In bronchiectasis, neutrophilic inflammation is associated with an increased risk of exacerbations and disease progression. Brensocatib, an oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), targets neutrophil serine proteases, key mediators of neutrophilic inflammation.

In a phase 3, double-blind trial, we randomly assigned patients with bronchiectasis (in a 1:1:1 ratio for adults and a 2:2:1 ratio for adolescents) to receive brensocatib (10 mg or 25 mg once per day) or placebo. The primary end point was the annualized rate of adjudicated pulmonary exacerbations over a 52-week period. The secondary end points, listed in hierarchical testing order, were the time to the first exacerbation during the 52-week period; the percentage of patients remaining exacerbation-free at week 52; the change in forced expiratory volume in 1 second (FEV); the annualized rate of severe exacerbations; and change in quality of life.

A total of 1721 patients (1680 adults and 41 adolescents) underwent randomization and received brensocatib or placebo. The annualized rate of pulmonary exacerbations was 1.02 in the 10-mg brensocatib group, 1.04 in the 25-mg brensocatib group, and 1.29 in the placebo group (rate ratio, brensocatib vs. placebo, 0.79 [95% confidence interval {CI}, 0.68 to 0.92; adjusted P = 0.004] with the 10-mg dose and 0.81 [95% CI, 0.69 to 0.94; adjusted P = 0.005] with the 25-mg dose). The hazard ratio for the time to the first exacerbation was 0.81 (95% CI, 0.70 to 0.95; adjusted P = 0.02) with the 10-mg dose and 0.83 (95% CI, 0.70 to 0.97; adjusted P = 0.04) with the 25-mg dose. In each brensocatib group, 48.5% of patients remained exacerbation-free at week 52, as compared with 40.3% in the placebo group (rate ratio, 1.20 [95% CI, 1.06 to 1.37; adjusted P = 0.02] with the 10-mg dose and 1.18 [95% CI, 1.04 to 1.34; adjusted P = 0.04] with the 25-mg dose). At week 52, FEV had declined by 50 ml with the 10-mg dose, 24 ml with the 25-mg dose, and 62 ml with placebo (least-squares mean difference vs. placebo, 11 ml [95% CI, -14 to 37; adjusted P = 0.38] with the 10-mg dose and 38 ml [95% CI, 11 to 65; adjusted P = 0.04] with the 25-mg dose). The incidence of adverse events was similar across groups, except for a higher incidence of hyperkeratosis with brensocatib.

Among patients with bronchiectasis, once-daily treatment with brensocatib (10 mg or 25 mg) led to a lower annualized rate of pulmonary exacerbations than placebo, and the decline in FEV was less with the 25-mg dose of brensocatib than with placebo. (Funded by Insmed; ASPEN ClinicalTrials.gov number, NCT04594369; EudraCT number, 2020-003688-25.).