Late Breaking Abstract - A novel macrolide, EP395, in a LPS challenge in healthy volunteers

<bold>Background:</bold> EP395, a macrolide with anti-inflammatory effects in mouse lipopolysaccharide (LPS) challenge and negligible antimicrobial activity, is being developed as a potential treatment to reduce COPD exacerbations. <bold>Aims:</bold> To assess the pharmacodynamics of EP395 in response to LPS challenge. <bold>Methods:</bold> In this double-blind, placebo-controlled study (<ext-link>NCT05516316</ext-link>), 49 healthy, non-smoking volunteers were randomised to 375 mg EP395 or placebo for 3 weeks. An inhaled LPS challenge (2 µg) was then given, followed after 6 h by bronchoscopy for bronchoalveolar lavage fluid (BALF) collection. Blood samples were collected pre, 6 and 24 h after LPS challenge. <bold>Results:</bold> BALF concentrations of IL-6, TNF-α, MIP-1α, MIP-1β and MCP-1 were lower with EP395 than placebo, while IL-33, IL-8, and IL-1β were higher with EP395 than placebo (not significant). There was no difference in neutrophil number, but neutrophil elastase (NE) and myeloperoxidase were higher with EP395 than placebo (not significant). Geometric mean NE was 101.46 ng/mL (EP395) and 71.59 ng/mL (placebo) (difference p= 0.108). Serum concentrations of surfactant protein-D significantly increased in the EP395 group in response to LPS at both 6 h and 24 h compared with pre-LPS (mean pre-LPS 148.77 ng/mL; mean 24 h post-LPS 183.00 ng/mL) but not in the placebo group. The difference in the EP395 group, before and 24 h after LPS challenge was −0.33 (95 % CI −0.52, −0.14; p=0.0007), whilst the difference in the placebo group was −0.09 (95 % CI −0.28, 0.10; p=0.3351). EP395 was well tolerated. <bold>Conclusions:</bold> EP395 treatment increased the host defence response to inhaled LPS, including the epithelial response, whilst inhibiting inflammatory site pro-inflammatory mediators.