HLS- Factor XII Inhibitor for Surface Initiated Thrombosis

DESCRIPTIONprovided by applicantThis Phase I II Fast Track application is being re submitted under the NHLBI Small Business Topics of Special Interest for Fiscal YearHLSCertain life saving interventions such as cardiopulmonary bypassCPBextracorporeal membrane oxygenationECMOor ventricular assist deviceVADpump require the use of high dose heparin to maintain blood flow through the devices and or to prevent downstream thromboembolic complicationsSeveral other invasive vascular procedures also utilize profound temporal anticoagulationsuch as during and after prosthetic vascular graft implantationUnfortunatelyantithrombotic agents such as heparin inadvertently target vital hemostatic molecular mechanisms and can produce severe dose limiting hemorrhagic toxicityConsequentlythe level of anticoagulation must be limited to balance the risk of bleeding with thrombosisAs a resultthrombotic complications can be frequent and devastatingOur recent studies suggest that coagulation factor XIIFXIIcontributes to the progression of thrombosisand thereby is a potential target for a new class of antithrombotic drugsSince data suggests that FXII does not contribute to hemostasisand FXII deficiency is an asymptomatic condition in mammalsFXII inhibition is unlikely to have significant adverse effectsWe have generated a proprietary murine monoclonal antibodyHagainst human FXII that was created by immunizing FXII knockout miceand verified its anticoagulant and antithrombotic effects in preliminary primate experimentsThis proposed Phase I II Fast Track project will initiate the commercial development of a recombinant humanized version ofHrhHa product candidate that could be used as a stand alone or as an adjuvant anticoagulant to increase the antithrombotic efficacy of heparin without further increasing heparin associated bleeding risksThe Specific Aims for this project that will be necessary to supportHdevelopment towards an investigational new drugINDapplication are toEvaluate the antithrombotic effect of the murine anti FXII antibodyHin a primate model of experimental extracorporeal membrane oxygenationECMODetermine the activity and efficacy of recombinant humanizedHrhHandManufacture rhHfor use in GLP toxicity studiesThe rhHapproach represents a fundamentally new therapeutic anticoagulation concept since FXII inhibition is expected to reduce the formation of contact initiated blood clots in synthetic grafts and extracorporeal devices without a detrimental effect on residual bleeding control in critically illanticoagulated patientsSuccess of this project and reaching our critical milestones will lead directly to the next stage of product development that will consist of GLP toxicity and stability studiesIND preparation and filingfollowed by the initiation of phasefirstin human safety studies of our innovative antithrombotic drug candidate