MT Abreu et al. N Engl J Med 2026;395:1495-1504. Phase 2 Trial of Icotrokinra for Patients with Ulcerative Colitis
Background: “Icotrokinra (JNJ-77242113) is a first-in-class targeted oral peptide that precisely blocks the interleukin-23 receptor. The development of oral peptide therapeutics has historically been limited by poor epithelial membrane permeability, susceptibility to enzymatic degradation in the gastrointestinal tract, and low intestinal absorption.7 The cyclic peptide technology used in icotrokinra enables high stability and epithelial permeability.7 These features, in combination with high selectivity and potent binding of the interleukin-23 receptor, result in an orally administered peptide that effectively inhibits the interleukin-23 pathway.8,9“
Methods: This was a “phase 2b, double-blind, randomized trial of oral icotrokinra, a peptide that blocks the interleukin-23 receptor, in adults with moderately to severely active ulcerative colitis. Participants were assigned to receive icotrokinra at a once-daily dose of 400 mg, 200 mg, or 100 mg or placebo. The primary end point was clinical response at week 12.” A total of 252 participants underwent randomization.
Key findings:
- All the doses of icotrokinra were superior to placebo with respect to a clinical response at week 12, which occurred in 63% of the participants in the 400-mg group, 58% in the 200-mg group, and 55% in the 100-mg group, as compared with 27% in the placebo group (P<0.001)
- The percentage of participants with clinical remission at week 12 was also significantly higher in the 400-mg group than in the placebo group (30% vs. 11%, P=0.006), as were…the percentage of participants with endoscopic improvement (37% vs. 14%, P=0.002)
subscore or a rectal bleeding subscore of 0 or 1
a rectal bleeding subscore of 0, and an endoscopic subscore of 0 or 1.
and a rectal bleeding subscore of 0
Discussion:
- “The benefits of treatment with once-daily icotrokinra appeared to be generally sustained or improved through week 28 for all outcomes and doses tested.”
- “Although all the tested doses of icotrokinra appeared to attenuate systemic inflammation, the 400-mg and 200-mg doses appeared to result in greater reduction of the inflammatory burden than the 100-mg dose.”
- “The incidence of adverse events with icotrokinra was similar to that with placebo, and no dose–response relationship for adverse events was observed. Among the 212 participants treated with icotrokinra in this trial, no deaths, serious infections, or adverse events of special interest were reported through 28 weeks of treatment.”
My take: This is an important study indicating that an oral IL-23 can be effective for ulcerative colitis which is not surprising based on its previous effectiveness with plaque psoriasis, another immune-mediated disease. It would be helpful to determine the efficacy of this oral agent compared to the IV/SC IL-23 biologic medications (eg. risankizumab, guselkumab, and mirikizumab).
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