Development of a robust quantitative systems pharmacology model of amyloid beta and tau pathways for clinical trial design and decision making in Alzheimer's Disease and Dementia.

Project Summary Abstract Inthere were an estimatedmillion Americans living with Alzheimerandapos s DiseaseADat an annual healthcare cost of $billionAlzheimer s AssociationAD is characterized by accumulation of insoluble forms of amyloidAin brain interstitium and aggregation of the microtubule protein tau in neurofibrillary tangles in neuronsThe development of anti Atherapies is the leading effort for pharmaceutical industry for disease modificationHoweverdespite significant effort in research and developmentfromtoof the clinical trials of disease modifying treatments for Alzheimer s Disease have failedWhat is worse is the fact that in most cases it could not be conclusively decided whether these trials failed due tothe overall trial designthe specific mechanism of action of the drug candidateor the invalidity of the underlying scientific hypothesisKarranToynAs a consequence of the failure of anti Atrialsthere has been a shift to conduct studies with subjects at earlier stages of disease before clinical symptoms appear as well as a new focus on anti tau therapiesFor theanti Adrug candidates that currently remain in Phase I to III clinical trialsas well as those in preclinical developmentand all the anti tau therapies under developmentthere is an urgent need for tools and techniques that improve clinical decision makingand decrease the extremely high failure rateWe propose to build a computational quantitative systems pharmacologyQSPmodel for Abeta and tau disease related biology that captures their changes with different disease states sporadic AD patients and in the context of the autosomal dominant mutations in ADAD patientsThis model will integrate data and scientific knowledge gained in the pastThe model will also include drug disposition and distribution into the brain and mechanisms of action for the selected drugs with parameters calibrated against their clinical dataThis platform model can be expanded in the future to include additional drug sof interest to pharmaceutical developersWe anticipate the Aand Tau platform model will be used by pharmaceutical and biotech companies currently engaged inor contemplating clinical trials in AD to inform the design of future clinical trialsDevelop a quantitative mechanistic understanding of past clinical failuresInform preclinical and clinical biomarker strategiesThe ultimate goal is to help speed the delivery of novel therapeutics for AD patients Project Narrative Fromtoof the clinical trials of disease modifying treatments for Alzheimer s Disease have failedWe propose to develop a detailed computational model of Alzheimer s Disease that maximize our learning from past clinical failuresand guides future clinical trials to increase their success rateIf successfulthis work will have a significant impact on the costs and time to develop novel therapeutics in this critical area of unmet medical need and may help to bring better drugs to patients