Multi-functional anti-thrombotic therapy for coronary microvascular obstruction

Principal Investigator/Program Director (Last, First, Middle: Chen, Ridong
ABSTRACT
Adjunctive antithrombotic treatment with dual antiplatelet therapy (aspirin + P2Y12 antagonist) plus
anticoagulant (heparin or bivalirudin) is an established treatment regimen for percutaneous coronary intervention
(PCI) patients. Despite aggressive antithrombotic therapy, myocardial perfusion after PCI remains inadequate
in many patients. Recurrent thrombosis and dose-limiting bleeding complications continue to occur in a
significant number of patients. Attempts to further improve clinical outcomes have led to the development of
more potent platelet P2Y12 inhibitors including prasugrel and ticagrelor, and direct factor Xa inhibitors,
rivaroxaban and apixaban (not approved for PCI), but increase bleeding complications. Moreover, none of the
current antithrombotics provide effective protection against coronary microvascular obstruction. This results in
microinfarcts accompanied by inflammation, which is a determinant of patient prognosis, independent from
infarct size. Clearly, the next milestones for acute AMI treatment are to break the link between antithrombotic
potency and bleeding risk and to protect the myocardium and coronary microcirculation against reperfusion injury
that causes chronic adverse left ventricle remodeling and heart failure.
APT402 is a novel therapeutic fusion protein of an optimized human apyrase and annexin V that provides
antiplatelet, anticoagulant, and cardioprotective activities. We hypothesize that the fusion will target the
antithrombotic effect to the site of coronary thrombosis and synergistically attenuate thrombosis and reperfusion
injury with minimal bleeding risk. In a rabbit carotid artery electrical injury model, APT402 preferably bound to
the injured site and to the thrombus. Treatment with clopidogrel, ticagrelor, low molecular weight heparin, or
bivalirudin alone failed to fully prevent occlusion with significantly increased bleeding. In contrast, APT402
maintained 100% patency without increasing bleeding time, PT, or aPTT. Strikingly, APT402 more effectively
attenuated arterial thrombosis than ticagrelor plus bivalirudin. In this direct Phase II SBIR application, we propose
to determine whether acute treatment with APT402 more effectively protects microvascular circulation and
improves heart function in a clinically relevant model of thrombogenic myocardial infarction, while reducing
bleeding risks compared to ticagrelor plus heparin, the standard-of-care treatment during PCI in the
contemporary era of radial access. We have also assembled an experienced drug development team and will
advance critical activities necessary to enable IND filing.
Specific Aim 1. Using a porcine model of thrombogenic coronary microembolization, determine whether
APT402 more effectively reduces coronary microvascular obstruction and improves LV function 60 days after
reperfusion with less bleeding compared to ticagrelor plus heparin.
Specific Aim 2. Manufacture cGMP grade APT402.
Specific Aim 3. Evaluate nonclinical safety of APT402.
Successful completion of the proposed studies will strongly support IND filing and clinical trials to improve
outcomes for millions of patients with acute myocardial infarction and other thrombotic diseases.

Grant Number: 5R44HL169132-03
NIH Institute/Center: NIH
Principal Investigator: RIDONG CHEN