What is the recommended use and dosage of Ensifentrine for patients with chronic obstructive pulmonary disease (COPD)?

Ensifentrine for COPD: Recommended Use and Dosage

Ensifentrine is administered as 3 mg twice daily via nebulization for patients with moderate to severe COPD to improve lung function, reduce symptoms, and decrease exacerbation rates, and can be used as add-on therapy to existing long-acting bronchodilators. 1

Mechanism and Clinical Profile

Ensifentrine is a first-in-class selective dual phosphodiesterase 3 and 4 (PDE3/4) inhibitor that provides both bronchodilator and non-steroidal anti-inflammatory effects through a single molecule. 2, 1 This bifunctional mechanism distinguishes it from existing COPD therapies by simultaneously addressing airway obstruction and inflammation. 2

Approved Dosing Regimen

• The recommended dose is 3 mg administered twice daily via nebulization 3, 1
• Dose-ranging studies demonstrated efficacy across 0.75 mg to 6 mg twice daily, with optimal bronchodilation observed at 3 mg twice daily 3
• The 3 mg dose showed a placebo-adjusted improvement in peak FEV1 of 200 mL (95% CI: 131-270 mL) at 4 weeks 3
• Treatment duration in pivotal trials was 24 weeks, demonstrating sustained efficacy 1

Patient Selection Criteria

• Indicated for symptomatic patients aged 40-80 years with moderate to severe COPD 1
• Post-bronchodilator FEV1 should be 40-80% of predicted normal 3
• FEV1/FVC ratio ≤0.7 confirming airflow limitation 3
• Patients with persistent symptoms despite existing maintenance therapy are appropriate candidates 1

Clinical Efficacy Outcomes

Lung Function Improvements

• Ensifentrine significantly improved average FEV1 area under the curve (0-12 hours) by 87-94 mL versus placebo at 24 weeks in phase III trials 1
• Trough FEV1 (pre-dose) increased by 40.90 mL (95% CI: 19.65-62.15) at 12 weeks 4
• Peak FEV1 improvements were sustained throughout the 24-week treatment period 1

Symptom and Quality of Life Benefits

• Evaluating Respiratory Symptoms (E-RS) total score decreased by -0.81 points (95% CI: -1.36 to -0.27) at 24 weeks 4
• Transition Dyspnea Index (TDI) score improved by 0.96 points (95% CI: 0.62 to 1.29) at 24 weeks 4
• St. George's Respiratory Questionnaire (SGRQ) showed numerical improvements in quality of life, though not consistently reaching statistical significance across both pivotal trials 1, 4

Exacerbation Reduction

• Ensifentrine reduced the rate of moderate to severe exacerbations by 41% (rate ratio 0.59; 95% CI: 0.43-0.80; P<0.001) in pooled analysis 5
• Time to first exacerbation was significantly prolonged (hazard ratio 0.59; 95% CI: 0.44-0.81; P<0.001) 5
• Individual trial results showed rate ratios of 0.64 (ENHANCE-1) and 0.57 (ENHANCE-2) for exacerbation reduction 1
• Exacerbation benefits were consistent across patient subgroups including age, sex, COPD severity, eosinophil count, and exacerbation history 5

Use as Add-On Therapy

• Ensifentrine can be added to existing long-acting muscarinic antagonist (LAMA) or long-acting β2-agonist (LABA) therapy 1
• In pivotal trials, 62% of patients received concomitant LAMA or LABA therapy, and 18% received concomitant inhaled corticosteroid (ICS) therapy 5
• Efficacy was maintained regardless of background maintenance medication use 5
• This positions ensifentrine as an add-on option for patients with persistent symptoms or exacerbations despite standard bronchodilator therapy 1

Safety Profile

• Adverse event rates with ensifentrine were similar to placebo across all doses (33.3-44.4% vs 39.2% with placebo) 3
• The medication was well-tolerated across the dose range of 0.75-6 mg twice daily 3
• No significant safety concerns emerged during 24-week treatment periods in phase III trials 1
• The nebulized delivery route may be advantageous for patients with severe disease who have difficulty coordinating metered-dose inhalers 3

Clinical Context and Positioning

Ensifentrine addresses an unmet need for patients who continue experiencing symptoms and exacerbations despite maximal combined treatment with long-acting bronchodilators and inhaled corticosteroids. 3 Unlike roflumilast (an oral PDE4 inhibitor recommended for severe COPD with chronic bronchitis and frequent exacerbations 6), ensifentrine is administered via nebulization and combines PDE3 and PDE4 inhibition for potentially additive or synergistic effects. 3

The medication's ability to reduce exacerbations is particularly relevant given that exacerbations lead to irreversible lung function decline, decreased quality of life, and increased risk of subsequent exacerbations. 5 The numerical delay in transitioning from infrequent to frequent exacerbator status suggests potential disease-modifying effects. 5

Practical Implementation

• Administer via standard nebulizer device twice daily 1
• Can be initiated in patients already receiving LAMA, LABA, or ICS therapy without discontinuing existing medications 5, 1
• Monitor for symptomatic improvement in dyspnea and reduction in rescue medication use 4
• Assess exacerbation frequency over subsequent months to evaluate treatment response 5
• Higher doses (3 mg) are associated with more favorable outcomes compared to lower doses 4