Efficacy of Ensifentrine in Chronic Obstructive Pulmonary Disease (COPD): A Meta-analysis of Randomized Controlled Trials

Abstract Background: Chronic obstructive pulmonary disease (COPD) presents significant management challenges, as many patients continue to experience daily symptoms, exacerbations, and lung function decline despite optimal therapy with long-acting bronchodilators and inhaled corticosteroids. There is a need for novel treatment options targeting additional pathways to improve outcomes in this population. Ensifentrine, an inhaled dual inhibitor of phosphodiesterase (PDE)3 and PDE4, has demonstrated both bronchodilatory and anti-inflammatory effects in clinical studies with COPD patients and experimental models. This meta-analysis aims to assess the efficacy of ensifentrine compared to placebo in improving outcomes in COPD. Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the efficacy of ensifentrine in COPD. Major databases were searched to identify relevant studies, and a random-effects model was applied. The primary outcomes included changes in peak forced expiratory volume in 1 second (FEV1) as a bronchodilator response and morning trough FEV1 as an anti-inflammatory response. Additional outcomes assessed included changes in the Evaluating Respiratory Symptoms (E-RS) in COPD score, St. George's Respiratory Questionnaire (SGRQ) C-score, and Transition Dyspnea Index (TDI) total score. All RCTs reported data for 6 weeks, while two extended to 24 weeks, allowing a sub-analysis of long-term efficacy. Results: This meta-analysis includes four RCTs with a total of 1,876 participants. At 6 weeks, ensifentrine significantly improved peak FEV1 (Mean difference = 0.15 L; 95% CI: 0.13-0.18; p < 0.00001) and morning trough FEV1 (Mean difference = 0.04 L; 95% CI: 0.02-0.07; p = 0.0001) compared to placebo. Improvement in average FEV1 over 12 hours (AUC) also favored ensifentrine (Mean difference = 0.10 L; 95% CI: 0.07-0.12; p < 0.00001). Significant improvements were observed in E-RS in COPD score (Mean difference = -1.22; p < 0.00001), SGRQ C-score (Mean difference = -2.22; p = 0.001), and TDI total score (Mean difference = 0.66; p < 0.0001). In the 24-week sub-analysis, ensifentrine maintained the significant effects on peak FEV1 and morning trough FEV1. Conclusion: Ensifentrine demonstrated significant improvements in lung function and symptom scores compared to placebo in COPD patients, with early benefits at 6 weeks sustained over 24 weeks. This dual-action PDE3 and PDE4 inhibitor shows promise as a therapeutic option for patients who remain symptomatic despite standard treatments. Further long-term studies are needed to confirm these findings and define the role of ensifentrine in COPD management.