Non-cystic fibrosis bronchiectasis is a chronic and progressive lung disease, characterized by atypical airway dilation, impaired mucociliary clearance, recurrent bacterial infection, and relentless neutrophilic inflammation. Despite its clinical burden, management strategies for bronchiectasis have been largely reconfigured from related conditions, such as airway clearance physiotherapy, inhaled hypertonic saline, long-term macrolide antibiotics, and inhaled antimicrobials. International guidelines from the British Thoracic Society and the European Respiratory Society have codified these approaches, though the recommended treatments had not been proven efficacious in large, adequately powered randomized trials. Until 2025, there was no FDA-approved therapy specifically indicated for bronchiectasis.
The publication of the ASPEN trial in the New England Journal of Medicine by Chalmers and colleagues represents a seminal moment, not only because the study findings, but because this trial demonstrated that targeting the root mechanism of neutrophilic airway inflammation effectively translates into clinically meaningful reductions in exacerbation burden. Further, at the higher dose, attenuation of lung function decline was observed. For practicing pulmonologists, this encourages a reconceptualization of how disease-modifying therapy is approached in the treatment of bronchiectasis.
WHY DPP-1 INHIBITION MAKES SENSE
To appreciate the significance of the ASPEN results, it helps to understand the mechanistic logic behind brensocatib. The pathobiology of bronchiectasis centers on what has been termed the "vicious vortex,” which refers to a self-perpetuating cycle of chronic infection, neutrophilic inflammation, structural airway damage, and impaired host defense. Central to this cycle is the excessive activity of neutrophil serine proteases, particularly neutrophil elastase (NE), proteinase 3, and cathepsin G. These enzymes degrade airway structural proteins including elastin, impair mucociliary clearance by promoting mucus hypersecretion, and blunt innate immunity by cleaving antimicrobial peptides and reducing phagocyte effectiveness. Elevated sputum NE levels have been independently associated with greater exacerbation frequency, more rapid lung function decline, and more severe radiographic disease.
Dipeptidyl peptidase 1 (DPP-1), also known as cathepsin C, is the upstream enzyme responsible for activating neutrophil serine protease precursors during neutrophil maturation in the bone marrow. By inhibiting DPP-1 before these proteases are ever packaged into granules, brensocatib offers a fundamentally different and potentially more complete approach to reducing protease burden in the airway than downstream strategies targeting NE directly. This upstream mechanism means that brensocatib reduces the serine protease content of every neutrophil produced during the treatment period. This sustained, exposure-dependent effect was first validated pharmacodynamically in healthy volunteers and subsequently confirmed in the phase 2 WILLOW trial, where once-daily brensocatib at both 10 mg and 25 mg doses prolonged the time to first exacerbation and reduced exacerbation rates compared to placebo over 24 weeks.
DESIGN AND POPULATION OF THE ASPEN TRIAL
ASPEN was a phase 3, international, double-blind, placebo-controlled, randomized trial conducted across 390 sites in 35 countries. The trial enrolled 1,721 patients (1,680 adults and 41 adolescents) who were randomized in a 1:1:1 ratio (adults) to brensocatib 10 mg once daily, brensocatib 25 mg once daily, or placebo for 52 weeks, added on to existing standard-of-care management. The patient population was clinically representative of the real-world bronchiectasis cohort: predominantly female (64%), predominantly White (74%), with a mean age of approximately 60 years, a mean FEV1 of roughly 73-74% predicted, and moderate disease severity as reflected by Bronchiectasis Severity Index scores in the moderate range. Roughly one-third of patients had P. aeruginosa-positive sputum at screening, approximately 29% had three or more exacerbations in the prior 12 months, and a meaningful proportion were on long-term antibiotics at baseline.
The primary endpoint was the annualized rate of improved pulmonary exacerbations over the 52-week treatment period. Exacerbations were defined using modified consensus criteria requiring three or more qualifying symptoms for at least 48 hours leading to systemic antibiotic treatment. Secondary endpoints were tested hierarchically and included: 1) time to first exacerbation, 2) proportion of patients remaining exacerbation-free at week 52, 3) change in post-bronchodilator FEV1, 4) annualized rate of severe exacerbations, and 5) change in health-related quality of life using the Quality of Life-Bronchiectasis Respiratory Symptoms domain score.
CRITICAL FINDINGS AND EFFICACY ACROSS CLINICALLY MEANINGFUL ENDPOINTS
Exacerbation Reduction
The primary endpoint results were unambiguous. The annualized exacerbation rate was 1.29 in the placebo group, compared with 1.02 in the 10 mg group and 1.04 in the 25 mg group. This translates to rate ratios of 0.79 (adjusted p=0.004) and 0.81 (adjusted p=0.005) for the 10 mg and 25 mg doses respectively. In plain terms, this represents an approximately 20% reduction in exacerbation frequency with either dose.
The magnitude of this reduction is clinically important context. The EMBARC registry data and other real-world cohorts have consistently shown that each additional exacerbation per year is associated with accelerated FEV1 decline, decreased quality of life, and increased all-cause mortality. A 20% reduction in annualized exacerbation rate, while perhaps modest in absolute terms for the average patient, is likely to compound favorably over years of treatment and could be substantially larger in the highest-burden subgroups.
The secondary exacerbation endpoints reinforced the primary findings. Time to first exacerbation was meaningfully prolonged with both doses (hazard ratios 0.81 and 0.83 for 10 mg and 25 mg respectively). Perhaps more clinically intuitive is the proportion of patients remaining exacerbation-free at week 52, which amounted to 48.5% in both brensocatib groups versus 40.3% in the placebo group. This absolute difference of roughly 8 percentage points means that for every 12-13 patients treated with brensocatib, approximately one additional patient will reach a full year without an exacerbation.
Lung Function Preservation
The FEV1 data also deserve attention. At week 52, FEV1 had declined by 62 ml in the placebo group, 50 ml in the 10 mg group, and 24 ml in the 25 mg group. Only the 25 mg dose reached statistical significance (adjusted p=0.04), while the 10 mg dose did not (adjusted p=0.38) and statistical testing for the 10 mg dose was halted at this point per the hierarchical testing procedure.
The preservation of FEV1 by the 25 mg dose is critical to consider from a long-term disease-modification standpoint. Bronchiectasis is progressive, and no prior intervention has demonstrated the ability to slow lung function decline in a randomized controlled trial. A 38 ml attenuation of the annual FEV1 decline versus placebo, if sustained over years, could alter the trajectory of disease progression for a meaningful proportion of patients. The clinical threshold for significance here is not a fixed rule, but a 38 ml preservation of FEV1 over 52 weeks is biologically plausible as meaningful. Whether this effect is maintained or even amplified with longer treatment duration remains an important unanswered question.
Quality of Life
The quality of life data, while not reaching the threshold for statistical significance in the hierarchical testing framework, showed numerical improvements in the Respiratory Symptoms domain of the Quality of Life-Bronchiectasis questionnaire at week 52 (mean improvement of 6.84 points with the 10 mg dose and 8.58 points with the 25 mg dose, compared with 4.81 points with placebo). The minimum clinically important difference for this instrument is 8 points, meaning the 25 mg dose numerically crossed this threshold while placebo did not. These data provide supportive evidence that the exacerbation reduction and lung function preservation translate into patient-perceived benefit.
Safety: A Reassuring Profile with Important Caveats
The overall safety profile of brensocatib was favorable and, notably, the rate of serious adverse events and treatment-discontinuing adverse events was similar across all three groups. Death occurred in 3 patients (0.5%) in the 10 mg group, 4 (0.7%) in the 25 mg group, and 7 (1.2%) in the placebo group. The most common adverse events occurring more frequently with brensocatib than placebo were COVID-19 infection, nasopharyngitis, cough, and headache. For a drug that inhibits neutrophil serine protease function, the rate of bacterial was not elevated with either dose of brensocatib.
The most notable drug-specific safety signal was hyperkeratosis, which occurred in 1.4% of the 10 mg group and 3.0% of the 25 mg group, compared with 0.7% in the placebo group. The biological rationale for this finding is well-established: Papillon-Lefèvre syndrome, a rare autosomal recessive condition caused by near-complete loss-of-function mutations in the DPP1 gene, manifests with palmoplantar hyperkeratosis and periodontitis alongside severe periodontium destruction. In the ASPEN trial, the hyperkeratosis cases observed were predominantly mild to moderate and resolved during the trial period, with only one patient in the 25 mg group discontinuing treatment due to this adverse effect. Periodontitis or gingivitis was similarly infrequent and not more common in the brensocatib groups than placebo. Nevertheless, clinicians initiating brensocatib should counsel patients about skin monitoring and encourage dental follow-up, particularly at the 25 mg dose.
IMPLICATIONS FOR CLINICAL PRACTICE
Who Should Be Considered for Brensocatib?
The ASPEN trial enrolled a broadly representative bronchiectasis population, which means the benefit is likely generalizable across a wide range of patients. The enrolled cohort required a minimum of two exacerbations in the prior 12 months (or one for adolescents), which sets a reasonable threshold for considering therapy. Patients with idiopathic bronchiectasis, post-infectious bronchiectasis, and primary ciliary dyskinesia were all enrolled and benefit appeared consistent across prespecified subgroups (e.g. P. aeruginosa colonization status, number of prior exacerbations, geographic region, and baseline FEV1). This broadly positive subgroup picture suggests clinicians should not restrict brensocatib to a narrowly defined high-risk phenotype.
That said, the patients likely to derive the greatest absolute benefit are those at highest exacerbation burden. The 25 mg dose appears preferable in patients where lung function preservation is a priority, given the statistically significant and clinically meaningful attenuation of FEV1 decline demonstrated at that dose. The 10 mg dose offers a similar exacerbation benefit with a marginally lower rate of hyperkeratosis, which may influence shared decision-making with individual patients.
How Does Brensocatib Fit with Existing Treatments?
A critical feature of the ASPEN trial design is that brensocatib was added on to patients' existing standard-of-care management. Patients on long-term macrolides, inhaled antibiotics, and airway clearance techniques were included. This means the exacerbation reductions and lung function preservation demonstrated represent the incremental benefit of brensocatib beyond what current therapy already provides — a meaningful demonstration of additive efficacy. Clinicians should think of brensocatib not as a replacement for established management but as a complement to it, targeting the inflammatory component of disease that existing antibiotic-focused strategies do not adequately address.
The positioning of brensocatib relative to long-term therapy warrants particular attention. Both macrolides and brensocatib reduce exacerbations, but through entirely different mechanisms. Whether combination therapy with both agents offers additive benefit remains to be studied prospectively. Given the different mechanistic pathways and the safety signals associated with each, the combination is biologically rational and may ultimately prove beneficial for the highest-risk patients.
Disease Modification and Long-Term Perspective
Perhaps the most transformative implication of the ASPEN results is the question of whether bronchiectasis is a modifiable disease. The attenuation of FEV1 decline observed with the 25 mg dose raises the possibility that sufficiently early and sustained inhibition of neutrophilic inflammation could alter the long-term natural history of the condition. This would not merely suppress exacerbations in the short term but potentially preserve lung function over long-term therapy course. Longer-term extension studies and real-world registry data will be essential to confirm whether the FEV1 preservation signal persists, amplifies, or attenuates beyond 52 weeks. Post-marketing pharmacovigilance will also be needed to characterize the long-term safety of DPP-1 inhibition at therapeutic doses, particularly with regard to immune function, dental health, and skin integrity. Nonetheless, the ASPEN trial gives the field both a validated mechanism and a regulatory anchor for the first time.
Practical Considerations at the Point of Prescribing
Before initiating brensocatib, clinicians should confirm the diagnosis with high-resolution chest imaging performed within the preceding five years and ensure the exacerbation threshold has been met. Baseline dental evaluation is reasonable, and patients should be counseled about the possibility of skin changes. Current smokers were excluded from the trial, consistent with existing evidence that smoking confounds bronchiectasis management and potentially blunts anti-inflammatory treatments. Drug interactions should be considered in the context of polypharmacy common in this population. Patients on azithromycin should have an ECG performed as standard practice, a recommendation that applies independently of brensocatib. Monitoring of adherence is important, given that the mean adherence in ASPEN was 96.5% in a closely monitored trial setting. Real-world adherence to a once-daily oral agent may be lower, and the exacerbation benefit is likely to be exposure-dependent.
LIMITATIONS AND FUTURE DIRECTIONS
Despite its scale and quality, the ASPEN trial leaves several clinical questions unanswered. The trial duration of 52 weeks, while sufficient for regulatory approval and for demonstrating the primary endpoint, is relatively short for a chronic, lifelong disease. Whether the exacerbation reduction and FEV1 preservation are maintained, sustained, or even augmented over multiple years remains unknown. The trial was not powered to detect differences within smaller subgroups, meaning firm conclusions about specific etiological subgroups (e.g. patients with primary ciliary dyskinesia or those with very severe baseline airflow obstruction) cannot be drawn from the existing data. The trial was also conducted partly during the COVID-19 pandemic, which introduced some variability in the patient population presenting for enrollment, though the authors note that the annualized exacerbation rate in the placebo group was consistent with that observed in the pre-pandemic WILLOW trial.
The adolescent cohort, while biologically important and included with regulatory agreement, was limited to 41 patients and was powered only for descriptive safety and pharmacokinetic assessment. Pediatric prescribing decisions should await dedicated study data. Additionally, the lack of a validated biomarker to identify brensocatib responders prospectively is a gap that future translational research must address.
CONCLUSIONS
The ASPEN trial and the regulatory approval of brensocatib mark the conclusion of a long period in which bronchiectasis clinicians had limited disease-specific pharmacological options beyond antibiotics. By demonstrating that inhibiting DPP-1 and reducing neutrophil serine protease activity systemically leads to fewer exacerbations, more patients remaining exacerbation-free, and slower lung function decline over 52 weeks, brensocatib establishes proof-of-concept for anti-inflammatory therapy for bronchiectasis management. The safety profile provides important reassurance that partially suppressing neutrophil serine protease activity does not materially compromise host defense in this patient population at the doses studied. The ASPEN results should catalyze the field toward a more mechanistically informed approach to bronchiectasis and is a significant clinical step forward.
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