The dipeptidyl peptidase 1 inhibition landscape in bronchiectasis and its future direction.

Abstract

Bronchiectasis (BE) is a heterogeneous lung disease characterised by chronic neutrophilic inflammation. A "vicious vortex" develops through the interactions between neutrophilic inflammation, infection and impaired mucociliary clearance, leading to progressive structural lung damage and worsening lung function. As part of this neutrophilic inflammation, neutrophil serine proteases (NSPs) overwhelm their natural inhibitors, with high NSP levels being associated with pulmonary exacerbations in people with BE. NSPs, activated by dipeptidyl peptidase 1 (DPP1) during neutrophil maturation in the bone marrow, are released from neutrophils at sites of inflammation. Pharmacological inhibition of DPP1 is a compelling approach to reduce neutrophilic inflammation in BE. Three DPP1 inhibitors have had favourable results in clinical studies for BE, namely brensocatib, florensocatib and verducatib, with recent approval of brensocatib, a first-in-class DPP1 inhibitor, in the US and Europe, providing a promising treatment option for people with BE. Many questions about DPP1 inhibition remain, including long-term efficacy and safety, and efficacy in people with cystic fibrosis, primary COPD and immunodeficiencies, who were generally excluded from prior large studies. Despite the availability of cystic fibrosis transmembrane conductance regulator modulator therapy, many people with cystic fibrosis continue to have pulmonary exacerbations. The inclusion of a broad population with a range of aetiologies is key in the development of DPP1 inhibitors to support access to treatment for all those who could benefit. This review explores the current DPP1 inhibition landscape, discussing the clinical studies to date for these three novel DPP1 inhibitors and the evolution of DPP1 studies in BE.