PARIS — An investigational oral interleukin-23 (IL-23) inhibitor performed better and with fewer side effects than an established targeted oral agent for moderate-to-severe plaque psoriasis in two phase 3 trials that also included a placebo control.

In these trials, called ICONIC-ADVANCE 1 (ADV-1) and 2 (ADV-2), icotrokinra, a peptide designed to block the IL-23 receptor, “provided superior skin responses to both placebo and the JAK inhibitor deucravacitinib, but the rate of adverse events was lower on the novel agent, primarily due to fewer infections,” reported Linda Stein Gold, MD, director of dermatology clinical research, Henry Ford Health, Detroit.

In the ICONIC-LEAD and ICONIC-TOTAL phase 3 trials, reported earlier this year, icotrokinra was associated with rates of activity comparable to those previously reported with biologics but with a placebo-like safety profile. ADV-1 and ADV-2 are the first in a series of phase 3 active comparator trials now underway.

Active Comparator Trials Include > 1400 Patients

In these trials, reported on September 18 at the European Academy of Dermatology and Venereology (EADV) 2025 Congress, the three arms were 200 mg once-daily oral icotrokinra, 6 mg once-daily deucravacitinib, and placebo. Randomizations in ADV-1 and ADV-2 with 774 and 731 patients, respectively, were in a 2:2:1 ratio in ADV-1 and a 4:4:1 ratio in ADV-2.

The findings were nearly identical for efficacy and safety. For the two coprimary endpoints, investigator global assessment (IGA) of 0/1 — signifying clear or almost clear skin — and a Psoriasis Area and Severity Index score of 90% (PASI 90), curves in favor of icotrokinra separated from placebo quickly and continued to grow incrementally over the 16 weeks of the blinded study, according to Gold.

At week 16, the proportion of patients with IGA 0/1 was approximately 70% in the icotrokinra arms vs 10% in the placebo arms (P < .001), when data from the two trials were pooled. The PASI 90 response was approximately 55% vs 3% (P < .001).

Against the active comparator, the 70% IGA 0/1 result in the pooled icotrokinra arms was also statistically superior to the pooled 52% rate in the deucravacitinib arms (P < .001) from the two trials.

In follow-up out to 24 weeks, during which time patients initially randomly assigned to placebo were switched to icotrokinra, there was a substantial catch up among those previously treated with placebo, but the IGA 0/1 scores remain largely unchanged in the active treatment arms. However, PASI 90 scores climbed further, reaching about 66% in the pooled icotrokinra data but only climbing to about 49% in the pooled deucravacitinib arms (P < .001 for icotrokinra).

For PASI 100, a secondary outcome, the advantage of icotrokinra over deucravacitinib was superior at both 16 weeks (P < .001) and 24 weeks when the pooled rates were approximately 37% vs 18%, respectively (P < .001).

Adverse Event Rate Similar to That of Placebo

The rates of adverse events, particularly infections and infestations, were numerically higher with deucravacitinib than with icotrokinra, which were more similar to those with placebo. There was no substantial increase in the rate of adverse events from 16 to 24 weeks in any of the treatment arms. The safety profiles of both icotrokinra and deucravacitinib were consistent with those in previous clinical trials.

Icotrokinra is not considered a biologic. Rather it is a targeted oral peptide that binds to the IL-23 receptor to block its proinflammatory activity. This target is the same target of biologic IL-23 inhibitors, such as guselkumab, risankizumab, and tildrakizumab. If icotrokinra is approved, it will be the first oral therapy targeting IL-23 specifically, according to Jennifer Soung, MD, a clinician and researcher associated with Southern California Dermatology, Santa Ana, California.

Delivering a late breaker presentation on the results of a secondary extension analysis of the ICONIC-LEAD trial on September 17 at the EADV meeting, Soung remarked about the “impressive and consistently” low rate of adverse events seen in both adults and adolescents in the psoriasis trials to date.

This safety was also observed in the extension analysis, which involved re-randomizing responders at 24 weeks to remain on active therapy or switch to placebo.

Of the nearly 400 patients randomly assigned to icotrokinra in ICONIC-LEAD, 341 (82%) met the criteria for a response at 24 weeks, which was an IGA 0/1 or PASI 75, she reported. The randomization to continue on 200 mg once-daily icotrokinra or to start placebo was performed in a 1:1 ratio. The endpoint in this extension was median time to at least a 50% loss in the PASI response achieved at week 24.

Among those randomly assigned to remain on therapy, the majority were still responders at the end of 52 weeks. Specifically, 89% of those with a PASI 75 response, 84% of those with a PASI 90 response, and 82% of those with a IGA 0/1 response retained this level of response at the end of 52 weeks.

For those randomly assigned to placebo, the loss of response was remarkably slow, Soung reported. “It took almost 17 weeks for half of the patients to lose a PASI 75 response, and it took 10 weeks for patients to lose a PASI 90 response,” she said.

Soung further noted that response rates at 24 weeks were generally higher among adolescents in the ICONIC-LEAD trial. Of those with a PASI 90 response at 24 weeks, for example, 86% still had a PASI 90 response at the end of 52 weeks.

The proportion of icotrokinra-treated adolescents who achieved a PASI 75 or IGA 0/1 response increased over time, with 100% of patients randomly assigned to icotrokinra in the extension study reaching a PASI 75 response by week 32, she reported.

Lawrence Eichenfield, MD, chief of pediatric and adolescent dermatology at Rady Children’s Hospital, San Diego, agreed that the rates of response to icotrokinra among adolescents is “unprecedented” relative to any of the therapies currently available for moderate-to-severe psoriasis.

Providing more data on the adolescent subgroup (n = 66) of ICONIC-LEAD in a separate presentation at the EADV meeting on September 18, Eichenfield noted that the median age was 15 years, and the median duration of psoriasis was 5.2 years. The average body surface area involved was more than 25%.

Yet with a PASI 90 response rate approaching 90% at weeks 16 and 24, coupled with the placebo-like rate of adverse events, Eichenfield suggested the phase 3 data are highly encouraging. He expects oral icotrokinra to be a major addition to therapeutic options for psoriasis if other trials substantiate these results and regulatory approval is granted.

In July, Johnson & Johnson submitted an application to the US FDA for approval of icotrokinra for treating patients aged 12 years or older with moderate-to-severe plaque psoriasis.

Gold reported having financial relationships with AbbVie, Arcutis, Bristol Myers Squibb, Dermavant, Eli Lilly, Incyte, Ortho Diagnostics, Pfizer, Regeneron, Sanofi, and Johnson & Johnson, which provided funding for the icotrokinra trials. Soung reported having financial relationships with AbbVie, Amgen, Arcutis, Bristol Myers Squibb, Corval, Dermavant, Incyte, Union Chimique Belge, Eli Lilly, Leo Pharma, Novartis, Regeneron, Pfizer, Sanofi, and Johnson & Johnson. Eichenfield reported having financial relationships with more than 20 pharmaceutical companies, including Johnson & Johnson.