Advancing FGF13-Nav1.6 modulators to normalize Nucleus Accumbens activity for Cocaine Use Disorder

Iontx Inc., Galveston TX

Investigators

Abstract

ABSTRACT Cocaine use disorder (CUD) is a national public health emergency in the United States for which there are no FDA-approved medications. It is a chronic condition with a high relapse risk, driven by increased sensitivity of the mesocorticolimbic system to cocaine. At the circuitry level, relapse has been associated with excessive firing of nucleus accumbens (NAc) medium spiny neurons (MSNs). In these cells, firing is regulated by the voltage- gated Na+ channel Nav1.6 and its subunit, fibroblast growth factor 13 (FGF13). Recent findings from the IonTX team show that in vivo silencing of FGF13 in the NAc increases Nav1.6 currents and MSN firing, leading to reduced cocaine demand in a rat CUD model. Based on this, IonTX has identified a novel small-molecule enhancer of the FGF13/Nav1.6 complex, with plans to optimize it into a first-in-class CUD medication aimed at reducing relapse vulnerability. Through a validated multi-tier screening pipeline, initial optimizations of the hit compound 5788 have been performed, building meaningful structure-activity relationship (SAR) studies. Combining results from various assays and pharmacokinetic (PK) studies, the fast-fail strategy aims to expand the lead optimization campaign. The goal of this project is to conduct structure-activity relationship (SAR) analysis and optimization of compound 5788 (Aim 1), followed by pharmacokinetic (PK) studies of 5788 analogues (Aim 2), and in vivo efficacy studies using the rat cocaine self-administration model combined with quantitative electroencephalogram (qEEG) (Aim 3). Positive outcomes of these studies will form the basis for a risk-benefit assessment with pre-IND enabling preclinical studies for future pre-IND meeting with the FDA and entry into clinical trials. The goal is to identify a candidate with improved drug-like properties by the end of the 12-month budget period for future IND-enabling studies to treat CUD.