Anti-inflammatory effects of PDE3/4 inhibitor ensifentrine in peripheral blood mononuclear cells from COPD patients

Ensifentrine is a dual PDE3/4 inhibitor designed for inhaled administration. Clinical trials in COPD patients have shown improvements in lung function and symptoms with ensifentrine. Ensifentrine has shown anti-inflammatory effects in various models, but the effects in cells from COPD patients have not been studied. Peripheral blood mononuclear cells (PBMCs) from COPD patients (N=8) and HNS (N=8) were treated with ensifentrine, the corticosteroid dexamethasone or PDE4 inhibitors roflumilast and GSK256066 (all compounds 0.00001-1µM) for 1h prior to 24h stimulation with LPS (1ug/ml). Supernatants levels of TNFα were measured by ELISA. Dose response curves were used to generate IC₅₀ and maximal inhibitory effect data. All compounds decreased LPS induced TNFα in a concentration dependent manner in PBMCs from HNS and COPD patients (p<0.05) and there were no differences in maximal inhibition between compounds (Table 1). IC₅₀ values for ensifentrine were greater in both HNS and COPD PBMCs compared to all other compounds (Table 1). <bold>Table 1</bold> <table-wrap><object-id>erj;64/suppl_68/OA2775/TB1</object-id><object-id>T1</object-id><object-id>TB1</object-id><table><colgroup><col></col><col></col><col></col></colgroup><tbody><tr><td>Drug</td><td>IC₅₀ (nM)</td><td>Maximal effect (% inhibition at 1µM)</td></tr><tr><td></td><td>HNS</td><td>COPD</td><td>HNS</td><td>COPD</td></tr><tr><td>Ensifentrine</td><td>36</td><td>8.8</td><td>74.9</td><td>76.0</td></tr><tr><td>Dexamethasone</td><td>2</td><td>0.58</td><td>71.4</td><td>82.3</td></tr><tr><td>Roflumilast</td><td>2.2</td><td>2.2</td><td>73.4</td><td>79.9</td></tr><tr><td>GSK256066</td><td>6.8x10⁻³</td><td>6.6x10⁻³</td><td>80.3</td><td>79.5</td></tr></tbody></table></table-wrap> Ensifentrine demonstrated anti-inflammatory effects in COPD PBMCs. The maximal effects were similar to corticosteroids and other PDE4 inhibitors, while there were potency differences (IC₅₀) between compounds. These findings support potential anti-inflammatory effects of ensifentrine in COPD.