Abstract Background Obefazimod (Obe) is an oral, first-in-class enhancer of the anti-inflammatory microRNA miR-1241 showing efficacy and safety in ulcerative colitis (UC) patients2-4. A major complication of chronic inflammation in inflammatory bowel disease (IBD) is fibrosis, particularly in Crohn’s disease (CD). To date, no efficacious anti-fibrotic treatment for IBD patients is available. As miR-124 is reduced in fibrotic tissue and can suppress TGF-β, a central driver of fibrogenesis, we assessed whether Obe-mediated miR-124 induction affects collagen deposition and fibrotic markers in preclinical models. Methods Two sets of experiments were performed to assess the anti-fibrotic effects of Obe: (A) In vitro fibrosis was evaluated in the Scar-in-a-Jar (SiaJ) model using human small-intestinal fibroblasts, stimulated with an IBD-fibrotic cytokine cocktail (IBD-FC). Nintedanib, omipalisib and upadacitinib were used as comparators. Readouts included cytotoxicity, PRO-C3, and α-SMA. (B) In vivo effects were assessed in the chronic TNBS-colitis mouse model, where Obe (100 mg/kg) or control (vehicle or thalidomide) were administered orally either from day 5 (anti-inflammatory + fibrosis-preventive effect) or from day 20 (early-onset anti-fibrotic effect). Disease activity, body weight, colon parameters, histology and collagen deposition were analyzed. Statistics: ANOVA with multiple comparisons. Results In vitro, Obe induced a significant 50% reduction in PRO-C3 at day 12, compared with the IBD-FC condition and upadacitinib (live-cell–adjusted, p 0.0001 vs. IBD-FC; Fig. 1A). Notably, the IBD-FC SiaJ assay showed pathway specificity: nintedanib showed no activity, while omipalisib did (Fig 1B). Additionally, cell-number–adjusted analysis showed significant α-SMA reduction by Obe indicating a strong inhibition of fibroblast activation (p 0.0001 vs. IBD-FC, Fig 1B). In vivo, the known anti-inflammatory effects of Obe were confirmed in the chronic colitis model under both dosing schedules (Fig. 2A). Moreover, results from this initial experiment showed a reduction in the fibrosis score (Fig. 2B) and collagen deposition was reduced by ∼52% with day 5 dosing and ∼42% with day 20 dosing in the Sirius Red assay, whereas thalidomide as a positive control achieved ∼24%. (Fig. 2C). Conclusion These data support an anti-fibrotic effect of Obe in two well-established models, inhibiting collagen deposition and fibroblast activation. Initial in vivo mouse data, aligned with the in vitro findings, indicate that Obe may act in a unique way on both intestinal inflammation and fibrosis. These promising results provide a strong rationale to further investigate Obe’s anti-fibrotic potential in the ongoing phase 2b Crohn’s disease trial (NCT#06456593). References: 1.Apolit C et al. Clin Transl Gastroenterol. 2023;14(4):e00560 2.Vermeire S, et al. J Crohns Colitis. 2023; 17: 1689-1697 3.Vermeire S, et al. Gastroenterology 2021; 160: 2595-2598 4.Vermeire S, et al. The Lancet Gastroenterology 7: 1024-1035 Conflict of interest: 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 Magro, Fernando: Fernando Magro served as speaker and received honoraria from Abbvie, Arena, Biogen, Bristol-Myers Squibb, Falk, Ferring, Hospira, Janssen, Laboratórios Vitoria, Pfizer, Lilly, Merck Sharp & Dohme, Sandoz, Takeda, UCB, Vifor. 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 & ampJohnson, MD Education, MSD, Pfizer, Tr1xBio. 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. Santo, Julien: Employee of Abivax Garcel, Aude: Employee of Abivax D’Alessio, Silvia: I have served as a consultant for Ferring Pharmaceuticals, Cytoki Pharma, Dompè, Takeda, Attovia, Surrozen, Enthera Pehrsson, Martin: Employed at Nordic Bioscience A/S Mortensen, Joachim: Fulltime employee and stock owner at Nordic Bioscience Sorokina Alexdóttir, Marta: Fulltime employee at Nordic Bioscience Bay-Jensen, Anne-Christine: Fulltime employee and stock owner at Nordic Bioscience Karsdal, Morten Asser: Fulltime employee and stock owner at Nordic Bioscience Mosig, Rebecca: Employee of Abivax Rabbat, Chris: Employee of Pfizer, Inc. de la Rosa, Maurus: Employee of Abivax Cataldi, Fabio: 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.
Danese et al. (Thu,) studied this question.