The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma

Abstract

GSK256066 is a selective phosphodiesterase 4 inhibitor that can be given by inhalation, minimising the potential for side effects. We evaluated the effects of GSK256066 on airway responses to allergen challenge in mild asthmatics.

Methods: In a randomised, double blind, cross-over study, 24 steroid naive atopic asthmatics with both early (EAR) and late (LAR) responses to inhaled allergen received inhaled GSK256066 87.5 mcg once per day and placebo for 7 days, followed by allergen challenge. Methacholine reactivity was measured 24 h post-allergen. Plasma pharmacokinetics were measured. The primary endpoint was the effect on LAR.

Results: GSK256066 significantly reduced the LAR, attenuating the fall in minimum and weighted mean FEV1 by 26.2% (p = 0.007) and 34.3% (p = 0.005) respectively compared to placebo. GSK256066 significantly reduced the EAR, inhibiting the fall in minimum and weighted mean FEV1 by 40.9% (p = 0.014) and 57.2% (p = 0.014) respectively compared to placebo. There was no effect on pre-allergen FEV1 or methacholine reactivity post allergen. GSK256066 was well tolerated, with low systemic exposure; plasma levels were not measurable after 4 hours in the majority of subjects.

Conclusions: GSK256066 demonstrated a protective effect on the EAR and LAR. This is the first inhaled PDE4 inhibitor to show therapeutic potential in asthma.

Trial registration: ClinicalTrials.gov NCT00380354.

Figure 1

Flow chart showing study design. FeNO denotes exhaled nitric oxide. Allergen = inhaled allergen challenge. Methacholine = inhaled methacholine challenge.

Figure 2

Flow chart showing withdrawal of subjects during the study.

Figure 3

Early and late asthmatic response to inhaled allergen challenge after 7 days treatment with either GSK256066 or placebo. Means and 95% confidence intervals of change in FEV1 compared to post saline value shown.

Figure 4

Plot of individual derived plasma PK parameters AUC(0-t) and Cmax for GSK256066 on days 1 and 7. Summary Box and Whisker plot overlaid. Open squares represent individual values. Central line, box and whisker limits represent median, interquartile range and most extreme value with 1.5× interquartile range, respectively.