Submucosal injection of the RNA oligonucleotide GUT-1 in active ulcerative colitis patients: A randomized, double-blind, placebo-controlled phase 2a induction trial

Abstract

Abstract Background and aims Carbohydrate sulfotransferase 15 (CHST15) biosynthesizes sulfated matrix glycosaminoglycans and is implicated in intestinal inflammation and fibrosis. Here, we evaluate efficacy and safety of the double-stranded RNA oligonucleotide GUT-1, a specific blocker of CHST15, as induction therapy in patients with ulcerative colitis (UC). Methods In this randomized, double-blind, placebo-controlled, phase 2a study, we enrolled endoscopic active UC patients, refractory to conventional therapy, in 5 hospital centers across Germany. Patients were randomized 1:1:1 using a block randomized technique, to receive a single dosing of 25 nM GUT-1, 250 nM GUT-1, or placebo by endoscopic submucosal injections. The primary outcome measure was improvement of endoscopic lesions at weeks 2 or 4. The secondary outcome measures included clinical and histological responses. Safety was assessed in all patients who received treatment. Results Twenty-eight patients were screened, 24 randomized and 21 evaluated. Endoscopic improvement at weeks 2 or 4 was achieved by 71.4% in the GUT-1 250 nM, 0% in the GUT-1 25 nM and 28.6% in the placebo group. Clinical remission was shown by 57.1% in the GUT-1 250 nM, 0% in the GUT-1 25 nM and 14.3% in the placebo groups. Histological improvement was shown by 42.9% in the GUT-1 250 nM, 0% in the GUT-1 25 nM and 0% in the placebo groups. GUT-1 250 nM reduced CHST15 expression significantly and suppressed mucosal inflammation and fibrosis. GUT-1 application was well tolerated. Conclusion Single dosing by submucosal injection of GUT-1 repressed CHST15 mucosal expression and may represent a novel induction therapy by modulating tissue remodeling in UC