A New Treatment for Chronic Obstructive Pulmonary Disease: Ensifentrine Moves Closer

Chronic obstructive pulmonary disease (COPD) pharmacological therapy has advanced in recent years. Combining long-acting bronchodilators and inhaled corticosteroids (ICSs) as a single-inhaler triple therapy reduces mortality in patients with COPD at high exacerbation risk (1, 2). Blood eosinophil counts are now a biomarker that facilitates the prediction of ICS therapeutic efficacy (3). Despite these advances, we are limited to the same classes of drugs that have been around for decades. Although drugs with different mechanisms are needed, COPD drug development has been a graveyard for novel molecules.

Phosphodiesterase (PDE) inhibitors prevent the breakdown of the second messenger cAMP (4). Roflumilast is an orally administered PDE4 inhibitor with anti-inflammatory activity that reduces exacerbation rates in patients with COPD with a history of exacerbations plus chronic bronchitis (4, 5). However, roflumilast is not widely used because systemic exposure frequently causes intolerable adverse effects, notably weight loss and gastrointestinal disturbance (4, 5). To reduce systemic exposure, inhaled PDE inhibitors were developed (4). Ensifentrine is a PDE3 and PDE4 inhibitor with a greater potency for the former enzyme in vitro that is delivered by a nebulizer (4, 6, 7). PDE3 inhibition relaxes smooth muscle (4, 7), and early-phase clinical trials demonstrated acute bronchodilation with ensifentrine (6, 8). A novel bronchodilator mechanism of action in COPD had arrived.

Early clinical trials of short duration dissected the bronchodilator properties of ensifentrine. The peak effect of a single dose of ensifentrine was similar to that of salbutamol: a >200-ml increase in FEV₁ (8). PDE inhibitors prevent cAMP breakdown, whereas β-agonists increase cAMP formation, and combining ensifentrine with salbutamol produced additional benefit despite both drugs targeting cAMP, albeit by different mechanisms (4, 7, 8). Ensifentrine added to a long-acting muscarinic antagonist (LAMA) caused a >100-ml peak FEV₁ improvement versus LAMA monotherapy (8, 9), with better quality of life over 4 weeks measured by the St. George’s Respiratory Questionnaire (9). These early studies showed encouraging efficacy for ensifentrine, including when added to a LAMA, and identified 3 mg twice daily as the optimal dose (8–10).

In this issue of the Journal, Anzueto and colleagues (pp. 406–416) report the ENHANCE-1 and -2 (Ensifentrine as a Novel inhAled Nebulized COPD therapy) phase III studies, which have similar designs, each enrolling more than 750 patients with moderate to severe COPD and focusing on lung function and symptoms over a period of 24 weeks (11). Individuals with greater dyspnea at screening were recruited, requiring a modified medical research council score ⩾2. Long-acting bronchodilator monotherapy with or without ICSs was allowed, but the use of two long-acting bronchodilators or triple therapy was not permitted. Participants were randomized to receive ensifentrine 3 mg or placebo twice daily. For the primary endpoint at week 12, ensifentrine significantly improved average FEV₁ during the 12 hours after the dose compared with placebo, with mean differences of 87 and 94 ml in ENHANCE-1 and -2, respectively (P < 0.001). There were significant treatment differences for peak FEV₁ improvements (approximately 147 ml) and trough FEV₁ (measured pre-dose; 35 and 49 ml; P < 0.05), demonstrating a small residual lung function benefit. These positive lung function effects confirmed the bronchodilator effects of ensifentrine. The key question is whether participants experienced symptomatic benefit.

The St. George’s Respiratory Questionnaire score at week 24 showed a significant improvement with ensifentrine versus placebo in ENHANCE-1 (2.3 units) but not in ENHANCE-2, possibly due to a notable placebo response. Both studies showed significant treatment differences in favor of ensifentrine using the transition dyspnea index, reaching clinically meaningful levels (0.9–1.0; P < 0.001) (12). The inclusion enrichment with more breathless patients is important here, enabling the transition dyspnea index to demonstrate the relief of breathlessness associated with bronchodilation across both studies.

COPD clinical trials with exacerbations as the primary outcome usually enroll individuals with increased exacerbation risk (based on exacerbation history) and are ⩾1 year in duration to capture seasonal effects (1, 2). The ENHANCE populations were not enriched for exacerbation risk, with <30% reporting an exacerbation in the 15 months before screening, resulting in a relatively low annualized placebo exacerbation rate in both studies (approximately 0.42 per year). Nevertheless, ensifentrine significantly reduced exacerbation rates at 24 weeks by 36% and 43% in ENHANCE-1 and -2, respectively. These results should not be directly compared with clinical trials in cohorts at high exacerbation risk (1, 2). Nevertheless, long-acting bronchodilators can prevent COPD exacerbations (13, 14), and the ensifentrine effects on exacerbation prevention are compatible with long-acting bronchodilation. An unanswerable question is whether PDE4-related anti-inflammatory activity also contributed. There is currently no conclusive evidence that ensifentrine has anti-inflammatory effects in COPD. An inhaled lipopolysaccharide challenge provoking neutrophilic airway inflammation in healthy subjects showed a broad anti-inflammatory effect on sputum cell counts (6). However, whether this model resembles COPD or COPD exacerbations is open to debate. Perhaps debating the mechanism is an academic exercise, and the observed clinical benefit demonstrated in the ENHANCE studies is all we need to know.

The ENHANCE studies did not reveal cardiac safety issues or tolerability issues noted with oral PDE4 inhibitors (4, 5). Just more than half of the ENHANCE participants used maintenance inhaled treatment, with LAMA monotherapy and ICS/long-acting β-agonist combination being the most common. The clinical benefits of ensifentrine in maintenance treatment subgroups were similar to those in the main analysis. Although this supports the use of ensifentrine added to these treatments in clinical practice, it is not clear how this would compare with the use of a dual bronchodilator or triple therapy instead. Without this information, it is difficult to know how to position ensifentrine among the currently available combination inhaled treatment options.

Similarly, ensifentrine administered in addition to dual bronchodilators or triple treatment was not investigated in the ENHANCE studies. Why not? The combination of three bronchodilator mechanisms needs careful evaluation, which was beyond the scope of the ENHANCE studies but should now be high on the agenda.

The findings of the ENHANCE studies are almost overwhelmingly positive, showing that ensifentrine provides bronchodilation associated with meaningful clinical benefits. Hopefully, regulators will approve. Despite these impressive results, the discussion will quickly move to questions and comparisons that the ENHANCE trials did not investigate. For now, the authors and investigators should be congratulated on bringing this unique molecule closer to patients.