SCIKON INNOVATION, INC. — Department of Health and Human Services SBIR Phase II: 300

Description

Project Summary The high failure rate of drugs late in clinical development is an indication that nonclinical in vitro models and animal models are not accurately predicting compound performance in humansOnlyout ofmolecules identified by pharmaceutical companies as a potential drug candidate is successfully advanced through FDA approvalDrug toxicity in general and drug induced liver injuryDILIin particularrepresent the major cause of drug attrition or removal from the marketplaceThere is a critical gap between the need for predictive in vitro platforms to evaluate the effects of compounds on human health and the availability of solutions which meet the throughput and accuracy requiredTo meet this need for increased biological relevancethe next generation of toxicity testing is beginning to incorporate fluidics and more complex cellular models into in vitro compound safety and efficacy testingNon fluidicstatictissue culture plates have been a staple of the in vitro pharmaceutical testing market for decades and are the major model system used for liver safety testingHoweverstatic cell culture systems fail to generate biologically relevant gradient drug exposures and may lack the viability and metabolic competency essential for safety testingAdditionallythese static systems do not allow for discrimination between primary drug effects and those mediated by metabolic breakdown products or cellular responsesWhile these static systems afford a picture of the acute toxicity of the compound itselfthis picture is incompleteat bestand potentially leads to the progression of compounds with serious safety issues into animal studies and clinical trialsThese late stage failures come at huge financial costs to pharmaceutical companiescreating a significant need in the marketplace We have developed the SciFlowTMFluidic Culture System to address existing shortcomings in drug safety testingSciFlowis an innovativegravity drivenfluidic tissue culture system providing highly biologically relevant compound exposuresand an innate ability to distinguish between parent drug and metabolite effectsThe SciFlow System is based on a standardSBS compliantwell plate format with the addition of fluidic pathways connecting the wells along each row of the plateThis enables the evaluation of gradient compound concentrations on cellsunder dynamic one way fluidic conditions that are more representative of the in vivo environmentSciFlow is designed as an open platformsupporting the culture of many cell typesin both two dimensionalDand three dimensionalDformatsand in a more biologically relevant fashionTo validate its diverse culture capabilitiesSciFlow s compartments have been populated with cells representing a wide variety of phenotypes including primary liver cellshepatocyteshumandogratmouseetcand many diverse cell linesHepGHepaRGCacoetcPreliminary compound toxicity studies have been completedutilizing many biochemical and high content imaging assays to assess cellular outcomesThis proposal describes the development of an SOP to leverage the benefits of the SciFlowto provide improved drug induced liver injury predictionThe aims of this project are toOptimize existing exposure and assay protocols in the SciFlowUse optimized assays to test a library ofcompounds of known and varying DILI onliver cell modelsprimary human hepatocytesco cultures of primary human hepatocytes and non parenchymal cellsandHepaRG cellsUtilize that dataset to drive selection of a panel assays to include in a final SciFlow DILIpredictive SOPDemonstrate the capabilities of the SciFlow DILI predictive SOP in two blinded studiesThis work will be completed in collaboration with the UNC Eshelman School of Pharmacy Institute for Drug Safety SciencesThe outcomes of this study will be a complete solution for conducting predictive toxicology analyses on new drug candidates with previously unattainable levels of sensitivity and specificityThese accurate in vitro to in vivo extrapolationsIVIVEwill decrease the number of compounds with serious toxicity liabilities proceeding into the later pre clinical and early clinical drug developmentsaving pharmaceutical companies both time and money while enabling the ultimate goal of more rapidly providing safe and effective therapeutics