--- arxiv_id: PMC12912034 title: "Ensifentrine Added on to Dual Bronchodilator or Triple Therapy Demonstrates Clinically Meaningful Improvement in CAT Score in Symptomatic Patients with Chronic Obstructive Pulmonary Disease." authors: - Siler TM - Rheault T - Reyner D - MacDonald-Berko M - Davidson J - Rickard K difficulty: Intermediate tags: - COPD - Respiratory - Clinical Trial published_at: 2026 flecto_url: https://flecto.zer0ai.dev/papers/PMC12912034/ lang: en --- > Two-thirds of symptomatic COPD patients already on maximum maintenance therapy achieved a clinically meaningful CAT score improvement with add-on Ensifentrine in 12 weeks. ## Results ### Results ## Discussion ### Discussion & Conclusions This is the first study to characterize Ensifentrine's symptomatic benefit specifically in COPD patients already on dual or triple maintenance therapy. The strict inclusion/exclusion criteria of traditional RCTs often exclude such patients, creating a real-world evidence gap. This open-label study addresses that gap by directly targeting the population with persistent symptoms on maximum therapy. The higher response rate in dual therapy patients (80%) vs triple therapy patients (50%) may reflect the greater remaining room for improvement in patients not yet on ICS therapy. Patients on triple therapy already have ICS-mediated anti-inflammatory benefit, potentially reducing the incremental gain from Ensifentrine's PDE4 inhibition component. ## References ### References (click to expand) ### Selected key references. Full list available in the original PMC article. ## Page Title ### Ensifentrine Add-On in COPD: Phase 3b CAT Score Trial | Flecto ## Meta Description Phase 3b trial: Ensifentrine added to LABA/LAMA or triple therapy improved CAT score by ≥2 units in 67% of symptomatic COPD patients at Week 12. ## Hero, Cta ### Read on PMC ↗ ## Key Findings ### Key Findings This Phase 3b open-label trial (NCT06460493) enrolled 20 symptomatic COPD patients on stable dual or triple maintenance therapy and added Ensifentrine (3 mg inhaled BID) for 12 weeks. It is the first study specifically designed to evaluate Ensifentrine in this maximally treated population. Primary endpoint: proportion of patients with ≥2-unit CAT improvement at Week 12. ## Key Findings, Metric=Overall ### Overall CAT ≥2-unit responders at Week 12 ## Key Findings, Metric=Dual ### Dual therapy responders at Week 12 ## Key Findings, Metric=Lsm ### LSM CAT change from baseline (Week 12) — exceeds MCID of −2.0 ## Key Findings, Metric=Safety ### Well Tolerated ### Safety profile — consistent with known Ensifentrine data ## Background ### Background & Rationale COPD is a progressive respiratory condition causing chronic breathlessness, cough, mucus hypersecretion, and persistent airflow limitation. It is a leading cause of morbidity and mortality worldwide. Despite the availability of dual bronchodilator (LABA/LAMA) and triple therapy (LABA/LAMA/ICS), many patients remain symptomatic — reporting daily breathlessness and impaired quality of life. Traditional RCTs often exclude the most symptomatic patients using strict inclusion/exclusion criteria. This study was specifically designed to evaluate Ensifentrine in real-world-type patients who are symptomatic despite maximal maintenance therapy — a population that lacks effective add-on options. ## Background, Subcopd ### The Problem: Residual Symptoms on Maximum Therapy ## Background, Subdrug ### What is Ensifentrine? ## Background, Drug Ensifentrine (Verona Pharma/Merck) is a novel, selective, dual PDE3 and PDE4 inhibitor — the first in a new class. It combines two mechanisms in a single inhaled agent: ### PDE3 inhibition → bronchodilation (airway smooth muscle relaxation) ### PDE4 inhibition → anti-inflammatory effects (reduced neutrophil and eosinophil activation) FDA-approved (2024) for maintenance treatment of moderate-to-severe COPD; delivered via nebulizer BID ## Study Design ### Study Design & Patients ### Design ### Phase 3b, single-center, open-label, 12-week ### Population ### Age 40–80, mMRC dyspnea ≥2, CAT ≥10, moderate-to-severe COPD on stable dual or triple therapy ### Treatment ### Ensifentrine 3 mg inhaled BID added to existing dual or triple therapy ### Primary endpoint ### ≥2-unit improvement in CAT score from baseline at Week 12 ### Follow-up ### Visits at Day 1, Week 6, Week 12 + post-treatment safety follow-up ### Registration ### ClinicalTrials.gov NCT06460493 (registered June 10, 2024) ## Study Design, Figure=1 ### Patient Flow Figure 1. Patient disposition. 23 enrolled; 3 failed COPD severity screening, 2 withdrew before treatment, leaving 20 treated. 18 patients completed both Week 6 and Week 12 assessments and were included in the efficacy analysis. ## Study Design, Table=1 ### Baseline Characteristics (n=20) ## Results, Primary ### Primary Endpoint: CAT ≥2-Unit Improvement At Week 12, 67.0% (95% CI, 38.0%–100.0%) of patients achieved ≥2-unit CAT improvement — the pre-specified definition of a clinically meaningful response. Among dual therapy patients (LABA/LAMA, n=10), 80% were responders at Week 12 vs 50% at Week 6. Among triple therapy patients (LABA/LAMA/ICS, n=8), 50% were responders at Week 12 vs 38% at Week 6. The response rate was consistently higher in dual therapy patients. ## Results, Figure=2 Figure 2. Proportion of patients achieving ≥2-unit CAT improvement (primary endpoint) at Week 6 and Week 12, stratified by background therapy. The dual therapy group (LABA/LAMA) showed higher and increasing response rates: 50% at Week 6, 80% at Week 12. The triple therapy group showed 38% (Week 6) and 50% (Week 12). ## Results, Secondary ### Secondary Endpoint: LSM CAT Change from Baseline The LSM change in overall CAT score from baseline was −1.5 at Week 6 (95% CI not crossing MCID) and −2.3 at Week 12, which exceeds the Minimal Clinically Important Difference (MCID) threshold of −2.0 units. This demonstrates that the typical patient continued to improve between Week 6 and Week 12. ## Results, Figure=3 Figure 3. LSM change from baseline in CAT score at Week 6 (−1.5) and Week 12 (−2.3) with 95% CI. The MCID threshold of −2.0 (dotted line) is exceeded at Week 12 but not Week 6, demonstrating progressive symptomatic improvement over the treatment period. ## Results, Safety ### Safety Ensifentrine was well tolerated in this population. Adverse events were consistent with the known safety profile established in the larger Phase 3 ENHANCE-1 and ENHANCE-2 trials. No unexpected safety signals were observed. The study's open-label design and small sample size limit formal safety characterization. ## Discussion, Limitations ### Study Limitations ### Small sample size (n=18) : Wide 95% CI (38–100%) limits precision of the 67% estimate ### Single-center, open-label design : No blinding or comparator arm; placebo effect cannot be excluded ### Short duration (12 weeks) : Long-term durability of effect not assessed ### 100% male population : Limits generalizability to female COPD patients ## Discussion, Conclusions ### Conclusions Ensifentrine provided clinically meaningful improvement in CAT score in two-thirds of symptomatic COPD patients who remained symptomatic on dual or triple therapy. Key takeaways: ### 67% overall responder rate at Week 12 (≥2-unit CAT improvement) ### 80% response in dual therapy patients; 50% in triple therapy patients ### LSM CAT change of −2.3 at Week 12 exceeds MCID; well tolerated