Anti-inflammatory effect of a novel inhaled dual PDE3/4 inhibitor RPL554 in man, a unique "first-in-class" drug for the treatment of COPD & asthma

Background: Current bronchodilators have limited efficacy in severe COPD & asthma & the neutrophilic inflammation is not well treated. RPL554 is a novel, well tolerated dual PDE 3/4 inhibitor with significant bronchodilator properties in COPD & asthma, bronchoprotective effects in asthmatics & is anti-inflammatory pre-clinically. Aim: To evaluate the effect of RPL554 on inhaled lipopolysaccharide (LPS)-induced neutrophilia in sputum. Methods: In a randomised, double-blind, placebo (PBO)-controlled crossover study in 21 healthy subjects, RPL554 (0.018mg/kg)was inhaled using a jet nebuliser via an oro-nasal mask o.d for 6 days. On day 6 an inhaled LPS challenge was performed 1h post RPL554 or PBO using a Mefar dosimeter. Sputum was induced 6 & 24h post-LPS & cells/g sputum calculated. Results: RPL554 statistically significantly reduced total & individual cells, 6h post LPS vs PBO (Table 1). RPL554 was well-tolerated with AE’s being generally mild, transient & not different from PBO. RPL554’s PK properties were reproducible over 6 days. Table 1. Cells/g sputum Cells (x10 6 /g sputum) RPL554 PBO p value Neutrophils 6.81 11.38 0.002 Macrophages 1.16 1.58 0.044 Eosinophils 0.014 0.025 0.001 Lymphocytes 0.014 0.042 0.001 Bronchial cells 0.110 0.095 0.622 Total cells 8.66 13.57 0.002 Conclusions: RPL554 produced significant airway anti-inflammatory effects, including reducing neutrophil infiltration & is the first drug demonstrating bronchodilator & anti-inflammatory properties in one molecule. RPL554 is thus a promising “bifunctional” first in class treatment for patients with COPD or asthma and not well controlled on existing treatment.