Phase 3b Trial n=18 Analyzed 67% CAT Responders

Ensifentrine on Top of Dual or Triple Therapy Delivers Meaningful Symptom Relief in COPD

Int J Chron Obstruct Pulmon Dis · 2026

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.

Read on PMC ↗

Key Findings

67%

Overall CAT ≥2-unit responders at Week 12

80%

Dual therapy responders at Week 12

−2.3

LSM CAT change from baseline (Week 12) — exceeds MCID of −2.0

Well Tolerated

Safety profile — consistent with known Ensifentrine data

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.

Background & Rationale

The Problem: Residual Symptoms on Maximum Therapy

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.

What is Ensifentrine?

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 & Patients

DesignPhase 3b, single-center, open-label, 12-week

PopulationAge 40–80, mMRC dyspnea ≥2, CAT ≥10, moderate-to-severe COPD on stable dual or triple therapy

TreatmentEnsifentrine 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-upVisits at Day 1, Week 6, Week 12 + post-treatment safety follow-up

RegistrationClinicalTrials.gov NCT06460493 (registered June 10, 2024)

Patient Flow

Baseline Characteristics (n=20)

Characteristic	Value (n=20)
Mean age (SD)	71.3 (7.1) years
Male	100%
Current / ex-smokers	94%
Mean FEV₁ % predicted	56%
Mean baseline CAT score (SD)	13.7 (7.8)
Background dual therapy (LABA/LAMA)	56% (n=10)
Background triple therapy (LABA/LAMA/ICS)	44% (n=8)

Results

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.

CAT responders by therapy group — **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).

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.

LSM change in CAT score from baseline — **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.

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 & 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.

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

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

References (click to expand)

Selected key references. Full list available in the original PMC article.

Siler TM, et al. Ensifentrine Added on to Dual Bronchodilator or Triple Therapy. Int J Chron Obstruct Pulmon Dis. 2026. doi:10.2147/COPD.S589655
Calverley PM, et al. Ensifentrine, a Novel PDE3 and PDE4 Inhibitor for the Treatment of COPD. N Engl J Med. 2022;387(13):1159–1169.
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of COPD. 2024 Report.

B2B Content

Any content, beautifully transformed for your organization

PDFs, videos, web pages — we turn any source material into production-quality content. Rich HTML · Custom slides · Animated video.

View Services Contact Us