GMP Production of a Tau Oligomer Inhibitor to Enable Clinical Development forADRD

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Modified Project Summary/Abstract Section This application is for a Phase IIb (R44) renewal of AG066384 titled “GMP production of a tau oligomer inhibitor to enable clinical development for ADRD”. We completed the preclinical work and submitted our IND application to FDA and are ready to begin our first-in-human phase 1a study in January 2023. This application is to perform a study needed to prepare for a phase 1b clinical study designed to look for early clinical signs of efficacy/proof-of-concept by evaluating the response to treatment of relevant serum and CSF biomarkers in a double blinded study of patients with Alzheimer’s Disease (AD). This program is progressing to fill the urgent, growing unmet need for disease modifying therapeutics (DMT) for AD with an economical, DMT that is stable, oral, and that can be self-administered. If successful, it will have a tremendous impact on the more than 6.5 million Americans who currently have AD (projected to be 12.7 million by 2050) and their caregivers and will help reduce the current cost of $321 billion (projected to be $1 trillion by 2050) to our nation (Alzheimer's Association 2022 Alzheimer's Disease Facts and Figures). Results of the preclinical studies have shown that TO-0582 demonstrated: pharmacologic activity in two mouse models of tauopathy (htau, expressing the 6 CNS human tau isoforms representing tau aggregation in AD; JNPL3, that expresses 4R tau with the P301L mutation that represents four-repeat tauopathies), reasonable pharmacokinetic characteristics, minimal DDI potential, lack/minimal effects on cardiovascular, pulmonary and CNS systems, and a lack of genotoxicity. Relatively modest, non-adverse toxicity was observed in 28-day rat and dog GLP toxicity studies. The no adverse effect level for both the rat and dog 28-day studies were the highest dose tested. Additional testing at higher doses is necessary to demonstrate toxicity limiting dosing to establish a No Observed Adverse Effect Level (NOAEL) to enable dosing at sufficient levels in humans. Manufacture of kilogram quantities for non-clinical safety studies (NCSS) and drug pre-formulation work has been completed. The GMP batch met specifications for 24-month stability and was used to manufacture drug product OLX-07010 that has recently met specifications for 12-month stability testing. Methods development and manufacture of compound has been demonstrated at a 5 Kg scale (funded by 1R44AG077991-01A1). The Aims of this proposal are to synthesize 10 Kg of TO-0582AA and to use this material to perform studies to demonstrate toxicity limiting doses and NOAELs in rats and dogs. Manufacture of compound will be performed by Curia (Albany, NY), and the toxicity studies will be performed by Charles River Laboratories (Ashland, OH). As the National Institute on Aging is the primary Federal agency for AD research, the development of a DMT for AD has the highest relevance for its mission.