B33-13 IL-1R3 Antagonism With Sar445399 in Skin Challenge Model: Translational Evidence for Chronic Respiratory Diseases

Rationale SAR445399 is a novel monoclonal antibody targeting interleukin-1 receptor 3 (IL-1R3), a shared co-receptor critical for signalling by IL-1, IL-33, and IL-36 cytokines. Inhibition of IL-1R3 represents a promising therapeutic strategy for modulating inflammatory pathways in respiratory disease. We utilized skin challenge models in a Phase 1 study as a translational approach to evaluate pharmacodynamic (PD) effects on biomarkers relevant to respiratory disease pathophysiology. Methods We performed a biomarker analysis from the Phase 1 proof-of-mechanism study (PDY18058) evaluating SAR445399 in healthy subjects using lipopolysaccharide (LPS) and imiquimod (IMQ) skin challenge models. While this study employed skin challenge methodology, we specifically focused on biomarkers relevant to respiratory disease pathophysiology. Results Transcriptomic analysis demonstrated that SAR445399 inhibited IL-1β gene expression in skin biopsies. Proteomic analysis of suction blister fluid showed that SAR445399 reduced MMP-1 levels. Additionally, transcriptomic analysis revealed downregulation of pathways associated with neutrophilic inflammation. These findings from cutaneous tissue are particularly relevant for respiratory translation, given IL-1β’s role as a key upstream regulator of neutrophilic inflammation and MMP production—both well-established biomarkers implicated in airway remodelling and chronic respiratory disease pathophysiology. Conclusions SAR445399 effectively modulates IL-1β gene expression and reduces MMP-1 levels in skin challenge models. These biomarkers, although measured in cutaneous tissue, have direct relevance to respiratory disease pathophysiology as well. The observed effects on neutrophilic inflammation pathways provide compelling translational evidence supporting evaluation of SAR445399 in respiratory indications This abstract is funded by: Sanofi