Phosphodiesterase Inhibition as a Therapeutic Strategy for Chronic Obstructive Pulmonary Disease: Where We Have Been and What Lies Ahead

Chronic obstructive pulmonary disease (COPD) is a highly prevalent inflammatory lung condition characterized by chronic respiratory symptoms and airflow obstruction that often lead to diminished quality of life. Non-pharmacologic management for patients with COPD involves smoking cessation and healthy lifestyle changes. Pharmacologic treatments include inhaled bronchodilators with or without the use of inhaled corticosteroids, which can be administered through inhalation or nebulization. In addition, oral medications including macrolide antibiotics and phosphodiesterase (PDE) 4 inhibitors can help reduce exacerbation risk. However, many of these medications provide suboptimal disease control, owing to limited efficacy, increased risk of adverse events with long-term use, or difficulty in administration technique. PDE3 plays an important role in maintaining smooth muscle function, and PDE4 plays a crucial role in the inflammatory response in airway smooth muscle. Direct molecular inhibition of PDE3 or PDE4 has been shown to provide benefit in COPD. Dual PDE3 and PDE4 inhibition may therefore have synergistic anti-inflammatory and bronchodilator effects. These results have been observed in clinical trials of nebulized ensifentrine, a novel, dual-action PDE3 and PDE4 inhibitor that is the first in its class to be approved by the US Food and Drug Administration for maintenance treatment of COPD in adult patients. In this review, we explore the pathophysiologic mechanisms of COPD, describe current paradigms and methods of drug delivery for the treatment of the disease, and illustrate how dual inhibition of PDE3 and PDE4 may provide additional benefit to current standard-of-care regimens.