Factor XI inhibitor for thrombosis

Project Summary Although potent antithrombotic agents are availableall of these drugs inadvertently target vital hemostatic molecular mechanismsresulting in dose limiting hemorrhagic toxicity that restrict their useDue to a lack of safe thromboprophylaxisthrombotic blood vessel occlusions continue to be extremely prevalentand result in a wide range of severe disease conditions that remain the leading causes of death and severe chronic disability in the U SConsequentlythere is a significant and urgent unmet medical need for a safer antithrombotic treatment that is effective when used alone or can safely improve the efficacy of existing antithrombotic drugsThe proposed research will continue the development of our uniqueand highly specific humanized anti factor XIFXImonoclonal antibodyAXIMABtermed xisomabGfor the safe prevention and treatment of thrombosisWe have already reached and exceeded our Phase II SBIR milestones byDemonstrating that the humanized AXIMABGbinds to FXI and inhibits baboon and human FXI procoagulant activity in vitroand that doses as low asmg kg are antithrombotic in disease modelsProducinggrams ofGformulated and sterile filledwith ongoing shelf life stabilitymonths atCandDetermining the no observed adverse effect levelNOAELforGin GLP grade toxicity studieswhich was found to be andgtfold above the maximum anticipated pharmacological effect doseThese data have led to the submission of Aronoraandapos s first investigational new drugINDapplication to the FDAwhich was subsequently accepted on MaythOur phasefirst in human study began on Junethwith no adverse events associated withGnoted in the first dosing cohortmg kgThis Phase IIB Bridge Awardcombined with our secured matching fundswill provide essential support for continued product development towards advanced proof of concept clinical studiesThe specific aim for this project is to initiate a phasea clinical trial evaluating the safety and early antithrombotic efficacy of xisomabGin end stage renal diseaseESRDpatients on hemodialysisHDThe milestone for success will be to demonstrate that the FXI antibody xisomabGis safe in this small group of hemodialysis patients when incorporated into the standard hemodialysis procedureThe xisomabGapproach represents a fundamentally new anticoagulation concept since the contribution of FXI and the contact system to pathological coagulation appears to far outweigh its role in normal hemostasisThereforeGcould be an effective antithrombotic strategy that is exceptionally safeSuccess of this Phase IIB research and achievement of our critical and final milestone will lead directly into the next stage of product development consisting of licensing our drug candidate to Bayer AGwho will take on the ultimate responsibility of performing subsequent and definitive trials in HD and other indications to the benefit of patients who are in desperate need of safe thromboprophylaxis Project Narrative While anticoagulant drugsblood thinnersimprove the outcome of blood clot related diseasese gheart attackstrokevenous thrombosisor procedurese gkidney dialysiscardiopulmonary bypasstheir usefulness is compromised by potentially severe bleeding related side effectsConsequentlythere remains an urgent unmet medical need for safer anticoagulant treatmentsThe proposed research addresses this need by continuing the clinical development of a new antithrombotic drug candidatexisomabGwhich has been shown in definitive primate studies to potently inhibit blood clot formation without increasing bleedingand thus may safely enhance the effectiveness of current anticoagulants or provide a safe and effective treatment alternative