Drug Offers Novel Approach for Airway Diseases

For patients with asthma or chronic obstructive pulmonary disease (COPD), a new dual-acting drug called RPL554 has the potential to both reverse bronchodilation and reduce inflammation more quickly and with fewer adverse effects than current therapies, according to the results of a new study.

“RPL554 should be considered a substantial advance in the management of patients with chronic airways obstruction as it is the only new class of bronchodilator drug for several decades and the only bronchodilator that is also an anti-inflammatory drug at the same dose,” study leader Clive Page, who is Professor of Pharmacology and Director of the Sackler Institute of Pulmonary Pharmacology at King’s College London, United Kingdom, told ConsultantLive.

The unique inhaled dual inhibitor works by impeding the ability of 2 enzymes from the phosphodiesterase family, PDE3 and PDE4. It inhibits processes that help relax airway smooth muscle and reduce inflammation.

Between February 2009 and January 2013, 4 small proof-of-concept clinical trials in the Netherlands, Italy, and the United Kingdom assessed the safety and efficacy of inhaled RPL554 in 39 healthy patients and 40 patients who had mild to moderate airway diseases (asthma, 28; COPD, 12).

In the patients with COPD, a single dose of nebulized RPL554 improved respiratory function, producing a 17% increase in forced expiratory volume in 1 second, a bronchodilator response at least as effective as that of the widely use β₂-agonist Salbutamol, said Professor Page.

In patients with asthma or COPD, there was rapid bronchodilation, with peak effects similar to those produced with inhaled β₂-agonists. The bronchodilator effects were maintained with repeated dosing for 6 days in patients with asthma.

In addition, bacterial lipopolysaccharide-induced neutrophilia was inhibited by RPL554 in the healthy patients, demonstrating the anti-inflammatory actions of this drug. Overall, RPL554 was well tolerated and patients in the treatment and placebo groups experienced similar rates of adverse events, which were generally mild, Professor Page said.

“Although other PDE4 inhibitors can cause gastrointestinal side effects when given orally, none were reported at any dose of RPL554 tested in these trials,” he noted.

"These studies give us a glimpse into the potential bronchodilator, bronchoprotective, and anti-inflammatory effects of this drug,” Professor Page stated. “So far, trials have run for 7 days or less and there is a need to look at longer-lasting effects. Further studies are needed to better understand the full potential of this new therapy for COPD and asthma.” He said plans are in the works for several studies to investigate the ability of RPL554 to provide additional clinical benefit on top of existing therapy in patients with COPD.

“In the longer term we plan a new dry powder formulation of RPL554 for twice-daily maintenance therapy for outpatient use to treat patients with asthma or COPD,” said Professor Page. “This could be a new approach to treating patients with asthma or COPD as an alternative to current combination inhalers that contain long-acting β-agonists and inhaled corticosteroids, although further work is required to demonstrate the optimal place of this new drug.”

The researchers published their results in the October 25, 2013, issue of The Lancet Respiratory Medicine.