DOP67 MB310: From Clinical FMT to a Phase 1 Study with a Defined, Orally Administered Live Bacterial Therapeutic for Mild Moderate Ulcerative Colitis

Abstract

Abstract Background The composition of the gut microbiome is a key determinant in inflammatory bowel disease. Consequently, modifying the composition of the gut microbiota has the potential to transform the treatment of ulcerative colitis (UC). The clinical use of faecal microbiota transplantation (FMT) has become widespread, especially for the treatment of C. difficile associated diseases, as a method of changing the composition of the gut microbiome from a diseased to a healthy state. FMT is, by its nature, an undefined and variable therapy due to differences between donors. Microbiotica has taken a "patient-first" discovery approach to identify a defined consortium, which is being developed as a live bacterial therapeutic for treatment of mild-to-moderate UC patients in a Phase 1b clinical trial, the COMPOSER-1 study, in 2024. Methods A clinical trial in UC patients (Costello et al., 2019), in which patients were treated with FMT from healthy donors, showed a 32% clinical remission rate in the active treatment group, as compared to 9% in the placebo arm. Donor, pre-treatment recipient, and post-FMT recipient samples were analysed using shotgun metagenomic sequencing. All samples were analysed using Microbiotica’s precision microbiome analysis platform to identify bacteria associated with patient response. These bacteria were assessed in cellular assays using relevant human cell/cell lines including: Caco2, dendritic cells, M1 macrophages, and CD4+ T-cells. Results We defined a signature of therapeutic response based on bacteria that engrafted from the donor into UC patients and were associated with clinical benefit. A sub-species level analysis identified 8 bacteria, which have been developed into a defined live bacterial therapeutic, MB310. The consortium bacteria enhanced the barrier integrity of an epithelial cell monolayer, and protected the barrier from inflammatory challenge by LPS. In vitro, the bacteria also have an anti-inflammatory effect when incubated with different primary innate immune cells, dendritic cells and M1 macrophages. Specific MB310 bacteria, either directly or via metabolites, are able to regulate T-cell responses. Conclusion In summary, we have identified a consortium of bacteria using patient-first discovery in a successful FMT study that is being developed as a treatment for UC. The consortium of 8 bacteria is able to impact multiple disease-relevant mechanisms including epithelial barrier integrity and immunomodulation. MB310 is being advanced to a first-in-human study in 2024 to explore safety and initial signs of efficacy. Costello, et al. (2019) Jama 321.2: 156-164.