P90 JNJ-77242113 induces a strong and durable pharmacodynamic response in serum and skin of patients with moderate-to-severe psoriasis: 1-year results from FRONTIERs 1 and 2

Abstract JNJ-77242113 (JNJ-2113), a targeted oral peptide that binds the interleukin (IL)-23-receptor to inhibit IL-23 signalling, showed superior clinical efficacy vs. placebo at Week(W) 16 of FRONTIER-1 in patients with moderate-to-severe plaque psoriasis, which correlated with strong serum and skin pharmacodynamic (PD) responses (Bissonnette R, Pinter A, Ferris LK et al. An oral interleukin-23-receptor antagonist peptide for plaque psoriasis. N Engl J Med 2024; 390:510–21). Here, we evaluated JNJ-2113 systemic PD responses through W52 and further characterized the JNJ-2113 skin PD effect, including relationships with clinical response, utilizing tape-strip skin sampling. FRONTIER-1 randomized (1:1:1:1:1:1; 41-43pts/arm) participants to 25 mg QD, 25 mg BID, 50 mg QD, 100 mg QD, 100 mg BID, or placebo through W16. Patients continuing to FRONTIER-2 received the same JNJ-2113 regimen or crossed-over from placebo→100 mg QD through a total of 52-weeks of treatment. Both targeted [β-Defensin-2 (BD-2)/IL-22/IL-17A/IL-17F/IL-23] and broad (5400+ protein Olink® Explore HT) proteomics were conducted using serum samples collected through W52. The BD-2 and Olink® Explore-HT assays were performed on protein lysates extracted from tape-strip samples of lesional and non-lesional skin collected through W16, and correlation between BD-2 levels and psoriasis area and severity index (PASI) scores was evaluated. JNJ-2113 drove significant, rapid, dose-related reductions in serum psoriasis disease biomarker (BD-2/IL-22/IL-17A/IL-17F) levels that continued through W52; largest reductions were with JNJ-2113 100 mg BID [W52 fold-change (FC) from baseline: -3.63/-1.19/-1.03/-1.49, respectively]. Notably, through W52, JNJ-2113 had minimal impact on serum IL-23 (W52 FC from baseline: −0.09) or cytokines involved in broad immune response through W52 as assessed via Olink® Explore-HT. Consistent with serum results, JNJ-2113 100 mg BID significantly reduced BD-2 levels in W16 lesional skin to levels seen in non-lesional skin; this reduction correlated with PASI. Broad proteomics of tape-strip samples showed baseline lesional samples were significantly enriched for psoriasis-relevant proteins (BD-2/IL-22/IL-17A/IL-19 and others) and clustered away from non-lesional samples. Importantly, JNJ-2113 100 mg BID reduced psoriasis-related proteins in W16 tape-strip lesional samples, with a protein signature like non-lesional samples but distinct from baseline lesional and W16 placebo samples, suggesting JNJ-2113 normalized skin inflammation. JNJ-2113 selectively blocked IL-23-driven inflammation and induced a dose-related PD response, with rapid and sustained reduction of biomarkers of the IL-23 pathway and psoriasis disease severity through 1-year of treatment. JNJ-2113 also normalized skin biomarkers, which correlated with reductions in PASI, to drive disease improvement. Our novel approach to tape-strip-derived proteomics demonstrates this minimally invasive alternative to skin biopsies can be used to evaluate disease biology and characterize local treatment response in psoriatic patients.