P0616Rectal insulin is safe and well tolerated in active ulcerative colitis: a first-in-human study of a novel epithelial-targeting strategy

Abstract Background The intestinal epithelium is central to the interaction between luminal antigens and the mucosal immune system. Current IBD therapies mainly target immune cells, and no clinically validated epithelial-targeted strategy exists. The insulin receptor in colonic epithelial cells has recently been identified as cytoprotective in experimental colitis 1, suggesting that topical rectal insulin could promote mucosal healing. We conducted a first-in-human study primarily to assess the safety and systemic exposure of rectal insulin in patients with active ulcerative colitis (UC). Methods Phase 1b, randomized, double-blind, placebo-controlled, cross-over trial in 6 patients with active UC (SCCAI 5 - 9) at two sites. Each patient received three single rectal instillations of 100 mL isotonic saline: placebo, 50 IU, and 100 IU regular insulin (Actrapid), separated by ≥ 1-week washout. Plasma glucose and insulin were measured at baseline and 15 - 210 min post-dose; electrolytes were assessed at baseline. Clinical symptoms were monitored throughout. SCCAI was reassessed one week after the final instillation (post hoc). Results No clinical symptoms of hypoglycaemia or other safety signals were observed. No biochemical hypoglycaemia (glucose 3.5 mmol/L) occurred. Mean nadir glucose (±SEM) was 4.44 ±0.20 (placebo), 4.05 ±0.07 (50 IU), and 3.98 ±0.11 mmol/L (100 IU). Individual pairwise comparisons versus placebo were non-significant (Wilcoxon signed-rank test). Post hoc exploratory analysis of SCCAI showed that 1/6 patients (17%) had unchanged disease activity and 5/6 (83%) had decreased disease activity, of whom 3/6 (50% of all patients) achieved remission-level scores. Conclusion Single-dose rectal insulin (50–100 IU) in active UC appears safe and well tolerated, without clinical or biochemical hypoglycaemia. A post hoc exploratory assessment of disease activity was encouraging and, together with these first-in-human safety data, supports the feasibility of epithelial insulin receptor targeting as a novel, potentially safe, first-in-class treatment strategy in UC and justifies larger controlled trials Reference: 1) Yassin M, Sadowska Z, Tritsaris K, et al. Rectal insulin instillation inhibits inflammation and tumor development in chemically-induced colitis. J Crohns Colitis. Aug 18 2018;12(12):1459-1474. doi:10.1093/ecco-jcc/jjy112 Conflict of interest: Romanczyk, Tomasz: No conflict of interest Filip, Rafal: No confict of interest to declare Magdalena, Lesińska: No conflict of interest Polak, Anna: Head of Clinical Development, Enterotarget ApS Shareholder of Enterotarget ApS Pratt, Sebastien: Shareholder of EnteroTarget ApS Partner, Zuger Capital AG, Zug, Switzerland T. Troelsen, Jesper: Shareholder of EnteroTarget ApS Rogler, Gerhard: Grant: Abbvie, Ardeypharm, Augurix, Calypso, FALK, Flamentera, MSD, Lilly, Novartis, Pfizer, Roche, Takeda, Tillots, UCB and Zeller Personal Fees: Abbvie, Arena, Augurix, BMS, Boehringer, Calypso, Celgene, FALK, Ferring, Fisher, Genentech, Gilead, Janssen, Lilly, MSD, Novartis, Pfizer, Phadia, Roche, UCB, Takeda, Tillots, Vifor, Vital Solutions and Zeller Non-financial Support: Novartis Other: Roche, Pharmabiome Prof. Dr. Olsen, Jørgen: CEO of Enterotarget ApS, Shareholder of EnteroTarget ApS