Dupilumab reduces mucus plugging and volume: phase 4 VESTIGE trial

<bold>Introduction:</bold> Mucus hypersecretion resulting from type 2 inflammatory cytokines (e.g., interleukin [IL]-13) drives intermittent airway obstruction and remodelling. Dupilumab blocks the IL-4/13 receptor, improves lung function, and reduces rates of severe exacerbations in patients with asthma, with an acceptable safety profile. The VESTIGE study (<ext-link>NCT04400318</ext-link>) assessed dupilumab impact on airway mucus plugging and volume, inflammation, and lung function. <bold>Methods:</bold> Patients (21-70 years) with uncontrolled moderate-to-severe asthma, elevated type 2 biomarkers (baseline blood eosinophil count≥300 cells/µL; fractional exhaled nitric oxide [FeNO]≥25 ppb), pre-bronchodilator percent predicted forced expiratory volume in 1 second (pre-BD ppFEV1)≤80%, and ≥1 exacerbation year prior were randomized 2:1 to add-on dupilumab 300 mg (N=72) or matched placebo (PBO, N=37) q2w for 24 weeks. We quantified occluded bronchopulmonary segments to give mucus plug scores (0–20). Voxels per mucus plug, measured by CT, gave mucus volumes. We also assessed FeNO and pre-BD ppFEV1 at Week 24. <bold>Results:</bold> The dupilumab group had reduced mucus scores (least squares mean difference [LSMD][SE] from baseline:–4.9 [0.8] points vs PBO; nominal <italic>P</italic><0.001) and volumes (–0.11 [0.02] mL; nominal <italic>P</italic><0.001), were 9.8 times more likely to achieve FeNO<25 ppb (<italic>P</italic><0.001), and improved in pre-BD ppFEV1 (LSMD[SE]: 13.8 [3.1] %, nominal <italic>P</italic><0.001). Improvements from baseline to Week 24 in pre-BD ppFEV1 correlated with lower mucus score in the dupilumab group (Pearson’s correlation coefficient: –0.61 (<italic>P</italic><0.0001)). <bold>Conclusion:</bold> Dupilumab treatment led to reductions in airway mucus plugging, mucus volume, and inflammation, likely contributing to improved lung function.