AX-158 proof-of-mechanism safety study: Evaluating a novel T cell receptor (TCR) signal modulator in patients with mild-to-moderate plaque psoriasis (NCT05725057)

Summary: Background: Nck binding to TCRs directly amplifies T cell responses to low-affinity antigens, contributing to autoimmune diseases. AX-158 is a first-in-class oral candidate that inhibits the Nck-SH3.1 domain to selectively disrupt Nck-TCR interaction. AX-158 may help prevent self-reactive T cell responses that drive autoimmune pathobiology. Type of Study: A Phase 2a, prospective, randomized, double-blind, placebo-controlled safety and efficacy study of AX-158. Methods: Patients were randomized to receive AX-158 (N=21) or placebo (N=10). Safety and standard psoriasis efficacy endpoints were assessed. Histological markers, expression of psoriasis-related genes, and markers of immune activity were evaluated. Results: Few AEs were reported with a single incidence (4.8%) of Grade 2 neutropenia in the AX-158 arm. No serious AEs were reported. Moderate disease patients (PASI<u>></u>6) treated with AX-158 showed a positive response trend (34.6%). Using RT-PCR for expression of IL-17A and IL-17F, a group of 12/21 (57%) progressive responders (wk 4<wk2<baseline values) were identified different for drug vs. placebo treatment (p = 0.04). In extended RNAseq analysis, responder group showed 52% improvement in pathologic IL-17A levels; 281 genes of the psoriasis transcriptome were significantly down-regulated (p< 0.05). Using GSVA, multiple psoriasis-related gene sets were significantly modulated and by Ingenuity Pathway analysis, IL-17 pathways in psoriasis and neutrophil trap pathways were significantly modulated (p< 0.0001) in patients who received AX-158. Conclusion: AX-158 administration was found to be safe and well-tolerated, matching previous Phase 1 experience. Biomarker analyses revealed significant and consistent responses that validate Nck immunomodulation as a therapeutic approach to psoriasis with potential universal applicability to other autoimmune diseases. Donald S. Batty¹, Christopher VanDeusen¹, Sandra Garcet², James Krueger² 1. Artax Biopharma, Inc., Cambridge, MA, United States. 2. The Rockefeller University, New York, NY, United States. Clinical Research: Interventional Research