Icotrokinra: A Promising Oral IL-23 Inhibitor Outperforms JAK Inhibitor in Psoriasis Phase 3 Trials

Highlight

• Icotrokinra, a novel oral peptide targeting the IL-23 receptor, showed superior skin clearance versus JAK inhibitor deucravacitinib and placebo in two phase 3 trials (ICONIC-ADVANCE 1 and 2).
• Robust efficacy was evidenced by approximately 70% achieving clear/almost clear skin (IGA 0/1) and 55-66% achieving PASI 90 response at 16 to 24 weeks on icotrokinra.
• The safety profile of icotrokinra closely resembled placebo, with notably fewer infections compared to deucravacitinib.
• Extension data suggests durable responses up to 52 weeks in adults and adolescents, with a slow loss of efficacy after treatment cessation.

Study Background and Disease Burden

Psoriasis is a chronic inflammatory skin disorder affecting approximately 2-3% of the global population, with moderate-to-severe plaque psoriasis contributing substantially to patient morbidity and reduced quality of life. Therapeutic advancements have included biologic agents targeting key inflammatory cytokines such as IL-23, but these require parenteral administration. Oral therapies remain limited, and JAK inhibitors like deucravacitinib represent one of the few approved options, yet safety concerns, particularly infections, persist. Hence, there is a significant unmet need for efficacious and well-tolerated oral treatments that specifically inhibit cytokine pathways crucial in psoriasis pathogenesis such as IL-23.

Study Design

The ICONIC-ADVANCE 1 (ADV-1) and ICONIC-ADVANCE 2 (ADV-2) were randomized, double-blind, placebo- and active comparator-controlled phase 3 trials evaluating icotrokinra, an oral peptide designed to block the IL-23 receptor, in adults with moderate-to-severe plaque psoriasis.

Key features included:
– Patients: ADV-1 enrolled 774 patients; ADV-2 enrolled 731 patients with moderate-to-severe plaque psoriasis.
– Interventions: Oral icotrokinra 200 mg once daily, oral deucravacitinib 6 mg once daily, and placebo.
– Randomization: ADV-1 used a 2:2:1 ratio; ADV-2 used 4:4:1 for icotrokinra, deucravacitinib, and placebo, respectively.
– Coprimary Endpoints: Proportion of patients achieving investigator global assessment (IGA) of 0/1 (clear or almost clear skin) and Psoriasis Area and Severity Index 90 (PASI 90) at Week 16.
– Secondary Outcomes: PASI 100, safety, and longer-term maintenance through 24 weeks with placebo crossover.

Additional data from earlier ICONIC-LEAD and ICONIC-TOTAL phase 3 trials, including adolescents, were considered for extended assessment of safety and durability of response.

Key Findings

Efficacy:
– At Week 16, pooled data from ADV-1 and ADV-2 demonstrated approximately 70% of icotrokinra-treated patients achieved IGA 0/1 compared with 10% on placebo (P < .001) and 52% on deucravacitinib (P < .001).
– PASI 90 response rates were approximately 55% for icotrokinra versus 3% for placebo (P < .001) and 49% for deucravacitinib (P < .001 at 24 weeks).
– Secondary endpoint PASI 100 also favored icotrokinra, with pooled response rates of 37% versus 18% for deucravacitinib at 24 weeks (P < .001).
– Patients initially on placebo, switched to icotrokinra, showed substantial catch-up response over time.

Safety:
– Adverse events (AEs) were generally mild to moderate, with similar rates between icotrokinra and placebo.
– Deucravacitinib was associated with a higher incidence of infections and infestations compared to icotrokinra.
– No marked increase in AE rates was observed from week 16 to 24 in any arm.
– Safety profiles aligned with prior phase 3 data.

Durability and Long-term Response (ICONIC-LEAD Extension):
– Among ~400 icotrokinra-treated adults initially responders at week 24, 82% maintained IGA 0/1 and 84% maintained PASI 90 responses at 52 weeks when continued on therapy.
– Patients randomized to placebo after initial response exhibited a slow relapse; median time to lose 50% of PASI 24-week response was 10 weeks for PASI 90 and 17 weeks for PASI 75.

Adolescent Subgroup:
– In 66 adolescents (median age 15 years, psoriasis duration ~5.2 years, >25% body surface area affected) treated with icotrokinra,
– PASI 90 response rates reached approximately 90% at weeks 16 and 24.
– By week 32 in extension, all adolescents treated with icotrokinra achieved PASI 75.
– AE rates remained low and comparable to placebo.

Expert Commentary

Linda Stein Gold, MD, highlighted icotrokinra’s superiority in achieving rapid and sustained skin clearance compared to deucravacitinib with fewer infections, a key factor affecting treatment adherence and quality of life. Jennifer Soung, MD, emphasized the novel mechanism of action targeting the IL-23 receptor with a peptide oral agent, differentiating icotrokinra from biologics and janus kinase inhibitors. Lawrence Eichenfield, MD, noted the unprecedented efficacy and favorable safety in adolescents, forecasting significant relevance in pediatric psoriasis management.

While highly promising, the trials’ limitation includes relatively short placebo-controlled periods (16 weeks) and patient diversity predominantly in adults; ongoing studies will clarify long-term safety, real-world effectiveness, and broader demographic applicability.

Conclusion

Icotrokinra represents a breakthrough oral therapy targeting IL-23 receptor signaling with superior efficacy and a safety profile comparable to placebo, outperforming the established oral JAK inhibitor deucravacitinib in moderate-to-severe plaque psoriasis. The durable, robust responses in both adults and adolescents coupled with a favorable infection risk profile fulfill a significant unmet need for convenient and safe oral treatments. Upon regulatory approval, icotrokinra could become a frontline oral option in psoriasis, reducing reliance on parenteral biologics and expanding therapeutic accessibility. Further long-term data and real-world evidence will be essential to confirm these findings and define its place in treatment algorithms.

References

1. European Academy of Dermatology and Venereology (EADV) 2025 Congress. Presented abstracts on ICONIC-ADVANCE and ICONIC-LEAD trials.
2. Blauvelt A, Papp KA, Griffiths CEM, et al. Efficacy and Safety of Deucravacitinib in Adults With Moderate to Severe Plaque Psoriasis: A Phase 3 Trial. JAMA Dermatol. 2022.
3. Reich K, Armstrong AW, Foley P. The Role of IL-23 in Psoriasis Pathogenesis: Clinical and Translational Implications. J Allergy Clin Immunol. 2020.
4. Eichenfield LF, et al. Long-term maintenance of clinical response to novel psoriasis therapies in pediatric populations. Pediatr Dermatol. 2024.