Ensifentrine

The efficacy and safety of ensifentrine, a novel PDE3/PDE4 inhibitor, were previously evaluated in the ENHANCE-1 (NCT04535986) and ENHANCE-2 (NCT04542057) trials. Here, we present a pooled post-hoc subgroup analysis of patients according to background chronic obstructive pulmonary disease (COPD) maintenance medication regimens.

This analysis aimed to explore the efficacy and safety of ensifentrine in patients receiving long-acting muscarinic antagonists (LAMA) or long-acting beta-agonists with inhaled corticosteroids (LABA + ICS).

Eligible patients had moderate to severe COPD, were aged 40–80 years, and were symptomatic at randomization. Patients were randomized 5:3, receiving twice-daily ensifentrine 3 mg or placebo via standard jet nebulizer over 24 weeks.

The pooled post-hoc analysis included 485 LAMA patients and 272 LABA + ICS patients. Ensifentrine showed lung function improvement over placebo at week 12, including average FEV1 AUC0–12 h in the LAMA (placebo-corrected least squares mean change from baseline [LSMC], 92 mL; 95% CI, 54, 131; p < 0.001) and LABA + ICS subgroups (LSMC, 74 mL; 95% CI, 27, 121; p = 0.002). Ensifentrine reduced the rate and risk of exacerbations in both LAMA (48% and 50%, respectively) and LABA + ICS (51% and 56%, respectively) subgroups. Ensifentrine-treated patients reported improvement in symptoms and quality of life over 24 weeks. The safety profile of ensifentrine in each subgroup was similar to the profile in the pooled modified intention-to-treat population.

Nebulized ensifentrine offers a novel non-steroidal anti-inflammatory and bronchodilator treatment added to existing LAMA or LABA + ICS treatment options in patients with moderate to severe, symptomatic COPD.

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.