Dipeptidyl peptidase 1 (DPP-1) inhibitors offer a disease-based approach to managing non-cystic fibrosis bronchiectasis by targeting airway inflammation.
RT’s Three Key Takeaways:
- Targeted Inflammation Control: Dipeptidyl peptidase 1 (DPP-1) inhibitors represent a shift toward disease-modifying therapy by targeting neutrophilic airway inflammation.
- Clinical Trial Success: Data from the ASPEN and WILLOW trials demonstrated that brensocatib significantly reduces pulmonary exacerbations and can slow the decline of lung function in certain patient populations.
- Clinical Assessment Focus: Because no validated biomarkers currently exist to guide therapy, treatment decisions for these new agents remain dependent on clinical evaluations of symptom burden and exacerbation history.
DPP-1 inhibitors are beginning to change the treatment landscape for non-cystic fibrosis bronchiectasis, moving care beyond symptomatic management toward a targeted, disease-based approach. The approval of brensocatib in 2025 marked the first potential disease modifying therapy for noncystic fibrosis bronchiectasis and the first approved dipeptidyl peptidase 1 inhibitor.
Unlike traditional bronchiectasis care, which has largely focused on infection management, airway clearance techniques, and lung disease management, DPP-1 inhibition targets a central driver of disease activity: neutrophilic airway inflammation. By reversibly blocking the DPP-1 enzyme, also known as cathepsin C, in the bone marrow, these agents impair activation of neutrophil serine proteases, including neutrophil elastase, during myelopoiesis. This approach is intended to reduce protease mediated airway injury while preserving antimicrobial neutrophil function.
Clinical trial data have positioned brensocatib as a key emerging option for patients with bronchiectasis. In the phase 3 ASPEN and phase 2 WILLOW trials, once daily oral brensocatib significantly reduced pulmonary exacerbations compared with placebo. In ASPEN, the 25 mg dose also slowed decline in forced expiratory volume in 1 second among patients aged 12 years or older.
Early real world and observational clinical experience suggests DPP-1 inhibition may reduce health care use, decrease antibiotic use, improve respiratory symptoms and patient reported outcomes, and remain generally well tolerated. However, longer term data will be needed to clarify durability, safety, and optimal positioning in routine clinical care.
No validated biomarker currently guides DPP-1 inhibitor use in bronchiectasis. This separates bronchiectasis from asthma and chronic obstructive pulmonary disease, where blood eosinophils and other biomarkers can help direct biologic therapy.
For now, treatment decisions rely on clinical assessment of neutrophilic disease activity, exacerbation frequency, symptom burden, and overall clinical impact. Ongoing trials are expanding evaluation across broader bronchiectasis populations, including patients with lower exacerbation burden and parallel groups such as cystic fibrosis related bronchiectasis. These studies are expected to refine patient selection, dosing, and therapeutic positioning as DPP-1 inhibitors enter clinical practice.
Reference
Devarajan SR et al. DPP-1 inhibitors enter clinical practice. 2026. https://www.chestphysician.org/clinical-outlook-in-bronchiectasis-dpp-1-inhibitors-enter-clinical-practice/
This article was originally published by AMJ and was made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.
