SBIR-STTR Award

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 Aß 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).

Public Health Relevance Statement:
PROJECT NARRATIVE This research advances the development to market of a new therapeutic drug, T3D-959, that could enhance the health and reduce disability of Alzheimer's patients, which in turn, could significantly reduce the healthcare cost burden of Alzheimer's disease (AD). The innovative approach, educed by T3D-959, to improving cognition and function through correction of dysfunctional brain metabolism inherent in the disease, will enhance our knowledge of AD pathogenesis and provide insights into new avenues for AD drug development.

Project Terms:
AD dementia; Alzheimer Type Dementia; Alzheimer disease dementia; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimers Dementia; Primary Senile Degenerative Dementia; primary degenerative dementia; senile dementia of the Alzheimer type; Alzheimer's Disease; Animals; Carcinogenicity Tests; Carcinogen Tests; Carcinogenesis Tests; Carcinogenic Activity Tests; Carcinogenic Potency Tests; Tumorigenicity Tests; Cognition; Disease; Disorder; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Energy Metabolism; Energy Expenditure; Equilibrium; balance; balance function; Goals; Health; Homeostasis; Autoregulation; Physiological Homeostasis; Human; Modern Man; Inflammation; Marketing; United States National Institutes of Health; NIH; National Institutes of Health; Patients; Placebos; Sham Treatment; sham therapy; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Rattus; Common Rat Strains; Rat; Rats Mammals; Research; research and development; Development and Research; R & D; R&D; Research Design; Study Type; study design; Risk; Rodent; Rodentia; Rodents Mammals; Safety; Signal Transduction; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; statistics; Tissues; Body Tissues; Work; Amyloid beta-Protein; Alzheimer beta-Protein; Alzheimer's Amyloid beta-Protein; Alzheimer's amyloid; Amyloid Alzheimer's Dementia Amyloid Protein; Amyloid Beta-Peptide; Amyloid Protein A4; Amyloid ß; Amyloid ß-Peptide; Amyloid ß-Protein; Aß; a beta peptide; abeta; amyloid beta; amyloid-b protein; beta amyloid fibril; soluble amyloid precursor protein; Measures; Health Costs; Healthcare Costs; Health Care Costs; measurable outcome; outcome measurement; Outcome Measure; Blinded; Guidelines; improved; Area; Clinical; Phase; Multi-center trial; Multicenter Trials; Nuclear Receptors; Ensure; disability; insight; Funding; Agonist; Toxicokinetics; Phase 2 Clinical Trials; phase II protocol; Phase II Clinical Trials; Phase 3 Clinical Trials; phase III protocol; Phase III Clinical Trials; Metabolic; Knowledge; Life; Severities; Oral; Protocols documentation; Protocol; Test Result; brain metabolism; glucose metabolism; success; lipid metabolism; fat metabolism; Agreement; Pathogenesis; Reporting; Drug Exposure; carcinogenicity; drug development; executive function; executive control; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; small molecule; CD3D gene; CD3D; T3D; Dose; Data; Randomized; randomisation; randomization; randomly assigned; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Radiolabeled; radiolabeling; radiologically labeled; Placebo Control; placebo controlled; pre-clinical; preclinical; aberrant protein folding; abnormal protein folding; pathologic protein folding; protein misfolding; Advanced Development; designing; design; tangle formation; neurofibrillary tangle formation; Outcome; tumorigenic; innovate; innovative; innovation; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; tumor; primary outcome; secondary outcome; bio-markers; biologic marker; biomarker; Biological Markers; drug candidate; arm; abnormal brain function; brain impairment; dysfunctional brain; brain dysfunction; clinical development; phase 3 evaluation; phase III evaluation; phase III testing; phase 3 testing; data deposition; data submission; Alzheimer's patient; patient living with Alzheimer's disease; patient suffering from Alzheimer's disease; patient with Alzheimer's; patient with Alzheimer's disease; Alzheimer's disease patient; new chemical entity