Bronchodilator effect of a novel inhaled dual PDE3/4 inhibitor, RPL554, in mild allergic asthma & rhinitis

Background: RPL554 is a novel inhaled dual phosphodiesterase (PDE) 3 & 4 inhibitor with long-acting bronchodilator & anti-inflammatory effects in preclinical models. Aims and Objectives: To evaluate RPL554 safety & efficacy in mild allergic asthma & rhinitis. Methods: In 2 randomised, double-blind, placebo-controlled, crossover trials, 10 mild allergic asthmatics (M; 20-50y; FEV1: 82-112%prd; PC20Mch: 0.07-1.49mg/mL; SABA prn only) and 10 allergic rhinitics (M; 19-44y; 6 with co-existing asthma; FEV1: 83-128%prd) were studied. In asthmatics, a methacholine challenge (PC20Mch) was done 1h from nebulisation start to assess bronchoprotection. Using a jet nebuliser, RPL554 0.018mg/kg was inhaled 10min via an oro-nasal mask. Standard safety & pharmacokinetic measurements were at predetermined times from nebulisation start with spirometry at pre-dose & regularly for 24h. Bronchodilation was assessed by FEV1 changes. Results: RPL554 was well-tolerated. Adverse events were mild, transient & generally of equal frequency in RPL554 & placebo groups with no significant changes in heart rate or systemic blood pressure noted. In asthmatics, RPL554 produced rapid, sustained bronchodilation, with a mean maximal FEV1 increase of 520mL (95%CI: 320-720mL; p<0.0001) or 15% increase from baseline vs. placebo. It also increased PC20MCh by mean 1.5 doubling doses (95%CI: 0.63– 2.3; p=0.004). In rhinitics, a maximal bronchodilator response occurred between 30min & 3h with a mean maximal FEV1 increase of 300mL or 7.5% increase (95%CI: 90-310mL; p=0.004). Conclusions: RPL554 produced safe, rapid, long-lasting bronchodilation in mild allergic asthmatics & rhinitics, with bronchoprotection in asthmatics.