1795-P: Bezisterim Treatment Is Associated with Changes in DNA Promoter Methylation Linked to Epigenetic Aging, Metabolic Risk, and Neurodegenerative Pathways

Introduction and Objective: Bezisterim is an oral anti-inflammatory, insulin sensitizing agent with neurosteroid properties in development for Alzheimer’s disease (AD), Parkinson’s, and long COVID. Prior work indicates bezisterim improves glucose tolerance and reduces insulin resistance. In a randomized, placebo-controlled trial in mild-to-moderate AD, bezisterim modulated inflammatory pathways (eg, NF-κB) and improved metabolic and inflammatory biomarkers with quantifiable cognitive/functional benefits. We now explore epigenetic age acceleration (EAA) and DNA promoter methylation changes with bezisterim affecting both AD and T2D risk. Methods: This exploratory post hoc study of bezisterim vs placebo analyzed EAA across 13 biological clocks, as well as promoter CpG methylation of 11,748 genes (using Illumina EPIC v2) relating to AD/T2D risk. Results: Bezisterim treatment was associated with statistically significant reductions in EAA across 13 clocks and significantly altered promoter methylation in 2581 genes (false discovery rate <0.05); 446 changes were directionally consistent with reduced expression of AD risk genes, 180 regarded as AD network hubs. Aggregate promoter methylation scores correlated with cognition and function metrics, AD biomarkers (Aβ42/40, GFAP, NfL, pTau217), metabolic measures (glucose, insulin, fructosamine, HOMA2-%S, lipids, BP, waist-hip ratio), and inflammatory markers (CRP, C1q). Of the 446 AD-linked genes, 156 were also associated with T2D risk, including 58 T2D hubs. Conclusion: This analysis of patients with AD shows bezisterim treatment was associated with epigenetic aging and promoter methylation changes linked to metabolic, inflammatory, and neurodegenerative pathways. These findings suggest a potential epigenetic mechanism for effects on insulin sensitivity and diabetes-related risk pathways. Further prospective studies are warranted to evaluate the relevance of these epigenetic changes in T2D/metabolic disease populations. Disclosure C. Reading: Employee; Current; BioVie Inc. J. Yan: Employee; Current; BioVie. Stock/Shareholder; Current; BioVie. C. Ahlem: Employee; Current; Biovie, Inc. P. Markham: Employee; Current; BioVie. S. OQuinn: Consultant; Current; BioVie Inc, Harmony Biosciences, Nuvie Bio. J.M. Palumbo: Other - BioVieFull-time employee and stockholderhttps://bioviepharma.com/; Current; BioVie. Other - Neurala BiosciencesConsulting Head of R&Dhttps://www.neurala.co/; Current; Neurala Biosciences. Other - Phocus Pharmaceuticals.Consultant Medical Advisor https://www.phocusrx.com/; Current; Phocus Pharmaceuticals. Other - VitalityIPMember of Advisory Boardhttps://vitalityip.ai/; Current; Vitality IP. Other - Aozora Science LLCPrincipalhttps://aozora-science.com/; Current; Aozora Science LLC. V.B. Dwaraka: Employee; Current; TruDiagnostic. M.A. Testa: Stock/Shareholder; Current; Phase V Technologies, Inc. D.C. Simonson: Board Member; Current; Phase V Technologies, Inc. Stock/Shareholder; Current; GI Windows.