Plaque psoriasis drug shows favourable signals for the treatment of ulcerative colitis.Icotrokinra—the first and only targeted oral peptide designed to selectively block the interleukin-23 receptor (IL-23R), which has been approved for the treatment of plaque psoriasis—shows multiple favourable signals for the treatment of ulcerative colitis (UC), according to updated data from the phase IIb ANTHEM-UC study.
Reduced inflammatory burden
“Precisely blocking the IL-23R with once-daily icotrokinra reduced IL-21–mediated inflammatory burden in the systemic circulation and in the tissue of UC patients,” said Dr Edward Loftus from the Mayo Foundation for Medical Education and Research, Rochester, Minnesota, US, at DDW 2026.
At week (W)12, all icotrokinra doses attenuated serum C-reactive protein (CRP) levels, with the greatest reductions observed with the 200- and 400-mg doses. The treatment effect with the 400-mg dose was sustained through W28 (nominal p<0.05). The same significant treatment effect at W28 was observed for faecal calprotectin (FCP) with the 200- and 400-mg doses (p<0.001). [DDW 2026, abstract 27]
Loftus noted that the CRP and FCP data were expressed as a log2 fold change (log2FC)—a log2FC of –1 represents a 50-percent decrease from baseline.
All icotrokinra doses markedly reduced serum levels of systemic IL-23 pathway biomarkers (IL-22, IL-17A, IL-17F) at W12 (p<0.001), with reductions sustained through W28. The most significant treatment effect was observed with the 400-mg dose across all biomarkers at both timepoints (p<0.001 for all).
All icotrokinra doses also reduced expression of gene sets associated with IL-23–driven inflammation in tissue at W12 and W28 relative to baseline (nominal p<0.0001 for all doses and timepoints).
Importantly, dampening of the tissue inflammatory burden with icotrokinra was sustained at W28 (p<0.0001).
With icotrokinra, 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. “These findings suggest that icotrokinra induced transcriptional changes that are consistent with dampening of IL-23–driven inflammation and normalization of the tissue transcriptome,” Loftus said.
“Overall, we show for the first time that blocking the IL-23R can inhibit IL-23–mediated inflammatory signalling in UC patients. Icotrokinra induced a sustained reduction in systemic and tissue biomarkers of inflammatory burden in UC,” said Loftus.
ADT-IR status
In ANTHEM-UC, 252 UC patients (mean age 41.6 years, 58.3 men, mean modified Mayo score 6.63, 58.7 percent with Mayo endoscopic subscore 3 [severe]) were randomized 1:1:1:1 to oral icotrokinra 100, 200, or 400 mg, or placebo QD. At W16, inadequate responders in the placebo group were switched to icotrokinra 400 mg; in the icotrokinra groups, they received a sham treatment.
Participants were stratified according to inadequate response/intolerance (IR) to advanced therapies (ADT) status: ADT-IR (IR to tumour necrosis factor-α, IL-12/23, and integrin receptor antagonists; Janus kinase inhibitors; or S1P modulators; n=109) or non–ADT-IR (IR to corticosteroids [CS], 6-mercaptopurine, or azathioprine, or CS dependence [ADT exposure without IR is allowed]; n=143). [DDW 2026, abstract 487]
Clinical response rates were generally higher with all icotrokinra doses vs placebo in both the ADT-IR (W12: 42.3–55.2 percent vs 17.9 percent; W28: 42.3–62.1 percent vs 25 percent) and non–ADT-IR subgroups (57.9–70.6 percent vs 34.3 percent and 65.8–77.8 percent vs 25.7 percent, respectively).
The rates of key secondary endpoints—symptomatic remission, clinical remission, endoscopic improvement, and histologic–endoscopic mucosal improvement—were maintained or improved with all icotrokinra doses in both ADT-IR and non–ADT-IR subgroups at W12 to W28.
Of note, more non–ADT-IR participants met the study endpoints than those in the ADT-IR subpopulation, Loftus noted.
“[Taken together,] participants with moderate-to-severe active UC experienced clinically meaningful efficacy with oral icotrokinra QD irrespective of ADT medication history,” Loftus said.
These results build on previously reported findings showing clinically meaningful outcomes with all icotrokinra doses from W12 through W28. [Am J Gastroenterol 2025;120(suppl 2):S312]
Studies are underway to evaluate icotrokinra for moderate-to-severe UC and Crohn’s disease in adults and adolescents.