TY - JOUR
T1 - Mirikizumab regulates genes involved in ulcerative colitis disease activity and anti-TNF resistance
T2 - results from a phase 2 study
AU - Steere, Boyd
AU - Schmitz, Jochen
AU - Powell, Nick
AU - Higgs, Richard
AU - Gottlieb, Klaus
AU - Liu, Yushi
AU - Jia, Bochao
AU - Tuttle, Jay L.
AU - Sandborn, William J.
AU - Sands, Bruce E.
AU - D'Haens, Geert
AU - Reinisch, Walter
AU - Krishnan, Venkatesh
N1 - Funding Information: The authors thank Taku Kobayashi of the Center for Advanced IBD Research and Treatment, Kitasato University, Kitasato Institute Hospital, Tokyo, Japan, for his insightful comments and discussion of the data, and the following employees of Eli Lilly: Linden Green for providing writing and editorial support, Meenu Kaur for providing analyst support, Catherine Milch for providing medical peer review and strategic analysis, and Ernst Dow for providing statistical and data review. Publisher Copyright: © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.
PY - 2023
Y1 - 2023
N2 - INTRODUCTION: Mirikizumab, a monoclonal antibody targeting the p19 subunit of interleukin (IL)-23, demonstrated efficacy and was well-tolerated in a phase 2 randomized clinical trial in patients with moderate-to-severe ulcerative colitis (UC) (NCT02589665). We explored gene expression changes in colonic tissue from study patients and their association with clinical outcomes. METHODS: Patients were randomized to receive intravenous placebo or 3 mirikizumab induction doses. Patient biopsies were collected at baseline and week 12, and differential gene expression was measured using a microarray platform and compared in all treatment groups to determine differential expression values between baseline and week 12. RESULTS: The greatest improvement in clinical outcomes and placebo-adjusted change from baseline in transcripts at week 12 was observed in the 200 mg mirikizumab group. Transcripts significantly modified by mirikizumab correlate with key UC disease activity indices (modified Mayo score, Geboes score, and Robarts Histopathology Index) and include MMP1, MMP3, S100A8, and IL1b. Changes in transcripts associated with increased disease activity were decreased after 12 weeks of mirikizumab treatment. Mirikizumab treatment affected transcripts associated with resistance to current therapies, including IL-1b, OSMR, FCGR3A and FCGR3B, and CXCL6, suggesting that anti-IL23p19 therapy modulates biological pathways involved in resistance to antitumor necrosis factor and Janus kinase inhibitors. DISCUSSION: This is the first large-scale gene expression study of inflamed mucosa from patients with UC treated with anti-IL23p19 therapy. These results provide molecular evidence for mucosal healing from an extensive survey of changes in transcripts that improve our understanding of the molecular effects of IL-23p19 inhibition in UC.
AB - INTRODUCTION: Mirikizumab, a monoclonal antibody targeting the p19 subunit of interleukin (IL)-23, demonstrated efficacy and was well-tolerated in a phase 2 randomized clinical trial in patients with moderate-to-severe ulcerative colitis (UC) (NCT02589665). We explored gene expression changes in colonic tissue from study patients and their association with clinical outcomes. METHODS: Patients were randomized to receive intravenous placebo or 3 mirikizumab induction doses. Patient biopsies were collected at baseline and week 12, and differential gene expression was measured using a microarray platform and compared in all treatment groups to determine differential expression values between baseline and week 12. RESULTS: The greatest improvement in clinical outcomes and placebo-adjusted change from baseline in transcripts at week 12 was observed in the 200 mg mirikizumab group. Transcripts significantly modified by mirikizumab correlate with key UC disease activity indices (modified Mayo score, Geboes score, and Robarts Histopathology Index) and include MMP1, MMP3, S100A8, and IL1b. Changes in transcripts associated with increased disease activity were decreased after 12 weeks of mirikizumab treatment. Mirikizumab treatment affected transcripts associated with resistance to current therapies, including IL-1b, OSMR, FCGR3A and FCGR3B, and CXCL6, suggesting that anti-IL23p19 therapy modulates biological pathways involved in resistance to antitumor necrosis factor and Janus kinase inhibitors. DISCUSSION: This is the first large-scale gene expression study of inflamed mucosa from patients with UC treated with anti-IL23p19 therapy. These results provide molecular evidence for mucosal healing from an extensive survey of changes in transcripts that improve our understanding of the molecular effects of IL-23p19 inhibition in UC.
KW - anti-TNF resistance
KW - molecular healing
KW - p-19 targeted IL23
UR - http://www.scopus.com/inward/record.url?scp=85150375787&partnerID=8YFLogxK
U2 - https://doi.org/10.14309/ctg.0000000000000578
DO - https://doi.org/10.14309/ctg.0000000000000578
M3 - Article
C2 - 36881820
SN - 2155-384X
VL - 14
JO - Clinical and translational gastroenterology
JF - Clinical and translational gastroenterology
IS - 7
M1 - e00578
ER -