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: Rationale and study design

Background Dysfunctional glucose and lipid metabolism are key drivers underlying pathological pathways ultimately resulting in Alzheimer’s disease (AD). T3D‐959 is a small molecule, orally delivered, brain penetrating, novel PPAR delta agonist with 15‐fold lower PPAR gamma potency that acts to maintain homeostasis of glucose and lipid metabolism. Ubiquitous brain expression of PPAR‐delta, its critical role in regulating glucose and lipid metabolism and phenotype of PPAR‐delta null mice, coupled with a promising safety profile and multiple efficacy signals in an exploratory Phase 2a clinical trial (NCT02560753) in patients with mild‐to‐moderate AD, provide the foundation for the next Phase 2 clinical trial, the PIONEER Study [Prospective therapy to Inhibit and Overcome Alzheimer's Disease Neurodegeneration via Brain EnErgetics and Metabolism Restoration]. Methods PIONEER is a randomized, double‐blind, placebo‐controlled, Phase 2 trial involving 256 mild to moderate AD patients (MMSE=16‐26) dosed orally once‐a‐day for 24‐weeks in 4 parallel arms (T3D‐959 active arms of 15mg, 30mg and 45mg QD and a placebo arm in a 1:1:1:1 ratio). Co‐primary outcome measures include the ADAS‐cog11 cognition and global function CGIC measures. Secondary and exploratory outcome measures include change from baseline in plasma Aβ 42/40 ratio, NfL and tau between subjects treated with T3D‐959 compared to placebo, evaluation of the effect of T3D‐959 compared with placebo on apathy as measured by the NPI, on functional decline as measured with ADCS‐ADL, on executive function as measured using the DSCT, on verbal fluency, on plasma metabolomic and proteomic biomarkers and change in absolute regional, and whole brain, cerebral metabolic rate for glucose (CMRgl) as assayed by FDG‐PET. Results Cognitive and functional endpoints, as well safety data will be presented and discussed. Conclusions PIONEER is designed to evaluate the efficacy and safety of multiple dose strengths of T3D‐959 in patients with mild to moderate severity AD.