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Introduction Icotrokinra is a targeted oral peptide that selectively blocks IL-23 receptor (IL-23R) activation. We evaluated the efficacy and safety of icotrokinra in adults with moderate-to-severe ulcerative colitis (UC) in a phase 2b, randomized, double-blind, placebo-controlled, treat-through, dose-ranging study (ANTHEM-UC).Methods Eligible patients (pts) with moderately to severely active UC defined as a modified Mayo score (mMS) of 5–9 (inclusive) and a Mayo endoscopy subscore (MES) ≥2 and history of inadequate response or intolerance (IR) to TNFa blockers, vedolizumab, ustekinumab, JAK inhibitors, or S1P modulators (BIO/JAKi/S1Pi-IR) or IR to corticosteroids (CS), azathioprine, or mercaptopurine were randomized 1:1:1:1 to once-daily (qd) oral icotrokinra 100 mg, 200 mg, 400 mg, or placebo (PBO).Primary endpoint was clinical response at Week 12 (W12); secondary endpoints: clinical remission, symptomatic remission, endoscopic improvement, and histologic-endoscopic mucosal improvement (HEMI) at W12. The study was powered to detect a treatment difference between icotrokinra 400 mg and PBO for the primary endpoint; it was not powered for secondary endpoints.Results Overall, 252 pts were randomized and received study medication (primary analysis population: mean age, 41.6 y; mean UC duration, 7.8 y; mean mMS, 6.63; mMS > 7 [severe], 31.9%; MES = 3 [severe], 58.7%; baseline CS use, 37.3%; BIO/JAKi/S1Pi-IR, 43.3%). Baseline characteristics were generally similar across groups.All icotrokinra doses met the primary endpoint, demonstrating superiority to PBO for clinical response at W12 (100 mg 54.7%, 200 mg 58.1%, 400 mg 63.5% vs PBO 27.0%; all p<0.001). Relative to PBO, significantly greater proportions of pts achieved clinical remission, symptomatic remission, and endoscopic improvement at W12 in the icotrokinra 400 mg group, with clinically meaningful differences for HEMI at W12 in the icotrokinra 400 mg group. Clinically meaningful differences were observed for icotrokinra 100 mg and 200 mg vs PBO at W12 across secondary endpoints. All icotrokinra doses demonstrated separation from PBO for symptomatic remission as early as W4.Across the PBO and 100 mg, 200 mg, and 400 mg icotrokinra groups, respectively, similar proportions of pts reported ≥1 AEs (50.8%, 50.0%, 45.2%, 46.0%), SAEs (4.8%, 0%, 3.2%, 1.6%), serious infections (1.6%, 0%, 0%, 0%), and AEs leading to discontinuation of study agent (7.9%, 0%, 6.5%, 1.6%) through W12. No opportunistic infections, tuberculosis, malignancies, clinically important hepatic disorders, MACE, or deaths were reported in icotrokinra treatment groups through W12.Conclusion Icotrokinra, the first-in-class targeted oral peptide that selectively blocks IL-23R activation, demonstrated efficacy and a favorable safety profile in pts with moderately to severely active UC.