0558: Early Systemic and Skin Pharmacodynamic Effects of Icotrokinra in Participants with Moderate-to-Severe Plaque Psoriasis: Results Through Week 24 of the Phase 3, ICONIC-LEAD Study

Background/Purpose: Icotrokinra (ICO), a first-in-class targeted oral peptide that blocks the interleukin (IL)-23R and inhibits IL-23 pathway signaling, is being evaluated in the phase 3 ICONIC-LEAD study in participants ≥12 years with moderate-to-severe plaque psoriasis (PsO). Study co-primary endpoints were met, with ICO demonstrating significantly higher Investigator’s Global Assessment (IGA) 0/1 (64.7% vs 8.3%) and Psoriasis Area and Severity Index (PASI) 90 (49.6% vs 4.4%) response rates vs placebo at Week (W) 16 (both p< 0.001). ICO pharmacodynamics were assessed via serum protein and skin transcriptomic analyses.

Methods: Participants (N=684) were randomized 2:1 to once-daily ICO 200 mg or placebo through W16. After W16, placebo participants transitioned to ICO (placebo®ICO). Serum collected at W0, W4, and W16 from a sub-cohort (n=166 for IL-22; n=167 for other analytes) and a distinct healthy control cohort (n=30; BioIVT, Hicksville, NY) was analyzed to determine soluble IL-17A, IL-17F, IL-19, IL-22, and BD-2 concentrations. Skin biopsies collected at W0 and W24 from consenting participants of an optional sub-study (n=65) were analyzed for mRNA expression. Comparisons between ICO and placebo used linear mixed-effect modeling that included effects for W0 levels, treatment-over-time interaction, and participant random effect.

Results: Serum IL-17A, IL-17F, IL-19, IL-22, and BD-2 levels were significantly higher in participants with PsO at baseline (W0) vs healthy control (p < 0.05). ICO significantly reduced serum biomarker levels vs placebo (all p< 0.05 at W4 and W16) and relative to W0 levels as early as W4 (p < 0.0001 for all analytes). Serum biomarker concentrations continued to decrease in participants receiving ICO, with levels at W16 (all p< 0.0001 vs W0) approaching those of healthy control. At W0, 1026 genes were significantly upregulated and 970 significantly downregulated (adjusted p< 0.05) in lesional vs non-lesional skin. At W24, ICO significantly reduced PsO-related gene set enrichment (MAD-3, MAD-5) and gene expression, including IL17A, IL17F, IL22, IL19, IL23A, and DEFB4A (all p< 0.0001 vs W0 lesional) to levels approaching those seen in W0 non-lesional skin. Similar significant reductions were observed after 8 weeks of ICO treatment in the placebo®ICO cohort (all p< 0.0001 vs W0 lesional).

Conclusion: Consistent with its mechanism of action of selectively and potently blocking the IL-23R, ICO significantly attenuated systemic and skin biomarkers related to IL-23 pathway activation and PsO disease severity. Findings demonstrated both early and substantial ICO effects, with levels of IL-23 pathway biomarkers of systemic and skin inflammation normalizing to a healthy state. Overall, these comprehensive biomarker findings are consistent with significant skin clearance achieved with this first targeted oral peptide to selectively inhibit IL-23 pathway activation.