RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED PHASE 1 STUDY OF ATH-063: A NOVEL, ORAL, ARTIFICIAL INTELLIGENCE-GENERATED DRUG FOR INFLAMMATORY BOWEL DISEASE

Abstract BACKGROUND ATH-063 is a first-in-class small molecule G9A methyltransferase inhibitor generated through use of the proprietary AthosOmics.AI platform that targets a gene network identified to be highly enriched in biologics-resistant Inflammatory Bowel Disease (IBD). ATH-063 directly targets G9A enzymatic activity in human CD4 T cells and GI epithelial cells, acting with a dual mechanism of action, suppressing pro-inflammatory responses through expansion and activation of FoxP3+ T regulatory cells (Tregs), and inducing direct gut mucosal healing through the up-regulation of tight junction proteins. Study Design (ClinicalTrials.gov ID: NCT05807971): A first-in-human randomized double-blind placebo-controlled study was conducted to evaluate the safety, tolerability, PK, and proof of mechanism of action of single ascending dose (SAD) and multiple-ascending dose (MAD) dosing regimens of ATH-063 in healthy participants. Four sequential cohorts of 8 participants (6 receiving ATH-063 and 2 receiving matched placebo were treated in both the SAD and MAD study phases at 4 dose levels (25, 75, 150, 250mg). Study Objectives The primary objective of the study was to evaluate the safety, dosing, and tolerability of ATH-063 following oral administration in healthy human subjects. Additional objectives included determining the ATH-063 PK and PD profiles. RESULTS Seventy-six subjects enrolled and completed the study. There were no deaths or SAEs, and no subject discontinuations due to TEAEs following dosing for up to 10 days. Vital signs, physical exams, ECGs and safety labs were all normal. PK analysis revealed a linear dose-dependent increase in ATH-063 blood concentration levels which achieved minimum-efficacy plasma drug concentration at the 75 mg. dose. A statistically significant increase (p < 0.001) in the number of activated FoxP3+ Tregs was found in all cohorts. ATH-063-induced Tregs showed enrichment of an activated Treg signature that included six well-known genes (IL-10, STAT5, LRRC32, TGF-beta, ITGAE, NRP1) related to Treg anti-inflammatory activity. ATH-063 blood levels positively correlated with Treg FoxP3 expression (p = 0.003), and negatively correlated with both Oncostatin-M (p = 0.012), a biomarker of TNFA-resistance, and with calprotectin monomers (S100A8/A9). ATH-063 also reduced the expression of pro-inflammatory cytokines (IL1B, IL6, MCP1) in peripheral blood mononuclear cells at all doses. CONCLUSIONS ATH-063 showed an favorable pharmacokinetics profile with no safety signals or dose limiting side effects identified. Furthermore, ATH-063 demonstrated target engagement with induction of a potent increase in the number and activity of blood FoxP3+ Tregs, while suppressing key pro-inflammatory markers. These results justify further clinical evaluation of ATH-063 efficacy in biologics-resistant IBD patients.