P74 Guselkumab clinical super-response is associated with faster normalization of blood and skin pathology: data from the Phase 3b GUIDE trial

Abstract The ongoing GUIDE trial (NCT03818035) examines the clinical and immunological impact of an extended dosing interval of guselkumab [an interleukin (IL)-23p19 subunit inhibitor] in patients with moderate-to-severe plaque-type psoriasis. A mechanistic substudy was conducted to explore the molecular differences in the skin and blood of ‘super-responder’ (SRe) and non-SRe patients. SRes were defined as patients achieving a psoriasis area and severity index (PASI) = 0 at both Week [W]20 and W28 following guselkumab treatment. RNA-sequencing was performed on non-lesional (at W0) and lesional skin samples (at W0, W4, W28, and W68) along with serum analyses of matching timepoints. Published gene sets related to psoriasis skin and cytokine-stimulated keratinocytes were used for gene set variation analysis. At W0, ∼1100 protein-coding transcripts were upregulated in lesional vs. non-lesional skin, and ∼3000 protein-coding transcripts were downregulated in lesional vs. non-lesional skin. Following treatment with guselkumab, robust pharmacodynamic changes were observed for immune- and psoriasis inflammation-related gene signatures. Faster changes were observed in SRes vs. non-SRes. Signatures related to psoriasis skin inflammation, IL-17-stimulated keratinocyte response, T-helper (Th)17 cells, and many keratinocyte subtypes (differentiated, proliferating and inflamed keratinocytes) were more significantly reduced in SRes vs. non-SRes as early as W4. By W28, all signatures that were upregulated at baseline in lesional vs. non-lesional skin were normalized in SRes, including molecular scar skin and Th17 pathway signatures. In contrast, among non-SRes, molecular scar and immune-cell-regulated signatures (including macrophage, Th22, mucosal-associated invariant T cells, and CD4+ T cells) were <75% normalized at W28. In both SRes and non-SRes, signatures initially downregulated in lesional vs. non-lesional skin at W0, including those for adipocytes, smooth muscles, meta-analysis-derived psoriasis downregulated genes, and IL-17-stimulated KC downregulated genes, represent the few signatures that did not return to non-lesional skin levels after 68 weeks of guselkumab treatment. Consistent with the effect of guselkumab on inflammatory processes in the skin as observed via RNA sequencing, guselkumab treatment decreased the serum levels of several inflammatory mediators as early as W4. The levels of IL-17A, IL-17F and IL-22 were comparable in SRes and non-SRes, while the reduction in beta defensin-2 level was more pronounced in SRes at W4 and W28. These reductions were maintained to W68. In summary, molecular analyses of SRes and non-SRes in the GUIDE clinical trial show kinetic and quantitative differences in the response to guselkumab treatment.