DOP116 Preclinical characterization of IMU-856, an orally available epigenetic modulator of gut barrier function and regeneration
Authors: Wirth M , Peelen E , Elhag S , Buriánek F , Mihajlović J , Pröbstl D , Fonseca J , Kehler I , Schreieck A , Vitt D , Muehler A , Kohlhof H 
Published: January 2025

Abstract

Background
A dysfunctional intestinal mucosal barrier is a key pathophysiological hallmark and driver of a broad range of gastrointestinal diseases, including inflammatory bowel disease (IBD). To date, there are no adequate treatment strategies to ameliorate impaired barrier function.
IMU-856 is an orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6), a histone/non-histone protein deacetylase and transcriptional regulator that targets the restoration of intestinal barrier function and regeneration of bowel epithelium without having any direct effect on the immune system. A double-blind, randomized, placebo-controlled phase 1/1b clinical trial of IMU-856 has been completed [1]. IMU-856 was shown to be safe and well-tolerated with a benign adverse event profile and pharmacokinetics that allow once-daily dosing. In Part C, a ‘proof of concept study’ in patients with celiac disease, IMU-856 demonstrated positive effects in four key dimensions of clinical outcome: protecting gut architecture, improving patients' symptoms severity, biomarker response and enhancing nutrient absorption.

Methods
In the presented preclinical studies, the target specificity and effects of IMU-856 on intestinal barrier function and regeneration were elucidated by in-vitro sirtuin activity assays, transepithelial electrical resistance (TEER) assays, dextran sulphate sodium (DSS)-induced colitis mouse models and gene expression analysis (bulk RNA sequencing). Moreover, potential immune suppressive effects of IMU-856 were assessed in stimulated human peripheral blood mononuclear cells (PBMCs). Multiple biomarkers related to health of intestinal epithelium and of enteric function were also assessed in preclinical studies and in the phase 1 trial.

Results
IMU-856 is a highly selective and potent modulator of SIRT6. In TEER assays, IMU-856 treatment enhanced the epithelial barrier recovery of Caco-2 monolayers after a destructive cytokine challenge and modulated tight junction protein levels. IMU-856 demonstrated activity in acute DSS-induced colitis models by reducing the severity of colitis, improving the mucosal architecture and preserving functional enterocytes (upregulation of enterocyte marker genes and the plasma biomarker citrulline). No effects of IMU-856 on T-cell proliferation and cytokine secretion (interferon-g (IFN-g)) were observed in human PBMCs.

Conclusion
IMU-856 data indicate restoration of intestinal barrier function and promotion of physiological mucosal regeneration without direct immunosuppressive effects and may therefore offer potential for the treatment of IBD and other gastrointestinal diseases with compromised barrier function.

References
1.Daveson AJM, Stubbs R, Polasek TM, Isola J, Anderson R, Tye-Din JA, et al. Safety, clinical activity, pharmacodynamics, and pharmacokinetics of IMU-856, a SIRT6 modulator, in coeliac disease: a first-in-human, randomised, double-blind, placebo-controlled, phase 1 trial. The Lancet Gastroenterology & Hepatology. 2024;0. doi:10.1016/S2468-1253(24)00248-6