DOP075Mirikizumab mediates clinical benefit through distinct mucosal cellular mechanisms in Crohn’s disease.

Abstract Background Interleukin (IL) -23 blockade is effective in Crohn’s disease (CD), yet the cellular mechanisms of clinical responses to selective IL-23 p19 inhibition are unclear. 1 High-resolution profiling of mucosal cell populations by single-nuclei RNA sequencing (snRNA-seq) offers insight into treatment-specific immunologic and epithelial remodeling. 2 Here, we compare cellular effects of placebo versus mirikizumab (miri) (anti–IL-23 p19) on ileal mucosa and link them to clinical outcomes in patients with moderately-to-severely active CD. Methods Ileal biopsies from 35 patients in the Phase 3 VIVID-1 trial (treated with placebo or miri) were analyzed by snRNA-seq (10x Genomics; 131, 934 high-quality nuclei) at baseline, Week (W) 12, and W52. 3 Cell types were annotated using canonical markers. Differential abundance of cell populations was assessed using three complementary frameworks: generalized linear mixed models (GLMM), scCODA (Bayesian), 4 and paired t-tests. Directional consistency and reproducibility across the frameworks were assessed to identify reliable trends in cell-proportion changes upon the treatment. We used regression analyses with GLMM to evaluate associations between cell-type proportion changes and clinical outcomes. Results snRNA-seq captured all major ileal cell lineages (Figure 1A, B). Miri treatment led to early reductions in activated plasmablasts (C17), CCR7+ dendritic cells (C27), and activated T-cells (C11₁) (Figure 1C), followed by gradual decreases in B-effector cells (C6), plasma cells (C19), and inflammatory monocytes (C9) through W52. Secretory epithelial goblet (C8) and goblet progenitor (C34) cells expanded progressively, while Paneth cells (C31) and absorptive stress-adapted enterocytes (C1) (Figure 1C) increased later in therapy (Table 1A). These shifts indicate mucosal healing and barrier restoration as defined by RHI. In contrast, placebo-treated samples showed no reproducible trends across methods for these cell types (Figure 1D). Regression analyses revealed miri-specific correlations between cell proportion changes and improved bowel urgency and histology symptoms (Figure 1E). Conclusion snRNA-seq analyses from the VIVID-1 trial reveal that miri treatment leads to reductions in inflammatory immune cells and recovery of secretory and absorptive epithelial cells in ileal mucosa from patients with CD. These cellular changes align with improved mucosal healing (by histopathological barrier integrity) and reduced bowel symptoms via distinct cellular mechanisms. Further studies with larger sample sizes are necessary to validate mechanistic differences within the IL-23 pathway and provide a framework for treatment in CD. References: 1. Dziegielewski C, Yuan Y, Ma C, et al. IL-23p19 Antagonists vs Ustekinumab for Treatment of Crohn’s Disease: A Meta-Analysis of Randomized Controlled Trials. Official journal of the American College of Gastroenterology | ACG. 2025;120 (10): 2260-2267. doi: 10. 14309/ajg. 0000000000003406 2. Maddipatla SC, Kolachala VL, Venkateswaran S, et al. Assessing Cellular and Transcriptional Diversity of Ileal Mucosa Among Treatment-Naïve and Treated Crohn’s Disease. Inflamm Bowel Dis. Feb 1 2023;29 (2): 274-285. doi: 10. 1093/ibd/izac201 3. Slyper M, Porter CBM, Ashenberg O, et al. A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors. Nature Medicine. 2020/05/01 2020;26 (5): 792-802. doi: 10. 1038/s41591-020-0844-1 4. Büttner M, Ostner J, Müller CL, Theis FJ, Schubert B. scCODA is a Bayesian model for compositional single-cell data analysis. Nature Communications. 2021/11/25 2021;12 (1): 6876. doi: 10. 1038/s41467-021-27150-6 Conflict of interest: Steere, Boyd: Employee of Eli Lilly and Company. Jain, Dhawal: Dhawal Jain is an employee and shareholder of Eli Lilly and Company Munoz Briones, Javier: Employee and shareholder of Eli Lilly and Company Fisher, Deborah: Employee and shareholder of Eli Lilly and Company Deepak, Parakkal: Parakkal Deepak has received research support under a sponsored research agreement unrelated to the data in the abstract from AbbVie, Johnson and Johnson, Sanofi, Merck, Teva, Direct Biologics, Tr1x, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Prometheus Biosciences, Takeda Pharmaceuticals, Roche Genentech, Eli Lilly, AstraZeneca, Spyre and Agomab, has received consulting fees from Johnson and Johnson, Abbvie, Merck, Sobi, Celltrion, Fresenius Kabi, Asahi Kasei Pharma, Sandoz and CorEvitas, LLC and has served on the board of the Srategic Alliance for Intercultural Advocacy in GI. Jairath, Vipul: Consulting Fees: Abbvie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, BMS, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Janssen, Lilly, Merck, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Pendopharm, Pioneering Medicine, Pfizer, Prometheus, Roche/Genentech, Sanofi, SCOPE, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Tillotts, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma. Reinisch, Walter: Personal Fees: WR has served as a speaker for AbbVie, Alfasigma, Celltrion, Ferring, JNJ, Galapagos Medice, Lilly, MSD, Roche, Pfizer, Sobi, Takeda, as a consultant for AbbVie, Agomab, Alfasigma, Alvotech, Amgen, Anaptys Bio, AOP Orphan, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead, Index Pharma, Janssen, Medahead, Merck, Microbiotica, Pfizer, Sanofi, Teva, Takeda as an advisory board member for AbbVie, Alfasigma, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, JNJ, Pfizer, Teva and has received research funding from AbbVie, JNJ, Sandoz, Sanofi, Takeda. Sands, Bruce E: Grant: Janssen, Bristol Myers Squibb, Pfizer Personal Fees: Abivax SA Abbvie Adiso Therapeutics Agomab Therapeutics Alimentiv Amgen AnaptysBio AstraZeneca Biora Therapeutics Boehringer-Ingeleim Bristol Myers Squibb Celltrion, Inc. ClostraBio Cytoki Pharma EcoR1 Capital Eli Lilly and Company Enthera Equilium, Inc. Ensho Therapeutics Evommune Ferring Galapagos Genentech, Inc. Gilead Sciences GlaxoSmithKline Gossamer Bio Imhotex Immunyx Pharma Ltd. Index Pharmaceuticals Innovation Pharmaceuticals Janssen Janssen Biotech Janssen Pharmaceutica NV Janssen Research & Development, LLC Janssen Scientific Affairs, LLC Janssen-Cilag PTY, Ltd. Johnson & Johnson Kaleido Kallyope Kyowa Kirin, Inc. Merck & Co. Microba Microbiotica Limited Mirador Therapeutics Morphic Therapeutic MRM Health NV Palisade Therapeutics Pfizer, Inc. Prometheus Biosciences Prometheus Laboratories Protagonist Therapeutics, Inc. Q32 Bio Sanofi Sorriso Therapeutics Surrozen Takeda Target RWE Teva TLL Pharmaceutical Tr1x Union Therapeutics Ventyx Biosciences Non-financial Support: Janssen, Pfizer, Lilly, Takeda, Bristol Myers Squibb Other: Stock/Stock Options from Ventyx Biosciences 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