What is Ensifetrine?

What is Ensifentrine?

Ensifentrine is a novel, first-in-class inhaled dual phosphodiesterase (PDE) 3 and 4 inhibitor approved for maintenance treatment of chronic obstructive pulmonary disease (COPD) that provides both bronchodilation and anti-inflammatory effects through nebulized administration. 1, 2

Mechanism of Action

Ensifentrine works through selective dual inhibition of two distinct enzyme pathways 2:

• PDE3 inhibition produces bronchodilation by relaxing airway smooth muscle, similar to how milrinone works in heart failure 3, 2
• PDE4 inhibition reduces airway inflammation by decreasing inflammatory mediator release from immune cells 2
• Combined effect on ciliary function improves mucociliary clearance in bronchial epithelia, helping patients clear secretions more effectively 2

This dual mechanism distinguishes ensifentrine from single-target bronchodilators like LABAs (which only target β2-receptors) or LAMAs (which only block muscarinic receptors). 2

Clinical Efficacy

Lung Function Improvements

The pivotal ENHANCE-1 and ENHANCE-2 Phase III trials demonstrated consistent bronchodilation 4:

• FEV1 improvement of 87-94 mL versus placebo at 12 hours post-dose (both trials P < 0.001) 4
• Trough FEV1 increased by approximately 41 mL at week 12, indicating sustained bronchodilation between doses 5
• These improvements occurred in patients with moderate to severe COPD (baseline FEV1 51-52% predicted) 4

Symptom and Quality of Life Benefits

Ensifentrine demonstrated early and progressive symptom relief 1, 4:

• Breathlessness improved from Week 2 onwards across all doses tested (P < 0.05), with the greatest effect on the dyspnea component of symptoms 1
• Transition Dyspnea Index scores increased by 0.96 points at 24 weeks, indicating meaningful improvement in breathlessness 5
• E-RS:COPD total scores decreased by 0.81 points at 24 weeks, reflecting overall symptom reduction 5
• The respiratory symptoms domain of quality of life showed the most pronounced improvement, though total SGRQ-C scores showed variable results between trials 1, 4

Exacerbation Reduction

A critical finding was ensifentrine's impact on disease stability 4, 6:

• 43-48% reduction in moderate or severe exacerbation rates across both ENHANCE trials (rate ratios 0.57-0.64, P ≤ 0.050) 4
• 38-42% reduction in time to first exacerbation (hazard ratios 0.58-0.62, P ≤ 0.038) 4
• These benefits occurred even when added to existing LAMA or LABA+ICS therapy, suggesting complementary mechanisms 6

Administration and Dosing

Ensifentrine 3 mg is administered twice daily via standard jet nebulizer over approximately 5-7 minutes 4, 6:

• The nebulized route ensures direct delivery to airways with minimal systemic exposure 2
• Doses ranging from 0.75-6 mg were studied, with 3 mg selected for Phase III trials based on optimal efficacy-to-tolerability ratio 1, 2
• Higher doses (6 mg) showed numerically greater effects but were not pursued in pivotal trials 1

Use with Existing COPD Therapies

Ensifentrine can be added to current maintenance treatments without dose adjustments 4, 6:

• In ENHANCE trials, 69% of patients were on concomitant LAMAs and 55% on LABAs, demonstrating compatibility with standard care 4
• Subgroup analysis showed consistent lung function improvements when added to LAMA (92 mL FEV1 increase) or LABA+ICS (74 mL increase) 6
• Exacerbation reductions were similar whether added to LAMA (48% reduction) or LABA+ICS (51% reduction) 6

This represents a distinct advantage over oral PDE4 inhibitors like roflumilast, which have significant systemic side effects and are typically reserved for severe COPD with frequent exacerbations. 2

Safety Profile

Ensifentrine demonstrated a favorable safety profile comparable to placebo 4, 6:

• Adverse event rates were similar between ensifentrine and placebo groups across all trials 4
• Unlike oral PDE4 inhibitors, ensifentrine did not show the typical class effects of nausea, diarrhea, or weight loss that limit tolerability of systemic PDE4 inhibition 2, 4
• The inhaled route minimizes systemic exposure while maximizing local airway effects 2

Important Safety Distinction

The FDA drug label information provided in the evidence 7 refers to isoniazid (INH), an antituberculosis medication, not ensifentrine. This appears to be a database error. Ensifentrine has no relation to tuberculosis treatment and does not carry the hepatotoxicity warnings or contraindications associated with isoniazid. 2, 4

Patient Population

Ensifentrine is indicated for patients with moderate to severe COPD who remain symptomatic 4, 5:

• Appropriate for patients aged 40-80 years with post-bronchodilator FEV1 40-80% predicted 1, 4
• Particularly beneficial for patients experiencing persistent dyspnea despite LAMA or LABA+ICS therapy 6
• Can be considered for patients with recurrent exacerbations requiring additional preventive therapy 4

Clinical Positioning

Ensifentrine fills a therapeutic gap by providing a non-steroidal anti-inflammatory option with bronchodilator effects that can be added to existing inhaled therapies 6, 5:

• Unlike inhaled corticosteroids, it provides anti-inflammatory effects without steroid-related risks (pneumonia, oral candidiasis, bone density loss) 6
• Unlike oral PDE4 inhibitors, it avoids gastrointestinal side effects through targeted pulmonary delivery 2
• The nebulized delivery may benefit patients with poor inhaler technique or those already using nebulizers for other medications 2

Evidence Quality

The evidence base for ensifentrine consists of two large, well-designed Phase III trials (ENHANCE-1 and ENHANCE-2) with 1,549 patients, supported by earlier Phase II dose-ranging studies 1, 4. The consistency of results across both pivotal trials, particularly for lung function and exacerbation outcomes, provides high-quality evidence for its efficacy. 4, 5