Anti-inflammatory agents for the management of COPD - Quo Vadis?

Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality around the globe. Its main characteristics are persistent respiratory symptoms and progressive airflow limitation, both of which are driven by chronic inflammation. Despite the use of maximum bronchodilation and in selected patients inhaled corticosteroids (ICS), current therapies neither halt disease progression nor prevent exacerbations and loss of lung function.

Recent research has focused on developing novel anti-inflammatory agents targeting specific pathways implicated in COPD pathogenesis, aiming to provide disease-modifying effects beyond symptomatic relief. Among these, inhaled phosphodiesterase 4 (PDE4) inhibitors and especially dual PDE3/4 inhibitors like ensifentrine have demonstrated promising anti-inflammatory and bronchodilator effects, with ensifentrine recently being added in our arsenal of treatment options. Additionally, biologic therapies targeting type 2 inflammation, particularly monoclonal antibodies (mAbs) focusing on interleukin-5 (IL-5) and interleukin-4/13 (IL-4/13) pathways have shown efficacy in reducing exacerbations in patients with eosinophilic COPD. Dupilumab, a mAb targeting IL-4/13, is the first biologic officially approved for COPD.

Other strategies under investigation include Janus kinase (JAK) and mitogen-activated protein kinase (MAPK) inhibitors, chemokine receptor antagonists and agents targeting products of inflammatory cells such as matrix metalloproteinases (MMPs) and neutrophil elastase. While some novel compounds have failed to demonstrate clinical benefit or were discontinued due to futility, the constantly evolving therapeutic landscape highlights the importance of a personalized approach, based on inflammatory phenotypes. Ongoing and future trials could elucidate the role of these innovative agents in improving outcomes for COPD patients and may reshape standard management paradigms.