Clinical Evaluation of T3D-959 as a Potential Disease Remedial Therapeutic for the Treatment of Alzheimer's Disease

DESCRIPTION provided by applicant The purpose of the proposed project is to conduct a Phase a mechanistic clinical proof of concept study of an investigational drug T D which is being developed for the treatment of cognitive and functional decline in Alzheimerandapos s disease patients T D has successfully completed Phase I studies and with data demonstrating robust entry into the brain in a rat pharmacokinetic study T D is a novel orally delivered small molecule dual nuclear receptor agonist formerly targeted as a type diabetes therapy and now being re positioned as a potential disease modifying therapy for Alzheimerandapos s disease AD and mild cognitive impairment MCI The project goal is to test the hypothesis that T D can mechanistically act in the brain of AD patients to produce desired changes in glucose metabolism as measured by FDG PET and brain function as measured by BOLD fMRI These imaging modalities are currently being utilized as surrogate measures of potential efficacy in treating AD If T D treatment produces desired changes in glucose metabolism and brain function the drug could have disease remedial potential and this study could provide supportive clinical data that justifies the pursuit of longer term clinical studies of the potentia of T D to slow stop or reverse cognitive and functional decline in AD patients The clinical trial is an adaptive sequential enrollment design involving mild to moderate AD patients dosed orally once a day for weeks The project has key objectives i To determine the potential of T D to improve cerebral glucose metabolism CMRgl Low CMRgl is a hallmark of AD and a better predictor of future cognitive impairment than amyloid plaqe or tau bundle load ii To determine the potential of T D to improve memory related hippocampal functional connectivity resting state default mode network activity iii Determine appropriate doses for future clinical studies dose range finding The therapeutic approach to be tested is based on two suppositions A ameliorating multiple pathologies in the disease with a single therapy may provide a superior clinical benefit than therapeutic approaches which target a single pathology e g beta amyloid plaques and B correcting insulin resistance in the brain a key driver of AD pathophysiology may be disease remedial PUBLIC HEALTH RELEVANCE Alzheimerandapos s disease today is the costliest disease to the American healthcare system with no marketed drug therapies that can slow stop or reverse the course of this malady The purpose of the proposed project is to conduct a mechanistic proof of concept Phase a study of an investigational drug T D which has successfully completed Phase I The project aims to demonstrate that T D has the potential to be an effective disease remedial drug therapy for treating cognitive impairment in Alzheimerandapos s disease The therapeutic approach to be tested is based on two suppositions A ameliorating multiple defects in the disease with a single therapy may provide a superior clinical benefit than therapeutic approaches which target a single defect e g beta amyloid plaques and B correcting insulin resistance in the brain a key driver of Alzheimerandapos s disease pathophysiology may alter the course of disease