Rob Storey Reader and Honorary Consultant in Cardiology, University of Sheffield The changing world of adjunctive pharmacology

2 Disclosures Company NameRelationship AstraZenecaResearch grants, speaker fees, consultant, travel Eli Lilly / Daiichi SankyoResearch grant, speaker fees, consultant, travel Schering-PloughResearch grant, consultant TevaConsultant NovartisConsultant The Medicines CompanyConsultant DynabyteResearch consumables

GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2. Storey RF. Curr Pharm Des. 2006;12: Targets for Platelet Inhibition Thromboxane A 2 5HT P2Y 12 ADP 5HT PLATELET ACTIVATION P2Y 1 5HT 2A PAR-1 PAR-4 Dense granule Thrombin generation Shape change  IIb  3   3 Fibrinogen  IIb  3 Aggregation Amplification Alpha granule Coagulation factors Inflammatory mediators TP  Coagulation GPVI Collagen ATP P2X 1 ASPIRIN x TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x TICAGRELOR CANGRELOR GP IIb/IIIa ANTAGONISTS xx SCH E5555 x TERUTROBAN x HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN Thrombin x

GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2. Storey RF. Curr Pharm Des. 2006;12: P2Y 12 as a therapeutic target Thromboxane A 2 5HT P2Y 12 ADP 5HT PLATELET ACTIVATION P2Y 1 5HT 2A PAR-1 PAR-4 Dense granule Thrombin generation Shape change  IIb  3   3 Fibrinogen  IIb  3 Aggregation Amplification Alpha granule Coagulation factors Inflammatory mediators TP  Coagulation GPVI Collagen ATP P2X 1 TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x TICAGRELOR CANGRELOR Thrombin

5 Activation/inactivation of clopidogrel CYP = cytochrome P450. Farid NA, et al. Clin Pharmacol Ther. 2007;81: S N O Cl S O N O N SH COOH O S N OH O Clopidogrel CYPs Esterases CYPs 2-Oxo-clopidogrelR SR26334(Inactive) OCH 3 3 3

Platelet aggregation before and 4 hours after clopidogrel 600 mg in patients undergoing PCI Whole blood single platelet counting in response to ADP 10 uM Patient with subacute stent thrombosis Smith SMG et al. Platelets 2006; 17:

VerifyNow P2Y12 assay 7

Multiplate MEA 8

Clinical outcomes according to platelet aggregometry results with MEA Sibbing, D. et al. JACC 2009; 53:

Sibbing, D. et al. Eur Heart J : Clopidogrel, CYP 2C19 and stent thrombosis

11 Prasugrel

Comparison of prasugrel with higher dose clopidogrel P< for each IPA (%; 20  M ADP) Hours14 Days IPA (%; 20  M ADP) P< Prasugrel 10 mg Clopidogrel 150 mg Wiviott et al Circ 2007 N=201 Prasugrel 60 mg Clopidogrel 600 mg

TRITON Study Design Double-blind ACS (STEMI or UA/NSTEMI) & Planned PCI ASA PRASUGREL 60 mg LD/ 10 mg MD CLOPIDOGREL 300 mg LD/ 75 mg MD 1 o endpoint: CV death, MI, Stroke 2 o endpoints:CV death, MI, Stroke, Rehosp-Rec Isch, CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies:Pharmacokinetic, Genomic Median duration of therapy - 12 months N= 13,600

HR 0.81 ( ) P= Prasugrel Clopidogrel Days Endpoint (%) HR 1.32 ( ) P=0.03 Prasugrel Clopidogrel events 35 events TRITON-TIMI study Balance of Efficacy and Safety CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 NNH = 167

TRITON-TIMI study TRITON-TIMI study Stent Thrombosis (ARC Definite + Probable) HR 0.48 P < Prasugrel Clopidogrel 2.4 (142) NNT= (68) Days Endpoint (%) Any Stent at Index PCI N= 12,844

TRITON Diabetic Subgroup HR 0.70 P<0.001 Days Endpoint (%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 N= Prasugrel Clopidogrel Prasugrel Clopidogrel

TRITON STEMI cohort Primary EP (CV death, MI and stroke at 15 months) Montalescot et al. ESC 2008 Time (Days) Proportion of patients (%) HR=0.79 (0.65–0.97) NNT=42 p=0.02 RRR=21% p=0.002 RRR=32% Clopidogrel Prasugrel Age-adjusted HR=0.81 ( )

TRITON Net Clinical Benefit Bleeding Risk Subgroups OVERALL >=60 kg < 60 kg < 75 >=75 No Yes Prior Stroke / TIA Age Wgt Risk (%) Prasugrel BetterClopidogrel Better HR P int = P int = 0.18 P int = 0.36 Post-hoc analysis

Ticagrelor The first oral reversible P2Y 12 antagonist

Time (hours) Onset Maintenance Offset IPA % Ticagrelor 180mg LD / 90 mg bd (n=54) Clopidogrel 600mg LD / 75 mg od (n=50) weeks * * * * * * * * * ‡ † †  ONSET/OFFSET Study IPA with ADP 5uM (final extent) Gurbel PA et al. Circulation 2009

PLATO PLATELET – VerifyNow P2Y12 assay comparing maintenance therapy with clopidogrel (C) vs ticagrelor (T) Storey RF et al. Presented at American Heart Association annual scientific sessions Nov 2009

No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,560 8,678 8,405 8,520 8,177 Days after randomisation 6,703 6,796 5,136 5,210 4,109 4, Cumulative incidence (%) Clopidogrel Ticagrelor ,279 HR 0.84 (95% CI 0.75–0.95), p= Clopidogrel Ticagrelor HR 0.79 (95% CI 0.69–0.91), p= ,291 9,333 8,865 8,294 8,780 8,822 8,589 Days after randomisation ,441 5,482 4,364 4,4198,626 Myocardial infarction Cardiovascular death Cumulative incidence (%) Secondary efficacy endpoints over time

Total major bleeding NS 0 K-M estimated rate (% per year) PLATO major bleeding TIMI major bleeding Red cell transfusion * PLATO life- threatening/ fatal bleeding Fatal bleeding Major bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the use of a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15; * Proportion of patients (%); NS = not significant Ticagrelor Clopidogrel

Non-CABG and CABG-related major bleeding p=0.026 p=0.025 NS 9 K-M estimated rate (% per year) Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding Ticagrelor Clopidogrel

PLATO - Dyspnoea All patients Ticagrelor (n=9,235) Clopidogrel (n=9,186) p value * Dyspnoea, % Any With discontinuation of study treatment <0.001 *p values were calculated using Fischer’s exact test

PLATO Conclusions Reversible, more intense P2Y 12 receptor inhibition for one year with ticagrelor in comparison with clopidogrel in a broad population with ST- and non-ST-elevation ACS provides –Reduction in myocardial infarction and stent thrombosis –Reduction in cardiovascular and total mortality –No change in the overall risk of major bleeding Ticagrelor is a more effective alternative than clopidogrel for the continuous prevention of ischaemic events, stent thrombosis and death in the acute and long-term treatment of patients with ACS Clinicians will need to learn how to identify and manage dyspnoea associated with ticagrelor

Cangrelor Intravenous reversible P2Y 12 antagonist

HO O OH N N NSF F F N HN S _ O _ P O _ O Cl P O O O P O _ O O O OH N N NSF F F N HN S 4Na + Inactivation by Dephosphorylation

BRIDGE study design (provisional) ACS treated with clopidogrel, scheduled for CABG Stop clopidogrel x days prior to CABG Cangrelor infusion Placebo infusion 1 o end point: Bleeding 2 o end points:Inhibition of platelet function, ischaemic events Primary objective: To assess safety of cangrelor compared to placebo prior to CABG surgery Stop x hours prior to CABG surgery PD measurements

Elinogrel Intravenous and oral reversible P2Y 12 antagonist

Elinogrel Reversible P2Y 12 inhibitor in phase 2/3 development IV and oral formulations Half-life ~12 hours Competitive mechanism of action – competes with ADP for binding to receptor, greater IPA for low vs high concentrations of ADP

32 Targeting PAR-1

GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2. Storey RF. Curr Pharm Des. 2006;12: Targets for Platelet Inhibition Thromboxane A 2 5HT P2Y 12 ADP 5HT PLATELET ACTIVATION P2Y 1 5HT 2A PAR-1 PAR-4 Dense granule Thrombin generation Shape change  IIb  3   3 Fibrinogen  IIb  3 Aggregation Amplification Alpha granule Coagulation factors Inflammatory mediators TP  Coagulation GPVI Collagen ATP P2X 1 ASPIRIN x TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x TICAGRELOR CANGRELOR GP IIb/IIIa ANTAGONISTS xx SCH E5555 x TERUTROBAN x HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN Thrombin x

No significant compromise to haemostasis with SCH T-1 = SCH mg/kg T-2 = Aspirin (10 mg/kg) plus Clopidogrel (2 mg/kg) T-3 = SCH , Aspirin plus Clopidogrel Cynomolgus monkey model. Chintala M et al. Arterioscl Thromb Vasc Biol. 2008; 28: e138–e139

Study started December 2007 Estimated study completion July 2011 TRACER Study Design Primary end point:CV death/MI/stroke/recurrent ischaemia with rehospitalisation/urgent coronary revascularisation 12-month minimum exposure (N=10,000) Standard therapy + placebo Standard therapy + SCH mg LD then 2.5 mg od Moderate- to High-Risk ACS patients (UA/NSTEMI, PCI, Medically-Managed, or CABG)

GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2. Storey RF. Curr Pharm Des. 2006;12: Thromboxane A 2 5HT P2Y 12 ADP 5HT P2Y 1 5HT 2A PAR-1 PAR-4 Dense granule Thrombin generation Shape change  IIb  3   3 Fibrinogen  IIb  3 Aggregation Amplification Alpha granule Coagulation factors Inflammatory mediators TP  Coagulation GPVI Collagen ATP P2X 1 ASPIRIN x TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x TICAGRELOR CANGRELOR GP IIb/IIIa ANTAGONISTS xx SCH E5555 x TERUTROBAN x HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN Thrombin x ? Questions