Inhibition of neutrophilic inflammation by targeting the airway epithelial barrier with EP395

Abstract

Respiratory epithelium acts as a first line of defence against external stimuli of biological and material origin. Several members of the macrolide class of antibiotics, particularly azithromycin have clinical benefit in the treatment of a range of respiratory diseases, including the ability to reduce exacerbations in patients with chronic obstructive pulmonary disease (COPD) (Albert, R.K. et al. NEJM 2011; 365: 689-698), in addition to their antimicrobial activity. We have recently demonstrated that macrolides can enhance epithelial barrier integrity (Aarson, A.J. et al. Respir Res 2019; 20: 129), as well exhibit anti-inflammatory activity, which has prompted us to develop non-antibiotic compounds with similar pharmacological actions, but without antimicrobial activity. EP395 is the lead compound of this new class of compounds we have termed “barriolides” and has recently entered a first time in human (FTIH) study and is expected to enter phase 2 clinical trials in mid-2022. We have now demonstrated that EP395 has significant anti-inflammatory effects in lipopolysaccharide (LPS) and respiratory syncytial virus (RSV)-induced neutrophilia in the lungs of mice. EP395 dose-dependently reduced neutrophil infiltration in LPS and RSV with ED50s of 3.7 (n=10) and 14 µmol/kg/week (n=8), respectively. Correspondingly, concentrations of key inflammatory cytokines, TNFα and IL-6 were also significantly reduced after 2 weeks’ pre-treatment, comparable to effects induced by azithromycin and roflumilast. These data support the potential for EP395, to modify diseases involving neutrophilic infiltration and epithelial barrier dysfunction, such as COPD.

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