Bimekizumab long-term response in psoriasis: Mechanistic insights into efficacy level and durability

Background: Bimekizumab (BKZ), an IL-17A and IL-17F inhibitor, has demonstrated a rapid and high level of complete skin clearance in patients with psoriasis and complete normalization of the transcriptional signature of lesional skin after 8 weeks. Objective: We sought to assess the durability of initial clinical response to BKZ for up to 4 years and investigate molecular mechanisms leading to the observed response. Methods: Clinical data were pooled from 3 1-year phase 3 feeder studies (BE VIVID, BE READY, and BE SURE) and their 3-year open-label extension (BE BRIGHT). Transcriptomic analyses were conducted on 3 independent single-cell RNA-sequencing data sets from lesional psoriasis biopsies and bulk RNA-sequencing data from a phase 2a study. Results: Among patients who achieved complete skin clearance after 16 weeks, continued to receive double-blind BKZ treatment, and entered BE BRIGHT, 73.0% achieved this response at the end of year 4 (N = 503; modified nonresponder imputation). Single-cell transcriptomic analyses revealed a group of tissue-resident memory T (T_RM) cells in lesional skin expressing IL17A and/or IL17F that are minimally present in healthy skin, postulated to constitute a pathogenic T_RM-cell subset. Prosurvival factors expressed in T_RM cells in lesional skin were identified, with IL7R shown to be more highly expressed in IL17F+ than in IL17A+ T_RM cells. Reversal of expression of these prosurvival factors, alongside a general T_RM gene signature, was demonstrated in bulk transcriptomic analyses after 8 weeks of treatment (2 BKZ doses). Conclusions: The strong durability and high response level observed with BKZ may be associated with normalization of pathogenic T_RM cells.