Preclinical development of a small molecule inhibitor of tau self‐association for Alzheimer’s disease and related dementias

Abstract

AbstractBackgroundThe approach for targeting toxic tau aggregates was to develop a small molecule inhibitor of tau self‐association that is agnostic to the types of aggregates formed. Pharmacodynamic studies of the lead compound in mouse models of tauopathy were performed. Therapeutic treatment of aged P301L tau JNPL3 mice showed reduced tau aggregation and improved motor behavior. Preventive treatment studies in young JNPL3 and htau mice with the lead also showed reduced tau aggregation. These results supported preclinical development of the lead to evaluate the potential of the compound for an Investigational New Drug Application (IND) submission to enable a first‐in‐human study.MethodProcess development and manufacturing of the compound was performed for the nonclinical safety studies (non‐GLP) and for drug substance (GLP) for clinical studies. To enable nonclinical studies, formulation work for oral administration of the compound was performed for pharmacokinetic studies to ensure sufficient oral bioavailibility for the toxicity studies. Dose range finding studies included a maximum tolerated dose (MTD) phase and a 14‐day repeat oral dosing phase in rat and dog (non‐GLP).ResultManufacture of the compound has been scaled to a 3 Kg batch size with 100% purity by HPLC (% area) as a single polymorph. Manufacture of capsule drug product for clinical studies was completed. Both the drug substance and drug product have shown good stability at room temperature storage. Oral bioavailibility was about 70% in rats and 40‐60% in dogs. Oral doses of 100, 300 and 1000 mg/kg/day in rats, and doses of 50 and 150 mg/kg/day in dogs for 14 days were well tolerated clinically, but the 500 mg/kg/day dose in dogs caused slight generalized tremors 1‐2 hours post‐dosing on multiple days. Hepatic effects were seen in both species, mostly at the higher doses in rats.ConclusionThe results of the 14‐day studies enabled the selection of doses for the 28‐day rat and dog toxicity studies (GLP). The results of these studies in combination with the array of studies required for the IND application have been completed. The results of these studies were generally favorable, and the application is being prepared for submission.