Preclinical Efficacy and Safety Evaluation of Oral AST-004 for Moderate Traumatic Brain Injury (TBI)

PROJECT SUMMARY Traumatic brain injuries (TBI), including concussions, are an area of significant unmet need with no approved therapeutics and a national burden of ~$77 billion annually. TBI is the global leading cause of post-injury death and disability, and over 2 million Americans sustain a TBI each year. Approximately 1 out of every 60 people in the U.S. lives with a TBI-related disability. The tremendous incidence and long-term consequences of TBI highlight the considerable epidemic at hand, and the need for neuroprotective treatments. Astrocyte Pharmaceuticals Inc. is developing the proprietary small molecule pharmaceutical agent AST-004 for acute administration to TBI patients that will dramatically improve the survival of neurons, affected brain tissue, and the long-term neurological deficits that have been linked to TBI. The proprietary approach at Astrocyte Pharmaceuticals differs significantly from historical neuroprotective attempts in that it focuses on a non- neuronal cell type, the astrocyte, which has only recently received broader attention as an important cellular target for successful therapeutic research. AST-004 enhances and maintains astrocyte mitochondrial function and improves multiple healing mechanisms including protection against edema, glutamate excitotoxicity, and oxidative stress. Previous NINDS Phase I STTR-funded research contributed to the identification of AST-004 and the demonstration of its efficacy when intravenously (IV) administered in a large animal pig TBI model. This promising IV therapy has advanced through Phase 1 human clinical trials as an in-hospital IV formulation. For the mild to moderate TBI population, an extended IV infusion is not a pragmatic or commercial option. To address this large patient population and enable further clinical trials, we are developing an oral tablet formulation for use outside the hospital setting. The goal of this Direct-to-Phase II project is to complete critical path preclinical activities to advance the oral formulation to the clinic. Specifically, the project aims to (1) verify efficacy using the oral route of administration in a large animal model of TBI, and (2) perform the FDA-required preclinical toxicology studies. Successful completion of this project will lead to an IND submission of the AST- 004 oral tablet formulation with the FDA and a subsequent Phase I clinical trial.