Specific antidotes in development for reversal of novel anticoagulants: A review

Recent Patents on Cardiovascular Drug Discovery

Volumn 9, Issue 1, 2014, Pages 2-10

  Gómez Outes, Antonio ^a   Suárez Gea, Ma L ^a   Lecumberri, Ramón ^b   Terleira Fernández, Ana I ^c,d   Vargas Castrillón, Emilio ^c,d  

^a Parque Empresarial Las Mercedes   (Spain)

^b UNIVERSITY CLINIC OF NAVARRA   (Spain)

^c HOSPITAL CLÍNICO SAN CARLOS   (Spain)

^d UNIVERSIDAD COMPLUTENSE DE MADRID   (Spain)

Author keywords

Andexanet alfa; Anivamersen; Anticoagulant; Antidote; Aripazine; Idarucizumab

Indexed keywords

ANDEXANET ALFA; ANIVAMERSEN; ANTICOAGULANT AGENT; ANTIDOTE; ARIPAZINE; BLOOD CLOTTING FACTOR 10A INHIBITOR; DABIGATRAN; FONDAPARINUX; IDARUCIZUMAB; LOW MOLECULAR WEIGHT HEPARIN; PEGNIVACOGIN; UNCLASSIFIED DRUG; APIXABAN; CIRAPARANTAG; EDOXABAN; PROTAMINE; RIVAROXABAN;

ANTICOAGULANT THERAPY; ARTICLE; BLOOD CLOTTING TIME; CLINICAL TRIAL (TOPIC); DRUG EFFECT; DRUG METABOLISM; HUMAN; IN VIVO STUDY; MEMBRANE BINDING; META ANALYSIS; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVERSAL REACTION; SYSTEMATIC REVIEW; ANIMAL; CHEMICALLY INDUCED; DRUG DESIGN; HEMORRHAGE; PATENT; THROMBOEMBOLISM; ANTICOAGULATION; BLEEDING; DISEASE SEVERITY; EXTRACORPOREAL CIRCULATION; HEART SURGERY; MULTICENTER STUDY (TOPIC); PHARMACOLOGICAL PARAMETERS; PHASE 4 CLINICAL TRIAL (TOPIC); REVIEW;

ANIMALS; ANTICOAGULANTS; ANTIDOTES; DRUG DESIGN; HEMORRHAGE; HUMANS; PATENTS AS TOPIC; THROMBOEMBOLISM;

EID: 84922329536     PISSN: 15748901     EISSN: 22123962     Source Type: Journal    
DOI: 10.2174/1574890109666141205132531     Document Type: Article

References (38)

1. [1] Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3(11): e442.
2. [2] Gómez-Outes A, Suárez-Gea ML, Calvo-Rojas G, Lecumberri R, Rocha E, Pozo-Hernández C, et al. Discovery of anticoagulant drugs: a historical perspective. Curr Drug Discov Technol 2012; 9(2): 83-104.
3. [3] European Medicines Agency. Pradaxa ®—summary of product characteristics. 2014. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Information/human/000829/WC500041059.pdf (Accessed on: September 19, 2014)
4. [4] European Medicines Agency. Xarelto ®—summary of product characteristics. 2014. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Information/human/000944/WC500057108.pdf (Accessed on: September 19, 2014)
5. [5] European Medicines Agency. Eliquis ®—summary of product characteristics. 2014. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_Product_Information/human/002148/WC500107728.pdf (Accessed on: September 19, 2014)
6. [6] Lip GY, Agnelli G. Edoxaban: a focused review of its clinical pharmacology. Eur Heart J 2014; 35(28): 1844-55.
7. [7] Suryanarayan D, Schulman S. Potential antidotes for reversal of old and new oral anticoagulants. Thromb Res 2014; 133(2 SUPPL): S158-S166.
8. [8] Gómez-Outes A, Suárez-Gea ML, Lecumberri R, Rocha E, Pozo-Hernández C, Vargas-Castrillón E. New parenteral anticoagulants in development. Ther Adv Cardiovasc Dis 2011; 5(1): 33-59.
9. [9] Schiele F, van Ryn J, Canada K, Newsome C, Sepulveda E, Park J, et al. A specific antidote for dabigatran: Functional and structural characterization. Blood 2013; 121(18): 3554-62.
10. [10] Grottke O, Honickel M, Van RJ, Rossaint R, ten Cate H, Spronk H. A specific antidote to dabigatran reduces blood loss in dabigatranand trauma-induced bleeding in pigs. J Am Coll Cardiol 2014; 63(12): A295 (abstract).
11. [11] Toth J, Gan G, Van RJ, Dursema H, Isler J, Coble K, et al. Reversal of dabigatran's anticoagulant activity in the monkey by a specific antidote and pharmacokinetic and pharmacodynamic modeling. Blood 2012; 120(21): 22 (abstract).
12. [12] Glund S, Stangier J, Schmohl M, De Smet M, Gansser D, Lang B, et al. A specific antidote for dabigatran: immediate, complete and sustained reversal of dabigatran induced anticoagulation in healthy male volunteers. Circulation 2013; 128: A17765 (abstract).
13. [13] Van RJ, Schmoll M, Pillu H, Gheyle L, Brys J, Moschetti V, et al. Effect of dabigatran on the ability to generate fibrin at a wound site and its reversal by idarucizumab, the antidote to dabigatran, in healthy volunteers: an exploratory marker of blood loss. Circulation 2014; 130: A18403 (abstract).
14. [14] Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013, 19(4): 446-51.
15. [15] Hollenbach SJ, Lu G, DeGuzman F, Tan S, Pratinkhya P, Pandey A, et al. Andexanet-alfa and PER977 (Aripazine) correct blood loss in a rabbit liver laceration model - only andexanet reverses markers of fXa-mediated anticoagulation. Circulation 2014; 130: A14657 (abstract).
16. [16] Crowther M, Levy G, Lu G, Conley PB, Castillo J, Hollenbach S, et al. Reversal of enoxaparin-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for direct and indirect FXa inhibitors - a phase 2 randomized, double-blind, placebo-controlled trial. J Thromb Haemost 2014; 12(1 SUPPL): COA01 (abstract).
17. [17] Crowther M, Mathur V, Kitt M, Lu G, Conley PB, Hollenbach S, et al. A phase 2 randomized, double blind, placebo-controlled trial demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), an antidote for Fxa inhibitors. Blood 2013; 122(21): 3636 (abstract).
18. [18] Crowther M, Kitt M, Lorenz T, Mathur V, Lu G, Hutchaleelaha A, et al. A phase 2 randomized, double-blind, placebo-controlled trial of PRT064445, a novel, universal antidote for direct and indirect factor Xa inhibitors. J Thromb Haemost 2013; 11(2 SUPPL): AS201 (abstract).
19. [19] Crowther M, Lu G, Conley P, Hollenbach S, Castillo J, Lawrence J, et al. Sustained reversal of apixaban anticoagulation with andexanet alfa using a bolus plus infusion regimen in a phase 2 placebo controlled trial. Eur Heart J 2014; 35(1 SUPPL): P738 (abstract).
20. [20] Portola Pharmaceuticals. Andexanet alfa: FXa Inhibitor Antidote. Available at: http://www.portola.com/clinical-development/andexanet-alfa-prt4445-fxa-inhibitor-antidote/ (Accessed on: September 20, 2014).
21. [21] Laulicht B, Bakhru S, Lee C, Baker C, Jiang X, Mathiowitz E, et al. Small molecule antidote for anticoagulants. Circulation 2012; 126: A11395 (abstract).
22. [22] Laulicht B, Bakhru S, Jiang X, Chen L, Pan D, Grosso M, et al. Antidote for new oral anticoagulants: mechanism of action and binding specificity of PER977. J Thromb Haemost 2013; 11(SUPPL.S2): AS 471 (abstract).
23. [23] Bakhru S, Laulicht B, Jiang X, Chen L, Grosso M, Morishima Y, et al. Reversal of anticoagulant-induced bleeding in external and internal bleeding models by PER977, a small molecule anticoagulant antidote. Circulation 2014; 130: A19361 (abstract).
24. [24] Ansell JE, Bakhru SH, Laulicht BE, Steiner SS, Grosso M, Brown K, et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 2014; DOI: 10.1056/NEJMc1411800.
25. [25] Dyke CK, Steinhubl SR, Kleiman NS, Cannon RO, Aberle LG, Lin M, et al. First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity. Circulation 2006; 114: 2490-7.
26. [26] Vavalle JP, Cohen MG. The REG1 anticoagulation system: a novel actively controlled factor IX inhibitor using RNA aptamer technology for treatment of acute coronary syndrome. Future Cardiol 2012; 8(3): 371-82.
27. [27] Vavalle JP, Rusconi CP, Zelenkofske S, Wargin WA, Ortel TL, Alexander JH, et al. The effect of the REG2 Anticoagulation System on thrombin generation kinetics: a pharmacodynamic and pharmacokinetic first-in-human study. J Thromb Thrombolysis 2014; 38(3): 275-84.
28. [28] Becker RC, Povsic T, Cohen MG, Rusconi CP, Sullenger B. Nucleic acid aptamers as antithrombotic agents: Opportunities in extracellular therapeutics. Thromb Haemost 2010; 103: 586-95.
29. [29] Cohen MG, Purdy DA, Rossi JS, Grinfeld LR, Myles SK, Aberle LH, et al. First clinical application of an actively reversible direct factor IXa inhibitor as an anticoagulation strategy in patients un dergoing percutaneous coronary intervention. Circulation 2010; 122(6): 614-22.
30. [30] Chan MY, Rusconi CP, Alexander JH, Tonkens RM, Harrington RA, Becker RC. A randomized, repeat-dose, pharmacodynamic and safety study of an antidote-controlled factor IXa inhibitor. J Thromb Haemost. 2008; 6(5):789-96.
31. [31] Povsic TJ, Vavalle JP, Aberle LH, Kasprzak JD, Cohen MG, Mehran R, et al. A Phase 2, randomized, partially blinded, activecontrolled study assessing the efficacy and safety of variable anticoagulation reversal using the REG1 system in patients with acute coronary syndromes: results of the RADAR trial. Eur Heart J 2013; 34(31): 2481-9.
32. [32] Povsic TJ, Vavalle JP, Alexander JH, Aberle LH, Zelenkofske SL, Becker RC, et al. Use of the REG1 anticoagulation system in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the phase II RADAR-PCI study. EuroIntervention 2014; 10(4): 431-8.
33. [33] Regado Biosciences. Press Release, 25th August 2014. Available at: http://regadobio.investorroom.com/2014-08-25-RegadoBiosciences-Permanently-Halts-REGULATE-PCI-Clinical-Trial (Accessed on: September 20, 2014)
34. [34] Dittmer, F., Buchmüller, A., Gerdes, C., Tersteegen, A., Gnoth, M., Linden, L., Harrenga, A., Grudzinska, J., Jeske, M., Schaefer, M., Birkenfeld, J., Paulsen, H., Finnern, R., Mayer-Bartschmid, A. Binding proteins to inhibitors of coagulation factors. WO2012098089A1 (2012).
35. [35] Keefe AD, Pai S, Ellington A. Aptamers as therapeutics. Nat Rev Drug Discov 2010; 9(7): 537-50.
36. [36] Teoh KH, Young E, Blackall MH, Roberts RS, Hirsh J. Can extra protamine eliminate heparin rebound following cardiopulmonary bypass surgery? J Thorac Cardiovasc Surg 2004; 128: 211-9.
37. [37] Lee FM, Chan AK, Lau KK, Chan HH. Reversal of new, factorspecific oral anticoagulants by rFVIIa, prothrombin complex concentrate and activated prothrombin complex concentrate: a review of animal and human studies. Thromb Res 2014; 133(5): 705-13.
38. [38] Ansell J. Factor Xa or thrombin: is factor Xa a better target? J Thromb Haemost 2007; 5(1 SUPPL): 60-4.