A randomised controlled trial of EP395, a novel anti-inflammatory macrolide, in stable COPD patients

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.

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.

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 Four patients were withdrawn due to adverse events (three EP395, one placebo).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.

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.