DOP073 Submucosal injection of the oligonucleotide STNM01 is able to induce clinical remission, mucosal healing and histological response in left-sided ulcerative colitis patients with moderate-to-severe disease

Background: The extracellular matrix component Carbohydrate sulfotransferase 15 (CHST15) biosynthesizes highly sulfated disaccharide units of chondroitin sulfate (CS), which facilitates mucosal inflammation and the onset of intestinal fibrotic lesions in chronically active ulcerative colitis. We evaluated the safety and efficacy of the double-strand RNA oligonucleotide STNM01 which inhibits the expression of the CHST15 gene in left-sided ulcerative colitis patients with active mucosal inflammation. Methods: We conducted a Phase 2a, randomized, multicenter, double-blind, parallel-group, placebo-controlled study of STNM01 in 24 patients with left-sided, refractory ulcerative colitis. Patients were randomized (1:1:1) to receive a single-dose endoscopic submucosal injection of 25 nM (n=8) or 250 nM (n=8) of STNM01 or placebo (n=8). Submucosal injections were evenly distributed across 8 mucosal sites from 5 cm to 35 cm. The primary endpoint was mucosal healing (Mayo endoscopic sub score ≤1) at day 14 or 28. Secondary endpoints included clinical response (decrease from baseline Mayo score of ≥3 points and ≥30%, plus decrease in rectal bleeding sub score ≥1 or absolute sub score ≤1), histological response (Geboes score) and endoscopic response (UCCIS) within 28 days. Results: At baseline, 50%–62% of patients had prior anti-TNF exposure across the treatment groups. The primary endpoint of mucosal healing at day 14 or 28 was reached by 62.5% in the STNM01 250 nM (p=0.0183) group vs. 28.6% in the placebo group. If one patient is excluded from evaluation, as his baseline Mayo endoscopic sub score was 1, the rate of mucosal healing increases to 71.4% in the STNM01 250 nM group (per protocol population). Clinical response was shown by 62.5% in the STNM01 250 nM group (p=0.3200) vs. 28.6% in the placebo group. Clinical remission was shown by 50.0% (p=0.0497) in the STNM01 250 nM group vs. 14.3% in the placebo group. UCCIS segmental score and the Geboes score from baseline to either day 14 or day 28 in the STNM01 250 nM treatment group were significantly reduced compared to that in the placebo group (p<0.01). Immunohistochemical analysis revealed statistically significant inhibition of CHST15 expression in the STNM01 250 nM treatment group compared to placebo (p<0.01). Reduced accumulation of mucosal lymphocytes and sulfation of L-selectin ligand on high endothelial venule-like vessels were also demonstrated upon STNM01 treatment. STNM01 application showed a good tolerability and safety profile. Conclusions: Submucosal injection of STNM01 was well tolerated and able to induce clinical remission, mucosal healing and histological response in left-sided ulcerative colitis patients, who did not respond sufficiently to conventional treatment.