Icotrokinra (ICO), a Novel Targeted Oral Peptide, in Patients (Pts) with Psoriatic Disease: Exploratory Assessments from a Phase 2 Psoriasis (PsO) Study Informing a Phase 3 Clinical Program in Psoriatic Arthritis (PsA)

Objectives PsA affects ~20-30% of patients with PsO, causing articular inflammation and impaired quality of life. ICO, a novel targeted oral peptide that binds IL-23 receptor, showed greater clinical response rates vs placebo and a favorable safety profile in moderate-to-severe plaque PsO in the Phase 2 FRONTIER 1&2 studies. We leveraged exploratory serum biomarker, Patient-Reported Outcomes Measurement Information Systems (PROMIS-29), and Psoriasis Area and Severity Index 75% improvement (PASI75) data from a subset of FRONTIER 1 patients with PsO and PsA (PsO+PsA) to support Phase 3 ICONIC-PsA 1 and ICONIC-PsA 2 studies. Methods Mean log fold-changes (logFC) in serum β-Defensin-2 (BD-2), IL-22, IL-17A and IL-17F levels were summarized for FRONTIER patients. Improvements ≥5-points in PROMIS-29 domains scores (or ≥2 for pain), and physical/mental component summary (PCS/MCS) scores, are considered clinically meaningful. ICO PsA Phase 3 sample sizes were informed by estimates from model-based analyses, including a meta-analysis that bridged FRONTIER 1 to PASI75 to expected American College of Rheumatology 20% improvement (ACR20) at Week (W)16 and meta-regression modeling that bridged ACR20 to secondary endpoints. Results 23/91 (25%) FRONTIER 1 patients had PsO+PsA (ICO, n=20; placebo, n=3). Among patients with biomarker data, mean logFC in serum BD-2, IL-22, IL-17A and IL-17F (data not shown) over time indicated consistent ICO pharmacodynamic effect between patients with PsO only and with PsO+PsA. ICO-treated PsO+PsA patients reported numerically greater mean changes from baseline (BL) at W16 vs placebo across PsA relevant PROMIS-29 domains, ie, improvements in physical function (7.7 vs 1) and reductions in fatigue (−7.4 vs 2.3 [worsening]), pain interference (−10.7 vs −1.3), and pain intensity (−3.5 vs −1.5). In 20 ICO-treated patients with PsO+PsA, 45% and 70% reported ≥5 point improvement from BL in PROMIS-29 PCS and MCS scores, respectively, vs no patients receiving placebo. ICONIC-PsA 1&2 sample sizes of 540 (5:5:5:3 to ICO Dose 1/2/placebo/active reference arm) and 750 (1:1:1 to ICO Dose 1/2/placebo) (Figure) were estimated to provide ≥90% power to detect significant differences between ICO and placebo. Given minorities are often under-recruited in PsA trials, the ICO PsA program aims to assess diverse populations. Figure 2: ICONIC PsA-1 (biologic-naïve [A]) and ICONIC PsA-2 (biologic-experienced [B]) study designs Conclusion Exploratory assessments from FRONTIER 1 showed comparable ICO pharmacodynamic effects between patients with PsO only, and with PsO+PsA. ICO-treated patients with PsO+PsA reported numerically greater improvements in PsA-relevant PROMIS-29 domains vs placebo. Informed by these post-hoc analyses and model-based meta-analyses, the multicenter, double-blind, placebo-controlled ICONIC-PsA 1 and ICONIC-PsA 2 studies will evaluate ICO in active PsA.