Abstract Rationale Despite the availability of various treatments for the maintenance of chronic obstructive pulmonary disease (COPD), many patients report persistent symptoms, with dyspnea being the most disruptive symptom.1 Ensifentrine is a novel, selective, dual inhibitor of phosphodiesterase (PDE)3 and PDE4 with bronchodilation and anti-inflammatory effects. In the Phase 3 ENHANCE program, ensifentrine improved symptoms in a broad population of patients with COPD. In this post-hoc pooled analysis, we evaluated the effect of ensifentrine in patients with significant symptoms at baseline according to two definitions. Methods The ENHANCE program included two global, multi-center, randomized, double-blind, placebo-controlled trials of patients age 40 to 80 with symptomatic, moderate-to-severe COPD (FEV1 30-70% predicted, mMRC ≥2). Permitted concomitant COPD maintenance medications included single bronchodilator therapy, with or without an inhaled corticosteroid. The primary endpoint of the trials was change from baseline to Week 12 average FEV1 AUC0-12h. Transition Dyspnea Index (TDI), Evaluating Respiratory Symptoms (E-RS), and St. George’s Respiratory Questionnaire (SGRQ) were evaluated at Weeks 6, 12, and 24. Here, the effect of ensifentrine on dyspnea and symptom outcomes was analyzed in patients with high dyspnea at baseline according to E-RS (breathlessness subdomain ≥ mean 6.7 or high symptoms at baseline according to SGRQ (symptoms subdomain ≥ mean 58.7). Results The pooled population included 975 ensifentrine-treated patients and 574 placebo-treated patients. 728 Patients had a baseline E-RS breathlessness score ≥ mean (6.7; ensifentrine, n = 473; placebo, n = 255) and 805 patients had a baseline SGRQ symptoms score ≥ mean (58.7; ensifentrine, n = 497; placebo, n = 308). These groups were not mutually exclusive. In patients with high symptoms at baseline according to either definition, ensifentrine resulted in significant improvements in TDI vs placebo at all time points (P 0.05 for all). TDI scores also exceeded the minimal clinically important difference (1.0) at all time points for patients treated with ensifentrine. Improvements in E-RS breathlessness and SGRQ symptoms subdomains were also observed with ensifentrine vs placebo at all time points, regardless of which definition was used for high symptoms at baseline. Conclusion Ensifentrine resulted in early and sustained improvements in COPD symptoms, including dyspnea, for patients with moderate-to-severe COPD and high levels of symptoms at baseline. These improvements were seen consistently across all patient-reported outcome measures evaluated, and using two different definitions of elevated symptoms. Ensifentrine offers a novel non-steroidal, anti-inflammatory mechanism of action that provides meaningful improvements in symptoms. 1. Mannino DM et al. Chronic Obstr Pulm Dis. 2025;12(4):317-327. This abstract is funded by: Verona Pharma, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Mahler et al. (Fri,) studied this question.
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