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. 2023 Nov 1;14(11):e00630.
doi: 10.14309/ctg.0000000000000630.

Mirikizumab-Induced Transcriptome Changes in Ulcerative Colitis Patient Biopsies at Week 12 Are Maintained Through Week 52

Travis Johnson  1 , Boyd Steere  2 , Pengyue Zhang  1 , Yong Zang  1 , Richard Higgs  2 , Catherine Milch  3 , Walter Reinisch  4 , Julian Panés  5 , Kun Huang  1 , Geert D'Haens  6 , Venkatesh Krishnan  2
Affiliations

Mirikizumab-Induced Transcriptome Changes in Ulcerative Colitis Patient Biopsies at Week 12 Are Maintained Through Week 52

Travis Johnson et al. Clin Transl Gastroenterol. .

Abstract

Introduction: Mirikizumab, an anti-interleukin-23p19 monoclonal antibody, demonstrated efficacy in phase 2 and 3 randomized clinical trials of patients with moderate-to-severe ulcerative colitis (UC). Previous results have shown that 12 weeks of mirikizumab treatment downregulated transcripts associated with UC disease activity and tumor necrosis factor inhibitor resistance. We assessed week-52 gene expression from week-12 responders receiving mirikizumab or placebo.

Methods: In the phase 2 AMAC study (NCT02589665), mirikizumab-treated patients achieving week-12 clinical response were rerandomized to mirikizumab 200 mg subcutaneous every 4 or 12 weeks through week 52 (N = 31). Week-12 placebo responders continued placebo through week 52 (N = 7). The limma R package clustered transcript changes in colonic mucosa biopsies from baseline to week 12 into differentially expressed genes (DEGs). Among DEGs, similarly expressed genes (DEGSEGs) maintaining week-12 expression through week 52 were identified.

Results: Of 89 DEGSEGs, 63 (70.8%) were present only in mirikizumab induction responders, 5 (5.6%) in placebo responders, and 21 (23.6%) in both. Week-12 magnitudes and week-52 consistency of transcript changes were greater in mirikizumab than in placebo responders (log2FC > 1). DEGSEG clusters (from 84 DEGSEGs identified in mirikizumab and mirikizumab/placebo responders) correlated to modified Mayo score (26/84 with Pearson correlation coefficient [PCC] >0.5) and Robarts Histopathology Index (55/84 with PCC >0.5), sustained through week 52.

Discussion: Mirikizumab responders had broader, more sustained transcriptional changes of greater magnitudes at week 52 vs placebo. Mirikizumab responder DEGSEGs suggest a distinct molecular healing pathway associated with mirikizumab interleukin-23 inhibition. The cluster's correlation with disease activity illustrates relationships between clinical, endoscopic, and molecular healing in UC.

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Conflict of interest statement

Guarantor of the article: Venkatesh Krishnan, MSc, PhD.

Specific author contributions: T.J.: contributed to conception of the work, design of the work, analysis of data for the work, interpretation of data for the work, drafting of the work, and critical revision of the work for important intellectual content. B.S.: contributed to analysis of data for the work, drafting of the work, and critical revision of the work for important intellectual content. P.Z., R.H., C.M., W.R., J.P., and G.D.: contributed to interpretation of data for the work and critical revision of the work for important intellectual content. Y.Z.: contributed to conception of the work, design of the work, interpretation of data for the work, and critical revision of the work for intellectual content. K.H.: contributed to design of the work, analysis of data for the work, interpretation of data for the work, and critical revision of the work for important intellectual content. V.K.: contributed to conception of the work, analysis of data for the work, interpretation of data for the work, drafting of the work, and critical revision of the work for important intellectual content.

Financial support: The study and analysis were funded by Eli Lilly and Company.

Potential competing interests: B.S., R.H., and V.K. are current employees and shareholders of Eli Lilly and Company. C.M. is a shareholder and former employee of Eli Lilly and Company. T.J., P.Z., Y.Z., and K.H. report no conflicts of interest. W.R. reports grant support and personal fees from Abbott Laboratories, AbbVie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnostik, and Merck Sharp & Dohme; and personal fees from Aptalis, Celltrion, Danone Austria, Elan, Ferring, Mitsubishi Tanabe Pharma Corporation, Otsuka, PDL BioPharma, Pharmacosmos, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult, Amgen, AM Pharma, Astellas, AstraZeneca, Avaxia, Bioclinica, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Covance, Galapagos, Genentech, Gilead Sciences, Grünenthal, ICON, Index Pharma, Inova, Janssen, Johnson and Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millennium, Nestle, Novartis, Ocera, Pfizer, Procter & Gamble, Prometheus, Robarts Clinical Trial, Second Genome, SetPoint Medical, TiGenix, UCB, Zyngenia, and 4SC. J.P. has received financial support for research from AbbVie and Pfizer; received lecture fee(s) from AbbVie, Ferring, Janssen, and Takeda; and received consultancy fees from AbbVie, Arena Pharmaceuticals, Athos, Boehringer Ingelheim, Celltrion, Ferring, Galapagos, Genentech, GSK, Janssen, Mirum Pharma, Morphic Therapeutic, Origo, Pandion, Pfizer, Progenity, Robarts, Roche, Takeda, Theravance, and Wassermann. G.D. has served as an advisor for AbbVie, Ablynx, Allergan, Alphabiomics, Amakem, Amgen, AM Pharma, Arena Pharmaceuticals, AstraZeneca, Avaxia, Biogen, BristolMyers Squibb, Boehringer Ingelheim, Celgene/Receptos, Celltrion, Cosmo, Echo Pharmaceuticals, Eli Lilly and Company, Engene, Ferring, Dr. Falk Pharma, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Gossamerbio, Hospira/Pfizer, Immunic, Johnson and Johnson, Kintai Therapeutics, Lycera, Medimetrics, Millennium/Takeda, Medtronics, Mitsubishi Pharma, Merck Sharp Dome, Mundipharma, Nextbiotics, Novo Nordisk, Otsuka, Pfizer/Hospira, Photopill, Prodigest, Prometheus Laboratories/Nestlé, Progenity, Protagonist, RedHill, Robarts Clinical Trials, Salix, Samsung Bioepis, Sandoz, Seres/Nestle, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant, and Vifor and has received speaker fees from AbbVie, Biogen, Ferring, Johnson and Johnson, Merck Sharp Dome, Mundipharma, Norgine, Pfizer, Samsung Bioepis, Shire, Millennium/Takeda, Tillotts, and Vifor.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Identified DEGSEGs. (a) A Venn diagram shows the DEGSEGs identified in the miri and PBO treatment arms. (b) The 21 miri-PBO intersecting DEGSEGs are plotted on a heatmap, showing their expression. In Figure 1b, rows are clustered based on expression, and columns are sorted by timepoint (week) and treatment arm (miri or PBO). Brackets indicate whether DEGSEGs were upregulated or downregulated. The black box indicates PBO responders at week 12, and the brown box indicates nonresponders (miri and PBO) at week 52. DEG, differentially expressed gene; DEGSEG, differentially expressed gene that is a similarly expressed gene; Mayo, Mayo score; miri, mirikizumab; PBO, placebo.
Figure 2.
Figure 2.
DEGs at weeks 12 and 52. (a) Volcano plot of baseline to week 12 and baseline to week 52 DEGs in mirikizumab responders, overlaid for all genes. (b) Top DEGs from baseline to week-12 DEGs (|FC|>2.4, P < 0.05) at weeks 12 and 52 in mirikizumab responders. (c) Volcano plot of baseline to week-12 and baseline to week-52 DEGs in placebo responders, overlaid for all genes. (d) Top DEGs identified in (b) from baseline to week-12 DEGs at weeks 12 and 52 in placebo responders. In (a) and (c), the same gene is connected by a solid black line between the week-12 and -52 timepoints. In (b) and (d), the same genes are plotted (i.e., the top baseline to week-12 DEGs in mirikizumab responders). DEG, differentially expressed gene; FC, fold change; NS, nonsignificant.
Figure 3.
Figure 3.
Identification of transcriptional “response.” (a) UMAP visualization of all mirikizumab and placebo treatment arm samples by timepoint and GMM cluster. (b) Transcriptional response and nonresponse clusters. (c) UMAP visualization of placebo treatment arm samples by timepoint. (d) Mirikizumab treatment arm samples by timepoint. In (b), (c), and (d), the dashed red line stratifies the transcriptional response and nonresponse clusters. In (c) and (d), each patient's samples are connected by a solid gray line. If the gray line crosses the dashed red line from baseline to week 12 and not from weeks 12 to 52, that patient is a transcriptional responder. GMM, Gaussian mixture model; UMAP, uniform manifold approximation and projection.
Figure 4.
Figure 4.
Correlation of mirikizumab responder DEGSEGs with UC disease activity indices. (a) PCC between DEGSEG changes from baseline to week 12 and RHI. (b) PCC between DEGSEG changes from baseline to week 52 and RHI. (c) PCC between DEGSEG changes from baseline to week 12 and Mayo score. (d) PCC between DEGSEG changes from baseline to week 52 and Mayo score. The 20 most positively correlated and 20 most negatively correlated genes are labeled in each panel. DEGSEG, differentially expressed gene that is a similarly expressed gene; NS, nonsignificant; PCC, Pearson correlation coefficient; RHI, Robarts Histopathology Index; UC, ulcerative colitis.
Figure 5.
Figure 5.
Pathway enrichment in the 84 mirikizumab and mirikizumab/placebo DEGSEGs. (a) Canonical IPA results for the top 10 most significant pathways. (b) Graphical summary of IPA results. DEGSEG, differentially expressed gene that is a similarly expressed gene; IL, interleukin; IPA, ingenuity pathway analysis.
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