A Novel Disease Modifying Therapy for Progression of Pulmonary Arterial Hypertension

Abstract Vasculonicsan Indiana based small business is developing a novel approach to reduce progression of pulmonary arterial hypertensionPAHVasculonics technology is a novel modulator of dimethylarginine dimethylaminohydrolaseDDAHwhich reduces asymmetric dimethyl arginineADMAand vascular pathology in PAHHigh levels of ADMA and reduced DDAH occur in patients and preclinical models of PAHIn addition to reducing nitric oxideNOsynthesishigh levels of ADMA induce mitochondrial dysfunctioncell deathinflammation and fibrosisPersistent high ADMA levels can contribute to the progressive vascular remodeling observed in PAHThe proof of concept that restauration of DDAH is therapeutic has been achieved by overexpression of DDAH gene which lowered ADMAimproved endothelial function and modified the pathology in the lungVasculonics is developing a pharmacological approach using a small molecule modulator of DDAH to reduce pathological levels of ADMA and reduce the progressive vasculopathy in PAHVasculonics has identified VNas a drug candidate which enhances transcription of DDAHin a promoter luciferase based screenIn a preclinical model of PAHVNhas shown robust efficacy by reducing occlusion of lung arteriesand improving lung and cardiac functionsVNis a novel molecule acting via a new mechanism for reducing vascular pathology in PAHIn order to advance VNto clinical phaseVasculonics will complete the following aims in phaseSBIRIn aimwe will test the dose dependent efficacy of VNon reducing progression of PAHIn preliminary studiesVNwas tested in the rat model of MCT induced PAH when delivered at the time of disease onsetThereforewe will test efficacy on disease progression in a highly rigorous Sugen hypoxia modelTreatment with VNwill beginweeks after disease onsetEfficacy will be determined afterweeks by using the end points of pulmonary artery pressureechocardiographyhistology and markers of vascular remodelingIn Aimwe will test efficacy of VNon top of a current vasodilator drug sildenafil to demonstrate its efficacy on disease progression in the settings similar to treatment in humansThe end points for efficacy in Sugen hypoxia model will be the same as listed in AimAt the end of Phase IVasculonics will have confirmed efficacy of VNin a model of PAH progressionand its efficacy on top of a vasodilator therapyThe Phase II efforts will focus on IND enabling CMCpharmacokinetics and safety studiesA significant market exists for PAH therapy with an estimated value in excess of $billion Project NarrativePulmonary arterial hypertension is a highly debilitating and fatal diseaseCurrent therapies targeted to the mechanisms of vasodilation reduce the symptoms of the disease and do not significantly impact disease progressionThe mortality of PAH patients remains highVasculonics is developing a novel approach to reduce disease progression and improve survival of PAH patients