From Promise to Serendipity: A Breath of Fresh Air Beyond Bronchodilation: Early Data on Hemodynamic and Functional Outcomes with Ensifentrine Nebulization in Severe COPD Associated Pulmonary Hypertension–A Six-Month Retrospective Observational Study

Background: Pulmonary hypertension (PH) is a frequent and serious complication of advanced chronic obstructive pulmonary disease (COPD) and is associated with poor prognosis and limited treatment options. Current management focuses on optimizing COPD care, while the role of pulmonary vasodilators remains controversial. Ensifentrine, a dual phosphodiesterase (PDE) 3/4 inhibitor with bronchodilatory and anti-inflammatory properties, may offer therapeutic benefit in COPD-associated PH. Objective: To retrospectively evaluate the effects of 6 months of nebulized ensifentrine on pulmonary hemodynamics and functional outcomes in patients with severe COPD and associated pre-capillary PH. Methods: We conducted a single-center, retrospective chart review of patients with GOLD stage III and IV COPD and confirmed pre-capillary PH (mean pulmonary artery pressure mPAP ≥20 mmHg, pulmonary vascular resistance PVR 2 Wood Units, pulmonary capillary wedge pressure ≤15 mmHg). Five patients treated with nebulized ensifentrine (3 mg twice daily) between September 2024 and May 2025 were analyzed. Hemodynamics via right heart catheterization (RHC) and 6-minute walk distance (6MWD) were assessed at baseline and at 6 months. Results: The cohort (mean age 76 years, 60% male, mean FEV₁ 33.4% predicted) demonstrated severe emphysema and PH (baseline mPAP 53.2 mmHg, PVR 9.5 WU, cardiac index 2.5 L/min/m²). After 6 months, mean changes were: mPAP: decrease by 1.6 mmHg Cardiac index: increase by 0.1 L/min/m² PVR: decrease by 1.0 WU 6MWD: Improved by 31 m mMRC dyspnea score improved from 3.6 to 3.2, CAT score from 23 to 21.6, and DLCO increased modestly (29%→31.2% predicted). No adverse events, exacerbations, or hospitalizations were observed during this period. The combination of ensifentrine with roflumilast was well tolerated. Conclusions: In this retrospective study, ensifentrine was safe and associated with modest improvements in pulmonary hemodynamics and functional status in severe COPD with pre-capillary PH. These preliminary findings warrant confirmation in larger, prospective controlled trials.