Journal article

View all Respiratory Digests

Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis

Author(s): Chalmers JD, Haworth CS, Metersky ML, for the Willow investigators

NEJM September 7, 2020

Respiratory infections
General respiratory patient care

Digest Author(s): Stylianos Loukides, e-Learning Director / 27 September, 2020

Patients with bronchiectasis are characterized by an intense inflammatory process which is mainly driven by an underlying neutrophilic based inflammation. Patients with bronchiectasis have frequent exacerbations which are mainly caused by bacteria and are closely related to neutrophilic inflammation. Already published evidence supports the role of neutrophil serine proteases, including neutrophil elastase, in patients with bronchiectasis. The above observation was confirmed in both stable and execarbation phase.

Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases. Therefore the Willow investigators conducted a phase 2phase 2, randomized, double-blind, placebo-controlled trial. Patients with bronchiectasis were randomly assigned, in a 1:1:1 ratio which corresponds to placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. 256 patients with bronchiectasis who had had at least two exacerbations in the previous year were initially assigned to aforementioned treatment schedule. Primary end point was the time to the first exacerbation while the rate of exacerbations, sputum neutrophil elastase activity, and safety were considered as secondary points and were simultaneously assessed.

In the 6-week screening period two dental visits were performed in order to establish baseline periodontal health. At randomization, the stratification schedule included both macrolide use and chronic colonization with Pseudomonas aeruginosa infection.

The Bresoncatib group experienced a low number of exacerbation compared to placebo and statistically the median value was not finally used. The 25th percentile of the time to the first exacerbation was 67 days in the placebo group, 134 days in the 10-mg brensocatib group, and 96 days in the 25-mg brensocatib group.The incidence rates of exacerbations according to trial group were as follows: in the placebo group, 1.37 exacerbations per person-year (95% CI, 1.02 to 1.84); in the 10-mg brensocatib group, 0.88 exacerbations per person-year (95% CI, 0.61 to 1.26); and in the 25-mg brensocatib group, 1.03 exacerbations per person-year (95% CI, 0.75 to 1.42). 36% lower rates for 10mg brensocatib group.During the 24-week treatment period, the mean concentrations of neutrophil elastase in sputum were lower with both brensocatib doses than with placebo. Lung function as assessed by FEV1 % pred and Quality of Life–Bronchiectasis questionnaire did not reach statistical significance. Finally the percentages of patients who had an adverse event during the treatment period that led to the discontinuation of the trial or the discontinuation of brensocatib or placebo were similar across the trial groups.

Comments:

  • The above study showed that among patients with bronchiectasis and frequent exacerbations the administration of a DPP-1 inhibitor resulted in beneficial effects in terms of time to first exacerbation, rates of exacerbations and levels of NE in sputum. Safety issues were not remarkable withing groups.
  • Considering that bronchiectatic patients are lacking targeting treatment strategies this promising trial needs further justification in a phase 3 design focusing on patients with frequent exacerbations and chronic colonizations with bacteria.