Ensifentrine: A First-in-class Bifunctional Drug for the Treatment of Chronic Obstructive Pulmonary Disease

Abstract

Ensifentrine is an inhaled ‘bifunctional’ dual phosphodiesterase 3/4 inhibitor that exhibits both bronchodilator and anti-inflammatory activities. Preclinical research has shown that ensifentrine can induce significant relaxation of human bronchi in vitro and suggested the possibility of a synergistic interaction between ensifentrine and β2-adrenoceptor agonists and, mainly, muscarinic receptor antagonists. Ensifentrine is the only dual phosphodiesterase 3/4 inhibitor under clinical development for the treatment of chronic obstructive pulmonary disease (COPD). It has been shown to induce bronchodilation, with a peak bronchodilator effect in patients with COPD similar to that seen after salbutamol administration, and anti-inflammatory activity in healthy individuals. Combined with standard bronchodilators (salbutamol, ipratropium or tiotropium), ensifentrine causes additional bronchodilation and, importantly, a significant reduction in hyperinflation in patients with stable moderate to severe COPD. A recent statement on the top-line phase III ENHANCE-2 study reported that ensifentrine induced significant bronchodilation and reduced the risk of moderate-to-severe COPD exacerbations in study participants. Ensifentrine continues to show promise as a novel drug for treating patients with COPD. Nevertheless, it is necessary to understand whether ensifentrine will be able to replace or reduce the use of currently available classes of bronchodilators, and/or whether it will be a valuable add-on therapy to the current standard of care to further optimize bronchodilation. Furthermore, it will be critical to clarify the anti-inflammatory profile of ensifentrine.