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

Abstract

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.

Keywords: Anti-inflammatory drugs; Chronic obstructive pulmonary disease; Ensifentrine; PDE3 and PDE4; Phosphodiesterase inhibitors; RPL554.

Fig. 1.

Percentage increase in baseline total lung resistance following exposure to increasing doses of intravenously administered acetylcholine in male Dunkin-Hartley guinea pigs 2 h following one 15-min exposure to vehicle or ensifentrine (0.1 mg/mL; a), and 5 h following one 15-min exposure daily for 4 days to vehicle or ensifentrine (0.3 mg/mL; b) in study 4. Data are mean ± SEM. Dose-response curves were generated following non-linear regression of the % increase in baseline RL using a 3rd-order polynomial. RL, total lung resistance.

Fig. 2.

Dose-response effect of inhaled ensifentrine (0.1, 0.3, and 1 mg/mL) on lower respiratory pressure (a), nasal airway resistance (b), as well as total cell count (c), and eosinophil count (d) from nasal lavage samples of male Dunkin-Hartley guinea pigs following OVA exposure in study 5. Data are mean ± SEM, n = 5–7/group. Ensifentrine (0.1, 0.3, and 1 mg/mL) was administered by vapor inhalation for 10 min. The OVA aerosol challenge was 45 min post-inhalation. Oxygen flow rate = 300 cc/min. a, b Measured with tracheal tubes and ventilation pumps, which allowed pulsatile air to pass to the lungs (72 St/min, 10 mL/kg) and the nasal cavity (8 mL/stoke, 72 St/min). c, d Nasal lavage performed 1 h post-allergen challenge. LRP, lower respiratory tract pressure; NAR, nasal airway resistance.

Fig. 3.

Effect of inhaled ensifentrine (0.3 mg/mL) or saline on absolute total cell counts (a) and eosinophil counts (b) from BAL fluid samples of male Dunkin-Hartley guinea pigs following sham or OVA exposure in study 6. Data are mean ± SEM, n = 4–6/group. Exposure to ensifentrine (0.3 mg/mL) or saline was 15 min. BAL, bronchioalveolar lavage; OVA, ovalbumin.

Fig. 4.

Effect of inhaled ensifentrine (0.3 mg/mL) or saline on absolute eosinophil counts in blood (a) and BAL fluid (b) samples from male M. fascicularis 6 h following A. suum exposure in study 8. Data are mean ± SEM, n = 5/group. Exposure to ensifentrine (0.3 mg/mL) or saline was 10 min.