The new macrolide EP395 reduces airway eosinophilic inflammation

Abstract

Blood eosinophil levels are used to guide treatment regimens for COPD patients. Patients who frequently exacerbate despite regular bronchodilator therapy may benefit from inhaled corticosteroids (ICS), particularly if they have evidence of eosinophilic inflammation (GOLD 2023). For patients who continue to exacerbate despite LABA/LAMA (Long-Acting Beta Agonists and Long-Acting Muscarinic Agonists) and ICS treatments, or who are not candidates for ICS, azithromycin off-label may be considered. We have previously shown that EP395, a macrolide with negligible antimicrobial activity, enhances epithelial barrier integrity and is effective in reducing neutrophilic inflammation across several airway inflammation models (ERJ 2023: 62 suppl 67; ERJ 2022: 60, suppl 66). To assess its potential scope as a treatment for COPD patients, we commenced a 2-week oral treatment of EP395 prior to sensitisation and during challenge with either ovalbumin (OVA) or house dust mite (HDM) in mice and guinea pigs, respectively. EP395 was effective in reducing total cell and eosinophil numbers in both models. In the OVA model, 0.4, 1.0, and 2.0 mg/kg/day EP395 dose-dependently reduced eosinophils, Th2 cytokines, and epithelial-derived TSLP. In the HDM model, eosinophil numbers were reduced by 60% with 2.0 mg/kg/day EP395, compared to those of control animals. Histology of the lung tissues also showed EP395 reduced accumulation of cells around the airways, as well as reducing vascular permeability compared to the control group. EP395 reduces both neutrophil and eosinophil numbers across a variety of animal airway challenge models, and thus, has potential as a therapy for COPD patients, irrespective of inflammation subtype.

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