IN‐VIVO EVALUATION OF APN‐1808, A TAU SMALL MOLECULE THERAPEUTIC

Abstract

AbstractBackgroundThe high value for Alzheimer’s Disease and other taupathies of a small molecule treatment that can alter disease course is widely acknowledged. We aim to investigate such a therapeutic by leveraging our small molecule CNS aggregated protein discovery platform.MethodOur small molecule discovery platform consists of our proprietary small molecule collection, unique PET imaging biomarkers and cryoEM structures. Our proprietary collection of CNS‐focused aggregated protein binding agents, previously developed by APRINOIA to map the structure‐activity relationship of its tau PET tracer programs, was screened for tau binding and further interrogated for other desirable properties such as selectivity and oral availability. Further efforts derived guidance from the cryoEM structure of our lead compound bound to Tau aggregates. These efforts resulted in our small molecule lead compound APN‐1808.Using rTg4510 mice, which over express 4R tau, we first investigated dose‐response by using in‐vivo PET imaging to measure percent occupancy of APN‐1808. Upon selecting an appropriate dose range, we engaged in 90 day, twice a day dosing of APN‐1808 in rTg4510 mice.ResultMice dosed with APN‐1808 showed improvements both biochemically and phenotypically over vehicle controls. Improvements included increase in synaptic protein level, reduction in overall tau burden, reduction in weight loss and other behavioral observations.ConclusionSeveral readouts showed improvement in the dosed groups compared to controls, including increase of synapse level, reduction of weight loss and reduction of total tau. Further investigations are ongoing.