Background: COPD airway microbiota is heterogeneous with distinct features associated with inflammatory phenotype. Astegolimab, a selective ST2 IgG2 monoclonal antibody targeting the IL33- ST2 axis, is implicated in infection driven exacerbations. We sought to explore the relationship of microbiome with clinical response in anti-ST2.

Methods: Moderate-to-very severe COPD patients recruited for a single-centre, double-blinded clinical trial were randomly assigned (1:1) to receive astegolimab 490mg or placebo every 4 weeks over 48 weeks. Sputum microbiome profiles were generated from baseline (n=65) and week 12 post treatment (n=56) samples using paired-end sequencing targeting the 16S rRNA V4 region. A negative binomial regression model was applied to investigate the effect of microbiome-parameters on exacerbation rates between astegolimab and placebo dichotomised by baseline median ?-diversity (Shannon index) and taxon features (Gammaproteobacteria:Firmicutes (GP:F)). Annualized exacerbation rate reduction (AERR) is expressed as percent [80% CI].

Results: The magnitude of AERR in participants receiving astegolimab versus placebo was greater in those with lower (37.0[8.6, 56.6]%, p = 0.11) versus higher baseline ?-diversity (9.7[-38.5, 41.1]%, p = 0.76);and in those with higher (40.6[10.2,60.7]%, p=0.11) versus lower GP:F ( -10.5[-55.0,21.1]%, p = 0.70). No significant within-subject differences in symptom score or lung function were observed in either high or low microbiome groups. There were no within or between-treatment differences in microbiome.

Conclusions: Distinct lung microbiome features may inform the treatment benefit of Astegolimab for reducing COPD exacerbation frequency.