Guselkumab clinical super response is associated with faster normalization of blood and skin pathology: data from Phase IIIb GUIDE trial

The ongoing GUIDE study (NCT03818035) examines the clinical and immunological impact of different dosing strategies of guselkumab (a specific interleukin [IL]-23 inhibitor) in patients with moderate-to-severe plaque-type psoriasis. A mechanistic substudy was conducted to explore molecular differences in skin and blood from ‘super-responder’ (SRe; PASI=0 at Week [W] 20 and W28) versus non-SRe patients. RNA-sequencing was performed on non lesional (W0) and lesional skin (W0, W4, W28, 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 and ∼3000 protein-coding transcripts were downregulated in lesional versus non-lesional skin. Following guselkumab treatment, immune- and psoriasis inflammation-related gene signatures showed robust pharmacodynamic changes. Faster changes were observed in SRes versus non-SRes. Signatures related to psoriasis skin inflammation, IL-17-stimulated keratinocyte response, Th17 cells and many keratinocyte subtypes (differentiated, proliferating and inflamed keratinocytes) were more significantly reduced in SRes versus non-SRes as early as W4. By W28, all signatures upregulated at baseline were normalized in SRes, including molecular scar skin and Th17 pathway signatures. In contrast, molecular scar and immune-cell-regulated signatures (including macrophage, Th22, mucosal-associated invariant T cells and CD4+ T cells) were <75% normalized in non-SRes at W28. In both SRes and non-SRes, signatures initially downregulated in lesional versus non-lesional skin at W0 (adipocytes, smooth muscles, meta-analysis-derived psoriasis downregulated genes, IL-17-stimulated KC downregulated genes) represent the few that did not return to non-lesional skin levels after 68 weeks of guselkumab treatment. Consistent with skin biomarker findings, guselkumab decreased serum levels of several inflammatory mediators as early as W4, with IL-17A, IL-17F and IL-22 levels being comparable in SRes and non-SRes, while the reduction in BD-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 show kinetic and quantitative differences in the response to guselkumab.