DOP012 Promising effects of IMU-856, an orally available epigenetic modulator of barrier regeneration - biomarker findings from a Phase 1 clinical study
Authors: Schreieck A , Pichetto Olanda I , Pröbstl D , Peelen E , Fonseca J , Wirth M , Kehler I , Vitt D , Kohlhof H , Mühler A 
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 which serves as a transcriptional regulator of intestinal barrier function and regeneration of bowel epithelium. In preclinical studies, IMU-856´s mechanism of action has been shown to avoid suppression of immune cells. This could present a new approach to treat intestinal barrier function associated diseases without the serious consequences associated with many immunosuppressive therapies.

Methods
This was a first-in-human, double-blind, randomized, placebo-controlled clinical trial of IMU-856 in healthy volunteers and patients with celiac disease. In the multiple ascending dose part, healthy human subjects were dosed once-daily for 14 consecutive days with IMU-856 at three different dose levels or placebo. Phase 1b was designed to assess safety and tolerability of IMU-856 at two different dose levels in patients with celiac disease during periods of gluten-free diet and a 15-day gluten challenge. Further objectives included pharmacokinetics and the assessment of histological changes. Biomarkers reflecting intestinal enterocyte function, intestinal integrity, nutrient absorption and general gut health were analyzed to assess the effect on the overall protection of gut architecture.

Results
IMU-856 was safe and well-tolerated with a benign adverse event profile and pharmacokinetics that allow once-daily dosing. There were no systematic clinically relevant findings relative to safety and tolerability. Treatment with IMU-856 improved the mass, metabolic function and health of intestinal enterocytes as measured by nutrient uptake as well as several biomarkers for intestinal function and integrity as well as general gut health [1].

Conclusion
IMU-856 is a safe, highly selective and potent epigenetic modulator, showing signals of improving the intestinal barrier function in patients with celiac disease undergoing a gluten challenge.The positive effects of IMU-856 on various biomarkers for intestinal function, overall health and integrity in conjunction with the protection of gut architecture show that IMU-856 may offer extensive potential in other gastrointestinal diseases with compromised intestinal barrier function like IBD.

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