Treatment with brensocatib significantly and safely extended the time to a first exacerbation and lowered flare rates in people with non-cystic fibrosis bronchiectasis (NCFBE), results from a Phase 2 trial show.
These benefits were observed across all subgroups in the WILLOW trial (NCT03218917). Findings also showed a trend toward a lesser decline in lung function among patients given brensocatib across this 24-week study, its researchers said.
The treatment’s use, however, did not lead to reported improvements in quality of life measures, and caused significantly more adverse events (excepting exacerbations) than a placebo.
Trial results were recently published in the New England Journal of Medicine, in the study “Phase 2 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis.” They were also shared at the virtual European Respiratory Society (ERS) International Congress 2020.
Brensocatib, initially developed by AstraZeneca and then licensed to Insmed in 2016, is an oral small molecule designed to lead to fewer exacerbations in bronchiectasis patients.
With this disease, inflammation is driven mainly by neutrophils, a kind of immune cell that, when activated, releases enzymes which eventually damage the lungs. Brensocatib blocks a molecule key to that activation, the dipeptidyl peptidase 1 (DPP1) protein.
The WILLOW trial investigated whether brensocatib could prevent flares and lung function decline in 256 adults with NCFBE. Enrolled across 14 countries, patients had had at least two exacerbations in the previous year, and were randomly assigned to a 10 mg or a 25 mg dose of brensocatib, or a placebo, once daily for 24 weeks (nearly six months).
Overall, more 90% of patients adhered to their assigned oral regimen, and over 80% completed the trial. Most patients were white, female, and older than 60.
The trial’s main goal was to determine if brensocatib delayed the time to a first exacerbation. As secondary measures, the researchers investigated the rate of exacerbations, lung function decline — measured as percent of the predicted forced expiratory volume in one second (FEV1) — changes in quality of life, and alterations in active neutrophil elastase, which is one of the enzymes released after neutrophil activation.
In a prior analysis, results showed that both brensocatib doses significantly delayed the time to a first exacerbation, and that the 10 mg dose also lowered the rate of exacerbations compared with a placebo.
Notably, while the risk of an exacerbation was 42% lower with the 10 mg dose and 38% with the 25 mg dose, those who attained undetectable neutrophil elastase levels after starting with brensocatib had an even greater reduction — by 72% — in the risk of exacerbations.
Researchers now reported additional results from WILLOW, showing that the 10 mg dose nearly doubled the time to a first exacerbation, and that both doses reduced the number of severe exacerbations by half.
In this analysis, they were unable to estimate the median time to a first exacerbation due to the low number of exacerbations in the brensocatib groups. For this reason, they measured the time it took for 25% of patients in each group to experience an exacerbation.
One quarter of placebo-group patients had an exacerbation within 67 days. It took 134 days for the same proportion of those given brensocatib at 10 mg dose to experience exacerbations. For those on the 25 mg dose, 97 days passed before 25% had flares.
Exacerbations were severe in 10 placebo patients, in five on the 10 mg brensocatib dose and four on the 25 mg dose.
Reductions in the risk of an exacerbation and in the rate of exacerbations were similar across subgroups, regardless of age, initial neutrophil elastase levels, number of exacerbations in the previous year, Pseudomonas aeruginosa infections, lung function, and bronchiectasis severity.
“The WILLOW study demonstrated that among patients with NCFBE who have a history of frequent exacerbations, treatment with brensocatib significantly prolonged the time to first exacerbation and reduced the risk of exacerbation over the treatment period. Annualized rates of exacerbation were also lower compared to placebo,” James Chalmers, PhD, study lead author and professor at the University of Dundee, said in a press release.
“These results are critically important given the lack of approved pharmaceutical therapies to reduce the risk of exacerbation—the major driver of morbidity and mortality in patients with bronchiectasis,” he added.
Both brensocatib doses reduced the decline in lung function by 1.5%, although those differences did not reach statistical significance. Likewise, no significant differences were observed regarding the impact of respiratory symptoms or cough on quality of live, the researchers found.
Brensocatib was generally well-tolerated. When exacerbations were excluded, similar rates of severe adverse events were recorded in all three groups during the treatment period, the study reported.
Headache and shortness of breath were the only common side effects with a significantly higher incidence in the 25 mg group relative to placebo group patients. Also compared with placebo, more people on the 10 mg dose reported dental problems, and skin problems were more common with the 25 mg dose.
All side effects resolved or had eased by the trial’s end, and rates of discontinuation were similar across groups: 7% in both brensocatib arms, and 11% among those on a placebo. One person in high-dose treatment group died due to bronchiectasis progression.
“These results show the potential clinical benefits of directly reducing inflammation in patients with bronchiectasis. Larger and longer-term trials to investigate the risks and benefits of this approach are now needed,” the scientists wrote.
Based on the findings, brensocatib was recently designated a breakthrough therapy by the U.S. Food and Drug Administration.
Insmed is now planning a Phase 3 clinical study of brensocatib in bronchiectasis patients.