Pharmacology and clinical trials of reversibly-binding P2Y12 inhibitors

Robert F. Storey

doi:10.1160/THS10-12-0769

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 105(S 06): S75-S81
DOI: 10.1160/THS10-12-0769

Thrombosis and Haemostasis Supplement

Schattauer GmbH

Pharmacology and clinical trials of reversibly-binding P2Y12 inhibitors

Authors

Robert F. Storey

¹Department of Cardiovascular Science, University of Sheffield, Sheffield, UK

Abstract

Summary

The important role of the P2Y12 receptor in amplification of platelet activation and associated responses and the limitations associated with clopidogrel therapy have led to the development of novel inhibitors of this receptor. Three reversibly-binding P2Y12 inhibitors are in phase 3 development, ticagrelor, cangrelor and elinogrel. The pharmacology and clinical trial data for each of these inhibitors are discussed and compared with relevant data for the thienopyridines clopidogrel and prasugrel.

Keywords

ADP receptors - antiplatelet agents - arterial thrombosis - platelet pharmacology - antiplatelet drugs

Full Text

References

References
1 Storey RF. Biology and pharmacology of the platelet P2Y12 receptor. Curr Pharm Des 2006; 12: 1255-1259.
2 Solum NO. Procoagulant expression in platelets and defects leading to clinical disorders. Arterioscler Thromb Vasc Biol 1999; 19: 2841-2846.
3 Daniel JL, Dangelmaier C, Jin J. et al. Molecular basis for ADP-induced platelet activation: I. Evidence for three distinct ADP receptors on human platelets. J Biol Chem 1998; 273: 2024-2029.
4 Storey RF, Sanderson HM, White AE. et al. The central role of the P2T receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol 2000; 110: 925-934.
5 Hechler B, Leon C, Vial C. et al. The P2Y1 receptor is necessary for adenosine-5’-diphosphate-induced platelet aggregation. Blood 1998; 92: 152-159.
6 Hechler B, Eckly A, Ohlmann P. et al. The P2Y1 receptor, necessary but not sufficient to support full ADP-induced platelet aggregation, is not the target of the drug clopidogrel. Br J Haematol 1998; 103: 858-866.
7 Trumel C, Payrastre B, Plantavid M. et al. A key role of adenosine diphosphate in the irreversible platelet aggregation induced by the PAR-1 activating peptide through the late activation of phosphoinositide 3-kinase. Blood 1999; 94: 4156-4165.
8 Cattaneo M, Lombardi R, Zighetti ML. et al. Deficiency of (33P)2MeS-ADP binding sites on platelets with secretion defect, normal granule stores and normal thromboxane A2 production: evidence that ADP potentiates platelet secretion independently of the formation of large platelet aggregates and thromboxane A2 production. Thromb Haemost 1997; 77: 986-990.
9 Ramstrom S, Ranby M, Lindahl TL. Effects of inhibition of P2Y1 and P2Y12 on whole blood clotting, coagulum elasticity and fibrinolysis resistance studied with free oscillation rheometry. Thromb Res 2003; 109: 315-322.
10 Goto S, Tamura N, Eto K. et al. Functional Significance of Adenosine 5’-Diphosphate Receptor (P2Y12) in Platelet Activation Initiated by Binding of von Wille-brand Factor to Platelet GP Ib{alpha} Induced by Conditions of High Shear Rate. Circulation 2002; 105: 2531-2536.
11 Foster CJ, Prosser DM, Agans JM. et al. Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs. J Clin Invest 2001; 107: 1591-1598.
12 Andre P, Delaney SM, LaRocca T. et al. P2Y12 regulates platelet adhesion/activation, thrombus growth, and thrombus stability in injured arteries. J Clin Invest 2003; 112: 398-406.
13 Goto S, Tamura N, Ishida H. et al. Dependence of Platelet Thrombus Stability on Sustained Glycoprotein IIb/IIIa Activation Through Adenosine 5’-Diphosphate Receptor Stimulation and Cyclic Calcium Signaling. J Am Coll Cardiol 2006; 47: 155-162.
14 Patil SB, Jackman LE, Francis SE. et al. Ticagrelor effectively and reversibly blocks murine platelet P2Y12-mediated thrombosis and demonstrates requirement for sustained P2Y12 inhibition to prevent subsequent neointima. Arterioscler Thromb Vasc Biol 2010; 30: 2385-2391.
15 Judge HM, Buckland R, Sugidachi A. et al. Relationship between degree of P2Y12 receptor blockade and inhibition of P2Y12-mediated platelet function. Thromb Haemost 2010; 103: 1210-1217.
16 Van Giezen JJJ, Nilsson L, Berntsson P. et al. Ticagrelor binds to human P2Y12 independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation. J Thromb Haemost 2009; 7: 1556-1565.
17 Storey RF, Husted S, Harrington RA. et al. Inhibition of Platelet Aggregation by AZD6140, A Reversible Oral P2Y12 Receptor Antagonist, Compared With Clopidogrel in Patients With Acute Coronary Syndromes. J Am Coll Cardiol 2007; 50: 1852-1856.
18 Gurbel PA, Bliden KP, Butler K. et al. Response to Ticagrelor in Clopidogrel Nonresponders and Responders and Effect of Switching Therapies: The RESPOND Study. Circulation 2010; 121: 1188-1199.
19 Storey RF, Wilcox RG, Heptinstall S. Comparison of the pharmacodynamic effects of the platelet ADP receptor antagonists clopidogrel and AR-C69931MX in patients with ischaemic heart disease. Platelets 2002; 13: 407-413.
20 Gurbel P, Bliden K, Antonino M. et al. The effect of elinogrel on high platelet reactivity during dual antiplatelet therapy and the relation to CYP 2C19*2 genotype: first experience in patients. J Thromb Haemost 2009; 8: 43-53.
21 Springthorpe B, Bailey A, Barton P. et al. From ATP to AZD6140: The discovery of an orally active reversible P2Y12 receptor antagonist for the prevention of thrombosis. Bioorgan Med Chem Lett 2007; 17: 6013-6018.
22 Gurbel PA, Bliden KP, Butler K. et al. Randomized Double-Blind Assessment of the ONSET and OFFSet of the Antiplatelet Effects of Ticagrelor versus Clopidogrel in Patients with Stable Coronary Artery Disease: The ONSET/OFFSET Study. Circulation 2009; 120: 2577-2585.
23 Storey RF, Angiolillo D, Patil S. et al. Inhibitory Effects of Ticagrelor Compared to Clopidogrel on Platelet Function in Patients with Acute Coronary Syndromes: the PLATO PLATELET Substudy. J Am Coll Cardiol 2010; 56: 1456-1462.
24 Wiviott SD, Trenk D, Frelinger AL. et al. Prasugrel Compared With High Loading-and Maintenance-Dose Clopidogrel in Patients With Planned Percutaneous Coronary Intervention: The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation Thrombolysis in Myocardial Infarction 44 Trial. Circulation 2007; 116: 2923-2932.
25 Butler K, Teng R. Pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of ticagrelor in healthy volunteers. Br J Clin Pharmacol 2010; 70: 65-77.
26 Teng R, Butler K. Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y<sub>12</sub> receptor antagonist, in healthy subjects. Eur J Clin Pharmacol 2010; 66: 487-496.
27 Husted S, Emanuelsson H, Heptinstall S. et al. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J 2006; 27: 1038-1047.
28 Storey R, Bliden K, Patil S. et al. Earlier recovery of platelet function after treatment cessation in ticagrelor-treated patients compared to clopidogrel high responders. European Society of Cardiology Annual Congress; 2010; Stockholm, Sweden; 2010.
29 Tantry US, Bliden KP, Wei C. et al. First Analysis of the Relation Between CYP2C19 Genotype and Pharmacodynamics in Patients Treated With Ticagrelor Versus Clopidogrel: The ONSET/OFFSET and RESPOND Genotype Studies. Circul Cardiovasc Genet. 2010 prepublished online.
30 Bjorkman J-A, Kirk I, van Giezen JJ. Abstract 245: AZD6140 Inhibits Adenosine Uptake Into Erythrocytes and Enhances Coronary Blood Flow After Local Ischemia or Intracoronary Adenosine Infusion. Circulation. 2007 116: II_28-c.
31 Wang K, Zhou X, Huang Y. et al. Adjunctive treatment with ticagrelor, but not clopidogrel, added to tPA enables sustained coronary artery recanalisation with recovery of myocardium perfusion in a canine coronary thrombosis model. Thromb Haemost 2010; 104: 609-617.
32 Ingall AH, Dixon J, Bailey A. et al. Antagonists of the platelet P2T receptor: a novel approach to antithrombotic therapy. J Med Chem 1999; 42: 213-220.
33 van Giezen JJJ, Humphries RG. Preclinical and Clinical Studies with Selective Reversible Direct P2Y12 Antagonists. Sem Thromb Haemost 2005; 31: 195-204.
34 Storey RF, Oldroyd KG, Wilcox RG. Open multicentre study of the P2T receptor antagonist AR-C69931MX assessing safety, tolerability and activity in patients with acute coronary syndromes. Thromb Haemost 2001; 85: 401-407.
35 Greenbaum AB, Grines CL, Bittl JA. et al. Initial experience with an intravenous P2Y12 platelet receptor antagonist in patients undergoing percutaneous coronary intervention: Results from a 2-part, phase II, multicenter, randomized, placebo-and active-controlled trial. Am Heart J 2006; 151: 689.e1-e10.
36 Steinhubl SR, Oh JJ, Oestreich JH. et al. Transitioning patients from cangrelor to clopidogrel: Pharmacodynamic evidence of a competitive effect. Thromb Res 2008; 121: 527-534.
37 Dovlatova N, Jakubowski J, Sugidachi A. et al. The reversible P2Y12 antagonist cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to produce irreversible inhibition of platelet function. J Thromb Haemost 2008; 6: 1153-1159.
38 Buckland R, Judge H, Sugidachi A. et al. Reversible binding of cangrelor to the P2Y12 receptor prevents the binding of clopidogrel and prasugrel active metabolites. XXII Congress of the International Society on Thrombosis and Haemostasis 2009. Thromb Haemost. 2009 7 (Suppl. 2): Abstract PP-TH-030.
39 Judge HM, Patil SB, Buckland RJ. et al. Potentiation of clopidogrel active metabolite formation by rifampicin leads to greater P2Y12 receptor blockade and inhibition of platelet aggregation following clopidogrel. J Thromb Haemost 2010; 8: 1820-1827.
40 Bouman HJ, Parlak E, Van Werkum JW. et al. Which platelet function test is suitable to monitor clopidogrel responsiveness? A pharmacokinetic analysis on the active metabolite of clopidogrel. J Thromb Haemost 2010; 8: 482-488.
41 Ueno M, Rao SV, Angiolillo DJ. Elinogrel: pharmacological principles, preclinical and early phase clinical testing. Future Cardiol 2010; 6: 445-453.
42 Storey RF, Bliden K, Patil SB. et al. Incidence of Dyspnea and Assessment of Cardiac and Pulmonary Function in Patients with Stable Coronary Artery Disease Receiving Ticagrelor, Clopidogrel or Placebo in the ONSET/OFFSET Study. J Am Coll Cardiol 2010; 56: 185-193.
43 Cannon CP, Husted S, Harrington RA. et al. 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 Syndrome: Primary Results of the DISPERSE-2 Trial. J Am Coll Cardiol 2007; 50: 1844-1851.
44 Wallentin L, Becker RC, Budaj A. et al. Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes. N Engl J Med 2009; 361: 1045-1057.
45 James S, Åkerblom A, Cannon CP. et al. Comparison of Ticagrelor, the first reversible oral P2Y12 receptor antagonist, with clopidogrel in patients with acute coronary syndromes: rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial. Am Heart J 2009; 157: 599-605.
46 Cannon CP, Harrington RA, James S. et al. Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study. Lancet 2010; 375: 283-293.
47 James S, Budaj A, Aylward P. et al. Ticagrelor Versus Clopidogrel in Acute Coronary Syndromes in Relation to Renal Function. Results From the Platelet Inhibition and Patient Outcomes (PLATO) Trial. Circulation 2010; 122: 1056-1067.
48 Hulot J-S, Bura A, Villard E. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood 2006; 108: 2244-2247.
49 Taubert D, von Beckerath N, Grimberg G. et al. Impact of P-glycoprotein on clopidogrel absorption. Clin Pharmacol Ther 2006; 80: 486-501.
50 Wallentin L, James S, Storey RF. et al. Effect of CYP2C19 and ABCB1 single nucleotide polymorphisms on outcomes of treatment with ticagrelor versus clopidogrel for acute coronary syndromes: a genetic substudy of the PLATO trial. Lancet 2010; 376: 1320-1328.
51 Storey RF, Becker R, Harrington R. et al. Increased incidence of dyspnoea associated with ticagrelor did not appear to adversely affect cardiovascular outcomes in the PLATO study. European Society of Cardiology Annual Congress; 2010; Stockholm, Sweden; 2010.
52 Scirica B, Cannon C, Emanuelsson H. et al. The Incidence of Arrhythmias and Clinical Arrhythmic Events in Patients with Acute Coronary Syndromes Treated with Ticagrelor or Clopidogrel in the PLATO Trial. J Am Coll Cardiol. 2010 55: A108.E1006.
53 James S, Angiolillo DJ, Cornel JH. et al. Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2010 prepublished online.
54 Harrington RA, Stone GW, McNulty S. et al. Platelet Inhibition with Cangrelor in Patients Undergoing PCI. N Engl J Med 2009; 361: 2318-2329.
55 Bhatt DL, Lincoff AM, Gibson CM. et al. Intravenous Platelet Blockade with Cangrelor during PCI. N Engl J Med 2009; 361: 2330-2341.
56 Berger JS, Roe MT, Gibson CM. et al. Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: The Early Rapid ReversAl of Platelet ThromboSis with Intravenous Elinogrel before PCI to Optimize REperfusion in Acute Myocardial Infarction (ERASE MI) pilot trial. Am Heart J 2009; 158: 998-1004.e1.
57 Leonardi S, Rao SV, Harrington RA. et al. Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y12-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATE-PCI). Am Heart J 2010; 160: 65-72.
58 Rao SV. The INNOVATE PCI study. American Heart Association Annual Scientific Sessions. 2010 Chicago, USA; 2010; Available at http://spoescardioorg/es lides/viewaspx?eevtid=40&fp=2036.
59 Wiviott SD, Braunwald E, Angiolillo DJ. et al. Greater Clinical Benefit of More Intensive Oral Antiplatelet Therapy With Prasugrel in Patients With Diabetes Mellitus in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel-Thrombolysis in Myocardial Infarction 38. Circulation 2008; 118: 1626-1636.
60 Montalescot G, Wiviott SD, Braunwald E. et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009; 373: 723-731.
61 Mega JL, Close SL, Wiviott SD. et al. Genetic variants in ABCB1 and CYP2C19 and cardiovascular outcomes after treatment with clopidogrel and prasugrel in the TRITON-TIMI 38 trial: a pharmacogenetic analysis. Lancet. 2010 in press.
62 Wiviott S, Braunwald E, McCabe C. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001-2015.
63 Gurbel PA, Bliden KP, Hayes KM. et al. The Relation of Dosing to Clopidogrel Responsiveness and the Incidence of High Post-Treatment Platelet Aggregation in Patients Undergoing Coronary Stenting. J Am Coll Cardiol 2005; 45: 1392-1396.
64 Held C, Åsenblad N, Bassand JP. et al. Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes Undergoing Coronary Artery Bypass Surgery: Results From the PLATO (Platelet Inhibition and Patient Outcomes) Trial. J Am Coll Cardiol. 2011 in press.
65 Serebruany VL. Mortality in the TRITON Trial: Update from the FDA Prasugrel Action Package. Am J Cardiol 2010; 105: 1356-1357.