(405) Efficacy of Brensocatib in Patients With Non-Cystic Fibrosis Bronchiectasis (Bronchiectasis) With vs Without Maintenance Use of Macrolides: An Analysis of the ASPEN Trial

Background: : Bronchiectasis is a chronic, progressive respiratory disease driven by neutrophilic inflammation and characterized by pulmonary exacerbations (PEx). Long-term macrolide use is recommended for patients (pts) with frequent PEx but does not target the underlying neutrophilic inflammation. Brensocatib, an oral, selective, competitive, reversible inhibitor of dipeptidyl peptidase 1, prevents activation of neutrophil serine proteases. In the phase 3 ASPEN trial (NCT04594369) brensocatib 10 and 25mg significantly reduced PEx burden vs pbo (annualized rate, time to first, increased odds of remaining PEx-free); 25mg also significantly reduced lung function decline and nominally significantly improved pt-reported symptoms.

Objective: : To report ASPEN findings in pts with (≥3 months) or without maintenance macrolide use.

Methods: : In ASPEN, pts with bronchiectasis and history of PEx in the 12 months before screening were randomized to once-daily brensocatib (10 or 25mg) or pbo for 52 wks (adults, 1:1:1; adolescents, 2:2:1). Endpoints assessed included annualized rate of adjudicated PEx, time to first PEx, severe PEx rate, change in post-bronchodilator forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), and Quality of Life-Bronchiectasis Respiratory Symptoms Domain score (QOL-B RSS).

Results: : Baseline characteristics were mostly balanced between treatment arms but with greater disease severity indicators in pts on maintenance macrolides, including a higher proportion of pts with ≥3 PEx in the prior 12 months and P. aeruginosa-positive sputum at screening.
Both brensocatib doses reduced PEx rates (RR [95% CI], with macrolides: brensocatib 10mg 0.79 [0.58-1.06], brensocatib 25mg 0.79 [0.58-1.08]; without macrolides: brensocatib 10mg 0.78 [0.66-0.93], brensocatib 25mg 0.80 [0.67-0.95]), prolonged time to first PEx (HR [95% CI], with macrolides: 10mg 0.93 [0.66-1.33], 25mg 0.85 [0.59-1.21]; without macrolides: 10mg 0.79 [0.66-0.94], 25mg 0.82 [0.68-0.98]), and increased odds of remaining PEx-free (OR [95% CI], with macrolides: 10mg 1.41 [0.78-2.57], 25mg 1.59 [0.88-2.90]); without macrolides: 10mg 1.44 [1.10-1.89], 25mg 1.40 [1.07-1.84]) vs pbo. Brensocatib 25mg reduced FEV1 and FVC decline and improved QOL-B RSS at wk 52 vs pbo regardless of macrolide use. Adverse events were similar across treatment groups but higher in pts on macrolides.

Conclusions: : Consistent with the overall population, brensocatib 10 and 25mg reduced PEx burden and brensocatib 25mg reduced lung function decline and numerically improved pt-reported symptoms vs pbo regardless of baseline macrolide use.

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