % 7.7 Total Bleeding Rate, % 8 8 6 6 4 4 2 2 AZD6140 90 mg bid AZD6140 180 mg bid Clopidogrel 75 mg qd AZD6140 90 mg bid AZD6140 180 mg bid Clopidogrel 75 mg qd Protocol-defined total bleeding rates were similar for all groups No evidence of dose-response pattern for major bleeds *Minor bleeding without major bleeding. Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2 Protocol-Defined Bleeding Rates (%) Within 48 Hours of Randomization Minor* Major 4.0 3.6 2.8 3.0 2.4 Total Bleeding Rate, % 2.0 1.3 1.0 0.0 AZD6140 90 mg bid n = 168 AZD6140 180 mg bid n = 159 AZD6140 270 mg ld n = 330 Clopidogrel 75 mg qd n = 327 *Minor bleeding without major bleeding. ld = loading dose. Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

DISPERSE2 Kaplan-Meier Efficacy Event Rates Through 4 Weeks End point, % (n) AZD6140 90 mg bid n = 334 180 mg bid n = 329 Clopidogrel 75 mg qd n = 327 All-cause death 1.9 (6) 1.0 (3) 0.6 (2) CV Death MI 2.2 (7) 3.5 (11) Stroke 0.0 (0) 0.3 (1) SRI 1.3 (4) RI 3.2 (10) 1.6 (4) 1.6 (5) CV death/MI/stroke 4.3 (14) 3.8 (12) None of these rates was statistically significantly different between groups RI = recurrent ischemia; SRI = severe recurrent ischemia. Because follow-up ranged from 4 to 12 weeks, incidence rates and Kaplan-Meier event rates will differ. Cannon C, et al. J Am Coll Cardiol 2007;50:1844-51. Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

DISPERSE2 Kaplan-Meier Efficacy Event Rates Through 12 Weeks End point, % (n) AZD6140 90 mg bid n = 334 180 mg bid n = 329 Clopidogrel 75 mg qd n = 327 All-cause death 2.4 (7) 1.7 (6) 1.3 (4) CV Death 1.9 (6) MI 3.8 (12) 2.5 (8) 5.6 (15) Stroke 0.6 (2) 0.0 (0) 0.3 (1) SRI 2.3 (5) 3.7 (9) 1.4 (3) RI 4.9 (13) 3.4 (9) 3.0 (9) CV death/MI/stroke 6.0 (19) 3.5 (11) 6.2 (17) None of these rates was statistically significantly different between groups Because follow-up ranged from 4 to 12 weeks, incidence rates and Kaplan-Meier event rates will differ. Cannon C, et al. J Am Coll Cardiol 2007;50:1844-51. Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

Cumulative Risk of an Event DISPERSE2 Cumulative Adjudicated Clinical End Point of CV Death/MI/Stroke Kaplan-Meier Estimates 20% 10% 5% 1 15% Cumulative Risk of an Event 11 21 31 41 51 61 71 81 91 AZD6140 90 mg bid AZD6140 180 mg bid Clopidogrel 75 mg daily Study Day Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

Cumulative Risk of an Event DISPERSE2 Cumulative Adjudicated Clinical End Point of MI Events Kaplan-Meier Estimates AZD6140 90 mg bid AZD6140 180 mg bid Clopidogrel 75 mg daily 20% 10% 5% 15% Cumulative Risk of an Event 1 11 21 31 41 51 61 71 81 91 Study Day Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

DISPERSE2 Crude Incidence of Non-Bleeding Adverse Events (%) Preferred term AZD6140 90 mg bid n = 334 AZD6140 180 mg bid n = 323 Clopidogrel 75 mg qd n = 327 Dyspnea* 10.5 15.8 6.4 Chest pain 7.5 7.4 8.9 Headache 9.6 6.5 8.6 Nausea 6.6 3.4 Dyspepsia 4.8 3.1 2.8 Insomnia 5.4 4.6 Diarrhea* 3.0 Hypotension 1.2 3.7 0.6 Dizziness 4.2 Syncope 1.5 Rash 0.9 1.9 Discontinuation rates due to adverse events were low and similar among all groups 6%, 7%, and 6% discontinued in the AZD6140 90 mg bid, AZD6140 180 mg bid, and clopidogrel 75 mg qd groups, respectively *p < 0.05. All other values are not significant. Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

DISPERSE2 Crude Incidence of Non-Bleeding Adverse Events (%) Preferred term AZD6140 90 mg bid n = 334 AZD6140 180 mg bid n = 323 Clopidogrel 75 mg qd n = 327 Dyspnea 10.5 15.8* 6.4 Chest pain 7.5 7.4 8.9 Headache 9.6 6.5 8.6 Nausea 6.6 3.4 Dyspepsia 4.8 3.1 2.8 Insomnia 5.4 4.6 Diarrhea 3.0 7.4* Hypotension 4.2* 3.7 0.6 Dizziness 4.2 Syncope 1.2 1.5 Rash 0.9 1.9 Discontinuation rates due to adverse events were low and similar among all groups 6%, 7%, and 6% discontinued in the AZD6140 90 mg bid, AZD6140 180 mg bid, and clopidogrel 75 mg qd groups, respectively *p < 0.05. All other values are not significant. The rate of 4.2% for hypotension for AZD6140 is a correction to the printed paper. Erratum pending. Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2

Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51. DISPERSE2 Conclusions AZD6140 shows similar safety and tolerability to clopidogrel AZD6140, a reversible inhibitor of the P2Y12 receptor, offers potential for flexibility by allowing rapid initiation of surgical procedures following discontinuation of drug 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;50:1844-51. DISPERSE2

Inhibition of Platelet Aggregation by AZD6140, A Reversible Oral P2Y12 Receptor Antagonist, Compared With Clopidogrel in Patients With Acute Coronary Syndromes Robert F. Storey, MD, Steen Husted, MD, Robert A. Harrington, MD, FACC, Stanley Heptinstall, PhD, Robert G. Wilcox, MD, Gary Peters, MD, Mark Wickens, BSc, Håkan Emanuelsson, MD, PhD, Paul Gurbel, MD, FACC, Peer Grande, MD, Christopher P. Cannon, MD, FACC J Am Coll Cardiol 2007;50:1852-6. DISPERSE2

DISPERSE2 PK/PD Substudy: Objective Substudy of DISPERSE2 assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD6140 in comparison to clopidogrel in clopidogrel- pretreated and clopidogrel-naïve patients with ACS Storey R, et al. J Am Coll Cardiol 2007;50:1852-6. DISPERSE2

DISPERSE2 PK/PD Substudy: Randomization of Clopidogrel-Naïve Patients Multiple Blood Sampling Evaluable Data n = 45 AZD6140 AZD6140 Clopidogrel 90 mg bid group 180 mg bid group 75 mg qd group n = 18 n = 13 n = 14 Initial dose AZD6140 AZD6140 AZD6140 AZD6140 Clopidogrel 90 mg 270 mg 270 mg 180 mg 300 mg n = 9 n = 9 n = 6 n = 7 n = 14 AZD6140 270 mg Loading Dose n = 15 50% of AZD6140 patients in each AZD6140 group received a 270-mg loading dose Storey R, et al. J Am Coll Cardiol 2007;50:1852-6. DISPERSE2

Clopidogrel-Pretreated Patients Multiple Blood Sampling DISPERSE2 PK/PD Substudy: Randomization of Clopidogrel-Pretreated Patients Clopidogrel-Pretreated Patients Multiple Blood Sampling Evaluable Data n = 44 AZD6140 AZD6140 Clopidogrel 90 mg bid group 180 mg bid group 75 mg qd group n = 18 n = 14 n = 12 Initial dose AZD6140 AZD6140 AZD6140 AZD6140 Clopidogrel 90 mg 270 mg 270 mg 180 mg 75 mg n = 9 n = 9 n = 7 n = 7 n = 12 AZD6140 270 mg Loading Dose n = 16 50% of AZD6140 patients in each AZD6140 group received a 270-mg loading dose Storey R, et al. J Am Coll Cardiol 2007;50:1852-6. DISPERSE2

DISPERSE2 PK/PD Substudy: Methods Collect samples Immediately prior to and 2, 4, 8, and 12 hours after AZD6140 or clopidogrel administration Measure platelet aggregation in platelet-rich plasma, maximal and final extent Using 20 µM ADP as agonist during optical aggregometry Maximal (maximum percentage aggregation) Final (percentage aggregation at 6 minutes after addition of ADP) Storey R, et al. J Am Coll Cardiol 2007;50:1852-6. DISPERSE2

Storey R, et al. J Am Coll Cardiol 2007;50:1852-6. DISPERSE2 PK/PD Substudy: Inhibition of Platelet Aggregation After Initial Doses on Day 1 in Clopidogrel Naïve patients Maximum Aggregation Response Final Aggregation Response 100 100 * 80 75 * 60 Mean % inhibition 50 Mean % inhibition 40 25 20 2 4 6 8 10 12 2 4 6 8 10 12 Time postdose (h) Time postdose (h) AZD6140 90 mg AZD6140 180 mg AZD6140 270 mg Clopidogrel 300 mg *p < 0.05 for AZD6140 versus clopidogrel. Mean ± SD. Storey R, et al. J Am Coll Cardiol 2007;50:1852-6. DISPERSE2

IPA After 4 Weeks of Treatment DISPERSE2 PK/PD Substudy: Individual IPA Responses in Clopidogrel-Naïve Patients Clopidogrel 300 mg AZD6140 180 mg 250 500 750 1000 * Area under the curve (IPA 0-8 h, final) 90 mg 270 mg 75 mg qd 180 mg bid 90 mg bid IPA After First Dose IPA After 4 Weeks of Treatment *p < 0.05 for AZD6140 versus clopidogrel Storey R, et al. J Am Coll Cardiol 2007;50:1852-6. DISPERSE2

Final Aggregation Response Maximum Aggregation Response DISPERSE2 PK/PD Substudy: Steady-State and 24 h Postdose IPA in Clopidogrel-Naïve Patients Final Aggregation Response Maximum Aggregation Response 100 100 * * * * * 80 * * 75 * * * * * * 60 * Mean % inhibition * 50 * * Mean % inhibition 40 25 20 † 2 4 6 8 10 12 24 2 4 6 8 10 12 24 Time postdose (h) Time postdose (h) AZD6140 90 mg AZD6140 180 mg Clopidogrel 75 mg *p < 0.05 for AZD6140 versus clopidogrel: †p < 0.05 for clopidogrel versus 2 h postdose. Mean ± SD. Storey R, et al. J Am Coll Cardiol 2007;50:1852-6. DISPERSE2

Storey R, et al. J Am Coll Cardiol 2007;50:1852-6. DISPERSE2 PK/PD Substudy: Suppression of Platelet Aggregation in Clopidogrel-Pretreated Patients 80 AZD6140 90 mg AZD6140 180 mg AZD6140 270 mg 60 Clopidogrel 75 mg Mean % platelet aggregation 40 20 * * * * * * * * * * * * 2 4 6 8 10 12 *p < 0.05 for AZD6140 versus clopidogrel. Time postdose (h) Storey R, et al. J Am Coll Cardiol 2007;50:1852-6. DISPERSE2

DISPERSE2 PK/PD Substudy: Summary and Conclusions AZD6140 yielded greater and more consistent inhibition of platelet aggregation than a standard regimen of clopidogrel in patients with non–ST-segment elevation ACS Inhibition of platelet aggregation occurred in a dose-dependent and reversible manner AZD6140 further suppressed platelet aggregation in patients who were previously receiving clopidogrel Storey R, et al. J Am Coll Cardiol 2007;50:1852-6. DISPERSE2