Objective: IMU-856 is an orally available and systemically acting small molecule modulator that targets Sirtuin 6, a protein which serves as a transcriptional regulator of intestinal barrier function and regeneration of bowel epithelium. In preclinical studies, the mechanism of IMU-856 has been shown to avoid suppression of immune cells. It may therefore maintain immune surveillance for patients during therapy, an important advantage versus chronic treatment with potentially immunosuppressive medications. IMU-856 mechanism of action could present a new approach to treat celiac disease and other intestinal barrier function associated diseases without the serious consequences associated with many immunosuppressive therapies.
The objectives of this phase 1/1b trial were to determine the safety, tolerability, and pharmacokinetics of IMU-856 in healthy volunteers and celiac disease patients, and to obtain proof of concept data.

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 single ascending dose part of the phase 1 clinical trial, healthy human subjects were randomized to either placebo or active treatment with single doses of IMU-856 at six different dose levels. In the multiple ascending dose part of this clinical trial, 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 the 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-days gluten challenge. Further objectives included pharmacokinetics, changes in malabsorption parameters and biomarkers for intestinal integrity such as citrulline as well as histological changes.

Results: IMU-856 was safe and well-tolerated with a benign adverse event profile and with pharmacokinetics that allow once-daily dosing. There were no systematic clinically relevant findings relative to safety and tolerability. Treatment with IMU-856 protected against gluten-induced histologic deterioration, reduced symptom severity and improved enterocyte health and function as measured by nutrient uptake and citrulline.

Conclusions: IMU-856 is a safe, highly selective and potent epigenetic modulator, showing first signals of improving the intestinal barrier function in patients with celiac disease undergoing a gluten challenge. Phase 1b provided proof of concept data for IMU-856 in patients with celiac disease during periods of gluten-free diet and 15-days gluten challenge, setting stage for a potential first-in-class oral celiac disease therapy. IMU-856 may offer extensive potential beyond celiac disease in other diseases, both intestinal and systemic, with compromised intestinal barrier function.

Juliano Fonseca

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