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

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Exploratory human clinical test results (Phase 2a study) of the investigational new drug T3D-959 in mild to moderate severity Alzheimer's disease patients have shown multiple efficacy signals indicating a potential to slow, stop or reverse the course of Alzheimer's disease (AD). The next stage in the development of this drug to eventual market is establishing clinical proof of concept (PoC) to validate these observed efficacy signals by testing in T3D-959 in a larger and longer second Phase 2 human clinical trial. The objective of the proposed project is to execute and complete this PoC study of T3D-959 in AD patients. The clinical trial will be a randomized, double-blind, placebo-controlled, multi-center Phase 2 trial (RCT) involving 120 mild to moderate AD patients dosed orally once-a-day for 24-weeks in 2 parallel arms (T3D-959 30mg active arm and a placebo arm in a 1:1 ratio). Co-primary outcome measures will include the ADAS-cog11 cognition measure and global function CDR-SB measure. Secondary and exploratory outcome measures will include the ADCS-ADL measure of activities of daily living and FDG-PET neuroimaging. Based on ADAS-cog11 data in the completed exploratory study, this RCT is 80% powered for significance; α=0.05, assuming an effect of a 4-point difference vs. placebo at 24-weeks, and a standard deviation of 7.8 pts. T3D-959 is being developed as a potential disease-modifying agent for the treatment of cognitive and functional decline in AD patients. In addition to the exploratory/feasibility Phase 2a clinical study in mild to moderate AD subjects, T3D-959 has successfully completed Phase I studies in normal individuals with an excellent safety and tolerability profile. In the non-placebo-controlled, dose range finding Phase 2a trial in 34 mild to moderate AD patients dosed orally once-a-day for 2-weeks with varying doses of T3D-959, there was observed; (a) rapid, high magnitude, durable improvement in ADAS-cog11 with a significant ApoE genotype association to response, (b) improvement in DSST (Digit Symbol Substitution Test), a second measure of executive function and (c) FDG-PET neuroimaging showing; (i) T3D-959 penetrated the brain to effect changes in glucose metabolism, (ii) T3D-959 increased glucose metabolism in the brain, (iii) a dose dependency to FDG-PET outcomes, (iv) T3D-959 may increase relative glucose metabolism in all AD-vulnerable regions of the brain prototypically glucose hypometabolic, (v) ApoE genotype influence on the effect of T3D-959 on relative glucose metabolism. There were no observed safety or tolerability issues. T3D-959 is a small molecule new chemical entity, orally delivered, dual nuclear receptor agonist and the first PPAR delta-activating compound to be developed for the treatment of AD. Uniquely, this drug also activates PPAR gamma (at 15-fold lower potency) which may provide potential additive or synergistic effects in regulating dysfunctional brain glucose energy and lipid metabolism in AD. PPAR delta and PPAR gamma are central regulators of glucose energy and lipid homeostasis.