Title: Developing a novel drug for neurobehavioral deficits in FASD

Summary Fetal Alcohol Spectrum Disorders (FASD) represent a range of lifelong cognitive, behavioral, and physical impairments caused by prenatal alcohol exposure (PAE). The estimated prevalence of FASD is 2.0-5.0% in the U.S. and Western Europe, causing substantial treatment costs. Currently available medications for FASD are essentially limited to the management of ADHD and anxiety, and there is a strong need for new medications to target other broader issues in FASD patients. Cogthera LLC aims to develop a drug to address cognitive and learning difficulties in FASD by targeting a novel mechanism mediated by the KCNN2 channel that we discovered to be affected by PAE. The patent for the use of peptide compounds targeting this mechanism is held by Children's National Hospital (CNH). These compounds have shown improvements of behavioral issues in a mouse model of FASD via intranasal application. Building upon the successful selection of the top candidate peptide FA-1 through initial efficacy and safety testing in the STTR Phase I study, this Phase II study focuses on the following objectives: Produce GLP-grade FA-1 and comprehensively characterize its drug-like properties, bioactivity, pharmacokinetics (PK), pharmacodynamics (PD), and safety in vitro (Aim 1); Optimize FA-1's formulation for intranasal administration, evaluate its efficacy in FASD animal models of acute and chronic maternal alcohol drinking, and obtain regulatory feedback through an INTERACT meeting with FDA to guide subsequent in vivo studies (Aim 2); Conduct single- dose and multiple-dose PK studies as well as toxicity and safety assessments of FA-1 in both rodent (mouse) and non-rodent (rabbit) models (Aim 3). These studies will generate critical preclinical data to establish safe and effective dosing regimens, thereby supporting regulatory approval and facilitating IND submission.