Introduction

A dysfunctional intestinal mucosal barrier is a key pathophysiological hallmark and driver of a broad range of gastrointestinal diseases including celiac disease and inflammatory bowel disease. 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. IMU-856 may represent a new approach to treat gastrointestinal diseases with compromised barrier function.

Aims & 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. Additionally, the Phase 1/1b study 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 mass and function, nutrient absorption, and enteroendocrine hormones like GLP-1 were analyzed to assess potential effects on gut health.

Results

IMU-856 was safe and well-tolerated with a benign adverse event profile and pharmacokinetics that allow once-daily dosing. Treatment with IMU-856 protected against gluten-induced histologic deterioration, improved the health and metabolic function of intestinal enterocytes as measured by nutrient uptake and citrulline [1], and had positive effects on enteroendocrine cells increasing endogenous GLP-1 levels in a dose-dependent manner.

Conclusion

IMU-856 is a safe, highly selective and potent epigenetic modulator, improving the intestinal barrier function in patients with celiac disease undergoing a gluten challenge.
Positive effects of IMU-856 on gut hormones and various biomarkers for overall gut health including intestinal function and integrity were observed. Therefore, IMU-856 may offer extensive potential for treatment of gastrointestinal diseases with compromised intestinal barrier function and metabolic diseases.

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.

Disclosure

AS, MW, EP: employees of Immunic AG, option and shareholders of Immunic, Inc.
IPO, JF, IK, SE: employees of Immunic AG, option and/or shareholders of Immunic, Inc.
HK: employee of Immunic AG, shareholder of Immunic, Inc., co-inventor of patents for the drug in investigation
DP: option holder of Immunic, Inc.
DV, AM: employees of Immunic AG and Immunic, Inc., shareholders of Immunic, Inc., co-inventors of patents for the drug in investigation