Rob Storey Reader and Honorary Consultant in Cardiology,

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  • 1) Male cynomolgus monkeys were dosed orally with the respective drugs as indicated. 2) Blood loss measurements: 1 hr after dosing the animals were anesthetized and surgically prepared for assessment of blood loss. Briefly, the femoral artery and vein were surgically isolated and cannulated with catheters (for measurement of blood pressure and infusion of anesthetic). Gauze was placed in this surgical site to absorb any blood lost at this site. In addition bleeding was initiated by making 2 cuts on the femoral muscle with the help of the Simplate® bleeding devices (which makes a uniform cut, 5 mm long and 1 mm deep). Blood loss was quantified by a simple calorimetric assay in which the blood absorbed onto the gauze was lysed using reagents and the hemoglobin content was measured. 3) Bleeding time: The forearm on the monkeys was shaved and a precision cut was made on the skin using the Simplate® bleeding device as mentioned above (used clinically in humans). Blood lost from this incision was absorbed onto a filter paper every 30 seconds. The time from initiation of the cut to when the bleeding stops is noted and represents the bleeding time. 4) Results: - Modest blood loss and bleeding time was observed in the vehicle group. - Administration of SCH 530348 (TRA) did not result in any further increase in bleeding time or blood loss. - Administration of aspirin plus clopidogrel resulted in a marked prolongation of template bleeding time (consistent with published reports in baboons) and increase in surgical blood loss - In a separate group co-administration of SCH 530348 on top of aspirin plus clopidogrel did not exacerbate the increases in bleeding time and blood loss observed with aspirin and clopidogrel - These findings demonstrate that there is no bleeding liability for TRA when used either alone or when added to the standard of care (aspirin and clopidogrel)
  • Rob Storey Reader and Honorary Consultant in Cardiology,

    1. 1. <ul><li>Rob Storey </li></ul><ul><li>Reader and Honorary Consultant in Cardiology, </li></ul><ul><li>University of Sheffield </li></ul>The changing world of adjunctive pharmacology
    2. 2. Disclosures <ul><li>Company Name Relationship </li></ul><ul><li>AstraZeneca Research grants, speaker fees, consultant, travel </li></ul><ul><li>Eli Lilly / Daiichi Sankyo Research grant, speaker fees, consultant, travel </li></ul><ul><li>Schering-Plough Research grant, consultant </li></ul><ul><li>Teva Consultant </li></ul><ul><li>Novartis Consultant </li></ul><ul><li>The Medicines Company Consultant </li></ul><ul><li>Dynabyte Research consumables </li></ul>
    3. 3. Targets for Platelet Inhibition GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2 . Storey RF. Curr Pharm Des . 2006;12:1255-1259. Thromboxane A 2 5HT P2Y 12 ADP ADP ADP 5HT PLATELET ACTIVATION P2Y 1 5HT 2A PAR-1 PAR-4 Dense granule Thrombin generation Shape change  IIb  3  IIb  3 Fibrinogen  IIb  3 Aggregation Amplification Alpha granule Coagulation factors Inflammatory mediators TP  Coagulation GPVI Collagen ATP ATP P2X 1 ASPIRIN x TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x TICAGRELOR CANGRELOR GP IIb/IIIa ANTAGONISTS x x SCH 530348 E5555 x TERUTROBAN x HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN Thrombin x
    4. 4. P2Y 12 as a therapeutic target GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2 . Storey RF. Curr Pharm Des . 2006;12:1255-1259. Thromboxane A 2 5HT P2Y 12 ADP ADP ADP 5HT PLATELET ACTIVATION P2Y 1 5HT 2A PAR-1 PAR-4 Dense granule Thrombin generation Shape change  IIb  3  IIb  3 Fibrinogen  IIb  3 Aggregation Amplification Alpha granule Coagulation factors Inflammatory mediators TP  Coagulation GPVI Collagen ATP ATP P2X 1 TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x TICAGRELOR CANGRELOR Thrombin
    5. 5. Activation/inactivation of clopidogrel CYP = cytochrome P450. Farid NA, et al. Clin Pharmacol Ther. 2007;81:735-741. S N O Cl S O N O Cl N S H C O O H O Cl S N O H O Cl Clopidogrel CYPs Esterases CYPs 2-Oxo-clopidogrel R-130964 SR26334 (Inactive) OCH 3 OCH 3 OCH 3
    6. 6. 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: 250-258
    7. 7. VerifyNow P2Y12 assay
    8. 8. Multiplate MEA
    9. 9. Clinical outcomes according to platelet aggregometry results with MEA Sibbing, D. et al. JACC 2009; 53: 849-56
    10. 10. Sibbing, D. et al. Eur Heart J 2009 30:916-922 Clopidogrel, CYP 2C19 and stent thrombosis
    11. 11. Prasugrel
    12. 12. Comparison of prasugrel with higher dose clopidogrel P<0.0001 for each IPA (%; 20  M ADP) Hours 14 Days IPA (%; 20  M ADP) P<0.0001 Prasugrel 10 mg Clopidogrel 150 mg Wiviott et al Circ 2007 N=201 Prasugrel 60 mg Clopidogrel 600 mg
    13. 13. 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
    14. 14. 0 5 10 15 0 30 60 90 180 270 360 450 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 TRITON-TIMI study Balance of Efficacy and Safety CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 NNH = 167
    15. 15. TRITON-TIMI study Stent Thrombosis (ARC Definite + Probable) 0 1 2 3 0 30 60 90 180 270 360 450 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
    16. 16. TRITON Diabetic Subgroup 0 2 4 6 8 10 12 14 16 18 0 30 60 90 180 270 360 450 HR 0.70 P<0.001 Days Endpoint (%) CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 N=3146 17.0 12.2 Prasugrel Clopidogrel Prasugrel Clopidogrel 2.6 2.5
    17. 17. TRITON STEMI cohort P rimary EP (CV death, MI and stroke at 15 months) Montalescot et al. ESC 2008 Time (Days) 5 10 15 0 0 50 100 150 200 250 300 350 400 450 Proportion of patients (%) 9.5 6.5 12.4 10.0 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 (0.66-0.99)
    18. 18. TRITON Net Clinical Benefit Bleeding Risk Subgroups OVERALL >=60 kg < 60 kg < 75 >=75 No Yes 0.5 1 2 Prior Stroke / TIA Age Wgt Risk (%) + 37 -16 -1 -16 +3 -14 -13 Prasugrel Better Clopidogrel Better HR P int = 0.006 P int = 0.18 P int = 0.36 Post-hoc analysis
    19. 19. Ticagrelor The first oral reversible P2Y 12 antagonist
    20. 20. Time (hours) Onset Maintenance Offset 100 90 80 70 60 50 40 30 20 10 0 IPA % 0 .5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240  ONSET/OFFSET Study IPA with ADP 5uM (final extent) Gurbel PA et al. Circulation 2009 Ticagrelor 180mg LD / 90 mg bd (n=54) Clopidogrel 600mg LD / 75 mg od (n=50) * * * * * * * * * ‡ † †  
    21. 21. 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
    22. 22. Secondary efficacy endpoints over time 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 4,191 0 60 120 180 240 300 360 6 5 4 3 2 1 0 7 Cumulative incidence (%) Clopidogrel Ticagrelor 5.8 6.9 8,279 HR 0.84 (95% CI 0.75–0.95), p=0.005 0 60 120 180 240 300 360 6 4 3 2 1 0 Clopidogrel Ticagrelor 4.0 5.1 HR 0.79 (95% CI 0.69–0.91), p=0.001 7 5 9,291 9,333 8,865 8,294 8,780 8,822 8,589 Days after randomisation 7079 7119 5,441 5,482 4,364 4,419 8,626 Myocardial infarction Cardiovascular death Cumulative incidence (%)
    23. 23. Total major bleeding NS NS NS NS NS 0 K-M estimated rate (% per year) PLATO major bleeding 1 2 3 4 5 6 7 8 9 10 12 11 13 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 11.6 11.2 7.9 7.7 8.9 8.9 5.8 5.8 0.3 0.3 Ticagrelor Clopidogrel
    24. 24. Non-CABG and CABG-related major bleeding p=0.026 p=0.025 NS NS 9 K-M estimated rate (% per year) Non-CABG PLATO major bleeding 8 7 6 5 4 3 2 1 0 Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding 4.5 3.8 2.8 2.2 7.4 7.9 5.3 5.8 Ticagrelor Clopidogrel
    25. 25. PLATO - Dyspnoea *p values were calculated using Fischer’s exact test All patients Ticagrelor (n=9,235) Clopidogrel (n=9,186) p value * Dyspnoea, % Any With discontinuation of study treatment 13.8 0.9 7.8 0.1 <0.001 <0.001
    26. 26. PLATO Conclusions <ul><li>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 </li></ul><ul><ul><li>Reduction in myocardial infarction and stent thrombosis </li></ul></ul><ul><ul><li>Reduction in cardiovascular and total mortality </li></ul></ul><ul><ul><li>No change in the overall risk of major bleeding </li></ul></ul><ul><li>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 </li></ul><ul><li>Clinicians will need to learn how to identify and manage dyspnoea associated with ticagrelor </li></ul>
    27. 27. Cangrelor Intravenous reversible P2Y 12 antagonist
    28. 28. Inactivation by Dephosphorylation HO O OH OH N N N S F F F N HN S _ O _ P O _ O Cl Cl P O O O P O _ O O O OH OH N N N S F F F N HN S 4Na +
    29. 29. 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
    30. 30. Elinogrel Intravenous and oral reversible P2Y 12 antagonist
    31. 31. Elinogrel <ul><li>Reversible P2Y 12 inhibitor in phase 2/3 development </li></ul><ul><li>IV and oral formulations </li></ul><ul><li>Half-life ~12 hours </li></ul><ul><li>Competitive mechanism of action – competes with ADP for binding to receptor, greater IPA for low vs high concentrations of ADP </li></ul>
    32. 32. Targeting PAR-1
    33. 33. Targets for Platelet Inhibition GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2 . Storey RF. Curr Pharm Des . 2006;12:1255-1259. Thromboxane A 2 5HT P2Y 12 ADP ADP ADP 5HT PLATELET ACTIVATION P2Y 1 5HT 2A PAR-1 PAR-4 Dense granule Thrombin generation Shape change  IIb  3  IIb  3 Fibrinogen  IIb  3 Aggregation Amplification Alpha granule Coagulation factors Inflammatory mediators TP  Coagulation GPVI Collagen ATP ATP P2X 1 ASPIRIN x TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x TICAGRELOR CANGRELOR GP IIb/IIIa ANTAGONISTS x x SCH 530348 E5555 x TERUTROBAN x HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN Thrombin x
    34. 34. No significant compromise to haemostasis with SCH 530348 T-1 = SCH 530348 1 mg/kg T-2 = Aspirin (10 mg/kg) plus Clopidogrel (2 mg/kg) T-3 = SCH 530348, Aspirin plus Clopidogrel Cynomolgus monkey model. Chintala M et al. Arterioscl Thromb Vasc Biol. 2008; 28: e138–e139
    35. 35. TRACER Study Design Study started December 2007 Estimated study completion July 2011 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 530548 40 mg LD then 2.5 mg od Moderate- to High-Risk ACS patients (UA/NSTEMI, PCI, Medically-Managed, or CABG)
    36. 36. GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2 . Storey RF. Curr Pharm Des . 2006;12:1255-1259. Thromboxane A 2 5HT P2Y 12 ADP ADP ADP 5HT P2Y 1 5HT 2A PAR-1 PAR-4 Dense granule Thrombin generation Shape change  IIb  3  IIb  3 Fibrinogen  IIb  3 Aggregation Amplification Alpha granule Coagulation factors Inflammatory mediators TP  Coagulation GPVI Collagen ATP ATP P2X 1 ASPIRIN x TICLOPIDINE CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x TICAGRELOR CANGRELOR GP IIb/IIIa ANTAGONISTS x x SCH 530348 E5555 x TERUTROBAN x HEPARINS FONDAPARINUX BIVALIRUDIN RIVAROXABAN APIXABAN DABIGATRAN Thrombin x ? Questions

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