T3D-959: A multi-faceted disease remedial drug candidate for the treatment of Alzheimer's disease

Abstract

T3D-959, a dual nuclear receptor agonist and former diabetes drug candidate has been repositioned as an Alzheimer's disease (AD)-modifying therapy. The ability of the Phase 1-completed drug to act in a multi-faceted manner to improve multiple AD pathologies was tested in vivo and ex vivo in a rat model of AD. The unique combination of mechanisms of action, PPAR delta as primary target and PPAR gamma as a secondary target, convey distinctive efficacy and safety profiles. Intracerebral (i.c.) streptozotocin (STZ)-exposed rats were used as an in vivo model of sporadic AD. Ex vivo studies of these animals used hippocampal/temporal lobe brain slice cultures for evaluating the effects of T3D-959. Twenty four hours after i.c. STZ treatment rat pups are sacrificed and brain slice cultures established for 24h prior to drug administration for 48h (0.5-1.0uM). In vivo studies involved dosing animals therapeutically after i.c. STZ exposure at 0.3 to 3.0mg/kg/d via oral gavage for 28d. Ex vivo results demonstrated significant improvements in neuronal cell survival, oxidative stress and brain morphology with nearly complete restoration of cortical architecture. Significant decreases in phospo-tau and restoration of beta amyloid peptide to normal levels was also observed. These ex vivo improvements in AD pathologies translated in vivo, with T3D-959 significantly improving both cognitive and motor function impairments, i.e. spatial learning and memory in the Morris water maze test and motor function in rotarod testing. Pre-clinical proof of concept has been demonstrated that T3D-959 can improve multiple pathologies of AD resulting in significant improvements in cognitive and motor function, two key impairments in AD. These results support two theses; (1) that effective disease modification in AD will require multiple pathologies be improved in concert, nuclear receptors as a target class provide that potential, and (2) treating AD as a metabolic disease has the potential to be disease remedial. A Phase 2a trial of T3D-959 in mild-to-moderate AD patients has been initiated.