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

Abstract Rationale Non-cystic fibrosis bronchiectasis (hereafter bronchiectasis) is a chronic and progressive respiratory disease. Neutrophilic inflammation plays a key role in the pathophysiology of bronchiectasis. Neutrophil serine proteases (NSPs), especially neutrophil elastase, have been associated with disease progression and poorer clinical outcomes. Current therapies do not directly target neutrophilic inflammation. Long-term macrolide use is recommended for patients with frequent exacerbations. Brensocatib, an oral, selective, competitive, and reversible inhibitor of dipeptidyl peptidase 1, prevents activation of NSPs. In the phase 3, randomized, double-blind ASPEN trial (NCT04594369), treatment with once-daily brensocatib 10- or 25-mg significantly reduced the annualized rate of adjudicated pulmonary exacerbations over 52 weeks vs placebo; the 25-mg dose also significantly reduced lung function decline and numerically improved patient-reported symptoms. Here, we report ASPEN subgroup analysis findings in patients with or without maintenance macrolide use. Methods ASPEN enrolled patients with bronchiectasis and a history of pulmonary exacerbations in the 12 months prior to screening (adults [18-85 years], ≥2; adolescents [12-<18 years], ≥1). Patients were randomized to receive once-daily brensocatib (10- or 25-mg) or matching placebo for 52 weeks (adults, 1:1:1; adolescents, 2:2:1). Subgroup analyses were explored in patients with or without maintenance macrolide use (≥3 months) at baseline. Endpoints were annualized exacerbation rate, time to first exacerbation, rate of severe exacerbation, change in post-bronchodilator forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC), and change in Quality of Life-Bronchiectasis Respiratory Symptoms Domain score (QOL-B RSS). Results Demographics were balanced, with some differences in baseline characteristics indicating greater disease severity among patients with maintenance macrolide use, including increased exacerbation rate and more exacerbations requiring hospitalization prior to enrollment. Patients with maintenance macrolide use experienced higher rates of exacerbations over the study period vs those without, regardless of treatment group (Table). Consistent with overall ASPEN results, brensocatib 10- and 25-mg reduced the annualized exacerbation rate, prolonged the time to first exacerbation, and increased the odds of remaining exacerbation-free in both subgroups (Table). Brensocatib 25-mg reduced both FEV1 and FVC decline, and numerically improved QOL-B RSS at week 52 vs placebo for patients regardless of baseline macrolide use (Table). Adverse events were similar across treatment groups, and consistent with the overall ASPEN results. Conclusions Consistent with the overall study population, both brensocatib doses reduced the annualized rate of exacerbations, and brensocatib 25-mg reduced lung function decline and numerically improved patient-reported symptoms regardless of maintenance macrolide use at baseline.