The PIONEER Study: A Multi‐center, Randomized, Double‐blind, Placebo‐controlled Phase 2 Trial of the Effects of T3D‐959 on Safety, Cognition, Function and Plasma Biomarkers in Mild to Moderate Alzheimer’s Disease Subjects: Study Update.

Abstract

AbstractBackgroundT3D‐959 is a novel (non‐amyloid/non‐tau‐directed) new chemical entity aimed at improving dysfunctional brain glucose energy and lipid metabolism in Alzheimer’s disease (AD). Dysfunctional brain metabolism in AD results from increasing resistance to insulin. Insulin resistance contributes to amyloid plaque formation, tau tangle formation and inflammation. T3D‐959, a brain‐penetrant, small molecule dual nuclear receptor agonist, acts as an insulin sensitizer to overcome insulin resistance to restore and maintain metabolic homeostasis.MethodPIONEER is a randomized, double‐blind, placebo‐controlled, Phase 2 trial involving 256 mild to moderate AD patients (MMSE = 14‐26) dosed orally once‐a‐day for 24‐weeks in 4 parallel arms (T3D‐959 15mg, 30mg, 45mg and placebo QD in a 1:1:1:1 ratio). Co‐primary outcome measures include the ADAS‐cog11 cognition and global function ADCS‐CGIC measures. Secondary outcome measures include DSCT and plasma Aβ 42/40 ratio. Exploratory outcome measures include plasma NfL tau, ptau217 and ptau181, apathy as measured by the NPI, expressive language function as measured by CFT, physical activity as measured by RAPA, plasma metabolomic and proteomic biomarkers and change in absolute regional, and whole brain, cerebral metabolic rate for glucose (CMRgl) as assayed by FDG‐PET.ResultPIONEER commenced in March 2021. The study is two‐thirds enrolled and ongoing [See ClinicalTrials.gov identifier NCT04251182]. Blinded, grouped, summary cognitive and functional endpoint data, as well safety data will be presented and discussed.ConclusionPIONEER is designed to evaluate the efficacy and safety of multiple dose strengths of T3D‐959 in patients with mild to moderate severity AD. Topline results are expected in 2023.