Icotrokinra

What is Icotrokinra?#

Icotrokinra (JNJ-2113, also known as JNJ-77242113 or PN-235) is a first-in-class investigational targeted oral peptide that selectively blocks the interleukin-23 (IL-23) receptor. Developed by Johnson & Johnson in collaboration with Protagonist Therapeutics, icotrokinra represents a paradigm shift in the treatment of immune-mediated inflammatory diseases by delivering the efficacy of injectable biologic therapy through a once-daily pill.

IL-23 is a key cytokine in the pathogenesis of psoriasis, driving the differentiation and activation of Th17 cells that produce the pro-inflammatory cytokines IL-17A, IL-17F, and IL-22. While injectable monoclonal antibodies targeting IL-23 (guselkumab, risankizumab, tildrakizumab) have demonstrated high efficacy in psoriasis, they require subcutaneous injections every 4-12 weeks. Icotrokinra offers the possibility of achieving comparable immune pathway blockade through oral administration.

Johnson & Johnson submitted a New Drug Application (NDA) to the FDA in July 2025, supported by data from four Phase 3 ICONIC trials. If approved, icotrokinra would be the first oral peptide therapy for moderate-to-severe plaque psoriasis.

Mechanism of Action#

Icotrokinra is a macrocyclic peptide containing both natural and noncanonical amino acids, cyclized through a disulfide bond. It binds to the extracellular domain of the IL-23 receptor (IL-23R) with exceptionally high affinity (KD = 7.1 pM), preventing IL-23 from engaging its receptor and activating downstream signaling:

• Receptor blockade: Binds to IL-23R with picomolar affinity, competitively blocking IL-23 binding
• STAT3 pathway inhibition: Prevents IL-23-induced STAT3 phosphorylation (IC50 = 5.6 pM in PBMCs)
• Selective targeting: Specifically blocks the IL-23 pathway without affecting IL-12 signaling, preserving Th1-mediated host defense
• Downstream cytokine reduction: Suppresses Th17 cell differentiation and production of IL-17A, IL-17F, and IL-22
• Oral bioavailability: Engineered macrocyclic structure confers resistance to gastrointestinal proteolysis and enables oral absorption

Unlike JAK inhibitors (tofacitinib) or TYK2 inhibitors (deucravacitinib) that broadly modulate multiple cytokine pathways, icotrokinra provides targeted blockade of the IL-23 axis specifically, potentially offering a more favorable risk-benefit profile.

Clinical Development#

Icotrokinra has been evaluated in an extensive clinical development program for plaque psoriasis:

FRONTIER 1 (Phase 2b)#

Published in NEJM 2024 (Bissonnette et al., PMID 38324484), this dose-finding trial tested five dose regimens against placebo in adults with moderate-to-severe plaque psoriasis. The highest dose (100 mg BID) achieved 79% PASI 75 at week 16 vs 9% placebo, with 45.2% achieving IGA 0 (complete clearance).

ICONIC-LEAD (Phase 3)#

Published in NEJM 2025 (PMID 41191940), this pivotal trial randomized adults and adolescents (12+) to icotrokinra 200 mg QD or placebo. At week 16, 65% of icotrokinra patients achieved IGA 0/1 vs 8% placebo, and 50% achieved PASI 90 vs 4% placebo (P<0.001 for both).

ICONIC-ADVANCE 1 & 2 (Phase 3)#

Published in the Lancet 2025 (PMID 40976249), these head-to-head trials demonstrated superiority of icotrokinra over deucravacitinib (the only other oral targeted therapy for psoriasis) at both week 16 and week 24.

ICONIC-TOTAL (Phase 3)#

Evaluated icotrokinra for difficult-to-treat scalp and genital psoriasis, with 72% of scalp psoriasis patients achieving clear/almost clear skin (ss-IGA 0/1) and 85% of genital psoriasis patients achieving sPGA-G 0/1 through week 52.

Beyond Psoriasis#

Icotrokinra is also being investigated in ulcerative colitis (ANTHEM-UC Phase 2b), where it demonstrated a 63.5% clinical response rate at week 12 vs 27% placebo at the highest dose (P<0.001).

Important Considerations#

Icotrokinra is an investigational medication that has not yet been approved by any regulatory authority. Key considerations include:

• An NDA was submitted to the FDA in July 2025, with a decision expected in 2026
• Safety data show adverse event rates comparable to placebo across the ICONIC program (49.1% vs 51.9%), with no new safety signals
• As an IL-23R antagonist, theoretical risks include reduced host defense against intracellular pathogens, though no signal for serious infections has emerged
• Long-term safety data beyond 52 weeks are still maturing from extension studies
• The 200 mg QD dose was selected for Phase 3 based on modeling from Phase 2b data rather than direct testing of this exact dose in Phase 2

Key Research Findings#

Oral Icotrokinra for Plaque Psoriasis in Adults and Adolescents, published in New England Journal of Medicine (Bissonnette R et al., 2025; PMID: 41191940):

• The study showed 65% IGA 0/1 response with icotrokinra vs 8% placebo at week 16
• The study showed 50% PASI 90 response vs 4% placebo at week 16 (P<0.001)
• Adverse events occurred at similar rates in both groups (49% each)

ICONIC-ADVANCE 1 & 2, published in Lancet (Stein Gold L et al., 2025; PMID: 40976249):

• Icotrokinra demonstrated superiority over deucravacitinib at weeks 16 and 24
• First head-to-head comparison of oral targeted therapies for psoriasis

Related Reading#

• Icotrokinra research studies and evidence
• Icotrokinra dosing protocols
• Icotrokinra side effects profile