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Dominick J. Angiolillo, MD, PhD, FACC, FESC Director of Cardiovascular Research Assistant Professor of Medicine Update on Novel Antiplatelet Agents Under.

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Presentation on theme: "Dominick J. Angiolillo, MD, PhD, FACC, FESC Director of Cardiovascular Research Assistant Professor of Medicine Update on Novel Antiplatelet Agents Under."— Presentation transcript:

1 Dominick J. Angiolillo, MD, PhD, FACC, FESC Director of Cardiovascular Research Assistant Professor of Medicine Update on Novel Antiplatelet Agents Under Advanced Clinical Development CRT 2008 Wednesday February 13 th, 2008

2 Presenter Disclosure Information Name: Dominick J Angiolillo Within the past 12 months, the presenter or their spouse/partner have had a financial interest/arrangement or affiliation with the organization listed below. Company Name:Relationship: Bristol Myers SquibbConsultant/Speaker bureau Sanofi-AventisConsultant/Speaker bureau Eli LillyConsultant/Speaker bureau Daiichi SankyoConsultant/Speaker bureau PortolaConsultant GSKEducational Grant

3 Novel ADP P2Y 12 receptor antagonist PrasugrelAZD6140Cangrelor

4 PrasugrelAZD6140Cangrelor

5 Ticlopidine (1 st generation) N S Cl Clopidogrel (2 nd generation) N S Cl O O CH 3 C Prasugrel (CS-747) (LY640315) (3 rd generation) N F O S O O CH 3 The Thienopyridine Family

6 Active Metabolite Formation HOOC * HS N N O O F F N N S S O O C C H H 3 3 C C O O F F Active Metabolite Prasugrel Sankyo Ann Report 51:1,1999Clopidogrel Pro-drugPro-drug Hepatic Metabolism Cytochrome P450 Active Metabolite N N S S O O F F O O HOOC * HS N N O O Cl OCH 3 Sem Vasc Med 3:113, 2003 Pre-hepatic metabolism Esterases in blood (? Small Intestine) O O 85% Inactive Metabolites Esterases in blood O O N N S S O O Cl O O CH 3 CC N N S S O O Cl O O CH 3 CC N N S S O O Cl O O CH 3 CC

7 Healthy volunteer crossover study IPA (20  M ADP) at 24 hours Brandt J et al. AHJ 2006 –20 0 20 40 60 80 100 100 Inhibition of platelet aggregation (%) Response to prasugrel 60 mg Response to clopidogrel 300 mg N=64

8 0 5 10 15 0306090180270360450 HR 0.81 (0.73-0.90) P=0.0004 Prasugrel Clopidogrel Days Endpoint (%) 12.1 9.9 HR 1.32 (1.03-1.68) P=0.03 Prasugrel Clopidogrel 1.8 2.4 138 events 35 events Balance of Efficacy and Safety CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 NNH = 167 Wiviott et al NEJM 2007

9 Stent Thrombosis (ARC Definite + Probable) 0 1 2 3 0306090180270360450 HR 0.48 P <0.0001 Prasugrel Clopidogrel 2.4 (142) NNT= 77 1.1 (68) Days Endpoint (%) Any Stent at Index PCI N= 12,844

10 Diabetic Subgroup 0 2 4 6 8 10 12 14 16 18 0306090180270360450 HR 0.70 P<0.001 Days Endpoint (%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 21 N=3146 17.0 12.2 Prasugrel Clopidogrel Prasugrel Clopidogrel 2.6 2.5 Wiviott et al NEJM 2007

11 Net Clinical Benefit Bleeding Risk Subgroups OVERALL >=60 kg < 60 kg < 75 >=75 No Yes 0.512 Prior Stroke / TIA Age Wgt Risk (%) + 54 -16 -16 +3 -14 -13 Prasugrel BetterClopidogrel Better HR P int = 0.006 P int = 0.18 P int = 0.36 Post-hoc analysis Wiviott et al NEJM 2007

12 Safety Significant increase in serious bleeding (32% increase) Avoid in pts with prior CVA/TIA Efficacy 1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis52% uTVR 34% MI 24% 2. An early and sustained benefit 3. Across ACS spectrum Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD Conclusions Higher IPA to Support PCI Net clinical benefit significantly favored Prasugrel Optimization of Prasugrel maintenance dosing in a minority of patients may help improve the benefit : risk balance

13 PRINCIPLE – TIMI 44 Comparison with Higher Dose Clopidogrel P<0.0001 for each IPA (%; 20  M ADP) Hours14 Days IPA (%; 20  M ADP) P<0.0001 Prasugrel 10 mg Clopidogrel 150 mg Wiviott et al Circulation 2007. N=201 Prasugrel 60 mg Clopidogrel 600 mg

14 Prasugrel studies in the pipeline S.W.A.P. – Phase II: Switching antiplatelet therapy (clopidogrel to prasugrel) S.W.A.P. – Phase II: Switching antiplatelet therapy (clopidogrel to prasugrel) ACAPULCO – Phase II: Prasugrel ( vs high dose clopidogrel (900mg LD/150mg MD) in ACS/PCI ACAPULCO – Phase II: Prasugrel ( vs high dose clopidogrel (900mg LD/150mg MD) in ACS/PCI TRILOGY – Phase III: Prasugrel vs clopidogrel in non- revascularized ACS TRILOGY – Phase III: Prasugrel vs clopidogrel in non- revascularized ACS OPTIMUS-3 – Phase II: Prasugrel vs high dose clopidogrel (600mg LD/150mg MD) in diabetes mellitus OPTIMUS-3 – Phase II: Prasugrel vs high dose clopidogrel (600mg LD/150mg MD) in diabetes mellitus

15 Novel ADP P2Y 12 receptor antagonist PrasugrelAZD6140Cangrelor

16 AZD6140 (Ticagrelor)  A non-thienopyridine, in the chemical class CPTP (CycloPentylTriazoloPyrimidine)  First oral reversible ADP P2Y 12 receptor antagonist  Direct acting via the P2Y 12 receptor - metabolism not required for activity  More potent platelet inhibitor than clopidogrel  A non-thienopyridine, in the chemical class CPTP (CycloPentylTriazoloPyrimidine)  First oral reversible ADP P2Y 12 receptor antagonist  Direct acting via the P2Y 12 receptor - metabolism not required for activity  More potent platelet inhibitor than clopidogrel HO HN HO OH OS F F N N N N N

17 DISPERSE: Faster, Greater and More Consistent IPA with AZD6140 vs clopidogrel Time, hours 0 20 40 60 80 100 AZD6140 (100 mg bd) 8128 Inhibition, % 24 Clopidogrel Inhibition, % Day 1Day 14Day 1Day 14 0 20 40 60 80 100 8128 24 42424242 Husted SE et al Eur Heart J 2006; 27: 1038-1047

18 DISPERSE2 Study Design DISPERSE2 was a double-blind, randomized study of AZD6140 compared with clopidogrel, both on a background of aspirin (75–100 mg od) 50% of patients in each AZD6140 arm received a loading dose of 270 mg In the clopidogrel arm, thienopyridine treatment-naïve patients received a 300-mg loading dose Randomization Visit 1 Day 1 Visit 2Visit 3Visit 4Follow-up Week 4Week 8Week 12Final Visit +7 days AZD6140 90 mg bid AZD6140 180 mg bid Clopidogrel 75 mg qd NSTE-ACS patients with onset of chest pain <48 hours n = 334 n = 329 n = 327 Cannon CP et al. J Am Coll Cardiol 2007

19 DISPERSE2 Adjudicated Bleeding Rates (%) Week 4 and Overall 0 2 4 6 8 10 Week 4 Total Bleeding Rate (%) 0 Overall Total Bleeding Rate (%) 12 2 4 6 8 10 12 9.6% 7.7% 8.0% 10.2% 9.2% AZD6140 90 mg bid N = 334 AZD6140 180 mg bid N = 323 Clopidogrel 75 mg qd N = 327 AZD6140 90 mg bid N = 334 AZD6140 180 mg bid N = 323 Clopidogrel 75 mg qd N = 327 Minor bleeding*Major bleeding Adjudicated total bleeding rates were similar for all groups No evidence of dose-response for major bleeds * Minor bleeding without major bleeding Cannon CP et al. J Am Coll Cardiol 2007

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21 DISPERSE-2: Non-bleeding adverse events 0 2 4 6 8 10 12 14 16 18Clop AZD6140 90 mg AZD6140 180 mg 0 2 4 6 8 10 12 14 16 18 Clop AZD6140 90 mg AZD6140 180 mg 4.4% 5.6% 9.9% 6.4% 10.5% 15.8% Ventricular Pauses >2.5 Seconds Dyspnea % % Discontinuation rates from non-bleeding adverse events were low and similar between groups

22 Primary endpoint:CVD/MI/stroke Secondary endpoint:CVD/MI/stroke/revascularization with PCI; CVD/MI/stroke, severe recurrent ischemia 12-month maximum exposure (Min = 6 mo, Max = 12 mo, Mean = 11 mo) (N=18,000) ASA + Clopidogrel 300 mg ld/75 mg qd 600 mg ld allowed in PCI ASA + AZD6140 180 mg ld/90 mg bid Moderate- to high-risk ACS patients (UA/NSTEMI/STEMI, PCI, medically managed, or CABG) ASA = acetylsalicylic acid; bid = twice daily; CVD = cardiovascular disease; ld = loading dose; MI = myocardial infarction; NSTEMI = non-ST- segment elevation MI; qd = once daily; STEMI = ST-segment elevation MI; UA = unstable angina. ClinicalTrials.gov Identifier: NCT00391872

23 Novel ADP P2Y 12 receptor antagonist PrasugrelAZD6140Cangrelor

24 Cangrelor (AR-C69931MX)  Parenteral ADP-P2Y 12 receptor antagonist  ATP analogue  Direct and Reversible P2Y 12 inhibitor  More potent than clopidogrel ~90% inhibition of platelet aggregation at 1 - 4 mcg/kg/min iv  Plasma half-life of 5-9 min.; 20 min. for return to normal platelet function O - O - O - O - OO HOOH PPPOO N HN N N N N S S CF 3 O Cl - O

25 % Inhibition of Aggregation Fold Increase in Bleeding Time 0 20 40 60 80 100 0 1 2 3 4 5 6 7 8 50100 50010002000 Aggregation Bleeding time + aspirin/heparin/GTN + placebo AR-C69931 (ng.kg -1.min -1 ) Stepped infusion period Recovery period 7 15 20 45 60 min Key Phase I result Rapid reversal of dose-dependent effect

26 Phase II clinical data: Compared with Abciximab in PCI Double-blind randomized trial performed in US 5.7% 5.4% 2.1% 1.0% Death, MI, revascularizationMajor bleed (TIMI criteria) Incidence of events up to 7-days AR-C69931MX report number SC931-5129 Part 2 Abciximab (N=94) Cangrelor (N=105) Greenbaum et al. Am Heart J. 2006;151:689.e1-689.e10

27 CHAMPION-PCI PCI (with or without stent) 1:1 Double blind, double dummy Placebo capsules (to match) Cangrelor bolus (30µg/kg) & infusion (4µg/kg/hour) Clopidogrel capsules (600mg) Placebo bolus & infusion (to match) 1º Endpoint: Death, MI, and uRevasc at 48 hours 2 º Endpoints: Death, MI, uRevasc at 30 days Death at 6 months and 1 year Index Procedure Study drug infusion (for at least 2 hours or the duration of the procedure, whichever is longer) Clopidogrel capsules (600 mg) Placebo capsules (to match) Clopidogrel Maintenance (at physician discretion) ++

28 Platelet Stimuli GP IIb/IIIa integrin ADP Epinephrine Collagen Thrombin Platelet Aggregation Serotonin Shear rate AA TxA 2 COX-1 ThrombinThrombinThrombin TxA 2

29 Thrombin ADP TXA 2 ADP P2Y 12 ADP (fibrinogenreceptor) GP IIb/IIIa Activation COX-1 clopidogrel bisulfate aspirin cAMP Oral Anti-PAR-1 receptors SCH 530348 E 5555 adapted from Schafer AI. Am J Med. 1996;101:199-209.

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34 TRA (SCH 530348) Program (29,500 pts) 1 o EP: Composite of CV death, MI, Stroke, and urgent revascularization TRA (SCH 530348) Program Evaluation of Efficacy and Safety in Acute and Chronic Atherothrombosis NSTEACS 10,000 pts 2º Prevention 19,500 pts SCH 530348PlaceboSCH 530348Placebo F/U: 30 days, 4,8,12 months, and 6 months thereafter F/U 1 yr minimum 1 o EP: Composite of CV death, MI, Stroke, urgent revascularization and Recurrent Ischemia w/ Rehosp

35 ……. to be continued !!!!!!!!!!!


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