Ted Bosworth
November 12, 2025
Icotrokinra, a novel oral interleukin (IL)-23 inhibitor, provided a level of response in moderate-to-severe plaque psoriasis that is similar to that previously reported with injectable biologics, according to 16-week results from a newly published phase 3 trial.
In a population with a median baseline Psoriasis Area and Severity Index (PASI) score of just under 20 (signifying 80% of skin affected), the Investigator’s Global Assessment (IGA) score of 0 or 1 (clear or almost clear skin) was achieved in 65% of patients by 16 weeks, reported Robert Bissonnette, MD, founder and chairman of Innovaderm Research, Montreal, Québec, Canada, and coauthors.
Icotrokinra is an oral peptide blocker of the IL-23 receptor. This mechanism is more selective for IL-23 than current biologics, according to Bissonnette.
No Oral Therapy Has Comparable Efficacy
No oral therapy has achieved this level of response in moderate-to-severe plaque psoriasis previously. Bissonnette said that this new drug, which was well tolerated, could be a major new option for psoriasis if approved.
“In my opinion, the main advantages of icotrokinra as compared to biologics targeting IL-23 is the oral administration and short half-life,” Bissonnette told Medscape Medical News. “A short half-life is very important when a patient needs to stop treatment before an upcoming surgery, because of an infection, or because they want to become pregnant.”
In this double-blind global study, called ICONIC-LEAD, 684 adults and adolescents aged 12 years or older with moderate-to-severe plaque psoriasis were randomized in a 2:1 ratio to 200-mg icotrokinra or to placebo once daily. Most (65%) were men and White individuals (72%). The results were published on November 5 in The New England Journal of Medicine.
The IGA 0/1 response at 16 weeks, which was one of two coprimary endpoints, was nearly 60% greater among those on icotrokinra than that among those on placebo (65% vs 8%). The other coprimary endpoint was a PASI 90 response (signifying 90% skin clearance), achieved in 50% and 4% of those on icotrokinra and placebo, respectively (P < .001 for both endpoints).
Multiple secondary efficacy endpoints were also highly positive for icotrokinra, including a PASI 100 response, which signifies complete resolution of skin involvement and was achieved in 27% of those in the icotrokinra group vs 1% of those in the placebo group (P < .001).
When response was evaluated separately in the adolescent subgroup, which represented approximately 10% of the study population, benefit was even more marked. (An IGA) score of 0/1 was achieved in 84% on icotrokinra vs 27% of those on placebo. The PASI 90 response in younger patients at 16 weeks was 70% and 14%, respectively.
The planned follow-up in this study, which transitioned placebo patients to active therapy at 16 weeks, is 156 weeks. At 24 weeks, those with a treatment response will be asked to participate in a randomized withdrawal and retreatment period with follow-up continuing through week 52. After week 52, an open-label follow-up will be maintained for an additional 2 years.
Five Phase 3 Psoriasis Trials Planned
In addition to the ICONIC-LEAD study, four other phase 3 trials with this agent in plaque psoriasis, including ICONIC-TOTAL, which is focusing on challenging sites of involvement, such as the scalp, genitals, hands, and feet, and ICONIC-ADVANCE, which involves an active comparator, are ongoing.
Although the 16-week results were the focus of the recent publication, the efficacy and safety data out to 24 weeks are also positive. Encouragingly, response rates have continued to climb. For those initiated and maintained on icotrokinra, the overall IGA 0/1 response reached 74%, the PASI 90 response reached 65%, and the PASI 100 response reached 40%.
At 16 weeks, the safety profile of icotrokinra relative to placebo has been remarkably similar, according to the published table of events. Those on icotrokinra and placebo had nearly the same adverse events leading to discontinuation (1% vs < 1%), serious adverse events (1% vs 3%), infection (23% vs 22%), and serious infections (< 1% vs 0%).
In a comparison at 24 weeks, those on icotrokinra continuously relative to those switched from placebo to icotrokinra were more likely to have had an infection (29% vs 10%), but adverse events leading to discontinuation (1% vs < 1%), serious adverse events (2% vs < 1%) and serious infections (< 1% vs 0%) occurred at low levels in both groups.
“Long term safety of icotrokinra is currently being studied. However, it is reassuring to see that the long-term safety of biologics targeting IL-23 has been excellent so far,” Bissonnette said.
A coauthor for the ICONIC-LEAD study, Mark G. Lebwohl, MD, dean for Clinical Therapeutics, Icahn School of Medicine at Mount Sinai, New York City, also expressed confidence in the safety of this mechanism of action.
“We already know that IL-23 blockade is very safe, so I would expect nothing less even with long-term use,” he told Medscape Medical News. He said that he expects icotrokinra to be studied in other diseases for which IL-23 inhibitor biologics are now used.
Citing data that patients prefer oral over injectable therapies, Bissonnette expects that a needle-free option for a high level of efficacy in plaque psoriasis will be welcome.
Adam Friedman, MD, professor and chair of dermatology at George Washington School of Medicine and Health Sciences, Washington, DC, agreed.
“An oral drug that has the efficacy of a biologic would disrupt our historic mindset,” Friedman told Medscape Medical News. Whether used as an alternative to an IL-23 inhibitor biologic or as a gateway to “get someone comfortable” with the activity of an IL-23 inhibitor, Friedman expects icotrokinra, if approved, to add a significant treatment option for plaque psoriasis.
“There would be a paradigm shift that would negate the need for needle averse or phobic patients to settle,” he said.
The ICONIC trials with icotrokinra received funding from Johnson & Johnson. Bissonnette reported financial relationships with AbbVie, Alumis, Amgen, AnaptysBio, Arcutis, BMS/Celgene, Dermavant, Eli Lilly, J&J (Janssen), LEO Pharma, Nimbus, Takeda, UCB, Ventyx Bio, Vyne, Xencor, Zai Lab and Zura Bio. Lebwohl reported financial relationships with AbbVie, Almirall, AltruBio, Apogee, Arcutis Biotherapeutics, AstraZeneca, Atomwise, Avotres, Boehringer Ingelheim, Bristol Myers Squibb, Cara, Castle Biosciences, Celltrion, Clexio, CorEvitas, Dermavant Sciences, Dermsquared, Evommune, Forte Biosciences, Galderma, Genentech, Incyte, Inozyme, Janssen, Lilly, LEO, Meiji Seika Pharma, Mindera, Pfizer, Sanofi-Regeneron, Seanergy Dermatology, Strata, Takeda, Trevi Therapeutics, Verrica, and UCB. Friedman reported no potential conflicts of interest.
