Clinical Development Enablement – Long Term Rodent Testing of the Carcinogenic Potential of the Alzheimer’s Disease Drug Candidate T3D-959

T3D-959 is a new chemical entity, orally delivered, small molecule, dual nuclear receptor agonist aimed at improving dysfunctional brain glucose energy and lipid metabolism in Alzheimer’s disease (AD), it is non- amyloid/non-tau-directed. Metabolic homeostasis, inherently altered in AD, leads to protein misfolding resulting in 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. 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 is in progress and will complete in early 2023. This Phase 2 randomized, double-blind, placebo- controlled ‘PIONEER’ Study 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. With the trial 75% completed preliminary results of blinded data, grouped as a single average of the 3 drug strength arms and placebo arm, show potential improvement in all 3 measures of cognition, function, and executive function, even before one subtracts out placebo data at trial conclusion and un-blinding. With an anticipated successful Phase 2 clinical trial on the horizon, it becomes prudent to conduct FDA-required, non-clinical trial studies necessary for initiation of Phase 3 clinical trials and New Drug Application submission (NDA for market approval) in alignment with the application’s broad, long-term objective to advance the development of T3D-959 to market in the most expeditious manner possible. The application’s goal is to examine the long-term carcinogenic potential of T3D-959 in rats per FDA guidelines as indicated in ICH guidance S1A for investigational new drugs, which requires 2 years of dosing in a least one rodent species (preferably rats) prior to market approval. The objectives of carcinogenicity studies are to identify a tumorigenic potential in animals and to assess the relevant risk in humans. The practice of requiring carcinogenicity studies in rodents was instituted for pharmaceuticals that are expected to be administered regularly, continuously over a period of at least 6 months (i.e., a substantial part of a patient's lifetime).