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

Abstract

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 Four patients were withdrawn due to AEs (3 EP395, 1 placebo).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 (95% CI [-0.787, ˗0.043] p=0.030), and MPO -0.282 ng/mL (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.

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Identifiers

ORCID for Karl J. Staples: orcid.org/0000-0003-3844-6457

ORCID for Jodie Ackland: orcid.org/0000-0003-3120-3620

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