ARF6 Inhibitors for Treatment of Acute Lung Injury

PROJECT SUMMARYAcute lung injuryALIand acute respiratory distress syndromeARDSresult from a common pathogenic processpulmonary injury or infection triggers an overwhelming inflammatory responsecytokine stormthat results in increased endothelial and epithelial permeability and efflux of inflammatory cellsproteinand water from the vascular system into the alveolar spaceThe further release of inflammatory agents from damaged lung tissue often triggers systemic inflammatory response syndromeSIRSand end organ failurethe main cause of death in ALI ARDSALI and ARDS are precipitated by diverse etiologies including aspirationinhalation injurybacterial and viral pneumoniastraumaburn injuryblood transfusionsepsisand other factorsIn factbiologic and chemical warfare agents are often selected for their ability to cause the devastating effects of ALI ARDSThe incidence of ALI is estimated to be approximatelycases perperson yearsImprovements in outcome have come about over the past decade due to improved strategies of mechanical ventilation and advances in general supportive measuresUnfortunatelyeven todaythe treatment for those afflicted remains largely supportive with a mortality rate of approximatelyNavigen s objective is to develop a small molecule ARFinhibitor as a treatment for ALI ARDSIn Phase Iwe presented ARFas a target for treatment of ALI ARDSand we shared data establishing the potential therapeutic value of inhibiting ARFto treat ALI ARDSThe specific aims of our Phase I application were to identify a number of ARFinhibitors with required potency and solubilityto characterize the pharmacokineticPKproperties of a small number of these compoundsand to obtain convincing in vivo proof of concept efficacy in a mouse model of LPS induced ALIexploring both dose response relationships and time of treatment effectsWe accomplished these goals and identified five compounds of interestSince submitting our Phase II application in Januarywe have made significant progress and have identified a lead candidateNAVto carry forward into Phase IINAVis a water soluble lysine prodrugdihydrochloride saltof NAVitself one of the leadingcandidates identified in Phase INAVhas the advantage of high water solubilitymaking it amenable to formulation for intravenousIVadministration in the hospital setting for treatment of ALI ARDSNAVis cleaved rapidly to release parent NAVin vivoand is effective in the mouse model of LPSinduced ALI as well as in Acinetobacter baumanniiABinduced pneumonia in neutropenic miceOver the next two years in Phase IIwe propose to accomplish the followingdemonstrate efficacy of NAVin two rat models of ALI using accepted outcome measurescharacterize the in vitro ADME and in vivo PK properties of NAVconduct initial toxicity studies of NAVin ratsmanufacture NAVand optimize an aqueous formulation of NAVfor IV administrationandhold a pre IND meeting with the FDA