Anti-Inflammatory Activity of Ensifentrine: A Novel, Selective Dual Inhibitor of Phosphodiesterase 3 and Phosphodiesterase 4

Ensifentrine is a novel, low-molecular-weight molecule that is a selective, dual inhibitor of phosphodiesterase (PDE)3 and PDE4. Inhibition of PDE3 has been shown to relax airway smooth muscle and inhibition of PDE4 to inhibit inflammatory responses and to stimulate the cystic fibrosis transmembrane conductance regulator in human airway epithelial cells through accumulation of intracellular cyclic adenosine monophosphate. Additionally, the dual inhibition of PDE3 and PDE4 demonstrates enhanced or synergistic effects compared with inhibition of either PDE3 or PDE4 alone on contraction of airway smooth muscle and suppression of inflammatory responses. Ensifentrine inhalation suspension 3 mg was recently approved in the USA for the maintenance treatment of chronic obstructive pulmonary disease in adult patients and is marketed under the trade name Ohtuvayre™. This manuscript describes further evidence that ensifentrine is a selective dual inhibitor of both human PDE3 and PDE4 enzymes and that this drug has significant anti-inflammatory activity in vivo in both allergic guinea pigs and non-human primates. This dual bronchodilator and anti-inflammatory activity of ensifentrine makes it a promising strategy as a novel inhaled "bifunctional" drug for the treatment of obstructive and inflammatory diseases of the respiratory tract. .