The convergent pathway of obstructive lung disease: the disease-modifying potential of dipeptidyl peptidase 1 inhibition in COPD, asthma and bronchiectasis overlap.

The management of chronic obstructive lung diseases, particularly severe asthma, chronic obstructive pulmonary disease (COPD) and non-cystic fibrosis bronchiectasis, is complicated by frequent overlap syndromes such as asthma-bronchiectasis overlap and bronchiectasis-COPD overlap syndrome. These overlapping phenotypes are characterized by severe symptoms, frequent exacerbations, accelerated lung function decline and increased mortality, driven by a common, destructive endotype: persistent, neutrophil-dominant airway inflammation. This inflammation is fuelled by the overactivity of neutrophil serine proteases, notably neutrophil elastase, which drives the self-perpetuating 'vicious vortex' of structural damage and infection. Traditional therapies, including inhaled corticosteroids and type 2 (T2) inflammation-targeted biologics, are often ineffective against this non-T2, neutrophilic inflammation. Brensocatib, a first-in-class, oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), offers a novel, targeted strategy. By inhibiting DPP1 - the master activator of neutrophil serine proteases in the bone marrow - brensocatib effectively 'disarms' neutrophils before they reach the lungs. The phase III ASPEN trial in non-cystic fibrosis bronchiectasis demonstrated its disease-modifying potential, showing a significant reduction in the annualized rate of exacerbations and, critically, a statistically significant slowing of the decline in forced expiratory volume in 1 second in the 25 mg arm (a benefit not observed with the 10 mg dose). Subgroup analysis confirmed consistent efficacy in the high-risk bronchiectasis-COPD overlap syndrome population. These findings validate DPP1 inhibition as a first potential disease-modifying therapy. This strategy is poised to fundamentally shift clinical focus from symptom control to the preservation of lung function for patients with severe, neutrophilic-driven neutrophilic overlap syndromes.