P1208 MH002, an optimized live biotherapeutic product, for the treatment of inflammatory bowel diseases, has mode-of-actions linked to restoration of intestinal dysbiosis, mucosal integrity, and immune homeostasis

Abstract

Abstract Background MH002 is a live biotherapeutic product consisting of 6 well-characterized commensal strains, that is in clinical development for the treatment of Ulcerative Colitis (UC) and acute Pouchitis. Both are multifactorial disorders which occur through a combination of dysregulated host inflammatory mechanisms and interactions with gut microbiota. Methods Faecal slurries of 6 UC patients with active disease were prepared to inoculate a standardized in vitro gut model (SHIME®) which mimics the colon microbiome of patients. A total of 24 simulators were run for 8d, with a single dose administration of MH002 (human equivalent dose [HED] ~1) or vehicle on Day0. Butyrate production in the simulators was quantified daily and host response effects were assessed in in vitro cell-based assays using samples from Day1. Caco-2 cells were co-cultured with human peripheral blood mononuclear cells and treated for 48h with Day1 samples, followed by transepithelial electrical resistance (TEER) and cytokine measurements. Wound healing was assessed by imaging of monolayers of T84 cells, scratched and treated with Day1 samples. Furthermore, the effects of MH002 (daily, 24d, HED ~30) on disease activity index (DAI; body weight [BW], stool consistency, occult blood), local inflammation, and mucosal damage were evaluated in acute dextran sulfate sodium (DSS) induced colitis, when administered to C57BL/6 mice (15/group) as from 14d prior to DSS intake, and compared to 5-aminosalicylate (5-ASA; daily, 24d, 150mg/kg) and vehicle. Animals were euthanized in the acute (Day7; 10/group) and recovery phase (Day11; 5/group). Results In vitro administration of MH002 to patient-derived colonic microbiomes restored within 1d butyrate production and increased efficiency to improve epithelial barrier integrity, modulate T-cell-mediated immune responses, and promote mucosal wound healing in in vitro cell cultures (Table 1). DSS intake induced a significant decrease in relative BW and an increase in DAI. A significant recovery (BW, DAI, stool consistency) was observed at Day11 for MH002 and 5-ASA. Moreover, at Day11, macroscopic inflammation (colon weight/length ratio) and histologic scores were lower with MH002 and 5-ASA as compared to vehicle (Figure 1). Conclusion By restoring intestinal dysbiosis and epithelial integrity, and attenuating local inflammation, MH002 treatment should lead to lower disease activity and, ultimately, to clinical remission without immune suppression. Indeed, study MH002-UC-201 in mild-to-moderate UC was completed with favourable treatment effects (endoscopic improvement, faecal calprotectin normalization, improved stool consistency) and no safety concerns (Abstract Vermeire et al.; EudraCT 2020-004355-33).