BACKGROUND: Macrolide antibiotics have immunomodulatory activity and when taken chronically reduce exacerbations of COPD. However, chronic use can cause bacterial resistance. EP395 (glasmacinal), a novel macrolide, is being developed as a treatment to reduce exacerbations of COPD without inducing antimicrobial resistance. METHODS: In this double-blind, placebo-controlled, phase 2a trial (NCT05572333), patients (>/=45 years old, diagnosed with COPD for >/=2 years and stable on at least one maintenance inhaled therapy) were randomised (2:1) to EP395 or placebo daily for 12 weeks. The primary objective was safety, with key secondary objectives assessing pharmacodynamic effects of EP395. RESULTS: A total of 61 patients were randomised (42 EP395, 19 placebo). A 12-week course of EP395 was well tolerated: no serious adverse events were considered related to EP395, and adverse events occurred in similar proportions in both groups (64.3% EP395, 63.2% placebo). Four patients were withdrawn due to adverse events (three EP395, one placebo). Sputum neutrophil elastase and myeloperoxidase, mediators of neutrophil activation, were reduced with EP395 (treatment difference (log scale): neutrophil elastase -0.415 ng.mL(-1), 95% CI -0.787 to -0.043 ng.mL(-1), p=0.030; myeloperoxidase -0.282 ng.mL(-1), 95% CI -0.640 to 0.076 ng.mL(-1), p=0.119). Relative changes in neutrophil elastase and myeloperoxidase from baseline with EP395 were 66% and 75%, respectively, of those observed with placebo. Exploratory 16S rRNA sequencing of sputum showed EP395 had no detectable effect on the lung microbiome, including the proportion of pathogenic Proteobacteria species. CONCLUSION: In patients with stable COPD, EP395 for 12 weeks was well tolerated, demonstrated selective anti-inflammatory activity and had no detectable effect on the lung microbiome.
