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Summary

APT102 represents a new paradigm for acute anti-thrombotic therapy; an approach that will decrease peri-procedural myocardial infarction and bleeding and thereby decrease long-term morbidity and mortality. APT102 is unique from current antiplatelet agents in structure, mechanism of action, anti-inflammatory and cardioprotective activity, and bleeding risk. It is expected to provide additional antithrombotic and cardioprotective efficacy when used alone, or as adjunctive therapy with other antithrombotic or thrombolytic agents, without increasing bleeding risk.



Clinical Need

Dual anti-platelet inhibition with aspirin and clopidogrel has been shown to result in a reduction in cardiovascular events in a variety of settings. Attempts to improve outcomes further have led to the development of more potent antiplatelet agents, but at a cost of increased bleeding complications. Net clinical adverse outcomes, which incorporate adverse cardiovascular events and major bleeding, remain as high as 7-12% in patients treated for myocardial infarction. Furthermore, long-term morbidity and mortality are dramatically increased in patients experiencing peri-procedural myocardial infarction or bleeding. Consequently, the search for an fast-acting antiplatelet agent with optimal ischemic protection and an acceptable bleeding risk remains the 'holy grail' of antiplatelet drug development.
 

Product

APT102 is a recombinant form of human apyrase; optimized as an anti-platelet and anti-inflammatory agent with an undetectable risk of bleeding. APT102 is the only recombinant human apyrase currently available that is appropriate for pharmaceutical development. Preclinical pharmacology has identified the following key attributes of APT102:
  • Strong antithrombotic efficacy
  • No evidence of bleeding
  • Anti-inflammatory efficacy
  • Cardioprotection from reperfusion injury
  • Rapid onset of action
  • 20-40 hour pharmacodynamic half-life after a single i.v. or s.c. dose

APT102 inhibits platelet activation and aggregation almost immediately upon i.v. administration and provides nearly complete platelet inhibition for at least 24 hr in dogs after a single bolus intravenous injection. APT102 demonstrated in vitro antiplatelet activity and in vivo antithrombotic efficacy in several well-characterized animal models of coronary thrombosis and stroke. Importantly, in every model evaluated, APT102 provided antithrombotic efficacy without increasing bleeding risk, even when administered in combination with other antithrombotic agents. APT102 also ameliorates ischemia/reperfusion injury and inflammatory response in several animal models, including lung transplantion.

Scientific publications

APT 102

1. J S, Broekman M, Mitsky T, Chen R, Marcus A. Antithrombotic Activity of a Novel Engineered Human Apyrase. Enzymatic Profile, Ex Vivo and In Vivo Properties. Blood. 104: abstract 530, 2004. Oral presentation.
2. Medina C, Jurasz P, Santos-Martinez MJ, J S, Mitsky T, Chen R.D. Radomski M. (2006). Platelet aggregation-induced by Caco-2 cells: Regulation by matrix metalloproteinase-2 and adenosine diphosphate. J. Pharmacol. Exp Ther. 317, 379-345.
3. Uluckan O, Eagleton M, Floyd D, Morgan E, Hirbe AC, Kramer M, Dowland N, Prior JL, Piwnica-Worms, J S, Chen R, Weilbaecher K (2008). APT102, a novel ADPase cooperates with aspirin to disrupt bone metastasis in mice. J Cellular Biochem. 104: 1311-1323.
4. Sugimoto S, Lin X, Lai J, Okazaki M, Das N, Li W, Krupnick A, Chen R, J S, Patterson GA, Kreisel D, Gelman AD (2009). Apyrase treatment prevents ischemia-reperfusion injury in rat lung isografts. J Thorac Cardiovasc Surg. 138: 752-759, 2009.
5. Wang C, Shabanzadeh AP, He C, Pegg CC. APT102 protects the ischemically injured brain in rats. Neuroscience 2010 meeting. Nov 14. Oral presentation.
6. Guanghua Sun, Xiurong Zhao, James Grotta, Sean Savitz, C Chen, Jaroslaw Aronowski. Apyrase, APT102, improves the rt-PA beneficial effect in thromboembolic stroke model. American Heart Association International stroke conference. Feb 9, 2011. Poster presentation.
7. Douglas Moeckel, Pamela Baum, Annie Nguyen, J S, R Chen, Dana Abendschein. A novel human apyrase prevents reocclusion and substantially decreases infarct size without bleeding prolongation after coronary fibrinolysis in dogs. Arteriosclerosis, thrombosis and vascular biology 2011 scientific sessions of American Heart Association. April 28, 2011. Oral presentation.
8. Ibrahim M, Wang X, Puyo CA, Montecalvo A, Huang HJ, Hachem RR, Andreetti C, Menna C, Chen R, Krupnick AS, Kreisel D, Rendina EA, Gelman AE. Human recombinant apyrase therapy protects against canine pulmonary ischemia-reperfusion injury. Heart Lung Transplant. 2014 (in press).
9. Moeckel D, Jeong SS, Sun X, Broekman MJ, Nguyen A, Drosopoulos JH, Marcus AJ, Robson SC, Chen R, Abendschein D. Optimizing human apyrase to treat arterial thrombosis and limit reperfusion injury without increasing bleeding risk. SciTransl Med. 248:248ra105. 2014.
10. Tan Z, Li X, Turner RC, Logsdon AF, Lucke-Wold B, DiPasquale K, Jeong SS, Chen R, Huber JD, Rosen CL. Combination treatment of r-tPA and an optimized human apyrase reduces mortality rate and hemorrhagic transformation 6h after ischemic stroke in aged female rats. Eur J Pharmacol. 738:368-73. 2014.

Human apyrases

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