CS6253 development for the treatment of apoE4 driven dementia includingAlzheimer's disease

Project summaryNo effective therapeutic modalities exist for Alzheimerandapos s diseaseADApoEallele is the number one genetic risk factor for AD increasing the riskfold in homozygotesbut the mechanism for the increased risk was not knownRecent reports advocate that apoEhas impaired cooperation with its lipidation protein the ATP Binding Cassette AABCAresulting in insufficient loading from glial cells to the apoEacceptor particleThe apoElipidation deficiency in turn is resulting in perturbed glial and neuron cell cholesterol homeostasisAaccumulationneuron degeneration and cognitive declineArtery TherapeuticsIncArteryhas focused more thanyears on developing ABCAagonistsoriginally as therapeutics for atherosclerotic cardiovascular diseaseABCApromotes cholesterol removal and helps maintain macrophageprotectivephenotypesThis results in atherosclerosis plaque reduction and stabilizationCSwas developed in a screening program and refocusing of the ABCAagonist program to brain penetrant therapeutics for apoEdementia including ADCSstabilizes ABCAand lowers the energy requirement for transferring cholesterol to apoEacceptor particles in a process involving oligomerization and cell membrane lipid rearrangementCSreduces Aplaque inx EFAD mice and prevents apoEdriven AD pathogenesis including intra neuronal Ain apoETR miceCSis a drugable molecule with a unique set of brain and plasma biomarkers of importance in translation to primate studiesCStreatment increases apoE receptor levels and reduces AD variables as Aand P tauCScauses statistically significant reductions in plasma apoJ CLU and neurofilament light indicating neuroprotection and shows unique changes in plasma and brain apoEOutside CNS CSreduces atherosclerosis and shows anti diabetic actionsThe favorable vascularmetabolic properties of CSmay contribute to protective effects in AD and in apoEnon chronic conditions as traumatic brain injurychemo brain and vascular complicationsWe propose a phasein which development feasibility is tested in non GLP NHP studiesPKmaximum toleratedsingledosedose range finding toxicologywith concomitant assessment of target engagement and other biomarkersNHPs have more similar lipid metabolism and BBB properties to humans than rodentsProvided phaseresults meet the pre defined go no go criteria for development feasibility a phasewill ensuePhaseincludes an IND enabling program with AD biomarker assessments to make CSready for clinical trials in humans with and without apoEproviding biomarker proof of conceptArtery is a San Francisco based small business entity with patents licensed from LBNLand ongoing collaborations under MTA with academic groups and pharma companiesArtery has the medical expertiseexperience and drug development network to successfully execute the suggested phaseand phase!Project narrativeApoEdriven Alzheimerandapos s disease is the leading cause of dementiaIt is characterized by an impaired cooperation between apoEand its lipidation proteinthe ATP Binding Cassette AABCAtransporter which a novel ABCAagonist CScan correctFollowing feasibility testing in monkeys IND enabling studies are performed to make Cready for human testing