P0868Obefazimod enhances miR-124 expression in blood and colon tissue and reduces the key inflammatory cytokines IL-17A and IL-6 in serum of patients with moderate-to-severely active ulcerative colitis: results from the Phase 3 ABTECT induction trials

Abstract Background Obefazimod (Obe) is an oral, once-daily (QD) small molecule that enhances expression of microRNA-124 (miR-124) and has shown improvements in clinical, endoscopic, and histologic endpoints in patients (pts) with moderate to severely active ulcerative colitis (UC) in Phase 2 trials 1-3 and the Phase 3 ABTECT 8-week induction trials (NCT05507203, NCT05507216). We assessed the effects of Obe on miR-124 expression in blood and colon tissue and serum cytokine levels from pts at baseline and week 8 (W8) of the ABTECT trials. Methods Absolute quantification of miR-124 copy number was performed at baseline and W8 using droplet digital PCR (ddPCR; QuantaSoft Pro). Folder change in miR-124 were available in 268 pairs of rectal, 673 pairs of sigmoidal biopsy samples, and 538 pairs of peripheral blood mononuclear cell (PBMC) samples from pts receiving Obe-25, Obe-50, or placebo (PBO). Cytokines IL-17A and IL-6 were measured by ELLA 5-plex (Biotechne) and S-Plex Human (MSD), respectively in 1126 and 1110 pairs of serum samples at baseline and W8 for IL-6 and IL-17A, respectively. For miR-124, estimates are from ANCOVA model with treatment and randomization stratification factors (inadequate response to advanced therapies -ATIR (yes/no), baseline oral corticosteroids - CS (yes/no), and for ABTECT-2 only, region (Japan/rest of world) as fixed factors, and log10-transformed baseline value as a covariate. P-values are two-sided and obtained using Dunn’s Test. For cytokines, estimates are from a MMRM model with fixed categorical effects for treatment, visit, treatment-by-visit interaction and randomization stratification factors (ATIR (yes/no), baseline oral CS (yes/no), and for ABTECT-2 only, region (Japan/rest of world), as well as a fixed continuous effect for the baseline value of the outcome of interest. An unstructured covariance matrix is used to model the within-subject variance-covariance structure. P-values are two sided. Results In both Phase 3 ABTECT trials, Obe-25 and 50 mg significantly enhanced expression of miR-124 in blood (p 0.0001 vs. PBO) and in rectal and sigmoidal tissue at W8 relative to PBO (p 0.0001 vs. PBO) (Fig. 1). In both ABTECT trials, Obe-25 and 50 mg significantly reduced IL-17A levels in serum at W8 compared with PBO (p 0.0001). IL-6 levels were decreased by Obe-25 (p = 0.0150) and Obe-50 (p = 0.0039) in serum of pts from ABTECT-1 and ABTECT-2 in comparison to PBO, respectively (Fig. 2). Conclusion In the ABTECT induction trials conducted in pts with UC, Obe was associated with enhanced expression of miR-124 and nominally statistically significant reductions in the pro-inflammatory cytokines IL-17A and IL-6. These findings are consistent with the Phase 2 trial results and reflect restoration of immune homeostasis. References: 1. Vermeire S, et al. J Crohns Colitis. 2023; 17: 1689-1697 2. Vermeire S, et al. Gastroenterology 2021; 160: 2595-2598 3. Vermeire S, et al. The Lancet Gastroenterology 7: 1024-1035 Conflict of interest: Siegmund, Britta: Grant: Pfizer Other: Consultant: Abbvie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Galapagos, Janssen/Johnson & Johnson, Materia Prima, MSD, Pfizer, Takeda, Wedbush Securities. Speaker: Abbvie, AlfaSigma, Bristol Myers Squibb, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, Ferring, Galapagos, Janssen/Johnson & Johnson, MD Education, MSD, Pfizer, Tr1xBio. Danese, Silvio: Personal Fees: AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor Lecture fees from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, Takeda Dubinsky, Marla C: Personal Fees: Consultant or Advisory Board: Abbvie, Abivax, Astra Zeneca, BMS, Celltrion, Gilead, Genentech, Janssen, Johnson and Johnson, Lilly, Merck, Pfizer, Prometheus Biosciences, Sanofi, Spyre, Target RWE, Takeda Other: Shareholder, Co-founder, Board of Directors of Trellus Health Co-Founder Mi Test Health Atreya, Raja: RA has served as a speaker, or consultant, or received research grants from AbbVie, Abivax, AlfaSigma, Arena Pharmaceuticals, Astra-Zeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Dr Falk Pharma, Galapagos, Gilead, GlaxoSmithKline, InDex Pharmaceuticals, Johnson & Johnson, Lilly, Materia Prima, Merck Sharpe & Dohme, Pfizer, Roche Pharma, Takeda Pharma, Viatris. Abecassis-Borgus, Audrey: Abivax employee Apolit, Cécile: Abivax employee Sandri, Johanna: Abivax employee Belda, Carole: No conflict of interest Amin, Priya: No conflict of interest Santo, Julien: Employee of Abivax Mosig, Rebecca: Employee of Abivax Jacobstein, Doug: Abivax employee Cataldi, Fabio: Employee of Abivax Rabbat, Chris: Employee of Abivax Howaldt, Stefanie: Dr. Howaldt served as the Principal Investigator for the presented study sponsored by Abivax. Verstockt, Bram: Research support from AbbVie, Biora Therapeutics, Celltrion, Landos, Pfizer, Sanofi, Sossei Heptares/Nxera and Takeda. Speaker’s fees from Abbvie, Agomab, Alfasigma, Biogen, Bristol Myers Squibb, Celltrion, Eli Lily, Falk, Ferring, Galapagos, Materia Prima, Johnson and Johnson, Pfizer, Sandoz, Takeda, Tillots Pharma, Truvion and Viatris. Consultancy fees from Abbvie, Alfasigma, Alimentiv, Anaptys Bio, Applied Strategic, Astrazeneca, Atheneum, BenevolentAI, Biora Therapeutics, Boxer Capital, Bristol Myers Squibb, Domain Therapeutics, Eli Lily, Galapagos, Guidepont, Landos, Merck, Mirador Therapeutics, Mylan, Nxera, Inotrem, Ipsos, Johnson and Johnson, Pfizer, Sandoz, Sanofi, Santa Ana Bio, Sapphire Therapeutics, Sosei Heptares, Takeda, Tillots Pharma and Viatris. Stock options Vagustim and Thethis Pharma. D’Haens, Geert: Grant: Pfizer, BMS, Johnson and Johnson, Abbvie, Alimentiv BV, Eli Lilly, Takeda, Prometheus Laboratories Personal Fees: Abbvie, Abivax, Agomab, Alimentiv, Anaptys Bio, AstraZeneca, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Galapagos, Glaxo Smith Kline, Dr Falk Pharma, Pfizer, Johnson and Johnson, Merck, Mirador, Polpharma, Procise Diagnostics, Prometheus Biosciences, Sorriso Pharma, Spyre, Takeda, Ventyx Dulai, Parambir: Grant: Takeda, Janssen, Pfizer, Abbvie, Polymedco, Buhlmann, Prometheus Personal Fees: Takeda, Janssen, Pfizer, Abbvie, Polymedco, Buhlmann, Prometheus