What is Ensifetrine?
Ensifentrine (brand name Ohtuvayre™) is a first-in-class, inhaled dual phosphodiesterase 3 and 4 (PDE3/4) inhibitor approved by the FDA for maintenance treatment of chronic obstructive pulmonary disease (COPD), offering both bronchodilator and anti-inflammatory effects in a single molecule. 1, 2
Mechanism of Action
Ensifentrine works through selective dual inhibition of PDE3 and PDE4 enzymes, though its affinity for PDE3 is approximately 3,440 times higher than for PDE4. 3 This bifunctional mechanism provides:
- Bronchodilation through PDE3 inhibition, which relaxes airway smooth muscle 4
- Anti-inflammatory activity through PDE4 inhibition, which suppresses airway inflammatory responses 3, 4
Clinical Efficacy
The FDA approval was based on two replicate Phase III trials (ENHANCE-1 and ENHANCE-2) conducted in 1,549 patients with moderate to severe symptomatic COPD:
Lung Function Improvements
- Significant improvement in FEV1 (forced expiratory volume in 1 second) compared to placebo 2
- ENHANCE-1: 87 mL improvement (95% CI: 55-119 mL; P < 0.001) 2
- ENHANCE-2: 94 mL improvement (95% CI: 65-124 mL; P < 0.001) 2
Exacerbation Reduction
- Reduced moderate or severe exacerbation rates over 24 weeks 2
- ENHANCE-1: 36% reduction (rate ratio 0.64; P = 0.050) 2
- ENHANCE-2: 43% reduction (rate ratio 0.57; P = 0.009) 2
- Increased time to first exacerbation in both trials (hazard ratios 0.62 and 0.58, respectively) 2
Symptom and Quality of Life
- Improved respiratory symptoms (Evaluating Respiratory Symptoms scale) and quality of life (St. George's Respiratory Questionnaire) in ENHANCE-1, though results were not replicated in ENHANCE-2 2
Clinical Positioning
Add-On Therapy Capability
Ensifentrine demonstrated efficacy when added to existing maintenance therapies: 2, 5
- 69% of trial participants were receiving concomitant long-acting muscarinic antagonists (LAMAs) 2
- 55% were receiving long-acting β2-agonists (LABAs) 2
- Provides additional bronchodilation beyond these standard therapies 5
Patient Population
Ensifentrine is indicated for patients with: 2
- Moderate to severe COPD (post-bronchodilator FEV1 approximately 50-52% of predicted normal)
- Ages 40-80 years
- Symptomatic disease despite current maintenance therapy
Administration and Safety
Formulation
- Nebulized formulation for inhalation 2, 4
- Designed for maintenance treatment, not acute exacerbations 4
Safety Profile
- Adverse event rates similar to placebo in Phase III trials 2
- Generally well tolerated 1, 5
- Unlike oral PDE4 inhibitors (such as roflumilast), the inhaled route may reduce systemic side effects 1
Clinical Considerations
Advantages
- First medication combining bronchodilator and anti-inflammatory effects in a single inhaled molecule 5, 4
- Can be added to LAMAs or LABAs without requiring triple therapy 5
- Reduces exacerbation risk, a key driver of COPD morbidity and mortality 2
Knowledge Gaps
- Limited data on benefit when added to inhaled corticosteroids (ICS) or triple therapy (ICS/LAMA/LABA combinations) 5
- Optimal positioning in treatment algorithms requires further clarification 5
- Long-term safety and efficacy data beyond 24 weeks are still emerging 2