Beyond the binary: NOA-104 as a novel modulator of the aryl hydrocarbon receptor for the treatment of inflammatory skin diseases

Summary: Abstract Body: Immune diseases involving barrier dysfunction, such as atopic dermatitis, psoriasis, or inflammatory bowel disease are characterized by a high degree of heterogeneity with chronic and sustained inflammation driving dysfunction of protective epithelial barriers. The aryl hydrocarbon receptor (AhR), a regulator of tissue homeostasis, has been demonstrated to induce differential transcriptional profiles and therapeutic pathways by different ligands to coordinate inflammatory signalling and repair barrier function. Herein, we describe a novel AhR modulating small molecule, NOA-104 for the treatment of inflammatory dermatological barrier diseases. Designed to more comprehensively modulate AhR to initiate a tailored signalling response, NOA-104 restores barrier function and resolves inflammation in pre-clinical models of atopic dermatitis. Through RNAseq, the NRF-2 pathway was demonstrated to be modulated alongside AhR in human keratinocytes. When challenged with menadione, NOA-104 treatment was demonstrated to reduce ROS induction in human keratinocytes. NOA-104 treatment on human keratinocytes induced with IL4/IL13 increased the genetic expression of filaggrin equivalent to a mechanistic competitor, while simultaneously reducing the gene expression of stat6 more effectively. In an MC903 murine model, NOA-104 treatment rapidly resolved scratching time (p < 0.01) and occurrence (p< 0.001) within 3 days of initiating treatment, while increasing gene expression of the barrier function protein filaggrin (p <0.05). Further, NOA-104 treatment significantly reduced gene expression of TH2-driven biomarkers, including IL-4 (p<0.01), IL-13 (p<0.05), and stat6 (p<0.001), more effectively when compared to a leading mechanistic competitor. These studies demonstrate the translation of in vitro to in vivo efficacy of NOA-104, supporting potential advancement towards the clinic; further work to follow. Serena Mandla¹, Katrina Vizely¹, Talia Fiaani¹, Michal Syonov¹, Carlie Goodall¹, Aliza Khaitin¹, Carla Spina¹ 1. Noa Therapeutics, Toronto, ON, Canada. Translational Studies: Cell and Molecular Biology