1. 1 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 P2Y 12 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.

2. 2 Background: AZD6140 and DISPERSE

3. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 1. van Giezen JJ, Humphries RG. Semin Thromb Hemost 2005;31:195-204. 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;50:1844-51.

4. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Husted S. Presented at ESC 2005. DISPERSE Study: Greater and More Consistent IPA With AZD6140 Than With Clopidogrel (Final Extent)

5. 5 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.

6. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. MI = myocardial infarction; NSTE-ACS = non-ST-segment elevation acute coronary syndromes. DISPERSE2 Main Study Objectives n 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 n 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 Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.

7. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. Randomization V1 Day 1 V2V3V4Follow-up Week 4Week 8Week 12Final Visit +7 days AZD6140 90 mg bid (n = 334) AZD6140 180 mg bid (n = 323) Clopidogrel 75 mg qd (n = 327) 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;50:1844-51.

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

9. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. DISPERSE2 Bleeding Definitions n 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 n Major bleeding (other) Significantly disabling, decrease in Hgb of 30–50 g/L, or transfusion of 2–3 units for bleeding n Minor bleeding Requires medical intervention to stop bleeding or transfusion of 1 unit for bleeding n 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.

10. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. BMI = body mass index; SD = standard deviation. DISPERSE2 Baseline Patient Characteristics AZD6140 90 mg bid n = 334 AZD6140 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, %616566 White race, %9594 Weight, kg; mean (SD)81 (± 17.0)81 (± 16.4)83 (± 16.5) BMI, kg/m 2 ; mean (SD)28 (± 5.4)29 (± 5.1)29 (± 5.0) Prior clopidogrel, %262728 Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.

11. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. *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. DISPERSE2 Kaplan-Meier Bleeding Events Rates Through Week 4 AZD6140 90 mg bid n = 334 AZD6140 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-threatening3.4 (11)3.2 (10)4.4 (14) Major―other3.7 (12)1.9 (6)2.5 (8) Minor, % (n)2.7 (9)3.8 (12)1.3 (4) Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.

12. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. DISPERSE2 Kaplan-Meier Bleeding Events Rates Through Week 12 AZD6140 90 mg bid n = 334 AZD6140 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-threatening4.5 (13)4.3 (14)5.4 (16) Major―other4.2 (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.

13. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. *Minor bleeding without major bleeding. Week 4 (Primary End Point) 0 2 4 6 8 10 12 AZD6140 90 mg bid AZD6140 180 mg bid Clopidogrel 75 mg qd Total Bleeding Rate, % Overall 0 2 4 6 8 10 12 AZD6140 90 mg bid AZD6140 180 mg bid Clopidogrel 75 mg qd 9.6 7.7 8.0 10.2 9.2 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;50:1844-51.

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

15. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 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. DISPERSE2 Kaplan-Meier Efficacy Event Rates Through 4 Weeks End point, % (n) AZD6140 90 mg bid n = 334 AZD6140 180 mg bid n = 329 Clopidogrel 75 mg qd n = 327 All-cause death1.9 (6)1.0 (3)0.6 (2) CV Death1.9 (6)1.0 (3)0.6 (2) MI2.2 (7)1.0 (3)3.5 (11) Stroke0.6 (2)0.0 (0)0.3 (1) SRI0.6 (2)1.3 (4)0.6 (2) RI3.2 (10)1.6 (4)1.6 (5) CV death/MI/stroke4.3 (14)1.9 (6)3.8 (12) n None of these rates was statistically significantly different between groups Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.

16. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 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. DISPERSE2 Kaplan-Meier Efficacy Event Rates Through 12 Weeks End point, % (n) AZD6140 90 mg bid n = 334 AZD6140 180 mg bid n = 329 Clopidogrel 75 mg qd n = 327 All-cause death2.4 (7)1.7 (6)1.3 (4) CV Death1.9 (6)1.7 (6)1.3 (4) MI3.8 (12)2.5 (8)5.6 (15) Stroke0.6 (2)0.0 (0)0.3 (1) SRI2.3 (5)3.7 (9)1.4 (3) RI4.9 (13)3.4 (9)3.0 (9) CV death/MI/stroke6.0 (19)3.5 (11)6.2 (17) n None of these rates was statistically significantly different between groups Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.

17. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 20% 10% 5% 0 1 15% Cumulative Risk of an Event 112131415161718191 AZD6140 90 mg bid AZD6140 180 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;50:1844-51.

18. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. 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% 0 15% Cumulative Risk of an Event 1112131415161718191 Study Day Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.

19. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. n 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. 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*10.515.86.4 Chest pain7.57.48.9 Headache9.66.58.6 Nausea6.66.53.4 Dyspepsia4.83.12.8 Insomnia5.44.62.8 Diarrhea*3.07.43.4 Hypotension1.23.70.6 Dizziness4.23.43.1 Syncope1.21.50.6 Rash0.91.90.6 Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.

20. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. n 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. 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 Dyspnea10.5 15.8*6.4 Chest pain7.57.48.9 Headache9.66.58.6 Nausea6.66.53.4 Dyspepsia4.83.12.8 Insomnia5.44.62.8 Diarrhea3.0 7.4*3.4 Hypotension 4.2*3.70.6 Dizziness4.23.43.1 Syncope1.21.50.6 Rash0.91.90.6 Cannon CP, et al. J Am Coll Cardiol 2007;50:1844-51.

21. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. DISPERSE2 Conclusions 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;50:1844-51.

22. 22 Inhibition of Platelet Aggregation by AZD6140, A Reversible Oral P2Y 12 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.

23. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. DISPERSE2 PK/PD Substudy: Objective n 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.

24. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. DISPERSE2 PK/PD Substudy: Randomization of Clopidogrel-Naïve Patients Clopidogrel-Naïve Patients Multiple Blood Sampling Evaluable Data n = 45 AZD6140 180 mg bid group n = 13 Clopidogrel 75 mg qd group n = 14 AZD6140 90 mg bid group n = 18 AZD6140 270 mg n = 6 AZD6140 90 mg n = 9 AZD6140 180 mg n = 7 AZD6140 270 mg n = 9 AZD6140 270 mg Loading Dose n = 15 Clopidogrel 300 mg n = 14 Initial dose 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.

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

26. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. DISPERSE2 PK/PD Substudy: Methods n Collect samples Immediately prior to and 2, 4, 8, and 12 hours after AZD6140 or clopidogrel administration n 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.

27. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. *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 024681012 0 25 50 75 100 Time postdose (h) Mean % inhibition * * * * * * * * * * * * 024681012 0 20 40 60 80 100 * * * * * * * * * * * * Time postdose (h) Mean % inhibition Maximum Aggregation ResponseFinal Aggregation Response AZD6140 180 mgAZD6140 90 mg Clopidogrel 300 mg AZD6140 270 mg Storey R, et al. J Am Coll Cardiol 2007;50:1852-6.

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

29. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. *p < 0.05 for AZD6140 versus clopidogrel: †p < 0.05 for clopidogrel versus 2 h postdose. Mean ± SD. Time postdose (h) Mean % inhibition * 024681012 0 25 50 75 100 24 * * * * * * * * * 024681012 0 20 40 60 80 100 24 * * * * * * * † Time postdose (h) Mean % inhibition Maximum Aggregation Response Final Aggregation Response DISPERSE2 PK/PD Substudy: Steady-State and 24 h Postdose IPA in Clopidogrel-Naïve Patients AZD6140 180 mgAZD6140 90 mgClopidogrel 75 mg Storey R, et al. J Am Coll Cardiol 2007;50:1852-6.

30. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. *p < 0.05 for AZD6140 versus clopidogrel. 024681012 0 20 40 60 80 * * * * * * * * * * * * Time postdose (h) Mean % platelet aggregation DISPERSE2 PK/PD Substudy: Suppression of Platelet Aggregation in Clopidogrel-Pretreated Patients Clopidogrel 75 mg AZD6140 180 mg AZD6140 90 mg AZD6140 270 mg Storey R, et al. J Am Coll Cardiol 2007;50:1852-6.

31. Data appearing in JACC is copyright ©2007 American College of Cardiology Foundation. Restrictions may apply. DISPERSE2 PK/PD Substudy: Summary and Conclusions n 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 n AZD6140 further suppressed platelet aggregation in patients who were previously receiving clopidogrel Storey R, et al. J Am Coll Cardiol 2007;50:1852-6.