First in Human Study of a Tau Self-Association Small Molecule Inhibitor in Healthy Volunteers

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PROJECT SUMMARY This program is focused on developing a disease-modifying drug for Alzheimer’s disease (AD) by advancing our lead compound into clinical development. There are no disease-modifying drugs for AD, and the prevalence of AD is increasing worldwide. This program is progressing to fill this need with a disease modifying drug that, if successful, 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 $1.1 trillion by 2050) to our nation (Alzheimer's Association 2022 Alzheimer's Disease Facts and Figures). Key requirements for treating early-stage AD include safe, efficacious, and cost-effective therapeutic interventions. This small molecule, CNS drug-like lead significantly fulfills these requirements based on our preliminary results. This highly differentiated tau self-association inhibitor targets tau self-association at the beginning of the tau aggregation cascade. Small molecules were screened and optimized using in vitro assays to select molecules that inhibit the formation of tau oligomers from tau monomers. In vitro pharmacology and pharmacokinetic (PK) studies in mice were used to select a lead compound for evaluation of in vivo efficacy. Preventive and therapeutic studies in two mouse models of tauopathy, representing tau aggregation in Alzheimer’s disease (AD) and four-repeat-tau tauopathies, demonstrated proof-of-concept and supported the selection of this compound for further development. Methods development and manufacture of 1.61 kg of the lead compound was completed for non-clinical safety studies. GMP manufacture of a 2.8 kg batch for initial clinical studies was completed, and pre-formulation studies for development of drug product are completed. The IND was submitted (June 1, 2022) for first in human (FIH) studies that are planned to initiate in late 2022 or early 2023. The awarded Phase 1a study is a double-blind, randomized, three-part study designed to evaluate the safety, tolerability, and pharmacokinetics of the tau self-association inhibitor, in single ascending doses, multiple ascending doses, and single dose in healthy elderly. This Supplement is to cover unanticipated incremental costs related to FDA comments on our IND submission which occurred after the parent application was submitted. The Aims of this two year Supplement are as follows: Aim 4. Implement and maintain a dose exposure PK model to ensure compliance with FDA imposed exposure limits. Aim 5. Convene an independent Data Safety Monitoring Board (DSMB) to ensure participant safety. It is urgent that these activities be supported and started as soon as possible as clinical activities cannot begin until both the PK/PD modeling is complete and the DSMB is in place. Any delay in providing this support will result in a delay to beginning clinical activities for this trial.