ICONIC-LEAD affirms oral icotrokinra benefits in plaque psoriasis

In the phase III ICONIC-LEAD trial, selective blockade of the interleukin(IL)-23 receptor with the targeted oral peptide icotrokinra is associated with higher rates of skin clearance and symptom relief in adults and adolescents with moderate-to-severe plaque psoriasis.

Compared with the placebo group, the icotrokinra group had a significantly higher proportion of participants who achieved IGA* 0/1 (clear skin/minimal disease; 65 percent vs 8 percent; p<0.001) and PASI 90** (50 percent vs 4 percent; p<0.001) at week 16.

Week 16 also saw more icotrokinra vs placebo recipients achieving PASI 75** (69 percent vs 11 percent), PASI 100** (27 percent vs <1 percent), and IGA 0 (33 percent vs 1 percent; p<0.001 for all) responses. [N Engl J Med 2025;393:1784-1795]

The researchers noted that the proportion of icotrokinra recipients who achieved clear skin at week 16 aligns with that reported with FDA-approved injectable biologics targeting IL-23 for adults. “However, given the differences in trial populations, the percentages of participants with a placebo response, and statistical methods, definitive conclusions about comparative efficacy cannot be drawn.”

The investigational arm also had more patients achieving PASI 75 at week 4 (15 percent vs 2 percent; p=0.002) and PASI 90 at week 8 (21 percent vs 1 percent; p<0.001) than the placebo arm.

Between baseline and week 16, the mean percentage of body surface area affected by psoriasis decreased substantially with icotrokinra (from 24.6 to 6.1) but not with placebo (from 27.1 to 22.6).

Subgroup analyses

Among participants with scalp-specific IGA ≥2 at baseline, more icotrokinra vs placebo recipients achieved IGA 0/1 by week 16 (72 percent vs 15 percent; p<0.001). “Across assessments, separation of response curves between icotrokinra and placebo was observed as early as week 4 or 8,” the investigators noted.

In adolescents, more icotrokinra vs placebo recipients achieved IGA 0/1 (84 percent vs 27 percent) and PASI 90 (70 percent vs 14 percent) at week 16. By week 24, IGA 0/1 and PASI 90 response rates with icotrokinra increased to 86 percent and 89 percent, respectively.

PROs, safety

Compared with the placebo arm, the experimental arm had more participants with a PSSD*** symptom score 0 (7 percent vs 1 percent; p=0.002 [week 8] and 20 percent vs 1 percent; p<0.001 [week 16]) and clinically meaningful improvement in PSSD itch score (19 percent vs 5 percent; p=0.002 [week 4] and 58 percent vs 13 percent; p<0.001 [week 16]).

The icotrokinra and placebo arms had similar incidences of adverse events (AEs; 49 percent each), serious AEs (1 percent and 3 percent), gastrointestinal AEs (6 percent each), infections (23 percent and 22 percent), and serious infections (<1 percent and 0 percent) through week 16. The most common AEs were nasopharyngitis (7 percent each) and upper respiratory tract infection (7 percent each).

Oral therapies offer advantages

Though highly effective, biologic therapies for plaque psoriasis are usually injectable, which can be challenging for individuals with anxiety and discomfort with needles, in adolescents and children, and among those who prefer oral alternatives. [J Adv Nurs 2019;75:30-42; J Health Econ Outcomes Res 2016;4:141-157; J Dermatol 2023;50:766-777]

“Oral therapy offers advantages over injectable biologics, including greater patient preference and convenience,” the researchers said. However, these are reportedly less effective than biologics and are associated with AEs. [Cochrane Database Syst Rev 2023;7:CD011535; Dermatol Ther (Heidelb) 2023;13:2839-2857; Br J Dermatol 2023;189:540-552] Moreover, apremilast is the only oral agent currently approved by the FDA and EMA for the treatment of patients aged 6 to <18 years. [Paediatr Drugs 2025;27:119-124]

In ICONIC-LEAD, 684 participants (mean age 42.6 years, 65 percent men, 10 percent adolescents) were randomized 2:1 to icotrokinra 200 mg QD for 24 weeks or placebo for 16 weeks, followed by transition to icotrokinra.

“This trial showed that once-daily icotrokinra … was effective for treating plaque psoriasis in adults and in adolescents, an age group with limited systemic treatment options,” the researchers concluded. They called for longer-term trials to shed more light on the benefit-risk profile of icotrokinra.