Antithrombotic Therapy with No Bleeding Risk for PCI

Adjunctive antithrombotic treatment with dual antiplatelet therapyaspirinP Yantagonistplus anticoagulantheparin or bivalirudinis a guideline mandated for percutaneous coronaryinterventionPCIpatientsDespite aggressive antithrombotic therapyhowevermyocardialperfusion after PCI remains inadequate in many patientsReocclusion from recurrent thrombosiscontinues to occurand dose limiting bleeding occurs in a significant minority of patientsAttempts to further improve clinical outcomes have led to the development of more potent plateletP Yinhibitors including prasugrel and ticagrelorand direct factor Xa inhibitorsrivaroxabanand apixabannot approved for PCIbut also increase bleeding complicationsMoreovernone ofthe current antithrombotics provide effective protection against reperfusion injurydefined asmyocardial damage caused by the restoration of coronary blood flow after occlusionReperfusioninjury accounts for up toof the final size of a myocardial infarcta major determinant forsubsequent mortality and morbidityIn patients undergoing PCIthe composite endpoint of adversecardiovascular events atdays after reperfusion remains as high asMeanwhilepatients suffer major bleedingThe vast majority of these adverse events occur within the firsthours post interventionClearlybeyond optimizing reperfusion therapythe next milestone is tobreak the link between antithrombotic potency and bleeding risk and protect the myocardium againstmicrovascular obstruction and necrosis that causes adverse left ventricle remodeling and heartfailure inof treated patientsAPTis a novel therapeutic fusion protein comprised of both antiplatelet and anticoagulantactivitiesWe hypothesize that fusion will target the antithrombotic effect to the site ofcoronary thrombosis and additively synergistically attenuate thrombosis and reperfusion injury withminimal bleeding riskIn the carotid electrical vascular injury model in rabbitswe observedAPTpreferably bound to injured siteand thrombusTreatment with clopidogrellow molecularweight heparinLMWHenoxaparinor bivalirudinAngiomaxdirect and reversible thrombininhibitorconsidered the safest FDA approved anticoagulantalone failed to fully preventocclusion with significantly increased bleedingIn contrastAPTmaintainedpatencywithout increasing bleeding timePTaPTTor insertion site hemorrhageIn this fast track SBIRapplicationwe will determine whether hyperacute treatment with APTis more effective toattenuate thrombosis and protect hearts in a highly clinically relevant porcine model of PCIwithout increasing bleeding compared to the standard of care treatment with a P Yantagonistplus anticoagulantSpecific AimProduce APTto support the proposed animal studiesPhase Iand establish a GLPCHO cell line for future cGMP manufacturingPhase IISpecific AimPhase ITo determine minimal effective dose and maximal tolerable dose in theelectrical injury model of arterial thrombosis in rabbitsSpecific AimPhase IITo determine in a porcine model of coronary thrombosis and PCI whetherAPTis more effective and safe to prevent recurrent arterial thrombosis and decrease reperfusioninjury withindays than P Yantagonist plus anticoagulant infusion We will determine whether treatment with a novel thrombus targeting fusion protein comprised ofboth antiplatelet and anticoagulant activities is more effective to attenuate thrombosis andprotect hearts in an established porcine model of percutaneous coronary intervention withoutincreasing bleeding complications compared to the standard of care treatment with a P Yantagonist plus anticoagulant