Targeted Therapeutics for Liver Disease

Project Abstract The blossoming diabetesobesity and metabolic syndrome epidemics have taken a toll on the North American liverThe incidence and prevalence of non alcoholic fatty liver diseaseNAFLDwhose genesis is in simple steatosisand non alcoholic steatohepatitisNASHare staggeringLeft untreatedNASH can progress to NASH with increasing levels of fibrosiscirrhosis and hepatocellular carcinomaHCCThis disease continues to present a challenge to the gastroenterologist who has fewif anycombat ready tools at his her disposalWhile a number of promising agents are in clinical trials in NASHnone has met approvalLiver disease is a chronic indication that will necessitate a long course of therapywhich brings with it the attendant risk of drug related side effectsThe proposed program seeks to advance a highly targeted therapeuticthat is bothpotentially effectiveand potentially safefor the treatment of NASHThis program is based on new information on the biology governing liver fibrosisvizthe Rho associated coiled coil kinaseROCKhepatic stellate cellHSCfibrosisROCKHSC fibrosisaxis and the synthesis of ANGa proprietaryorally bioavailablesmall molecule inhibitor that can potentially interrupt this cascadeUnder the aegis of this SBIR Phase I applicationwe will first obtain a profile of ANGpharmacokineticsPKand its exposure ICrelationshipSpecific AimIn Specific Aimwe will use these data to evaluate the efficacy of ANGin two etiologically distinct models of liver diseaseUnlike the first generation of dual ROCKandampinhibitorsit is anticipated that a selective ROCKinhibitor will not only prove efficacious in mitigating fibrosis but will also carry a lower risk of any side effects associated with chronic dosing Project Narrative The proposed drug discovery and development program seeks to advance a highly targetedand thereforepotentially efficacious and safe therapeutic for the treatment of non alcoholic steatohepatitis