Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial of T3D-959 in Mild to Moderate Alzheimer's Disease Subjects

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T3D-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). T3D-959 is an orally delivered small molecule dual nuclear receptor agonist that works to restore and maintain metabolic homeostasis, which when altered in AD, leads to protein misfolding which causes plaque formation, tangle formation and inflammation. Exploratory human clinical test results (Phase 2a study) of T3D-959 in mild to moderate severity AD patients have shown multiple efficacy signals indicating a potential to slow, stop or reverse the course of disease. The next stage in clinical development of this drug is to validate these observed efficacy signals in a larger and longer Phase 2 clinical trial statistically powered to measure significant differences versus placebo in outcome measures of cognition, function, and biomarkers of disease. The Phase 2 randomized, placebo-controlled ‘PIONEER’ Study (Prospective therapy to Inhibit and Overcome Alzheimer’s Disease Neurodegeneration via Brain EnErgetics and Metabolism Restoration) is assessing multiple T3D-959 dose strengths vs. placebo (15mg, 30mg & 45mg QD and placebo in a 1:1:1:1 ratio) to identify the most safe and effective dose or doses to use in subsequent Phase 3 testing. The multi-center trial involves 256 mild to moderate AD patients (MMSE=14-26) dosed orally once-a-day for 24-weeks. Co-primary outcome measures include the ADAS- cog11 cognition and ADCS-CGIC global function measures. Secondary outcome measures include executive function as measured by DSCT and change from baseline in plasma Aβ 42/40 ratio. PIONEER began enrollment in February 2020. Six weeks later, amid a growing Covid-19 pandemic, all screening and randomization of new subjects was discontinued with 33 already-randomized subjects continuing their dosing (“Covid Cohort”). In early April, due to the insurmountable barriers to study conduct posed by the COVID-19 pandemic, the trial was halted with cessation of study medication dosing for all randomized subjects. After two attempted resumptions of the study, each thwarted by pandemic surges, PIONEER successfully re-started on March 1, 2021, under an amended protocol with trial adaptations in response to the pandemic (DSMB, NIA, IRB and FDA approved). A new CRO has been contracted and new U.S. clinical trial sites have been added to replace those lost due to the pandemic. The pandemic-elicited delay of ca. 13 months resulted in significant unpredicted ‘sunk’ costs . The requested Administrative Supplement (AS) funding will be utilized to ensure that PIONEER can be completed in its totality and within the original proposed timeline, despite the pandemic- related delay. Pandemic-related adaptations to the study have been implemented including Covid-19 testing of all subjects, new inclusion criteria (e.g., CDR-SOB >3.0 and expanding MMSE range from 16-26 to 14-26), all electronic data management (CRIO eSource and eRegulatory), reducing patient test burdens, addition of a pre-planned, blinded interim analysis, and incorporation of additional biomarker assessments.