Treatment with the novel reversible dipeptidyl peptidase 1 (DPP1) inhibitor brensocatib prolonged time to first exacerbation for patients with non-cystic fibrosis bronchiectasis, and led to fewer exacerbations overall, a randomized phase II study found.
Among the 256 patients in the so-called WILLOW trial, brensocatib-treated patients showed a 40% lower risk for exacerbation over 24 weeks of treatment compared to those assigned to placebo, and the DPP1-inhibitor-treated patients had a lower annualized rate of exacerbations, reported James Chalmers, MBChB, PhD, of Ninewells Hospital and ľֱ School in Scotland.
The rate of severe exacerbations in patients receiving either a 10-mg dose or 25-mg dose of the DPP1 inhibitor was roughly half that reported in the placebo group.
Updated findings from the trial were presented during a late-breaking session at the virtual meeting of the and published simultaneously in the .
The phase II trial randomized patients with at least two bronchiectasis exacerbations over the previous year 1:1:1 to either 10 mg of brensocatib (n=82), 25 mg of brensocatib (n=87), or placebo (n=87), once daily for 24 weeks.
Compared to placebo, brensocatib significantly prolonged time to first pulmonary exacerbation over the 24-week treatment period, the study's primary endpoint, in both the 10-mg (P=0.03) and 25-mg (P=0.04) groups.
Risk of exacerbation at any time during the trial was reduced by 42% with the 10-mg dose (HR 0.58, 95% CI 0.35-0.95, P=0.03) and by 38% with the 25-mg dose (HR 0.62, 95% CI 0.38-0.99, P=0.046).
Incidence rates were 0.88 exacerbations per person-year with the 10-mg dose, 1.03 per person-year with the 25-mg dose, and 1.37 per person-year with placebo. Incident rate ratios (IRR) significantly favored the 10-mg dose versus placebo (IRR 0.64, 95% CI 0.42-0.98, P=0.04) and showed a numerical advantage for the 25-mg dose (IRR 0.75, 95% CI 0.50-1.13, P=0.17).
Brensocatib received FDA breakthrough therapy designation in June for adults with non-cystic fibrosis bronchiectasis, and developer Insmed has announced plans .
Chalmers said the WILLOW findings illustrate the potential clinical benefits of treatment that directly reduces inflammation in patients with bronchiectasis.
The experimental small-molecule inhibitor targets DPP1, which is the enzyme responsible for activating neutrophil serine proteases (NSPs) -- including neutrophil elastase -- when neutrophils are formed in the bone marrow. Neutrophil buildup in the airways is a characteristic of chronic inflammatory lung disease, resulting in excessive NSP activity, accelerated inflammation, and lung damage.
Subgroup analyses of WILLOW, presented by Chalmers at ERS, showed brensocatib to consistently prolong time to exacerbation and reduce exacerbation frequency regardless of baseline disease severity, P. aeruginosa infection, and sputum neutrophil elastase concentrations. Brensocatib also reduced sputum concentrations of all three NSPs examined (neutrophil elastase, proteinase 3, and cathepsin G).
"Over a period of 4 weeks, we saw very large reductions in neutrophil elastase activity in sputum, which was clearly different from the placebo group, with the impression of a dose-response relationship, with greater reductions in the 25-mg group," Chalmers said.
Those reductions were sustained across the study, he noted, but inflammation levels returned to baseline once the drug was withdrawn during a 4-week off-treatment period.
"Very similar patterns were observed for proteinase 3 and cathepsin G, suggesting that the mechanism of action -- the reduction of inflammation -- is what is leading to the reductions in exacerbations," Chalmers said.
He said that while neutrophil inhibition has been shown to increase the risk of infection in several previous trials, infection-related adverse events (AEs) were evenly distributed across active-treatment and placebo groups in the study (14% and 17% in the 10-mg and 25-mg brensocatib arms, and 18% in the placebo arm).
"[H]owever, we do not know whether brensocatib can be given without a long-term increase in risk of infection," Chalmers' group wrote in their study.
AEs leading to drug discontinuation were more common with placebo (11%) compared to the two brensocatib arms (7% in each).
The most common AEs with brensocatib were cough, headache, sputum increase, dyspnea, infective exacerbation of bronchiectasis, and diarrhea.
Skin-related toxicities (including hyperkeratosis) occurred in 12%, 15%, and 24% of patients in the 10 mg, 25 mg, and placebo study groups, respectively. Five patients developed hyperkeratosis: three in the 10-mg group, one in the 25-mg group, and one patient on placebo. The researchers cautioned that "the limited duration of the treatment period makes conclusions about this side effect difficult."
The study included extensive dental evaluations to closely monitor progression of periodontal disease. Rates of dental events were 16%, 10%, and 4%, in the 10-mg, 25-mg, and placebo groups, respectively. The proportion of patients with an increase in periodontal pocket depth of ≥2 mm and an absolute depth ≥5 mm (the threshold of concern for periodontal disease) was 11% in the 10-mg, 12% in the 25-mg group, and 12% in the placebo group.
No skin or dental adverse events were considered serious.
Disclosures
The WILLOW trial was funded by Insmed.
Chalmers reported relationships with Insmed, AstraZeneca, Boehringer Ingelheim, Chiesi, Gilead, GlaxoSmithKline, Novartis, and Zambon.
Primary Source
New England Journal of Medicine
Chalmers JD, et al "Phase 2 trial of the DPP-1 inhibitor brensocatib in bronchiectasis" N Engl J Med 2020; DOI: 10.1056/NEJMoa2021713.