DISCUSSION
inflammation, UC, PD, deaths, IBD
INFLAMMATION, MINOR
This study evaluated the safety, PK and PD of the NLRP3 inflammasome inhibitor selnoflast in patients with moderate to severe active UC.Selnoflast was safe and well‐tolerated in patients with UC. The reported AEs were non‐serious, and the majority were of mild intensity. None led to dose interruption or treatment discontinuation. There were no deaths or SAEs.The PK findings were consistent with those from a previous Entry‐into‐Humans study in healthy subjects (IZD334‐001; ClinicalTrials.gov NCT04086602), which tested doses from 20 to 600 mg under fasted conditions (unpublished results). After single administration in healthy subjects, there was a rapid increase in selnoflast plasma concentrations with a median TIn line with this, there was a rapid and sustained inhibition of mature IL‐1β release ex vivo in blood upon LPS stimulation after the first oral administration of selnoflast. These findings suggest target engagement with the NLRP3 inflammasome. On the other hand, there were only modest differences between the treatment arms in terms of biomarker response in the sigmoid colon tissue—reflecting only minor reduction of tissue IL‐1β. The contrast between the robust There was a marked reduction from baseline in neutrophils in the sigmoid colon tissue of three selnoflast‐treated patients, but no significant changes were observed in the active treatment arm as a whole. There were no clinical or histological effects observed, i.e. in the Geboes Score or Nancy Index, as expected for a study of only 1‐week duration.In our study, we used single‐cell RNA sequencing as an investigational tool for evaluating the effects of selnoflast on changes in cell composition and an IL‐1 gene signature in sigmoid colon tissue. None revealed major changes as would be expected if NLRP3 was a major driver of inflammation in active UC. Most published single‐cell RNA‐sequencing data from UC patients are derived from observational studies.The study was an innovative Phase 1b / proof of mechanism study, with the aim of reaching a decisive outcome using a rapid and lean design. This lean design naturally led to the limitations of our study, which are the small sample size and the short treatment duration. In lieu of validated assays for PD markers in tissue (e.g., mature IL‐1β), we analyzed an IL‐1 gene signature relevant in the context of IBD. Therefore, another limitation of this study is that we could only indirectly assess the effect of selnoflast on IL‐1β in colon tissue. Despite these limitations, the results from this study enabled us to reach the decision to terminate the development of selnoflast in UC within a rapid timeframe.