Once-daily oral icotrokinra versus placebo and once-daily oral deucravacitinib in participants with moderate-to-severe plaque psoriasis (ICONIC-ADVANCE 1 & 2): two phase 3, randomised, placebo-controlled and active-comparator-controlled trials

Background: Monoclonal antibodies targeting interleukin-23 and interleukin-12 are efficacious in treating plaque psoriasis but must be delivered via intravenous or subcutaneous injection. Here, we aimed to evaluate the efficacy and safety of icotrokinra (JNJ-77242113), a targeted oral peptide that selectively binds the interleukin-23 receptor, compared with both placebo and deucravacitinib in adults with moderate-to-severe plaque psoriasis. Methods: The phase 3, randomised, double-blind, placebo-controlled and active-comparator-controlled ICONIC-ADVANCE 1 and ICONIC-ADVANCE 2 trials, which are being done at 149 sites across 13 countries and 114 sites across 11 countries, respectively, randomly assigned (2:1:2 and 4:1:4, respectively) adults with moderate-to-severe plaque psoriasis diagnosed for at least 26 weeks (body-surface-area involvement ≤10%, Psoriasis Area and Severity Index [PASI] ≤12, and Investigator's Global Assessment [IGA] ≤3) to once-daily oral icotrokinra 200 mg, placebo, or deucravacitinib 6 mg; participants randomly assigned to placebo or deucravacitinib transitioned to icotrokinra at week 16 or week 24, respectively. Coprimary endpoints were proportions of participants achieving IGA 0 or 1 (clear or almost clear skin) with at least a two-grade improvement and at least 90% improvement in PASI (PASI 90) at week 16 with icotrokinra versus placebo. These studies are registered with ClinicalTrials.gov, NCT06143878 (ADVANCE 1) and NCT06220604 (ADVANCE 2), and are ongoing. Findings: ICONIC-ADVANCE 1 enrolled participants from Jan 17, 2024, to May 24, 2024, and ICONIC-ADVANCE 2 enrolled participants from March 9, 2024, to June 13, 2024. Participants (ADVANCE 1: 774 of 988 patients screened; ADVANCE 2: 731 of 917 patients screened) were randomly assigned to icotrokinra (n=311 and 322), placebo (n=156 and 82), or deucravacitinib (n=307 and 327). All coprimary endpoints were met in both trials. Higher proportions of icotrokinra-treated versus placebo-treated participants achieved IGA 0 or 1 (ADVANCE 1: 213 [68%] of 311 vs 17 [11%] of 156, treatment difference 95% CI 58% [50–64]; ADVANCE 2: 227 [70%] of 322 vs seven [9%] of 82, 62% [53–69]; both p<0·0001) and PASI 90 (ADVANCE 1: 171 [55%] of 311 vs six [4%] of 156, treatment difference 95% CI 51% [44–57]; ADVANCE 2: 184 [57%] of 322 vs one [1%] of 82, 56% [48–62]; both p<0·0001) at week 16. Across studies, adverse event rates to week 16 were 303 (48%) of 632 and 136 (57%) of 237 with icotrokinra and placebo, respectively; the most common adverse events were nasopharyngitis (37 [6%] of 632 and 13 [5%] of 237) and upper respiratory tract infection (23 [4%] of 632 and eight [3%] of 237). To week 24, adverse event rates were lower than with icotrokinra (359 [57%] of 632) than deucravacitinib (411 [65%] of 634). Interpretation: Icotrokinra showed superior clinical response rates versus placebo and deucravacitinib in phase 3 moderate-to-severe plaque psoriasis trials, with similar adverse event rates to placebo. These findings suggest the potential of once-daily oral icotrokinra to provide robust efficacy and a favourable safety profile. Funding: Johnson & Johnson.