Verona Pharma recently announced positive top-line results from a Phase 2a dose-finding clinical trial using its novel lead drug nebulized formulation of RPL554, a first-in-class inhaled drug under development for chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis.
RPL554 is an inhibitor of the phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4), two enzymes known to be of importance in the development and progression of immunological respiratory diseases. The drug has the potential to act as both a bronchodilator and an anti-inflammatory, which would make it significantly different from existing drugs. RPL554 is being developed as a nebulized treatment for acute exacerbations in patients with chronic obstructive pulmonary disorder (COPD) in a hospital or home-care setting.
In the double-blind, randomised, placebo-controlled, seven way crossover Phase 2a clinical trial, 29 patients with mild to moderate persistent asthma received four doses of nebulized RPL554 (0.4 to 24 mg), two doses of nebulised salbutamol (2.5 mg and 7.5 mg), or a placebo.
The trial met its primary endpoint, showing treatment with nebulized RPL554 demonstrated a dose-dependent bronchodilator response in patients with asthma. The pharmacokinetics of RPL554 were linear across the entire dose range. At the highest doses of both drugs, RPL554 produced the same maximum bronchodilator effect as salbutamol.
Even the lowest dose of RPL554 (0.4 mg) was found to be statistically significantly superior to the placebo as a bronchodilator. All doses of RPL554 were well tolerated. Therefore, the results support the use of RPL554 in a twice-daily regimen.
There were no major cardiovascular or gastrointestinal adverse events. There were fewer adverse events with RPL554 compared with salbutamol. Treatment with salbutamol caused tremor, tachycardia, palpitations, and a reduction in blood potassium levels. The large dosing range (60 fold) of RPL554 suggests a potentially large therapeutic index.
Verona Pharma, based in Cardiff in the United Kingdom, expects to report top-line data of the Phase 2 trial examining nebulized RPL554 as an add-on treatment to standard bronchodilators in the second quarter of 2016
“We are very excited by the results from our dose-finding study for RPL554,” Dr. Jan-Anders Karlsson, the CEO of Verona Pharma, said in a press release. “It is very pleasing that the maximum bronchodilator effect of RPL554 is comparable to that seen with the highest dose of salbutamol used in the study — a dose equivalent to the highest dose of salbutamol used to treat acute exacerbations of COPD in the emergency department. It is noteworthy that this was achieved with fewer adverse events.
“The data generated in this study emphasises its pronounced bronchodilator effect, and combined with its unique anti-inflammatory effects, we continue to believe that RPL554 could be an important and much-needed new treatment option, either alone or as an add-on to existing drugs for patients with COPD,” Karlsson said.
“This well-designed and successfully executed dose-ranging study of nebulized RPL554 in moderate asthmatics demonstrated the drug has a linear and thus predictable pharmacokinetic profile, and produced similar bronchodilation but with less side effects compared to a very high dose of salbutamol, used as a comparator,” said Prof. Leif Bjermer of Skane University in Lund, Sweden, lead investigator on this study.
The reported data will help inform dose selection in the Phase 2b trial, expected to begin in early 2017. In 2014, the nebulizer bronchodilator market was worth about $1 billion in the United States.
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