Abstract Background Icotrokinra is the first targeted oral peptide that selectively blocks the IL-23 receptor (IL-23R) and precisely inhibits the IL-23 pathway. In ANTHEM-UC—a Phase 2b, randomised, double-blind, placebo (PBO)-controlled, dose-ranging study in adults with moderately to severely active ulcerative colitis (UC)—all doses of icotrokinra achieved the primary endpoint of clinical response and delivered clinically meaningful improvements across key secondary endpoints at Week (W)12,1 which were maintained or improved at W28.2 Here we report the impact of icotrokinra on systemic and tissue biomarkers of inflammatory burden in UC. Methods Participants were randomised (1:1:1:1) to receive once-daily icotrokinra 100 mg, 200 mg, 400 mg, or PBO. Clinical inflammatory biomarkers, C-reactive protein (CRP) and faecal calprotectin (FCP), along with serum IL-23 pathway biomarkers (IL-22, IL-17A, and IL-17F) were used to determine the impact of icotrokinra on systemic inflammation. Gene expression changes in colonic biopsies were used to confirm tissue IL-23 pathway engagement and dampening of tissue inflammation with icotrokinra. Results At the W12 primary timepoint, all doses of icotrokinra attenuated levels of serum CRP and FCP (Figure 1). All doses of icotrokinra, but not PBO, markedly reduced serum levels of IL-22, IL-17A, and IL-17F at W12 relative to baseline. Greater reductions in these serum biomarkers of IL-23 pathway activation were observed with the 200 mg and 400 mg doses relative to the 100 mg dose (Figure 1, nominal p 0.05). All doses of icotrokinra, but not PBO, markedly reduced expression of gene sets associated with the IL-23–driven inflammation in tissue at W12 relative to baseline (Figure 2, nominal p 0.0001). With icotrokinra treatment, the tissue transcriptome more closely resembled that of healthy individuals, with decreased expression of gene sets associated with UC-relevant inflammatory cell types and increased expression of genes characteristic of healthy epithelial cells. Importantly, dampening of systemic and tissue inflammation with icotrokinra was sustained at W28 (Figures 1 13(suppl 8):172-3. 2. Jairath V, et al. Am J Gastroenterol. 2025 120;10(suppl 2):S312. Conflict of interest: Louis, Edouard: Education and Research Grants for my department: Abbvie, Takeda, Janssen, Pfizer, Fresenius-Kabi, Celltrion, EG pharma, Sandoz, Falk Personal Fees for conferences, advisory boards and consultancy: Abbvie, Takeda, Ferring, Pfizer, Janssen, Lilly, Galapagos, Celltrion, Arena, BMS, Falk, Biokuris, Fresenius-Kabi, Thabor Jairath, Vipul: Consulting fees from AbbVie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, Bristol Myers Squibb, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Johnson & Johnson, 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. Siegmund, Britta: Consultant for AbbVie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Galapagos, Johnson & Johnson, Materia Prima, MSD, Pfizer, Takeda, Wedbush Securities speaker for AbbVie, AlfaSigma, Bristol Myers Squibb, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, Ferring, Galapagos, Johnson & Johnson, MD Education, MSD, Pfizer, Tr1xBio grant from Pfizer. Kannan, Arun K: Employee and shareholder of Johnson & Johnson Zeeman, Martha: Employee and shareholder of Johnson & Johnson Hart, Amy: Employee and shareholder of Johnson & Johnson Strawn, David: Employee and shareholder of Johnson & Johnson Venkat, Swati: Employee and shareholder of Johnson & Johnson Tomsho, Lynn: Employee and shareholder of Johnson & Johnson Mcrae, Bradford: Employee and shareholder of Johnson & Johnson Ruane, Darren: Employee and shareholder of Johnson & Johnson Surace, Lindsey: Employee and shareholder of Johnson & Johnson Erondu, Ngozi: Employee and shareholder of Johnson & Johnson Zhan, Joyce: Employee and shareholder of Johnson & Johnson Chen, Minhu: I have received speaker honoraria from Takeda China, Xian Janssen, and AbbVie China, as well as research funding from Takeda (China). Chachu, Karen: Advisory board for Johnson & Johnson consultant for OptumRx Matsuoka, Katsuyoshi: Grant: Abbvie Inc., Mochida Pharmaceutical Co., Ltd., ZERIA Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., JIMRO Co., Ltd. Personal Fees: Mitsubishi Tanabe Pharma, Janssen Pharmaceutical K.K., Abbvie Inc., EA Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., ZERIA Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Kyorin Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Gilead Sciences, Celltrion Healthcare, Bristol-Myers Squibb Limdi, Jimmy: Speaker/consultancy fees from AbbVie, Abivax, Arena, BioHit, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Johnson & Johnson, MSD, Pfizer, Takeda research support from Galapagos, Takeda Rydzewska, Grazyna: Speaker and consultant fees from AbbVie, AlfaSigma, AstraZeneca, Bayer, Biocodex, Bristol Myers Squibb, Ferring, Johnson & Johnson, Lilly, PRO.MED.Pl, Recordati, Sanprobi, SOBI, Takeda travel/accommodation meeting expenses from AbbVie, Ferring, Takeda Abreu, Maria Teresa: Grant/Research Support: Janssen, Prometheus Bioscience, Takeda Consultant: Janssen, Prometheus Bioscience, Takeda Gilead, Eli Lilly, AbbVie Inc., Bristol Myers, Imedex, Loftus Jr, Edward V: Consultant/advisory board member for AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly and Company, Genentech, Gilead Sciences, Johnson & Johnson, Pfizer, Takeda, UCB.
Louis et al. (Thu,) studied this question.