The Future of New Inhaled Phosphodiesterase Inhibitors in Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is characterized by progressive, partially reversible airflow obstruction, chronic inflammation, airway remodeling, and excessive mucus production, which lead to daily symptoms and exacerbations affecting quality of life.¹ The same classes of therapy have formed COPD standard-of-care treatments for over 40 years and continue to do so. These include inhaled short- and long-acting bronchodilators (i.e., muscarinic antagonists [LAMA] and β2-agonists [LABA]) and inhaled corticosteroids (ICS).

Despite the use of combinations of dual and triple therapies within these classes, some COPD patients remain symptomatic.^2,3 An analysis of a phase III triple therapy registration study showed that up to 48% patients continue to exacerbate during their first year on triple therapy.³ COPD patients have a broad spectrum of clinical, physiological and biological features that vary significantly among individuals and evolve over time.⁴ There is, therefore, a need for novel treatments that provide additional bronchodilation, anti-inflammatory effects, reduce symptom burden, and prevent COPD exacerbations, along with a favorable safety profile.^5,6 Over the years, extensive research has pursued other classes of anti-inflammatory therapies for COPD. Phosphodiesterase-4 (PDE4) inhibitors have shown promise in the treatment of COPD. Roflumilast, which reduces neutrophilic inflammation, and dual PDE3/4 inhibitors, such as ensifentrine, which offer combined anti-inflammatory and bronchodilator properties, have shown positive clinical trial results.¹ Roflumilast is approved as an add-on therapy to reduce exacerbations in COPD patients with severe lung disease and frequent exacerbations.^7–9 The major limitations of oral roflumilast are side effects, mainly weight loss, nausea, vomiting and diarrhea, and psychiatric disorders.^8,9

Other PDE4 inhibitors, such as inhaled tanimilast, show potentially better tolerance than roflumilast.¹⁰ However, after full analysis of the Phase 3 PILASTER Main Cohort study in COPD, tanimilast did not meet its primary or key secondary endpoints, so Chiesi announced its decision to conclude all clinical trials in COPD and asthma with this product, although no safety concerns were identified.¹¹

Ensifentrine represents an improvement over the current PDE roflumilast, as it inhibits both PDE3 and PDE4. These 2 critical enzymes are key drivers of airway constriction and inflammation in COPD¹²: PDE3 regulates cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate in airway smooth muscle, which mediates bronchial tone¹³; PDE4 regulates cAMP and is involved in inflammatory cell activation and migration and cystic fibrosis transmembrane conductance regulator (CFTR) stimulation in bronchial epithelial cells.¹² Dual inhibition of PDE3 and PDE4 has shown enhanced or synergistic effects on airway smooth muscle contraction and inflammatory response suppression compared with inhibition of either PDE3 or PDE4 alone.^12,13 This dual mechanism of action is a promising strategy for treating obstructive and inflammatory diseases, including COPD, cystic fibrosis, and asthma.

Two Phase 3 trials with twice-daily nebulized ensifentrine demonstrated improvements in lung function, COPD symptoms, and quality of life,¹⁴ along with a reduction of airway inflammatory cells. ENHANCE (Ensifentrine as a Novel inhAled Nebulized COPD thErapy)-1 studied nebulized twice-daily ensifentrine 3 mg evaluated over 24 weeks (with 48-week safety subset); ENHANCE-2 also included patients with moderate to severe COPD.¹⁴ The overall ENHANCE program provided evidence supporting the efficacy and safety of ensifentrine in symptomatic moderate to severe COPD consistent with GOLD Group B, also when added to LAMA, LABA and LABA/ICS as current standard of care. Ensifentrine significantly improved lung function, as measured by forced expiratory volume in 1 second (FEV₁) and area under the curve compared to placebo. Specifically, ENHANCE-1 showed a mean increase in FEV₁ of 87 mL (95% CI 55–119 mL; p < 0.001); in ENHANCE-2, the mean FEV₁ increase was 94 mL (95% CI 65–124 mL; p < 0.001).¹⁴ These FEV₁ improvements persisted beyond week 12, indicating sustained improvement in lung function (28). Quality of life was measured using the St. George's Respiratory Questionnaire, which showed significant improvement in ENHANCE-1; however, ENHANCE-2 responses were not statistically significant.¹⁴ Patients also evaluated their respiratory symptoms using the transition dyspnea index. In a cohort of non-exacerbators, ensifentrine showed a 40% reduction in exacerbations compared to placebo; the ratio was 0.64 (95% CI 0.40–1.00; p = 0.050) in ENHANCE-1 and 0.57 (95% CI 0.38–0.87; p = 0.009) in ENHANCE-2¹⁴ (Fig. 1). Furthermore, there was a longer delay before the first exacerbation, and these benefits were consistent across subgroups with variable demographics, disease severity, and COPD treatment regimens. AE rates were similar in the ensifentrine and placebo groups. There were no trends or differences in incidence or type of adverse events between patients treated with ensifentrine and placebo, including pneumonia. Gastrointestinal disorders, frequently seen with oral PDE4 inhibitors within 4 weeks of starting treatment, were low and similar in both treatment groups.^14,15

Fig. 1.

Proportion of patients experiencing moderate-to-severe COPD exacerbations over a 24-week period in the ENHANCE-1 and ENHANCE-2 trials. The reduction in exacerbation rate was statistically significant (p = 0.050 for ENHANCE-1; p = 0.009 for ENHANCE-2).¹⁴.

Overall, ensifentrine represents a new approach to COPD management. It has both bronchodilator and anti-inflammatory actions, is well tolerated, and offers an option for patients who are not adequately controlled with existing therapies. For clinicians treating COPD, especially in patients who fail to respond to current inhaled therapies, ensifentrine can provide an additional improvement in lung function and decrease the risk of exacerbations. Further studies are needed to demonstrate the efficacy of ensifentrine in patients on triple therapy who continue to experience exacerbations and to provide data on its effects on mucus production.

Artificial intelligence involvement

No.

Authors’ contributions

N/A.

Funding

There is no funding involved for this manuscript.

Conflicts of interest

The author is a consultant for Verona Pharmaceutical.