Abstract
Despite advances in inhaled bronchodilator therapy, many patients with Chronic Obstructive Pulmonary Disease (COPD) remain symptomatic and experience activity limitation despite appropriate use of long-acting β?-agonists (LABAs), Long-Acting Muscarinic Antagonists (LAMAs), and Inhaled Corticosteroids (ICS).
Citation
Chapa-Rodriguez A, Abou-Elmagd T, Hafiz Sarwar (2026) Clinical Therapeutics: In Which Pa-tients with COPD Should Ensifentrine be Added to Standard Therapy?. SM J Fam Med 4(1)-2.
Introduction
WHY THIS TOPIC IS IMPORTANT
Despite advances in inhaled bronchodilator therapy, many patients with Chronic Obstructive Pulmonary Disease (COPD) remain symptomatic and experience activity limitation despite appropriate use of long-acting β₂-agonists (LABAs), Long-Acting Muscarinic Antagonists (LAMAs), and Inhaled Corticosteroids (ICS). Ensifentrine represents a novel dual‐mechanism option that may address persistent dyspnea and inflammation in this population.
WHAT IS ENSIFENTRINE AND HOW DOES IT WORK?
Ensifentrine (brand name Ohtuvayre) is a first-in-class inhaled dual Phosphodiesterase (PDE) 3 and 4 inhibitor, approved by the U.S. Food and Drug Administration in 2024 as twice-daily maintenance therapy for COPD. By blocking PDE3 and PDE4, ensifentrine increases intracellular Cyclic Adenosine Monophosphate (cAMP), resulting in bronchodilation and anti-inflammatory effects [1].- Bronchodilation results from inhibition of PDE3 in airway smooth muscle, increasing cAMP and promoting relaxation.- Anti-inflammatory activity arises from PDE4 inhibition in inflammatory cells (neutrophils, eosinophils, macrophages, lymphocytes, and fibroblasts), leading to reduced cytokine release [2-4]. Unlike inhaled corticosteroids, which demonstrate limited efficacy against neutrophilic inflammation in COPD due to reduced histone deacetylase 2 activity, ensifentrine directly suppresses cytokines such as IL-8 and TNF-α. Additionally, PDE4 inhibition activates the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), improving mucociliary clearance.
WHERE DOES ENSIFENTRINE FIT IN THE CURRENT TREATMENT LANDSCAPE?
The GOLD 2025 guidelines recommend a stepwise approach beginning with dual long-acting bronchodilators, with ICS reserved for patients with frequent exacerbations or blood eosinophil counts ≥300 cells/µL. Ensifentrine is not a replacement for guideline-directed inhaled therapies but may be considered as an adjunctive maintenance option for patients with persistent dyspnea or activity limitation despite optimized inhaler use.
WHAT DOES THE EVIDENCE SHOW?
Approval of ensifentrine was based on the ENHANCE-1 and ENHANCE-2 phase 3 trials, which enrolled over 1,500 patients with moderate-to-severe COPD (GOLD grades 2–3).
KEY FINDINGS- FEV
₁ improvement: +87 mL in ENHANCE-1 and +94 mL in ENHANCE-2 vs placebo.- Exacerbations: 36–43% reduction in moderate-to-severe exacerbations across studies.- Quality of life: 2–3 point improvement in St. George’s Respiratory Questionnaire (SGRQ).- Adverse events: Similar to placebo, with minimal gastrointestinal effects [5]. Benefits were observed regardless of background therapy (LAMA, LABA, or ICS). Although pooled data demonstrated a 36% reduction in moderate-to-severe exacerbations, this was not a prespecified primary endpoint. Accordingly, GOLD 2025 characterizes these findings as suggestive but requiring confirmation in targeted populations.
ADMINISTRATION AND PRACTICAL CONSIDERATIONS
Ensifentrine is delivered as a nebulized solution (0.75 mg/3 mL per dose) twice daily using a jet nebulizer, with each session lasting approximately five minutes. It should be administered separately from other nebulized medications to avoid drug stability issues. Minimal systemic absorption contributes to its favorable side-effect profile.
WHO ARE THE IDEAL CANDIDATES?
Ensifentrine is best thought of as a symptom-focused add-on therapy for moderate to severe COPD patients who remain short of breath despite appropriate inhaler use.
LIMITATIONS AND FUTURE DIRECTIONS
- Long-term safety beyond one year remains under investigation.
- Mortality benefit has not been demonstrated.
- Cost and access may initially limit use.
-Comparative effectiveness versus roflumilast or biologic therapies is unknown.
- Future trials should evaluate its role as a steroid-sparing agent or in patients intolerant to ICS.
HOW DOES ENSIFENTRINE DIFFER FROM ROFLUMILAST?
|
Feature |
Ensifentrine |
Roflumilast |
|
Mechanism |
Dual PDE3/4 inhibition |
PDE4 inhibition only |
|
Route |
Inhaled (nebulized) |
Oral |
|
Primary actions |
Bronchodilation + anti- inflammatory |
Anti-inflammatory only |
|
Tolerability |
Minimal GI effects |
Frequent nausea, diarrhea, weight loss |
PRACTICAL POINTS FOR CLINICIANS
1. Confirm inhaler technique and adherence before escalation.
2. Consider ensifentrine for patients with persistent dyspnea despite optimized therapy.
3. Continue existing maintenance regimen; ensifentrine is adjunctive.
4. Reassess response after 3–6 months.
5. Address cost and insurance coverage early.
KEY TAKEAWAYS
- Ensifentrine is the first inhaled dual PDE3/4 inhibitor for COPD.
- Improves lung function and symptoms with a placebo-like safety profile.
- Appropriate for symptomatic GOLD 2–3 patients who remain dyspneic despite optimized inhaler therapy.
- Long-term safety and comparative efficacy data are awaited
REFERENCES
- Faruqi MA, Khan MMKS, Mannino DM. Perspectives on ensifentrine and its therapeutic potential in the Treatment of COPD: Evidence to Date. Int J Chron Obstruct Pulmon Dis. 2024; 19: 11-16.
- Dransfield M, Rowe S, Vogelmeier CF, Wedzicha J, Criner GJ, Han MK, et al. Cystic fibrosis transmembrane conductance regulator: Roles in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2022; 205: 631-640.
- Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report. 2025.
- Ferguson GT, Anzueto A, Hanania NA. Long-term safety of nebulized formoterol: results of a twelve-month open-label clinical trial. Lancet Respir Med. 2024; 12: 23-34.
- Yappalparvi A, Balaraman AK, Padmapriya G, Gaidhane S, Kaur I, Lal M, et al. Safety and efficacy of ensifentrine in COPD: A systemic review and meta-analysis. Respir Med. 2025; 236: 107863.
- Matera MG, Calzetta L, Rogliani P. Exploring the Potential of PLGA Nanoparticles for Enhancing Pulmonary Drug Delivery. Pulm Pharmacol Ther. 2024; 79: 102196.