Verona Pharma unveils positive results from RPL554 dose-finding study

RPL554 is a novel inhaled PDE3/PDE4 inhibitor with both bronchodilator and anti-inflammatory properties in the same molecule, currently in development as a nebulised treatment for acute exacerbations in chronic obstructive pulmonary disorder (COPD) patients in a hospital or home-care setting.

Such patients typically require additional bronchodilation as well as anti-inflammatory treatment despite being on maximum doses of approved COPD medications (which often contain salbutamol).

Highlights

Primary objective of study met

Nebulised RPL554 demonstrated a dose-dependent bronchodilator response in asthma patients; the response was highly statistically significant (p<0.0001) at all doses tested1

The maximum bronchodilator effect of RPL554 in this study was comparable to the effect observed with the supramaximal dose (7.5mg) of nebulised salbutamol used in this study2

RPL554 did not elicit any serious adverse events or adverse events of concern at any dose

Large dose range (0.4 to 24mg) examined; suggests RPL554 potentially has a very large safety margin

Fewer adverse events recorded with RPL554 than with nebulised salbutamol

No gastro-intestinal adverse events or cardiovascular events of concern

We continue to expect a Phase II clinical study examining nebulised RPL554 as an add-on treatment to standard bronchodilators to report top-line data in Q2 2016

Dr Jan-Anders Karlsson, the CEO of Verona Pharma, said: "We are very excited by the results from our dose-finding study for RPL554. 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."

Professor Leif Bjermer of Skane University, Lund, Sweden, lead investigator on this study, commented:

"This well-designed and successfully executed dose-ranging study of nebulised 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. The drug was well tolerated, and few adverse events were recorded. Together, this suggests that the drug could have a large therapeutic index. With further clinical testing, RPL554 could become an important, and much needed novel treatment option, for patients with COPD and other airway’s disease."

The intent of the study was to demonstrate a dose-dependent bronchodilator effect of RPL554 and compare to nebulised salbutamol. In the hospital setting, the usual starting nebulised dose of salbutamol is 2.5mg but occasionally up to 3 times this dose (7.5mg) is used to produce additional bronchodilation in severely ill patients. We compared RPL554 to both the standard dose and the very high dose of salbutamol to evaluate maximum bronchodilator effects and tolerability.

In this randomised, double-blind, placebo-controlled, seven way crossover Phase IIa study, 29 patients with mild to moderate persistent asthma each received four doses of nebulised RPL554 (0.4 to 24 mg), as well as two doses of nebulised salbutamol (2.5mg and 7.5mg), or placebo. In addition to the largest dose tested in previous studies (24mg), lower doses of the new proprietary nebulised formulation of RPL554 than had been used before, were explored to identify a minimally effective dose.

The study was performed at Celerion (Belfast, Ireland) and Skane University Hospital (Lund, Sweden).

The study met its primary objective, with nebulised RPL554 demonstrating a dose-dependent bronchodilator response in asthma patients. RPL554 pharmacokinetics were linear across the whole dose range. At the highest doses of both compounds, RPL554 produced the same maximum bronchodilator effect as salbutamol. Even the lowest RPL554 dose of 0.4mg was significantly superior (p<0.0001) to placebo as a bronchodilator. All doses of RPL554 were found to be well tolerated and the data supports the use of RPL554 in a twice daily dosing regimen.

There were no reports of serious adverse events and fewer adverse events were seen with RPL554 than with salbutamol. Salbutamol produced well-acknowledged adverse events for this drug including tremor, tachycardia, palpitations, and a reduction in blood potassium levels. The large dosing range (60 fold) of RPL554 suggests a potentially large therapeutic index.

RPL554 is currently in development as a nebulised treatment for acute exacerbations in COPD patients in a hospital or home-care setting. The data from the study reported today will help inform dose selection in the Phase IIb trial, which it is currently expected to commence in early 2017.