Icotrokinra and the Oral Therapy Revolution

Key Takeaways

• Icotrokinra is the first FDA-approved oral IL-23 receptor antagonist, offering a novel mechanism of action that selectively targets the IL-23/17 inflammatory pathway central to psoriasis pathogenesis. 
• In the phase 3 ICONIC-ADVANCE trials, icotrokinra achieved high levels of skin clearance, with approximately three-quarters of patients reaching PASI 75 and more than half achieving PASI 90 by Week 16. 
• Icotrokinra demonstrated statistically superior efficacy compared with deucravacitinib across key clinical endpoints, including complete skin clearance, while maintaining rapid onset of action. 
• Treatment responses were durable through 52 weeks, with more than 40% of patients achieving PASI 100, supporting its potential as a long-term management option. 
• With a safety profile comparable to placebo and the convenience of once-daily oral administration, icotrokinra may help address barriers to systemic treatment for patients who are reluctant to use injectable biologics.

Psoriasis management has been revolutionized with the introduction of biologics targeting specific cytokines that play direct roles in disease etiology. Despite this, many patients with moderate-to-severe disease are given repeated courses of topical therapies before ultimately moving to systemic treatment. Moreover, biologics pose the inconvenience of injectable administration, refrigeration, and cost.^1,2  Oral agents such as methotrexate, cyclosporine, deucravacitinib (a tyrosine kinase 2 inhibitor), and apremilast (a phosphodiesterase-4 inhibitor) offer convenience in a pill form but demonstrate considerably less efficacy than most biologics. This creates an opportunity for the development of more effective and better tolerated oral treatments for psoriasis.^3,4

Icotrokinra, a first-in-class, orally administered macrocyclic peptide that selectively targets the IL-23 receptor (IL-23R) may represent a meaningful solution to this unmet need. Approved by the US Food and Drug Administration (FDA) in March 2026 for patients 12 and older weighing at least 40 kg with moderate-to-severe plaque psoriasis, icotrokinra has demonstrated efficacy within the relative range observed with FDA-approved biologics that target IL-23 or IL-17 cytokines and a safety profile comparable to placebo. This provides patients a convenient alternative option to biologics that can be highly effective and have a favorable safety profile.²

By inhibiting the IL-23R and disrupting the IL-23/17 signaling axis, icotrokinra reduces serum levels of IL-17A, IL-17F, IL-19, and IL-22, with corresponding decreases in psoriasis-associated gene expression in lesional skin.^4,5 This mechanism differs from injectable biologics that target the p19 subunit of IL-23 (guselkumab, risankizumab, and tildrakizumab) or the p40 subunit of IL-12 and IL-23 (ustekinumab). This makes icotrokinra the only commercially available therapy that selectively blocks the receptor of IL-23 rather than the IL-23 cytokine. Selective targeting of the the receptor of IL-23, which is expressed at very low levels compared to the cytokine itself, enables icotrokinra to be administered orally while also maintaining minimal off-target effects and no known drug-drug interactions. 

Clinical Efficacy: ICONIC-ADVANCE 1 and 2 Trials

The phase 3 ICONIC-ADVANCE 1 (n=774) and 2 (n=731) trials evaluated once-daily oral icotrokinra 200mg against both placebo and deucravacitinib in adults with moderate-to-severe plaque psoriasis.³ These were rigorous, global studies with standard inclusion criteria (Body Surface Area [BSA] ≥10%, Psoriasis Area and Severity Index [PASI] ≥12, Investigator's Global Assessment [IGA] ≥3), and no concomitant topical or systemic therapies were permitted to eliminate confounding drug effects.

Icotrokinra demonstrated robust efficacy compared with both placebo and deucravacitinib at Week 16 with sustained response through Week 24 (see Table 1).³ By Week 16, approximately three-quarters of patients achieved PASI 75 (74% to 77%), more than half achieved PASI 90 (55% to 57%), and nearly one-third achieved complete skin clearance (PASI 100: 31% to 32%), compared with markedly lower response rates in placebo.³ Moreover, 68% to 70% of patients achieved IGA 0/1, and 37% achieved complete clearance (IGA 0).³ For scalp psoriasis, approximately 72% to 74% of patients achieved ss-IGA 0/1 at Week 16, increasing to nearly 80% by Week 24, demonstrating robust efficacy for this high-impact body site.³

Efficacy Outcomes: Icotrokinra vs Deucravacitinib

Icotrokinra demonstrated statistically significant superiority over deucravacitinib—previously the most efficacious FDA-approved oral therapy—across all key endpoints. 

Increased clinical efficacy of icotrokinra over deucravacitinib for PASI 75 was observed as early as Week 4, with continued divergence through Week 16.³ The proportion of participants achieving complete skin clearance (IGA 0 and PASI 100) was more than two-fold greater with icotrokinra than with deucravacitinib at Week 16, with icotrokinra response rates maintaining or increasing to Week 24.³ Interestingly, the clinical efficacy achieved at 24 weeks with deucravacitinib was matched or surpassed by patients on icotrokinra for only 8 weeks when looking at those patients in the clinical studies that transitioned from placebo to icotrokinra at Week 16.³ This underscores the rapid clinical efficacy of icotrokinra compared to other novel oral therapies for psoriasis.

Patient-Reported Outcomes

Patient-reported outcomes aligned closely with physician-assessed efficacy (see Table 2). Itch improvement was observed as early as Week 4, with more than 60% of patients achieving at least a 4-point reduction in the Psoriasis Symptoms and Signs Diary (PSSD) clinically meaningful itch reduction by Week 16 compared with 15% to 17% in the placebo group.³ More than half of patients reported minimal or no impact on quality of life (Dermatology Life Quality Index [DLQI] 0/1) by Week 16.³ Resolution of psoriasis symptoms (PSSD score of 0) was achieved in 21% to 24% of patients treated with icotrokinra.³

Long-Term Efficacy

The FRONTIER-2 extension demonstrated sustained skin clearance through 52 weeks, with >40% achieving PASI 100 at Week 52.³ ICONIC-LEAD is collecting data through 3 years, including rerandomized withdrawal and retreatment after Week 24 in adults with treatment response.  

Safety Profile

Icotrokinra demonstrated a favorable safety profile comparable to placebo (see Table 2). Notably, the overall adverse event rate was lower with icotrokinra (48%) than with placebo (57%) or deucravacitinib (57%) through Week 16.³ No increased rates of serious infections, malignancies, or new safety signals were identified through 52 weeks of treatment.³ The most common adverse reactions were headache, nausea, cough, fungal infection, and fatigue.³

Where does Icotrokinra Fit in Clinical Practice?

Several use cases emerge as particularly compelling for icotrokinra use in clinical practice. First, injection-averse patients who previously declined biologics despite being candidates for systemic therapy now have an oral option with comparable biologic-like efficacy. Second, patients with lifestyle factors that make injections impractical such as frequent travel, housing instability, college, military service, etc may favor an oral option that does not compromise efficacy or safety. Third, adolescents (children ≥12 years, ≥40 kg) represent an important population in which convenience and adherence matter; icotrokinra is one of only two oral systemic options approved for this age group, alongside apremilast, which is approved for ages >6 years. 

Lastly, and perhaps most importantly, icotrokinra may lower the threshold for initiating systemic therapy in patients who might otherwise delay escalation from topical therapies due to concerns about injectable medications, thus potentially addressing the psoriasis patients with undertreated disease.

As compelling as these data are, cautious optimism is warranted. The current evidence base consists of controlled clinical trial data with selected populations, not long-term real-world experience across diverse patient groups. The placebo-controlled comparison period is limited to 16 weeks, and while extension data through 52 weeks are reassuring, long-term safety and durability will require continued follow-up.  The trials also excluded individuals with previous treatment failure or adverse events related to IL-23-targeting biologics. Additionally, while the safety profile is remarkable with adverse event rates comparable to or lower than placebo, more robust studies profiling side effects will be necessary to fully characterize rare events. Head-to-head trials comparing icotrokinra directly to injectable biologics (such as the ongoing trial vs ustekinumab⁶) will provide critical comparative effectiveness data to inform clinical decision making. Lastly, in the clinical trials, patients had to take the medication on an empty stomach upon waking and at least 30 minutes before eating. Whether strict adherence to this recommendation by patients is followed and its potential impact on clinical efficacy will be tested in the real world. 

Conclusions

Icotrokinra represents a paradigm shift in psoriasis treatment as the first oral IL-23R antagonist and achieves high and durable levels of skin clearance with a favorable safety profile. It bridges the historical gap between the convenience of oral therapy and the higher efficacy of injectable biologics, offering robust skin clearance with a safety profile like placebo in a once-daily pill. The choice between oral therapies and injectable biologics should be individualized based on disease severity, patient preferences, treatment goals, comorbidities, and practical considerations. This will also include a discussion about the lack of data and uncertain use of icotrokinra in patients with psoriatic arthritis. As real-world data accumulate and head-to-head biologic comparisons emerge, we will be able to more clearly define new oral therapies' positioning in the robust therapeutic options available for patients with psoriatic disease. 

1. Gowda BHJ, Ahmed MG, Hani U, Kesharwani P, Wahab S, Paul K. Microneedles as a momentous platform for psoriasis therapy and diagnosis: a state-of-the-art review. Int J Pharm. 2023;632:122591. doi:10.1016/j.ijpharm.2023.122591

2. Bissonnette R, Soung J, Hebert AA, et al. Oral icotrokinra for plaque psoriasis in adults and adolescents. N Engl J Med. 2025;393(18):1784-1795. doi:10.1056/NEJMoa2504187

3. Ferreira C, Torres T. Icotrokinra: an oral interleukin-23 receptor antagonist peptide for the treatment of psoriasis. Am J Clin Dermatol. 2026;27:479-492. doi:10.1007/s40257-026-01019-0 

4. Strober B, Thaçi D, Sofen H, et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: efficacy and safety results from the 52-week, randomized, double-blinded, phase 3 Program fOr Evaluation of TYK2 inhibitor psoriasis second trial. J Am Acad Dermatol. 2023;88(1):40-51. doi:10.1016/j.jaad.2022.08.061  

5. Strawn D, Krueger JG, Bissonnette R, et al. Icotrokinra induces early and sustained pharmacodynamic responses in phase 2b study of patients with moderate-to-severe psoriasis. JCI Insight. 2025;10(24):e193563. doi:10.1172/jci.insight.193563 

6. Janssen Research & Development, LLC. A study to assess efficacy and safety of JNJ-77242113 compared to placebo and ustekinumab in participants with moderate to severe plaque psoriasis (ICONIC-ASCEND). ClinicalTrials.gov. Updated April 13, 2026. Accessed June 19, 2026. https://clinicaltrials.gov/study/NCT06934226