P75 Bimekizumab led to rapid and deep normalization of molecular signatures associated with psoriasis area and severity index sub-components and disease activity, preceding clinical skin clearance

Abstract To better understand the complete and rapid effects of bimekizumab (BKZ) on psoriatic skin at both a molecular and clinical level, we assessed the three psoriasis area and severity index (PASI) sub-components (erythema, thickness and scaling) and their associated gene signatures. Analysis of these individual measures is important given they can be obscured in the overall weighted composite score and may contribute to its complexity, as well as some inter-observer variability. Gene sets linked with PASI sub-components and disease activity were curated using public gene ontologies and refined based on genes found to be dysregulated in psoriasis. The dysregulation of these psoriasis-specific, PASI sub-component gene sets and their normalization post-BKZ treatment was assessed using bulk RNA-seq data from a Phase 2a trial.1 The rapid and durable effects of BKZ on the PASI sub-scores were evaluated in BE RADIANT, a Phase 3b trial.2 After two 320 mg doses, by Week 8 of BE RADIANT, BKZ-randomized patients achieved mean reductions of 89.0, 92.1 and 93.3% from baseline in erythema, thickness and scaling sub-scores, respectively. By Week 12, all three sub-components showed ≥95% mean improvement, which was maintained to Year 1 (Week 48), indicating clinical predictivity for sustainable skin clearance as early as Week 12. At the molecular level, bulk RNA-seq data from the Phase 2a trial showed complete normalization (to non-lesional levels and beyond; median % improvement 95.7–105.3%) of the gene sets associated with the PASI sub-components and disease activity by Week 8, after two doses. Furthermore, dysregulation of selected markers associated with erythema (CXCL8), thickness (KRT16) and scaling (LORICRIN) was observed in lesional psoriatic tissue (confirmed by RNAscope imaging) and normalized post-BKZ treatment. A correlation between baseline changes in interleukin (IL)17A/IL17F expression levels and mean gene expression changes in each curated gene set was identified (R = 0.36–0.60, FDR < 0.05), consistent with the known direct effect of IL17 on keratinocytes. BKZ treatment resulted in significant improvement of all PASI sub-scores by Week 12 and led to fast and deep normalization of the molecular signatures associated with these sub-components by Week 8. These findings show that clinically apparent skin clearance is preceded by molecular disease resolution. All three sub-components were equally normalized post-BKZ treatment, indicating each is reliable in evaluating clinical response to BKZ.