Psoriasis is a chronic, immune-mediated inflammatory disease with substantial impact on quality of life. While biologic therapies targeting interleukin (IL)-23 and IL-17 have set new efficacy and safety benchmarks, currently available oral agents offer limited potency or tolerability. There remains an unmet need for an oral therapy that combines the convenience of oral administration with the efficacy and safety of biologic agents. Icotrokinra, a first-in-class, orally administered macrocyclic peptide that selectively targets the IL-23 receptor (IL-23R), has been evaluated across phase 2 and 3 clinical trials in moderate-to-severe plaque psoriasis. This review aimed to provide an overview of icotrokinra in psoriasis, based on a literature search up to December 2025 using PubMed and supplemented by conference abstracts, industry communications, and ClinicalTrials.gov. In the phase 2b FRONTIER-1 trial, icotrokinra demonstrated a clear dose–response relationship, with sustained efficacy through 52 weeks in the FRONTIER-2 long-term extension. In the pivotal phase 3 ICONIC-ADVANCE-1 and ICONIC-ADVANCE-2 studies, icotrokinra was superior to placebo in achieving the primary endpoints of Investigator’s Global Assessment (IGA) score 0/1 (clear or almost clear skin) and ≥ 90% improvement in the Psoriasis Area and Severity Index (PASI90) at week 16, and demonstrated greater efficacy than deucravacitinib at week 24, while maintaining a favorable safety profile. Long-term results from ICONIC-LEAD confirmed durable efficacy through 52 weeks, while ICONIC-TOTAL demonstrated consistent outcomes in scalp, genital, and palmoplantar psoriasis. Adverse events were mostly mild and comparable to placebo, with no new safety signals or pharmacokinetic concerns. Icotrokinra is the first oral IL-23R antagonist to achieve high and durable levels of skin clearance with a favorable safety profile, highlighting the potential of selective oral IL-23R blockade with minimal off-target or drug–drug interaction potential, thereby overcoming key limitations of oral small molecules.
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