Fernandez, C.

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. 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; brensocatib 25-mg also significantly reduced lung function decline and improved patient-reported symptoms. Here, we further evaluate the impact of brensocatib on lung function in patients with bronchiectasis. 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). Post-hoc analyses were conducted to evaluate the extent of lung function response to treatment, as measured by change from baseline in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) over the 52-week treatment period in patients who did vs did not have ≥1 on-study pulmonary exacerbation, and the level of change in post-BD FEV1 and forced vital capacity (FVC) at week 52. Results A total of 583 patients received brensocatib 10-mg, 575 received brensocatib 25-mg, and 563 received placebo. Overall, a greater decline in FEV1 was observed among patients with ≥1 on-study pulmonary exacerbation vs those without. Treatment with brensocatib 10-mg or 25-mg led to less FEV1 decline at week 52 vs placebo for patients regardless of on-study exacerbation (no exacerbation: -42mL, -8mL, vs -48mL; ≥1 exacerbation: -59mL, -41mL, vs -70mL, for 10-mg, 25-mg brensocatib and placebo, respectively [Figure]). In the overall population, no change or an improvement (≥0 mL difference vs baseline) in post-BD FEV1 at week 52 was observed in 38.7%, 45.4%, and 31.2% of patients in the brensocatib 10-mg, 25-mg, and placebo groups, respectively. Similar impacts of brensocatib were observed in FVC (no change or improvement, 10-mg: 41.3%; 25-mg: 48.9%; placebo: 31.8%). Conclusions Overall, greater lung function decline was observed in patients who had on-study pulmonary exacerbations vs those who did not. Brensocatib 25-mg reduced lung function decline vs placebo regardless of whether patients had on-study exacerbations, consistent with overall ASPEN results.