Brensocatib prolongs time to first pulmonary exacerbation in patients with bronchiectasis
Treatment with brensocatib for 24 weeks significantly prolonged time to first pulmonary exacerbation in patients with non-cystic fibrosis bronchiectasis compared with placebo, according to results from the WILLOW study.
Brensocatib (Insmed) is a small molecule, oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP1) that interrupts neutrophilic inflammatory processes in the lung. As Healio previously reported, brensocatib received FDA breakthrough therapy designation in mid-June to treat adults with non-cystic fibrosis bronchiectasis.
“Currently, bronchiectasis guidelines recommended airway clearance and mucoactive therapies to target abnormally disorderly clearance and macrolides in inhaled antibiotics to target bacterial colonization or infection,” James D. Chalmers, MBChB, PhD, British Lung Foundation Chair of Respiratory Research at University of Dundee, United Kingdom, said during a presentation at the American Thoracic Society’s Breaking News virtual briefing. “But we have no treatment at the moment that directly targets the neutrophilic inflammation that is the hallmark of bronchiectasis.”
The phase 2, randomized, double-blind, placebo-controlled, parallel-group WILLOW trial was designed to evaluate the safety and efficacy of brensocatib in patients with non-cystic fibrosis bronchiectasis. Primary endpoint was first time to first pulmonary exacerbation over the 24-week treatment period.
Researchers enrolled 256 patients with bronchiectasis who had at least two documented pulmonary exacerbations within the previous year; 87 patients (mean age, 64 years; 63.2% women) were randomly assigned to receive placebo, 82 patients (mean age, 64.6 years; 69.5% women) to receive brensocatib 10 mg and 87 patients (mean age. 63.7 years; 71.3% women) to receive brensocatib 25 mg.
Results showed that brensocatib 10 mg (HR = 0.58; 95% CI, 0.35-0.95; P = .029) and brensocatib 25 mg (HR = 0.62; 95% CI, 0.38-0.99; P = .046) significantly prolonged time to first exacerbation over 24 weeks compared with placebo.
The rate of exacerbations over the 24-week treatment period was 48.3% in the placebo group compared with 31.7% in the brensocatib 10 mg group (P for comparison = .033) and 33.3% in the brensocatib 25 mg group (P for comparison = .038). The annualized exacerbation rate was 1.37 exacerbations per patient per year in the placebo group compared with 0.88 exacerbations per patient per year in the brensocatib 10 mg group (P for comparison = .041) and 1.03 exacerbations per patient per year in the brensocatib 25 mg group (P for comparison = .167), according to Chalmers.
Both 10 mg and 25 mg brensocatib doses significantly reduced sputum neutrophil elastase concentration compared with placebo, which was sustained throughout the study (P = .034 for 10 mg; P = .021 for 25 mg).
In addition, Chalmers presented new data from a pooled analysis of patients treated with either dosage of brensocatib. In this analysis, patients treated with brensocatib who achieved sputum neutrophil elastase below the limit of quantification after baseline had a lower incidence of pulmonary exacerbations compared with those who had a quantifiable level of sputum neutrophil elastase after baseline. Risk for exacerbation in these patients was 72% lower.
Adverse events resulting in treatment discontinuation were higher in the placebo group (10.6%) compared with brensocatib 10 mg (7.4%) and 25 mg (6.7%). The most common adverse events in patients treated with brensocatib were cough, headache, sputum increase, dyspnea, infective exacerbation of bronchiectasis, diarrhea, fatigue and upper respiratory tract infection.
Rates of skin events, including hyperkeratosis, were 11.8% in the placebo group, 14.8% in the 10 mg brensocatib group and 23.6% in the 25 mg brensocatib group. Rates of infections considered adverse events of special interest were 17.6% with placebo, 13.6% with 10 mg brensocatib and 16.9% with 25 mg brensocatib. Rates of dental events were 3.5% with placebo, 15% with 10 mg brensocatib and 10.1% with 25 mg brensocatib. Chalmers said the WILLOW study included extensive dental evaluations to monitor progression of periodontal disease. The results did not raise a signal about dental safety. The percentage of patients with a change in periodontal pocket depth of 2 mm or more and absolute value of 5 mm or more, which is the threshold of concern for periodontal disease, was 11.6% in the placebo group, 11.3% in the 10 mg brensocatib group and 12.3% in the 25 mg brensocatib group, according to the data presented.
“This is a landmark trial for people with bronchiectasis because this is a drug that for the first time appears to be able to target directly neutrophilic inflammation, resulting in clinical benefits,” Chalmers said. “If these results are confirmed in a phase 3 trial, this may represent a novel nonantibiotic treatment to prevent exacerbations in bronchiectasis.”
According to a company press release, Insmed will begin a phase 3 program for brensocatib in bronchiectasis in late 2020.