Phase III ASPEN Trial Shows Brensocatib Reduces Exacerbations, Lung Function Decline in Bronchiectasis

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Brensocatib was found to significantly lower the annualized rate of pulmonary exacerbations and lung function decline compared to placebo in patients with non-cystic fibrosis bronchiectasis, according to results of the Phase III ASPEN trial (NCT04594369) published by The New England Journal of Medicine (NEJM).^1,2 The progressive condition carries a high burden of frequent exacerbations that reduce lung function and quality of life, elevating the risk of premature death from any cause. In February, the FDA granted Priority Review status to a New Drug Application (NDA) for brensocatib for this patient population based on data from the ASPEN trial.³

"Bronchiectasis is a debilitating disease characterized by pulmonary exacerbations, which contribute to lung function decline and severely impact quality of life," lead trial author James Chalmers, MBChB, PhD, professor and consultant respiratory physician at the School of Medicine, University of Dundee, UK, said in a press release. "With limited treatment options and no approved therapies, the burden of exacerbations remains high, with many patients experiencing multiple episodes each year. For the first time, the ASPEN data published in NEJM demonstrates that a treatment which targets inflammation can reduce exacerbations and slow the rate of lung function decline. This is an exciting development and represents a potentially transformative breakthrough for people living with bronchiectasis, offering new hope for patients with this challenging condition if brensocatib is approved."⁴

Brensocatib is an oral, selective, competitive, and reversible dipeptidyl peptidase 1 (DPP1) inhibitor. Results from the Phase II WILLOW trial evaluating the drug in adult patients with bronchiectasis found that brensocatib administered once daily at doses of 10-mg or 25-mg for 24 weeks prolonged time to first exacerbation and reduced the rate of exacerbations compared to placebo.⁴

Trial Design

The double-blind ASPEN trial enrolled 1680 adults and 41 adolescents with bronchiectasis. Adult patients were randomly assigned in a 1:1:1 ratio and adolescents were randomly assigned 2:2:1 ratio to receive brensocatib at a daily dose of 10 mg, 25 mg, or placebo.

The trial’s primary endpoint was annualized rate of adjudicated pulmonary exacerbations over 52-weeks. Key secondary endpoints included time to first exacerbation over 52 weeks; percentage of patients who are exacerbation-free at week 52; change in forced expiratory volume in 1 second (FEV₁); annualized rate of severe exacerbations; and quality of life changes.

Results show an annualized rate of pulmonary exacerbations at 1.02 in the 10-mg brensocatib cohort, 1.04 in the 25-mg brensocatib cohort, and 1.29 in the placebo cohort (rate ratio, brensocatib vs. placebo, 0.79 at the 10-mg dose [95% confidence interval {CI}, 0.68 to 0.92; adjusted P=0.004] and 0.81 at the 25-mg dose [95% CI, 0.69 to 0.94; adjusted P=0.005]). The hazard ratio for time to first exacerbation was 0.81 in the 10-mg dosing cohort (95% CI, 0.70 to 0.95; adjusted P=0.02) and 0.83 in the 25-mg dosing cohort (95% CI, 0.70 to 0.97; adjusted P=0.04).

Across both brensocatib dosing cohorts, 48.5% of patients were exacerbation-free at week 52 compared to 40.3% in the placebo cohort (rate ratio, 1.20 [95% CI, 1.06 to 1.37; adjusted P=0.02] with the 10-mg dose and 1.18 [95% CI, 1.04 to 1.34; adjusted P=0.04] with the 25-mg dose). At week 52, FEV₁ dropped by 50 ml in the 10-mg dosing cohort, 24 ml in the 25-mg dosing cohort, and 62 ml in the placebo cohort (least-squares mean difference vs. placebo, 11 ml [95% CI, −14 to 37; adjusted P=0.38] with the 10-mg dose and 38 ml [95% CI, 11 to 65; adjusted P=0.04] with the 25-mg dose).

“In our trial, brensocatib, when added to patients’ existing treatment, was shown to have a clinically meaningful effect on the burden of exacerbations in this patient population,” the study authors wrote. “The additional effect of the 25-mg dose of brensocatib on slowing the decline in lung function may be related to improved mucus properties or diminished airway inflammation. Slowing the decline in lung function is important, because the level of lung function is strongly associated with increased morbidity and mortality among patients with bronchiectasis.”¹

In terms of safety, adverse events were similar across the cohorts, but there was a higher incidence of hyperkeratosis among patients administered brensocatib. The FDA assigned the NDA for brensocatib with a Prescription Drug User Fee Act target action date of August 12, 2025.

"Currently, people with bronchiectasis have no approved treatments to address the frequent, damaging exacerbations that are the hallmark of this disease," Martina Flammer, MD, MBA, chief medical officer of Insmed, said in the release. "Brensocatib has the potential to be the first approved therapy to fill this critical unmet need in the care of patients with bronchiectasis, as well as the first approved (DPP1) inhibitor—a new mechanism of action with the potential to address a range of neutrophil-mediated inflammatory diseases. The ASPEN trial represents a transformative step forward for the millions of people globally diagnosed with bronchiectasis."⁴

References

1. Chalmers J., et al. Phase 3 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis. N Engl J Med 2025;392:1569-1581. VOL. 392 NO. 16.

2. A Study to Assess the Efficacy, Safety, and Tolerability of Brensocatib in Participants With Non-Cystic Fibrosis Bronchiectasis (ASPEN). ClinicalTrials.gov. Updated November 12, 2024. Accessed April 24, 2025. https://clinicaltrials.gov/study/NCT04594369

3. FDA Grants Priority Review to Insmed's Brensocatib for Treatment of Bronchiectasis with PDUFA Target Action Date Set for August 12, 2025. News release. Insmed Incorporated. February 6, 2025. Accessed April 24, 2025. https://www.prnewswire.com/news-releases/fda-grants-priority-review-to-insmeds-brensocatib-for-treatment-of-bronchiectasis-with-pdufa-target-action-date-set-for-august-12-2025-302369466.html

4. New England Journal of Medicine Publishes Positive Results from Insmed's Pivotal Phase 3 ASPEN Study of Brensocatib in Patients with Bronchiectasis. News release. Insmed Incorporated. April 23, 2025. Accessed April 24, 2025. https://prnmedia.prnewswire.com/news-releases/new-england-journal-of-medicine-publishes-positive-results-from-insmeds-pivotal-phase-3-aspen-study-of-brensocatib-in-patients-with-bronchiectasis-302436049.html