What literature is available to support the use of brensocatib in individuals with bronchiectasis?

Introduction
Non-cystic fibrosis bronchiectasis (NCFB) is a heterogeneous, irreversible airway disease characterized by permanent dilation of the bronchi accompanied by bronchial wall thickening, mucous plugging, and chronic peribronchial inflammation.¹ It arises from a convergence of impaired mucociliary clearance, recurrent or persistent infection, and a dysregulated inflammatory response that together produce progressive structural airway damage.² Non-cystic fibrosis bronchiectasis affects an estimated 500,000 adults in the United States (U.S.). Its prevalence increases significantly with age, rising from approximately 43 cases per 100,000 individuals aged 45 to 54 years to about 373 cases per 100,000 among those aged 65 to 74 years. Etiologies are diverse and include postinfectious injury, airway obstruction from intrinsic or extrinsic lesions, primary or secondary immunodeficiencies, allergic bronchopulmonary aspergillosis, congenital or structural disorders such as primary ciliary dyskinesia, aspiration syndromes, and infection with nontuberculous mycobacteria.^1,2 Twenty-five to fifty percent of cases are considered idiopathic despite comprehensive evaluation.²

Clinical manifestations of bronchiectasis range from chronic cough and daily sputum production to recurrent respiratory exacerbations, hemoptysis, progressive dyspnea, systemic inflammation, and, in advanced cases, respiratory failure and weight loss.^1,2 High-resolution computed tomography (CT) is the diagnostic standard and typically demonstrates bronchial dilation relative to accompanying vessels, lack of bronchial tapering, and contributing features such as bronchiectasis distribution, which may suggest specific causes. Etiologic investigation should include targeted microbiology, immunologic testing, assessment for aspiration risk, and evaluation for treatable conditions. Identification of an underlying disorder influences prognosis and management. Treatment strategies focus on breaking the cycle of infection and inflammation to reduce the risk of exacerbation and improve symptoms. Airway clearance, targeted antimicrobial therapy, and management of any underlying causes are primary treatment strategies. Until now, there have been no targeted pharmacologic therapies approved for NCFB, aside from the use of antimicrobial agents directed at underlying infections. This article aims to summarize literature to support the use of brensocatib, a newly approved agent for the treatment of NCFB.

Standard of care
There are currently no U.S. guidelines for the overall management of NCFB other than recommendations addressing specific complications, such as the need for airway clearance. As a result, most guidance comes from European organizations, with the most recent set of guidelines published in 2025 by the European Respiratory Society.³ Current standards of care for NCFB emphasize early recognition of disease using age-appropriate criteria, followed by an individualized, multidisciplinary plan aimed at preserving lung function, reducing exacerbations, and optimizing quality of life (QoL).² Nonpharmacologic measures, such as recommended vaccinations, nutrition optimization, avoidance of smoking and pollutants, pulmonary rehabilitation, regular exercise, infection control counseling, and attention to psychosocial needs, are integral components of comprehensive care.³ Targeted bronchiectasis care begins with identification of any treatable causes and comorbidities (including immunodeficiency, primary ciliary dyskinesia, aspiration risk, and microbial pathogens) and continues with regular monitoring, typically every 3 to 6 months in children and at least annually in stable adults, using clinical review, spirometry when appropriate, pulse oximetry and periodic sputum culture to detect new or resistant pathogens.

Airway clearance delivered by physiotherapists with expertise in bronchiectasis is a cornerstone of therapy and should be individualized by method and frequency.³ Decisions made on type of airway clearance therapy may be impacted by age. For most adults and adolescents, an oscillatory device with positive expiratory pressure is enough to help mobilize mucus, along with general exercise and coughing techniques.^2-5 It should be intensified during exacerbations and reassessed regularly. Antibiotic management is guided by airway microbiology obtained via sputum cultures.^1-3 Acute exacerbations are treated with an appropriate systemic antibiotic course (commonly 14 days). When Pseudomonas aeruginosa (P. aeruginosa) is newly isolated, a targeted eradication attempt is recommended to prevent long-term complications, as there is an increased risk of serious adverse events compared to colonization by other organisms.³ Long-term macrolide therapy is indicated for patients with frequent exacerbations after careful consideration of benefits, adherence, and resistance risks. Inhaled antibiotics are reserved for select adults with chronic P. aeruginosa and recurrent exacerbations. The routine use of mucolytics, such as recombinant human DNase, is contraindicated in NCFB. Although hypertonic saline or mannitol are not recommended for routine use, they may be trialed selectively under supervision.

Severe, uncontrolled, or refractory disease is marked by exacerbations and recurrent infections that are often resistant to antibiotics, leading to significant hemoptysis, which can be life-threatening. ^2,3 Surgical resection is an infrequent option for localized, refractory disease and should be considered only after maximal medical therapy within a multidisciplinary program. For patients with severe refractory disease despite proper medical management lung transplants can be considered as a last-line option if the patient is under the age of 65 years.²

Drug overview
On August 12, 2025, the Food and Drug Administration (FDA) approved brensocatib, a first-in-class competitive reversible inhibitor of dipeptidyl peptidase (DPP-1) for the treatment of NCFB in adults and children aged 12 years and older.⁶ This novel drug and class of medication may prove paramount in addressing limitations of the current standard of care. An overview of brensocatib is provided in Table 1.

Mechanism of Action
Brensocatib is an oral, competitive, reversible inhibitor of DPP‑1, the protease responsible for activating neutrophil serine proteases (NSPs) such as neutrophil elastase, proteinase 3, and cathepsin G during neutrophil maturation in the bone marrow.⁷ Because NSPs drive neutrophil-mediated tissue injury and perpetuate airway inflammation in NCFB, pharmacologic blockade of DPP-1 with brensocatib reduces NSP activation and downstream proteolytic activity. By lowering NSP activity systemically and in the airways, brensocatib attenuates neutrophil-driven inflammation and protease-mediated lung damage, thereby interrupting a central pathogenic mechanism that contributes to exacerbations and progressive structural lung destruction in NCFB. Table 2 summarizes important pharmacokinetic properties of brensocatib.

Safety considerations
Brensocatib carries specific precautions due to an increased risk of dermatological, gingival, and periodontal adverse effects.⁷ For this reason, patients prescribed brensocatib should be referred to a dermatologist and undergo regular dental evaluations. The most frequently reported adverse effects include upper respiratory tract infections, headaches, rash, dry skin, hyperkeratosis, and hypertension. Less common side effects include elevated liver enzymes, incidence of skin cancers, and alopecia.

Brensocatib is primarily metabolized by cytochrome P450 (CYP) 3A4, making drug–drug interactions an important consideration.⁷ Use of CYP3A4 inducers may reduce drug exposure, potentially diminishing therapeutic benefit, while CYP3A4 inhibitors may increase exposure, increasing the risk of adverse reactions. Careful evaluation of a patient’s concurrent medications is essential to anticipate potential interactions. Patients should be advised to consult their healthcare provider before starting any new therapies. Additionally, live attenuated vaccines should be avoided during treatment, as it is unknown if the safety or effectiveness of the vaccines will be affected by brensocatib.

Literature Review
The safety and efficacy of brensocatib were established based on data from 2 clinical trials: the WILLOW phase 2 trial and the ASPEN phase 3 trial.

The phase 2 WILLOW trial was a randomized, double‑blind, placebo-controlled, dose-ranging study that enrolled 256 adults with CT-confirmed NCFB and at least 2 antibiotic-treated exacerbations in the prior 12 months.⁸ Patients were randomized 1:1:1 to receive placebo, brensocatib 10 mg, or brensocatib 25 mg once daily for 24 weeks. Randomization was stratified based on long-term macrolide use (defined as more than 6 months of treatment prior to the screening visit) and the presence of P. aeruginosa infection. The primary endpoint was the time to the first protocol-defined exacerbation during the trial period. Secondary endpoints included exacerbation rate, change in post-bronchodilator forced expiratory volume in 1 second (FEV1), health-related QoL measures, and change in sputum neutrophil elastase activity.

At baseline, patients were predominantly older adults (mean age: ~64 years), with a majority being female and White.⁸ The median bronchiectasis severity score was consistent with moderate disease. Across randomized groups, 28% to 41% of patients had at least 3 prior exacerbations in the previous year and 34% to 38% of patients had been hospitalized for an exacerbation in the previous year. Around one-third were positive for P. aeruginosa, and a minority had long-term macrolide use. Sputum neutrophil elastase levels varied, with roughly one-third in the high range. Approximately 22% to 29% of patients and 15% to 20% of patients had comorbidities of asthma and chronic obstructive pulmonary disease (COPD), respectively. Brensocatib significantly prolonged the time to first exacerbation compared to placebo at both doses, to the extent that a mean could not be estimated, therefore, the twenty-fifth percentile of the time to first exacerbation was used. The twenty-fifth percentile of time to first exacerbation was 67 days in the placebo group, 134 days in the 10 mg brensocatib group (adjusted hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.35 to 0.95; P = 0.03 vs placebo), and 96 days in the 25 mg brensocatib group (adjusted HR, 0.62; 95% CI, 0.38 to 0.99; P = 0.04 vs placebo). The percentage of patients experiencing 1 or more exacerbations was lower in the brensocatib groups (32% for 10 mg; 33% for 25 mg) than placebo (48%), and the incidence‑rate ratio (IRR) for exacerbations was reduced for the 10‑mg dose (IRR, 0.64; 95% CI, 0.42 to 0.98; P = 0.04) while the 25‑mg dose showed a numerical but not statistically significant reduction. No meaningful differences in the concentrations of sputum neutrophil elastase were observed between the brensocatib groups and the placebo group, although the study was not powered to detect differences on this endpoint. Changes in FEV1 and QoL domain scores did not reach clinically meaningful thresholds in the 24-week period in the brensocatib groups versus placebo. Safety analyses in WILLOW showed similar rates of serious adverse events across groups. There was a higher overall incidence of non-exacerbation adverse events with brensocatib compared to placebo, more investigator-reported dental events with 10 mg brensocatib versus placebo, and more skin events with 25 mg brensocatib versus placebo. No clear signal of increased infections was observed over 24 weeks.

Post hoc and prespecified subgroup assessments from WILLOW examined the consistency of effect across baseline disease characteristics.⁹ In pooled WILLOW subgroup analyses (both brensocatib doses combined) the reduction in time to first exacerbation and lower annualized exacerbation rates were statistically significant and consistently observed across key baseline disease characteristic subgroups, including across strata defined by Bronchiectasis Severity Index, prior exacerbation frequency, blood eosinophil count (<300 vs ≥300 cells/µL), long‑term macrolide use, and P. aeruginosa culture status.

The phase 3 ASPEN trial was a multinational, double-blind, placebo-controlled study that randomized 1,721 patients (1680 adults and 41 adolescents) to brensocatib 10 mg, brensocatib 25 mg, or placebo for 52 weeks, with annualized pulmonary exacerbation rate over 52 weeks as the primary endpoint and a prespecified hierarchy of secondary endpoints (time to first exacerbation, percent of patients remaining exacerbation free at week 52, change in FEV1, annualized severe exacerbation rate, and respiratory symptom QoL).^10,11 Patients were predominantly female and White, with a mean age in the mid-60s. About one-third had P. aeruginosa infection, and nearly 30% had 3 or more exacerbations in the previous year. Asthma and COPD were comorbidities in 17.3% to 19.7% of patients and 13.2% to 18.1% of patients across groups, respectively. Baseline characteristics were generally balanced across treatment groups.

In ASPEN, both brensocatib doses had significantly lower annualized rates of pulmonary exacerbations compared to placebo (brensocatib 10 mg, 1.02; brensocatib 25 mg, 1.04; placebo, 1.29).¹¹ Rate ratios in the 10 mg group versus placebo were 0.79 (95% CI, 0.68 to 0.92; adjusted P = 0.004) and 0.81 in the 25 mg group versus placebo (95% CI, 0.69 to 0.94; adjusted P = 0.005). Time to first exacerbation was improved with HRs of 0.81 with the 10 mg dose (95% CI, 0.70 to 0.95; adjusted P=0.02) and 0.83 with the 25 mg dose (95% CI, 0.70 to 0.97; adjusted P=0.04), and the proportion of patients who remained exacerbation-free at week 52 was higher in both brensocatib groups (48.5%) compared with placebo (40.3%). Lung function analysis at week 52 showed a smaller decline in post-bronchodilator FEV1 with brensocatib 25 mg (LS mean difference vs. placebo, 38 mL; 95% CI, 11 to 65; adjusted P = 0.04); the 10 mg comparison did not meet significance within the hierarchical testing procedure. The annualized rate of severe exacerbations was numerically lower with brensocatib but did not reach statistical significance after adjustment. Safety in ASPEN was overall similar across treatment groups. Common adverse events reported more frequently with brensocatib included COVID-19, nasopharyngitis, cough, and headache. Adverse events of special interest included dose-related increases in hyperkeratosis (more frequent with 25 mg brensocatib) and infrequent reports of periodontitis or gingivitis, while pneumonia occurred more frequently in the placebo group, and serious adverse events frequency was similar across groups. ASPEN reported generally consistent efficacy across prespecified subgroups and supported the primary finding of reduced annual exacerbation rates in a broad international population.

Conclusion
Brensocatib represents the first targeted DPP-1 inhibitor approved for NCFB, offering a novel approach to reducing NSP–driven airway injury. Pivotal phase 2 (WILLOW) and phase 3 (ASPEN) trials consistently demonstrated that brensocatib lowers the rate of pulmonary exacerbations and prolongs time to first exacerbation compared to placebo across a broad population of adults (and adolescents in ASPEN). Clinical benefits were most clearly demonstrated in the reduction of exacerbations. Improvements in lung function and QoL measures were modest or limited by hierarchical testing and study duration. Further studies are needed to determine the extent of effect brensocatib has on these outcomes. Overall, brensocatib is a significant addition to the therapeutic landscape for NCFB, shifting the focus toward the modulation of neutrophil-mediated injury and offering an FDA-approved pharmacologic option to reduce exacerbations in patients with persistent, exacerbation-prone disease.

References

1. Baron RM, Baron BW, Barshak MB. Bronchiectasis. In: Longo D, Fauci A, Kasper D, Hauser S, Jameson J, Loscalzo J, Holland S, Langford C. eds. Harrison’s Principles of Internal Medicine, 22nd ed. McGraw Hill; 2026. Accessed November 10, 2025. https://accesspharmacy.mhmedical.com/content.aspx?bookid=3541§ionid=294354972
2. Barker AF, Karamooz E. Non-cystic fibrosis bronchiectasis in adults: a review. JAMA. 2025;334(3):253-264. doi:10.1001/jama.2025.2680
3. Chalmers JD, Haworth CS, Flume P, et al. European Respiratory Society clinical practice guideline for the management of adult bronchiectasis. Eur Respir J. Published online September 28, 2025. doi:10.1183/13993003.01126-2025
4. Hill AT, Barker AF, Bolser DC, et al. Treating cough due to non-CF and CF bronchiectasis with nonpharmacological airway clearance: CHEST expert panel report. Chest. 2018;153(4):986-993. doi:10.1016/j.chest.2018.01.014
5. Strickland SL, Rubin BK, Haas CF, Volsko TA, Drescher GS, O’Malley CA. AARC clinical practice guideline: effectiveness of pharmacologic airway clearance therapies in hospitalized patients. Respir Care. 2015;60(7):1071-1077. doi:10.4187/respcare.04165
6. FDA approves BRINSUPRI™ (brensocatib) as the first and only treatment for non-cystic fibrosis bronchiectasis, a serious, chronic lung disease. Insmed Incorporated. Published August 12, 2025. Accessed November 21, 2025. https://investor.insmed.com/2025-08-12-FDA-Approves-BRINSUPRI-TM-brensocatib-as-the-First-and-Only-Treatment-for-Non-Cystic-Fibrosis-Bronchiectasis,-a-Serious,-Chronic-Lung-Disease
7. Brinsupri. Package insert. Insmed Incorporated; 2025.
8. Chalmers JD, Haworth CS, Metersky ML, et al. Phase 2 trial of the DPP-1 inhibitor brensocatib in bronchiectasis. N Engl J Med. 2020;383(22):2127-2137. doi:10.1056/NEJMoa2021713
9. Chalmers JD, Loebinger MR, Teper A, et al. Brensocatib in patients with bronchiectasis: subgroup analyses from the WILLOW trial. ERJ Open Res. 2025;11(1):00505-2024. doi:10.1183/23120541.00505-2024
10. Chalmers JD, Burgel PR, Daley CL, et al. Brensocatib in non-cystic fibrosis bronchiectasis: ASPEN protocol and baseline characteristics. ERJ Open Res. 2024;10(4):00151-2024. doi:10.1183/23120541.00151-2024
11. Chalmers JD, Burgel PR, Daley CL, et al. Phase 3 trial of the DPP-1 inhibitor brensocatib in bronchiectasis. N Engl J Med. 2025;392(16):1569-1581. doi:10.1056/NEJMoa2411664

Prepared by:
Chris Bechakas
PharmD Candidate Class of 2026
University of Illinois Chicago Retzky College of Pharmacy

Reviewed by:
Rachel Brunner, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois Chicago Retzky College of Pharmacy

January 2026

The information presented is current as of November 14, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.