What question did this study set out to answer?

This research aims to identify a gene expression panel predictive of treatment response to Mirikizumab in patients with ulcerative colitis.

January 23, 2026

P0953A panel of 11 genes from colon and rectum biopsies in the LUCENT-URGE study shows utility for predicting responses to mirikizumab treatment of Ulcerative Colitis

Key Points

This research aims to identify a gene expression panel predictive of treatment response to Mirikizumab in patients with ulcerative colitis.
Collected colon and rectum biopsies from 145 and 151 participants, respectively, at baseline, Week 12, and Week 28.
Measured gene expression levels of a specific 11-gene panel using qRT-PCR with a housekeeping gene for normalization.
Conducted machine learning analyses and logistic regression models to evaluate predictive utility of the gene panel based on clinical metrics.
At Weeks 12 and 28, significant changes in gene expression were observed in responders compared to non-responders.
Baseline expression of the gene panel predicted treatment response with AUC values exceeding 68% at Week 12 and 74% at Week 28.
Specific genes provided the highest accuracy for predicting histo-endoscopic mucosal improvement and clinical remission based on bivariate analyses.

Abstract

Abstract Background Mirikizumab (MIRI), an anti-Interleukin (IL) -23p19 IgG4 antibody, has demonstrated efficacy as a treatment for ulcerative colitis (UC) and changes in colon gene expression have been shown to correlate with disease activity indices at weeks (W) 12 and 521, 2. Machine-learning analyses revealed a signature of 11 genes associated with response to MIRI. We investigated expression changes of this gene signature between MIRI-Responders (MIRI-R) and non-responders (MIRI-NR) and its predictive utility for treatment response related to key clinical metrics in the LUCENT-URGE (NCT05767021) Phase 3b study of participants (Pts) with moderately-to-severely active UC. Methods Colon n = 145 and rectum n = 151 mucosa biopsies were collected at baseline, W12 (colon n = 145, rectum n = 148), and W28 (colon n = 114, rectum n = 119). Levels of ABI1, AQP8, CXCL1, DEFB4B, HNF4A, IL1B, IL23A, MMP3, OTOP2, PTPRC, and SLC26A2 genes were obtained using qRT-PCR, with RPLP0 as a housekeeping gene. MIRI-induced gene expression changes were measured as changes from baseline to W12 and W28 derived from mixed model with repeated measurements using the NLME package3. To evaluate the predictive utility of this gene signature, stepwise logistic regression models were performed per clinical metric at W12 and W28 to identify the most informative gene subsets, using MASS package for feature selection. Baseline expression of these differentially expressed genes was used for predictive utility analyses. For each clinical outcome analyzed, the AUC provided the predictive value of the 11-gene panel for endpoint achievement. Results At W12 and W28, MIRI significantly (p ≤ 0. 05) modulated colon and rectum gene expression versus W0 in MIRI-R and MIRI-NR (Fig 1A and B). Baseline gene expression predicted MIRI-R and MIRI-NR according to the endpoints, W12 (AUC68%) and W28 (AUC74%) (Table 1). Patients achieving W12 colon HEMI (Histo-Endoscopic Mucosal Improvement-Colon) were identified with the highest accuracy using a combination of colon CXCL1, IL23A, DEFB4B, SLC26A2, and AQP8 baseline expressions (AUC=75. 6%), and at W28 with MMP3, IL1B, DEFB4B, SLC26A2, and AQP8 (AUC=81. 3%). W12 Clinical remission achievement was classified with rectal CXCL1, HNF4A, and IL23A (AUC=78. 7%) and W28 with rectal AQP8, IL1B, IL23A, and PTPRC (AUC=78. 7%) (Table 1, Fig 1C). Conclusion 1. MIRI efficacy is associated with robust colon and rectum DEFB4B, CXCL1, MMP3, IL1B, IL23A, and PTPRC downregulations, and HNF4A, OTOP2, SLC26A2, and AQP8 upregulations through W28. 2. In this work we demonstrate the utility of baseline expression of the above gene panel as a predictive biomarker for MIRI treatment response as defined by key treatment outcomes, including BU in the AMBZ trial. References: 1. Steere B, Schmitz J, Powell N, et al. Mirikizumab Regulates Genes Involved in Ulcerative Colitis Disease Activity and Anti-TNF Resistance: Results From a Phase 2 Study. Clinical and Translational Gastroenterology 2023;14 (7). DOI: 10. 14309/ctg. 0000000000000578. 2. T J, B S, P Z, et al. Mirikizumab-Induced Transcriptome Changes in Ulcerative Colitis Patient Biopsies at Week 12 Are Maintained Through Week 52 - PubMed. Clinical and translational gastroenterology 11/01/2023;14 (11). DOI: 10. 14309/ctg. 0000000000000630. 3. Pinheiro, J. , Bates, D. , DebRoy, S. , Sarkar, D. , & R Core Team. (2021). nlme: Linear and Nonlinear Mixed Effects Models. https: //CRAN. R-project. org/package=nlme 4. MASS R package: Venables, W. N. , & Ripley, B. D. (2002). Modern Applied Statistics with S (4th ed. ). Springer. Conflict of interest: Munoz Briones, Javier: Employee and shareholder of Eli Lilly and Company. Eastman, William: Eli Lilly employee and shareholder. Moses, Richard: Employed by Eli Lilly Own Eli Lilly stock Colombel, Jean-Frédéric: Grant: AbbVie, Janssen Pharmaceuticals, Takeda, Prometheus and Bristol Myers Squibb Lectures from: AbbVie, Roche and Takeda Other: AbbVie, Amgen, AnaptysBio, Allergan, Apini, Arena Pharmaceuticals, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, candidrx Celgene, Celltrion, Clearview Curogen, Eli Lilly, Envision Pharma Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Roche, Janssen Pharmaceuticals, Kaleido Biosciences, Immunic, Iterative Scopes, Landos, Microba Life Science, Merck, Mirador, Novartis, Otsuka Pharmaceutical, Owkin, Pfizer, Protagonist Therapeutics, Sanofi, Sun Pharma, Takeda, Teva, TiGenix, and is holding stock options in Intestinal Biotech Development Feagan, Brian Gordon: Consulting Fees: AbbVie, Abivax, Adaxion, Adiso, AgomAB Therapeutics, Akros, Alira Health, Ally Bridge Group, Apini Therapeutics, Argenx, Attovia Tx, Avoro Capital Advisors, Belmore Law, Biora Therapeutics, Blackbird Laboratories, Boehringer-Ingelheim, BMS, Boxer Capital, Celgene/BMS, Clarivate, Connect Biopharm, EcoR1, Eli Lilly, Ensho Therapeutics, Equillium, Evida, Enveda, Evommune Inc. Faes Farma, First Wave, Forbion, Galapagos, Genentech/Roche, General Atlantic, Genesis Therapeutics, Gerson Lehrman Group, Gilead, Guidepoint, Imhotex, ImiDomics, Immunic Therapeutics, Janssen, Japan Tobacco Inc. , LifeMine Therapeutics, Mage Biologics, Merck, Mirador Therapeutics, Mobius Care, Monte Rosa Tx, Morphic Therapeutics, Nimbus Therapeutics, Novartis, Nxera, OncoC3, Palisade Bio, Pendopharm, Pfizer, Q32 Bio, REDX, Roche, Sanofi, Sobi, Sorriso, Spyre Therapeutics, Sun Pharma, Surrozen Inc. , Synedgen, Takeda, Tegus Inc. , Teva, Tillotts, Trex Bio, TR1X Inc. TVM Lifesciences, Ventyx Biosciences, Versant Ventures, Vida Ventures, Ysios Capital, Zagbio Stock Shareholder: Connect Biopharm, EnGene, Evida, SRT, Imidomics, Enveda 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. 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 Steere, Boyd: Employee and shareholder of Eli Lilly and Company.

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