Dual PDE3/PDE4 inhibitor may be effective treatment for asthma and COPD

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1. RPL554, a dual PDE3/PDE4 inhibitor, showed significant bronchodilator effects in patients with asthma and COPD. 

2. RPL554 demonstrated anti-inflammatory activity as measured by sputum neutrophil content. 

Evidence Rating Level: 2 (Good)            

Study Rundown: Four exploratory clinical trials were conducted to evaluate the safety and efficacy of RPL554, a dual phosphodiesterase (PDE) 3 and PDE 4 inhibitor, for the treatment of asthma and COPD. Prior research has shown that PDE3 inhibition results in bronchodilation, whereas PDE4 inhibitors exert an anti-inflammatory effect. In this study, nebulized RPL554 demonstrated efficacy as a bronchodilator in COPD and asthma patients. It also reduced inflammation in healthy patients exposed to lipopolysaccharide (LPS) challenge. RPL554 was well tolerated with side effects similar to those reported with placebo. This is contrast to other PDE inhibitors, such as oral roflumilast, which often cause significant gastrointestinal symptoms.

These preliminary results are encouraging; new treatments for asthma and COPD are needed as many patients have suboptimal outcomes with existing bronchodilators (e.g. b2-agonists and anti-muscarinics) and anti-inflammatory agents (e.g. corticosteroids). Future research will be needed to confirm findings in a larger study population and to assess efficacy and side effects with prolonged treatment; subjects in the current study received a maximum of 6 repeated daily doses of RPL554.  Another limitation is that not all trials were double-blinded, with the COPD study being open-label. Importantly, other PDE inhibitors have cardiovascular effects (e.g. increased inotropy). While RPL554 did not appear to impact cardiac function, careful examination of potential adverse effects will be required in subsequent studies.

Click to read the study in The Lancet

Click to read an accompanying comment in The Lancet

Relevant Reading: Dual PDE3/4 inhibitors as therapeutic agents for chronic obstructive pulmonary disease

Study author, Dr. Clive Page, King’s College London, UK, talks to 2 Minute Medicine:

“Although other PDE4 inhibitors can cause gastrointestinal side effects when given orally, none were reported at any dose of RPL554 tested in these trials. These studies give us a glimpse into the potential bronchodilator, bronchoprotective, and anti-inflammatory effects of this drug. 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.”

In-Depth [randomized controlled trial]: Four proof-of-concept clinical trials were performed to study the safety and efficacy of RPL554; overall, 39 healthy patients, 28 allergic asthmatics, and 12 patients with COPD were studied. Patients received either nebulized RPL554 in a citrate phosphate buffer or placebo (citrate phosphate buffer alone). Bronchodilator efficacy was assessed by measuring change from baseline FEV1. Study 1 examined safety and efficacy in healthy subjects and allergic asthmatics. Study 2 assessed for tachyphylaxis of bronchodilator effects after 6 daily doses. Study 3 investigated safety and efficacy in patients with COPD. Study 4, which involved healthy subjects, assessed the anti-inflammatory effect of RPL554 on LPS-induced inflammatory cell recruitment to airways, as measured by sputum neutrophil content.

In each of the studies, nebulized RPL554 was well tolerated and side effects were similar to those experienced in the placebo-treated group. Maximum increases in FEV1 were seen approximately one hour after RPL554 administration. In allergic asthma, the increase in FEV1 at one hour was 520 mL greater with RPL554 than placebo (95% CI 320-720, p<0.0001). RPL554 continued to be effective after 6 days of daily administration. In COPD patients, the increase in FEV1 was 194 mL greater with RPL554 than placebo (95% CI 104-284, p<0.0001). RPL554 did not significantly reduce the percentage of neutrophils found in sputum 6 h after LPS challenge (80.3% in RPL554 group vs. 84.2% in placebo group, p=0.15). However, the absolute numbers of sputum neutrophils were reduced in the RPL554 group (6.81 x 106cells per gram sputum vs. 13.57 x 106 cells per gram sputum in placebo group, p=0.002), as were the absolute numbers of other immune cells (i.e. macrophages, eosinophils, and lymphocytes).

By Hayley Walker and Mimmie Kwong

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