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

Background Macrolide antibiotics have immunomodulatory activity and 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 (aged ≥45 years, 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 Sixty-one patients were randomised (42 EP395, 19 placebo). Twelve weeks EP395 was well tolerated: no serious adverse events (AEs) were considered related to EP395, and AEs occurred in similar proportions in both groups (64.3% EP395, and 63.2% placebo). Four patients were withdrawn due to AEs (3 EP395, 1 placebo). Sputum neutrophil elastase (NE) and myeloperoxidase (MPO), mediators of neutrophil activation, were reduced with EP395 (treatment difference [log scale]: NE −0.415 ng·mL −1 (95% CI [−0.787, −0.043] p=0.030), and MPO −0.282 ng·mL −1 (95% CI [−0.640, 0.076] p=0.119). Relative changes of NE and MPO 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 impact on the lung microbiome, including the proportion of pathogenic Proteobacteria species. Conclusion In stable COPD patients, EP395 for 12 weeks was well-tolerated, demonstrated selective anti-inflammatory activity, and had no detectable impact on the lung microbiome.