Icotrokinra's Oral IL-23R Approval: Efficacy Credible, HTA Comparator Gap Is the Decisive Risk

European Commission Approves Icotrokinra for Plaque Psoriasis

Johnson & Johnson EMEA announced that the European Commission (EC) has approved ICOTYDE™ (icotrokinra), a first-in-class targeted oral peptide, for adults and adolescents (aged ≥12 years and weighing ≥40 kg) with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. Icotrokinra, an IL-23 receptor antagonist, demonstrated high levels of skin clearance, with approximately 70% of patients achieving clear or almost clear skin (IGA 0/1) and 55% achieving PASI 90 at Week 16 in head-to-head Phase 3 studies. The drug also showed a favorable safety profile, with adverse reactions within 1.1% of placebo rates through Week 16 and no new safety signals through Week 52, offering a convenient once-daily oral option.

• ICOTYDE™ (icotrokinra) is the first targeted oral peptide designed to precisely block the IL-23 receptor, representing a significant scientific advancement in plaque psoriasis treatment. This once-daily oral therapy offers a convenient and innovative option for patients, addressing the need for systemic treatments beyond topicals and providing an alternative to injectable biologics.
• The EC approval is supported by comprehensive data from the Phase 3 ICONIC clinical development program, involving 2,500 patients across four studies. In head-to-head studies, icotrokinra achieved approximately 70% of patients with clear or almost clear skin (IGA 0/1) and 55% with a PASI 90 response at Week 16, demonstrating high levels of skin clearance compared to active comparators.
• Icotrokinra consistently demonstrated a favorable safety profile across all four Phase 3 studies. Rates of adverse reactions for icotrokinra-treated patients were within 1.1% of placebo rates through Week 16, and no new safety signals were observed through Week 52, providing reassurance for long-term use in a chronic condition like plaque psoriasis.

The Unmet Need for Oral IL-23R Targeted Therapies

Despite significant advances in biologic and small-molecule therapies, moderate-to-severe plaque psoriasis continues to present substantial clinical and patient-centered challenges that limit long-term treatment success.

• Immunogenicity and loss of efficacy over time: All biotherapeutics, including monoclonal antibodies, carry immunogenic potential through the formation of anti-drug antibodies (ADAs), which can result in loss of response and adverse events such as hypersensitivity reactions. Loss of efficacy accounted for 67% of all drug discontinuations in a large real-world registry cohort, underscoring this as a major area of unmet medical need. Biologic drug survival varies considerably by agent — median survival was 30 months for etanercept, 44 months for infliximab, and 59 months for adalimumab — and switching from one biologic to another is associated with further impairment of drug survival.

• Treatment burden and patient dissatisfaction with administration: In a survey of 209 psoriasis patients in remission on biologics, 18.2% reported pain, distress, or anxiety related to injection administration, and 38.0% expressed dissatisfaction with the financial burden of biologic therapy. Preference research in the United States further confirms that patients were willing to accept a reduction in the percentage achieving clear or almost-clear skin from approximately 70% to 40% to avoid home injections in favor of a topical treatment, with topical and oral routes ranked as the most preferred modes of administration over subcutaneous or intravenous options.

• Financial burden and uncertainty around treatment duration: Even among patients reporting high satisfaction with therapeutic efficacy (98.6%), concerns regarding treatment cost and uncertainty about the duration of therapy remained prominent, highlighting that clinical response alone does not resolve the full burden experienced by patients on long-term biologic therapy.

• Absence of standardized dose-reduction strategies: For patients achieving low disease activity or remission on IL-17A inhibitors such as secukinumab and ixekizumab, no standardized dose-reduction guidelines exist. Extended dosing intervals (e.g., from Q4W to Q8W) have been evaluated, with 67.7% of patients sustaining PASI90 and 61.2% maintaining PASI100 at 36 weeks — suggesting feasibility, but also indicating that a meaningful proportion of patients experience disease reactivation without optimized maintenance protocols.

• Safety monitoring requirements over prolonged exposure: Long-term safety data across multiple biologics — including ustekinumab (up to 5 years, 8998 patient-years) and certolizumab pegol (up to 144 weeks, 2231.3 patient-years) — demonstrate generally stable adverse event profiles without cumulative toxicity, yet ongoing monitoring for serious infections, malignancies, and major adverse cardiovascular events remains a clinical requirement that adds complexity to long-term disease management.

Key Efficacy and Safety Outcomes from ICONIC Program

Three recent phase 2–3 studies illustrate the evolving treatment landscape for moderate-to-severe plaque psoriasis. The IMMbrace trial evaluated subcutaneous risankizumab 150 mg (administered at weeks 0, 4, and 16) against oral methotrexate (5 mg weekly, escalated up to 25 mg) in a randomized, double-blind, double-dummy, active-controlled design conducted in Brazil. Among 98 randomized patients, risankizumab demonstrated superior efficacy at week 28, with 84.0% of patients achieving PASI 90 versus 35.4% in the methotrexate arm (p < 0.001), and sPGA 0/1 rates of 90.0% versus 64.6% (p ≤ 0.001). Efficacy was maintained through week 112, and adverse event rates were similar between the two groups, with no new safety findings observed over the extended period.

A separate phase 3, multinational, randomized, double-blind, placebo-controlled trial assessed continuous risankizumab therapy versus treatment withdrawal in adults with moderate-to-severe plaque psoriasis. At week 16, 73.2% of patients receiving risankizumab achieved PASI 90 versus 2.0% on placebo, and 83.5% achieved sPGA 0/1 versus 7.0% on placebo (p < 0.001 for both). Among week-28 responders rerandomized to continued risankizumab or withdrawal, sPGA 0/1 was maintained by 87.4% versus 61.3% at week 52, and by 81.1% versus 7.1% at week 104 (p < 0.001 for both). Rates of treatment-emergent adverse events were similar between risankizumab (45.7%) and placebo (49.0%) in the initial treatment phase and remained stable over the two-year trial, with no unexpected safety findings.

The phase 2b zasocitinib (TAK-279) trial evaluated a highly selective allosteric TYK2 inhibitor administered orally once daily at doses of 2, 5, 15, or 30 mg versus placebo over 12 weeks across 55 centers in the US and Canada. PASI 75 at week 12 was achieved by 18%, 44%, 68%, and 67% of patients receiving zasocitinib at 2, 5, 15, and 30 mg, respectively, compared with 6% on placebo. PASI 100 demonstrated a dose response across all doses, with 33% of patients receiving zasocitinib 30 mg achieving complete clearance. Treatment-emergent adverse events occurred in 44% of placebo patients and 53%–62% of patients across the four zasocitinib dose groups, with no dose dependency and no clinically meaningful longitudinal differences in laboratory parameters.

Beyond Psoriasis: Icotrokinra's Expanding Pipeline

Icotrokinra (JNJ-77242113) is advancing beyond plaque psoriasis into additional immune-mediated inflammatory diseases, reflecting the broad pathogenic role of the IL-23 pathway across conditions. Ongoing phase 2 and phase 3 clinical studies are evaluating its therapeutic potential in psoriatic arthritis and ulcerative colitis.

Icotrokinra: A New Era for Oral Psoriasis Therapy

The European Commission's approval of ICOTYDE™ (icotrokinra) for moderate-to-severe plaque psoriasis marks a pivotal moment, introducing the first-in-class targeted oral peptide that selectively blocks the IL-23 receptor. This represents a significant advancement, as it directly addresses a long-standing unmet need for highly effective oral treatment options in immune-mediated inflammatory diseases. For patients, particularly adolescents and adults who prefer non-injectable therapies or have needle aversion, icotrokinra offers a compelling once-daily oral alternative with efficacy rates (70% IGA 0/1, 55% PASI 90 at Week 16) that rival some injectable biologics, coupled with a safety profile comparable to placebo through 52 weeks.

Strategically, this approval validates the oral peptide platform, opening doors for Johnson & Johnson to explore icotrokinra's potential in other IMIDs like psoriatic arthritis and ulcerative colitis. Its demonstrated superiority over deucravacitinib, another oral therapy, positions icotrokinra as a frontrunner in the oral psoriasis landscape, setting a new benchmark for efficacy in this modality. This will undoubtedly intensify competition, prompting both oral and injectable market players to reassess their strategies.

However, several considerations warrant attention. While icotrokinra's efficacy is robust for an oral agent, matching-adjusted indirect comparisons suggest that leading injectable IL-23 inhibitors, such as risankizumab, may still offer higher peak clinical response rates. This potential efficacy gap could influence prescribing decisions for clinicians prioritizing maximal clearance. Furthermore, while short-term safety data are reassuring, the full long-term benefit-risk profile and durability of icotrokinra in real-world settings will require ongoing evaluation. Finally, as a novel, potentially premium-priced oral therapy, securing broad market access and favorable reimbursement across diverse European healthcare systems will be crucial for its commercial success in a competitive therapeutic landscape.