DOP136MH002, an optimized live biotherapeutic product, for the treatment of mild to moderate Ulcerative Colitis: exploratory insights from a first-in-disease, double-blind, randomized clinical trial

Background Treatment options for patients with mild-to-moderate ulcerative colitis (UC) failing 5-ASA are limited. MH002 is an optimized Live biotherapeutic product (LBP) consisting of 6 non-pathogenic, wellcharacterized commensal bacteria. Its anticipated mechanism is reversion of dysregulated host inflammatory mechanisms, interactions with gut microbiota, and induction of mucosal healing. Methods In this 2:1-randomized, double-blind, placebo-controlled first-in-disease study (EudraCT 2020-001355-33), 45 patients with mild to moderate active UC (Modified Mayo Score [MMS] =4-8 but including Mayo Endoscopic Sub-score [MES] ≥2) received treatment with 1.2x1010 eqCFU MH002 or placebo (PBO) once daily for 8 + 8 wks. The primary endpoint was the rate of treatment-emergent adverse events (TEAEs). Here, a post-hoc analysis investigating response based on the patients baseline characteristics is reported as well as observed alterations in fecal microbiome. Results MH002 treatment was safe and well tolerated, and resulted in clinically meaningful improvements in disease activity and inflammatory parameters1. Stratifying patients based on their MES score at baseline (MES 2 or 3), showed for MES=2, an improvement of clinical symptoms and endoscopic healing with clinical remission of 4/15 (27%) and 1/10 (10%) on MH002 and PBO, respectively. However, in patients with MES=3, while clinical symptoms and endoscopic healing improved, clinical remission was not observed at week8. Furthermore, the evolution of fecal calprotectin (FCP) levels in patients with MES=2 or MES=3 at baseline showed an earlier onset of decrease in the MES=2 group (week 2 for MES=2 and week 10 for MES=3). In terms of microbiome alterations, significant increase in α-diversity was observed with treatment response, which is indicative of eubiosis restoration. In parallel, reduction of different taxa described to be associated with IBD such as Enterobacterales, Campylobacterales and Mycobiome occurred with continued changes beyond week8 when exposed to MH002. While no depletion of background microbiome with vancomycin was included, making MH002 strain detection technically challenging, up to 4 product strains could still be detected in the MH002 treated patients. However, no link between specific strain detection patterns and therapeutic effects could be observed. Conclusion These data suggest that in order to reach clinical remission in patients with MES=3 and to reach more pronounced microbiome shifts, a treatment period longer than 8 wks may be needed. Also, absence of a vancomycin microbiome depletion allows to study the general microbiome recovery in patients. These data allow optimization of the next clinical study protocol. Reference: Vermeire S, Dewint P, Vansteelant M, et al. Safety and efficacy of MH002, an optimized live biotherapeutic product, for the treatment of mild to moderate ulcerative colitis: a first-in-disease, double-blind, randomized clinical trial. JCC. 2024, 18(S1). Conflict of interest: Conrath, Katja: paid consultant for MRM Health, shareholder of MRM Health Bolca, Selin: shareholder of MRM Health de Leeuw, Marcel: employee of MRM Health Shareholder of MRM Health Possemiers, Sam: Paid consultant of MRM Health Shareholder of MRM Health Haazen, Ludo: Paid consultant for MRM Health Shareholder of MRM Health Vermeire, Séverine: financial support for research from AbbVie, J & J, Pfizer, Takeda and Galapagos speakers’ and/or consultancy fees from AbbVie, Abivax, AbolerISPharma, AgomAb, Alimentiv, Arena Pharmaceuticals, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech-Roche, Gilead, GSK, Hospira, Imidomics, Janssen, J&J, Lilly, Materia Prima, Mestag Therapeutics, MiroBio, Morphic, MRM Health, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Surrozen, Takeda, Theravance, Tillots Pharma AG, VectivBio, Ventyx, Zealand Pharma.