Phase 2a, Randomized, Double-blind, Placebo-Controlled Study of Inhalation Solution Formulation of LABA and LAMA Combination (Indacaterol and Glycopyrrolate) for Nebulization Delivery in COPD

Authors: A S Tutuncu, et al.

This Phase 2a randomized, double-blind, placebo-controlled crossover study evaluated the safety and efficacy of a nebulized fixed-dose combination of indacaterol and glycopyrrolate, in patients with chronic obstructive pulmonary disease (COPD). A total of 16 patients with moderate-to-severe COPD were included. The mean age was 68 years, mean disease duration was 12 years, mean post-bronchodilator forced expiratory volume in 1 second (FEV1) was 60.2% predicted, and mean FEV1/forced vital capacity (FVC) ratio was 49.7%. Patients received two dose levels (100/50 μg and 200/100 μg) delivered via nebulizer, with washout periods between treatments. Pulmonary function was assessed using serial spirometry over 24 hours. It  was well tolerated at both dose levels. The lower dose (100/50 μg) produced a rapid and statistically significant bronchodilator response compared with placebo. The standardized change from baseline in FEV1 area under the curve over 24 hours was 0.251±0.031 L (p<0.001), while the peak change in FEV1 was 0.311±0.035 L (p<0.001). The bronchodilator response was clinically meaningful and similar at both dose levels. Pharmacokinetic exposure was also comparable to previously published data for dry powder inhaler formulations of the same long-acting beta-agonist (LABA) and long-acting muscarinic antagonist (LAMA) combination.

Overall, nebulized fixed-dose combination of indacaterol and glycopyrrolate demonstrated favorable efficacy and safety as a once-daily LABA/LAMA therapy in patients with moderate-to-severe COPD.

Demographic and Clinical Characteristics of Patients with COPD Initiating Treatment with Ensifentrine: A Real-World Claims Analysis

Authors: W W Labaki, et al.

This retrospective real-world study evaluated the demographic and clinical characteristics of patients newly initiated on ensifentrine for chronic obstructive pulmonary disease (COPD) in the United States. The analysis used claims data from the Komodo Research Database and included 13,848 patients who initiated ensifentrine between August 2024 and August 2025. Patients were required to have at least 12 months of continuous enrollment before treatment initiation. The median age was 74 years, with 80% of patients aged 65–84 years. Female patients comprised 51.6% of the cohort. Most patients were covered by Medicare (85.6%), followed by commercial insurance (11.6%) and Medicaid (2.6%). More than half of patients (51.2%) were receiving concurrent triple inhaler therapy with long-acting beta-agonist/long-acting muscarinic antagonist/inhaled corticosteroid (LABA/LAMA/ICS). Concurrent LABA/LAMA therapy and LAMA/ICS therapy were reported in 4.1% and 4.2% of patients, respectively. Other background therapies included roflumilast (12.8%) and biologics (7.8%), including dupilumab, mepolizumab, benralizumab, and tezepelumab. Home oxygen therapy was used by 35.9% of patients. Common comorbidities included hypertension (56.7%), cardiac arrhythmias (31.1%), peripheral vascular disease (24.4%), congestive heart failure (23.8%), and diabetes (21.2%). Asthma was present in 15.2% and osteoporosis in 12.2% of patients. A history of pneumonia within the previous 12 months was reported in 21.8% of patients. Based on Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2025 classification, 63.1% of patients were in GOLD groups A/B and 36.9% were in group E.

Overall, ensifentrine was prescribed across a broad range of COPD patients with varying disease severity, comorbidities, and background treatment regimens during its first year of clinical use.

The Effect of Ensifentrine on Symptoms in Highly Symptomatic Patients at Baseline According to Two Definitions: A Post-hoc Pooled Analysis of the ENHANCE Trials

Authors: D A Mahler, et al.

This post-hoc pooled analysis from the Phase 3 ENHANCE trials evaluated the effect of ensifentrine on symptoms and dyspnea in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) who had high symptom burden at baseline. The pooled analysis included 975 patients treated with ensifentrine and 574 patients receiving placebo. Patients were categorized as highly symptomatic based on Evaluating Respiratory Symptoms (E-RS) breathlessness scores ≥6.7 or St. George’s Respiratory Questionnaire (SGRQ) symptom scores ≥58.7 at baseline. A total of 728 patients had high baseline E-RS breathlessness scores, while 805 patients had high baseline SGRQ symptom scores. Compared with placebo, ensifentrine significantly improved Transition Dyspnea Index (TDI) scores at Weeks 6, 12, and 24 across both symptom-defined groups (p<0.05 for all). TDI improvements with ensifentrine also exceeded the minimal clinically important difference of 1.0 at all evaluated time points. Ensifentrine additionally improved E-RS breathlessness and SGRQ symptom subdomain scores compared with placebo throughout the study period, regardless of how high symptom burden was defined.

Overall, ensifentrine provided early and sustained improvements in dyspnea and respiratory symptoms in patients with moderate-to-severe COPD and high baseline symptom burden.

Earlier Onset of Bronchodilation with Revefenacin: New Analyses from Phase 3 COPD Trials

Authors: E J Moran, et al.

This analysis from the Phase 3 revefenacin program evaluated the onset of bronchodilation after the first dose of revefenacin (REV), a once-daily nebulized long-acting muscarinic antagonist, in patients with chronic obstructive pulmonary disease (COPD). The analysis included pooled intent-to-treat (ITT) data from two Phase 3 studies and a prespecified 24-hour spirometry sub-study. Least-squares (LS) mean changes in forced expiratory volume in 1 second (FEV1) were assessed at early post-dose timepoints on Day 1. In the pooled ITT analysis, LS mean FEV1 increased by 90 mL at 15 minutes and 132 mL at 30 minutes after revefenacin administration. In the individual Phase 3 studies, FEV1 improvements first exceeded 100 mL above baseline at 30 minutes post-dose. In the 24-hour spirometry sub-study, revefenacin demonstrated significant bronchodilation within 15 minutes, with a mean FEV1 improvement of 116 mL from baseline and a placebo-corrected LS mean difference of 145 mL (95% confidence interval [CI], 99–191; p<0.001). Similarly, the pooled ITT analysis showed a placebo-corrected mean difference of 114 mL at 15 minutes (95% CI, 94–134), exceeding the minimum clinically important difference. Baseline characteristics were similar between the sub-study and ITT populations.

Overall, revefenacin demonstrated rapid and clinically meaningful bronchodilation beginning within 15 minutes and sustained through 30 minutes after the initial dose in patients with COPD.

Exacerbation Outcomes with Revefenacin in COPD Patients with Cardiovascular Risk or History: Exploratory Analyses from Study 0128

Authors: E J Moran, et al.

This exploratory analysis from the 52-week Phase 3 Study 0128 evaluated the effect of revefenacin (REV) on acute exacerbation risk in patients with chronic obstructive pulmonary disease (COPD) and cardiovascular (CV) risk or disease history. The study included 1,055 patients with moderate-to-very-severe COPD randomized to once-daily nebulized revefenacin 175 mcg or tiotropium (TIO). The impact of treatment on risk of acute exacerbations of COPD (AECOPD) was assessed in COPD patients with cardiovascular risk factors or a history of ischemic heart disease. Overall, 280 patients (27%) experienced at least one AECOPD during the study period. Treatment with revefenacin was associated with lower odds of experiencing ≥1 AECOPD compared with tiotropium (odds ratio [OR] 0.67; 95% confidence interval [CI], 0.46–0.97). Among patients with CV risk factors or ischemic heart disease, revefenacin did not increase exacerbation risk relative to tiotropium. Rates of moderate-to-severe AECOPDs also consistently favored revefenacin, although hospitalization events were too few for definitive conclusions. Baseline characteristics and CV risk profiles were similar between treatment groups.

Overall, the findings suggest that revefenacin may reduce COPD exacerbation risk compared with tiotropium, including in patients with cardiovascular comorbidities.

Comparative Effectiveness of Ensifentrine vs Roflumilast on Clinical Outcomes in Chronic Obstructive Pulmonary Disease

Authors: R M Shaik, et al.

This retrospective cohort study compared outcomes in patients with chronic obstructive pulmonary disease (COPD) treated with ensifentrine or roflumilast using the TriNetX database across 65 U.S. healthcare organizations. Patients with at least two COPD exacerbations between 2022 and 2025 were identified. After propensity-score matching, 697 patients receiving ensifentrine were compared with 697 patients receiving roflumilast. No significant difference in acute COPD exacerbations was observed at 3 months. However, by 6 months, patients receiving ensifentrine had a significantly lower risk of exacerbations (RR 0.78, 95% CI 0.68–0.90). At 3 months, ensifentrine use was also associated with a reduced risk of hospitalization (RR 0.76, 95% CI 0.62–0.94). By 6 months, patients treated with ensifentrine demonstrated lower risks of emergency department visits (RR 0.76, 95% CI 0.64–0.92), hospital admissions (RR 0.73, 95% CI 0.61–0.87), pneumonia (RR 0.65, 95% CI 0.51–0.84), diarrhea (RR 0.42, 95% CI 0.25–0.71), and depression/anxiety (RR 0.81, 95% CI 0.67–0.98). No significant differences were identified in acute respiratory failure, mechanical ventilation, mortality, or cardiovascular events.

Compared with roflumilast, ensifentrine demonstrated more favorable outcomes across multiple clinical endpoints, including COPD exacerbations, hospitalization, and pneumonia. 

Real-World COPD Assessment Test (CAT) Outcomes of Patients Initiating Ensifentrine: 3 Month Interim Analysis of the RELIEF Study

Authors: G R Washko, et al.

This interim analysis from the 6-month observational RELIEF study evaluated symptom changes in patients with chronic obstructive pulmonary disease (COPD) after initiation of ensifentrine. The study included 132 patients receiving stable maintenance therapy with dual long-acting beta-agonist/long-acting muscarinic antagonist (LABA/LAMA) or triple LABA/LAMA/inhaled corticosteroid (ICS) therapy for at least 3 months before starting ensifentrine. The median age was 72 years, average COPD duration was 10 years, and 96.2% of patients were receiving triple therapy. Among patients with baseline COPD Assessment Test (CAT) scores ≥10, the mean baseline CAT score was 24.6. After ensifentrine initiation, the mean CAT score improved to 20.3 at 1 month and 19.9 at 3 months. Improvements were also observed in CAT symptom domains: Cough: -0.5 at 1 month and -0.7 at 3 months, Phlegm: -0.6 at 1 month and -0.8 at 3 months. At 1 month, 64.9% of patients achieved a clinically meaningful CAT response (≥2-point reduction from baseline), while 65% remained responders at 3 months.

Overall, symptomatic COPD patients on standard therapy showed rapid, sustained improvement after initiating ensifentrine, with clinically meaningful CAT score reductions at 1 and 3 months, particularly in those on stable triple therapy. 

Health Care Resource Utilization and Exacerbations in Patients Starting Ensifentrine: A Real-World Claims Analysis

Authors: T Siddharthan, et al.

This real-world pre/post analysis evaluated the impact of ensifentrine on severe exacerbations and healthcare resource utilization in patients with chronic obstructive pulmonary disease (COPD) receiving dual or triple maintenance therapy. Using the Komodo Research Database, 2,372 patients who initiated ensifentrine between June and November 2024 were analyzed. Among them, 363 patients were receiving concurrent dual therapy and 2,009 were receiving triple therapy. At baseline, 36.6% of patients were classified as Global Initiative for Chronic Obstructive Lung Disease (GOLD) group E, and 16.5% had concomitant asthma. Following ensifentrine initiation, the annual rate of severe COPD exacerbations decreased by 11% compared with the pre-treatment period (p<0.05). Annualized COPD-related emergency room visits were reduced by 17% (p<0.05), while outpatient healthcare resource utilization increased by 21% (p<0.05). In patients receiving triple therapy, severe exacerbations decreased by 11%, emergency room visits decreased by 17%, and outpatient healthcare utilization increased by 19% (p<0.05 for all).

Overall, addition of ensifentrine to dual or triple maintenance therapy was associated with reduced severe exacerbations and lower emergency healthcare use in patients with COPD.

Modulating Inflammation in the Target Tissue: Anti-Inflammatory Effects of Ensifentrine in Medium Bronchi and Small Airways of COPD Donors

Authors: P A Rogliani, et al.

This preclinical study evaluated the anti-inflammatory effects of ensifentrine in airway tissues and epithelial cells obtained from patients with chronic obstructive pulmonary disease (COPD). Human medium bronchi, small airways, and primary bronchial epithelial cells from COPD donors were exposed to lipopolysaccharide (LPS)-induced inflammation and treated with ensifentrine or roflumilast. The effects of ensifentrine in combination with commonly used inhaled therapies such as isoeffective concentrations with formoterol, glycopyrronium, formoterol+glycopyrronium, formoterol+beclometasone, and formoterol+glycopyrronium+beclometasone were also assessed. Ensifentrine demonstrated concentration-dependent anti-inflammatory activity in medium bronchi, small airways, and epithelial cells, with effects comparable to roflumilast. At EC30 concentration, ensifentrine reduced LPS-induced inflammation by 84.3% in medium bronchi and 64.8% in small airways. At EC50 concentration, inflammation reductions increased to 94.4% and 90.9%, respectively. Synergistic anti-inflammatory interactions were observed in approximately 31.4% of treatment combinations. The greatest synergistic effects were seen with interleukin-10 (IL-10), with a mean delta effect of 15.3%. In small airways, synergistic effects were also observed for IL-25, granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor-alpha (TNF-α), with delta from 10% to 18%. Combinations containing glycopyrronium produced larger and more frequent synergistic anti-inflammatory effects compared with expected additive effects (p<0.05).

Overall, ensifentrine demonstrated potent anti-inflammatory activity in COPD airway tissues and showed synergistic effects when combined with certain inhaled therapies, particularly glycopyrronium-containing regimens.

Mechanism of Ensifentrine Protection Against Endothelial Injury in COPD-Associated Pulmonary Hypertension

Authors: K Nishino, et al.

This preclinical study investigated the role of cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)/exchange protein directly activated by cAMP (EPAC) signaling in endothelial injury associated with chronic obstructive pulmonary disease-related pulmonary hypertension (COPD-PH). Spatial transcriptomic analysis was performed on lung tissue from patients with COPD-PH and COPD without pulmonary hypertension. The study identified downregulation of key cAMP signaling components and upregulation of phosphodiesterase 4D (PDE4D) and phosphodiesterase 3A (PDE3A) in pulmonary capillary endothelial cells in COPD-PH lungs. Human lung microvascular endothelial cells exposed to cigarette smoke extract demonstrated barrier dysfunction and cell injury. Treatment with the phosphodiesterase 3/4 inhibitor ensifentrine preserved vascular endothelial cadherin (VE-cadherin) and zonula occludens-1 (ZO-1) localization and maintained endothelial barrier function during cigarette smoke exposure. Ensifentrine also reduced cleaved poly (ADP-ribose) polymerase (PARP) levels by 40% (p<0.01) and lactate dehydrogenase (LDH) release by 50% (p=0.017), indicating reduced apoptosis and cell injury. Inhibition of PKA or EPAC abolished the protective effects of ensifentrine and worsened cigarette smoke-induced endothelial dysfunction.

Overall, the findings suggest that impaired cAMP-PKA/EPAC signaling contributes to endothelial injury in COPD-associated pulmonary hypertension, and that phosphodiesterase 3/4 inhibition with ensifentrine may help restore endothelial function.

ATS 2026, May15 –20, Orlando, Florida