Novel small-molecule modulator for coeliac disease promising in phase 1 trial

The orally available and systemically acting small molecule modulator of sirtuin 6 (SIRT6) IMU-856 for coeliac disease demonstrates clinical activity with favourable safety profile, according to data from a phase 1 trial.

The trial was conducted in three parts. Part A included healthy participants who were randomly assigned to receive single ascending doses of IMU-856, ranging from 10 to 160 mg, or matching placebo. Results from part A were used to select three doses for part B to evaluate the safety, tolerability, and pharmacokinetics of IMU-856 once daily for 14 days using the same randomization procedure. Part C included patients with well controlled coeliac disease who were randomly assigned to receive either low-dose or high-dose IMU-856 or placebo once daily for 28 days, on top of a 15-day gluten challenge starting on day 14.

Safety and tolerability of IMU-856 were assessed, with safety analyses involving all patients who received at least one dose of the study drug.

A total of 71 healthy participants were enrolled in parts A and B, including 52 who were assigned to IMU-856 and 19 to placebo. The IMU-856 doses used in parts A and B were 10 mg (n=6), 20 mg (n=6), 40 mg (n=13), 80 mg (n=12), 120 mg (n=4), and 160 mg (n=11). Part C included 43 patients, including 14 who received IMU-856 80 mg, 15 who received IMU-856 160 mg, and 14 who received placebo.

Treatment-emergent adverse events (TEAEs) were documented in 24 participants (73 percent) in part A and 15 (79 percent) in part B who received any dose of IMU-856 and in six participants (50 percent) in part A and five (71 percent) in part B who received placebo. Most of the TEAEs were mild.

In part C, TEAEs occurred in 26 patients (90 percent) in the combined IMU-856 groups and in 10 (71 percent) in the placebo group. The most common TEAEs among IMU-856-treated patients included headache (45 percent), nausea (31 percent), diarrhoea (28 percent), and abdominal distension (24 percent).

Two serious adverse events occurred with IMU-856 treatment, a case of bacterial myocarditis in part B and a case of biliary colic in part C, both of which were unrelated to the drug. None of the participants died, experienced dose-limiting toxicities, or had systematic safety laboratory changes during the study.

As for efficacy in part C, villous height decreased by a mean of 20.9 μm among patients who received IMU-856 80 mg, by 22.5 μm among those who received IMU-856 160 mg, and by 60.3 μm among those who received placebo.