• James D Chalmers, Charles S Haworth, Mark L Metersky, Michael R Loebinger, Francesco Blasi, Oriol Sibila, Anne E O'Donnell, Eugene J Sullivan, Kevin C Mange, Carlos Fernandez, Jun Zou, Charles L Daley, and WILLOW Investigators.
• From the Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee (J.D.C.), Royal Papworth Hospital NHS Foundation Trust and Department of Medicine, University of Cambridge, Cambridge (C.S.H.), and Royal Brompton and Harefield NHS Foundation Trust and Imperial College, London (M.R.L.) - all in the United Kingdom; the University of Connecticut School of Medicine, Farmington (M.L.M.); the Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, and the Department of Pathophysiology and Transplantation, University of Milan, Milan (F.B.); the Department of Pulmonary Medicine, Respiratory Institute, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, and University of Barcelona, Barcelona (O.S.); the Division of Pulmonary, Critical Care, and Sleep Medicine, Georgetown University Medical Center, Washington, DC (A.E.O.); Insmed, Bridgewater, NJ (E.J.S., K.C.M., C.F., J.Z.); and the Department of Medicine, National Jewish Health and the University of Colorado, Denver (C.L.D.).
• N. Engl. J. Med. 2020 Nov 26; 383 (22): 2127-2137.

BackgroundPatients with bronchiectasis have frequent exacerbations that are thought to be related to neutrophilic inflammation. The activity and quantity of neutrophil serine proteases, including neutrophil elastase, are increased in the sputum of patients with bronchiectasis at baseline and increase further during exacerbations. Brensocatib (INS1007) is an oral reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), an enzyme responsible for the activation of neutrophil serine proteases.MethodsIn a phase 2, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1:1 ratio, patients with bronchiectasis who had had at least two exacerbations in the previous year to receive placebo, 10 mg of brensocatib, or 25 mg of brensocatib once daily for 24 weeks. The time to the first exacerbation (primary end point), the rate of exacerbations (secondary end point), sputum neutrophil elastase activity, and safety were assessed.ResultsOf 256 patients, 87 were assigned to receive placebo, 82 to receive 10 mg of brensocatib, and 87 to receive 25 mg of brensocatib. 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. Brensocatib treatment prolonged the time to the first exacerbation as compared with placebo (P = 0.03 for 10-mg brensocatib vs. placebo; P = 0.04 for 25-mg brensocatib vs. placebo). The adjusted hazard ratio for exacerbation in the comparison of brensocatib with placebo was 0.58 (95% confidence interval [CI], 0.35 to 0.95) in the 10-mg group (P = 0.03) and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group (P = 0.046). The incidence-rate ratio was 0.64 (95% CI, 0.42 to 0.98) in the 10-mg group, as compared with placebo (P = 0.04), and 0.75 (95% CI, 0.50 to 1.13) in the 25-mg group, as compared with placebo (P = 0.17). With both brensocatib doses, sputum neutrophil elastase activity was reduced from baseline over the 24-week treatment period. The incidence of dental and skin adverse events of special interest was higher with the 10-mg and 25-mg brensocatib doses, respectively, than with placebo.ConclusionsIn this 24-week trial, reduction of neutrophil serine protease activity with brensocatib in patients with bronchiectasis was associated with improvements in bronchiectasis clinical outcomes. (Funded by Insmed; WILLOW ClinicalTrials.gov number, NCT03218917.).Copyright © 2020 Massachusetts Medical Society.

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