The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma.
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.
Singh
Dave
D
The University of Manchester, Manchester Academic Health Science Centre, University Hospital Of South Manchester NHS Foundation Trust, Manchester M23 9LT, UK. dsingh@meu.org.uk
Petavy
Frank
F
Macdonald
Alex J
AJ
Lazaar
Aili L
AL
O'Connor
Brian J
BJ
D000280:Administration, Inhalation; D000634:Aminoquinolines / Q000008:administration & dosage*; D001249:Asthma / Q000175:diagnosis* / Q000188:drug therapy*; D001985:Bronchial Provocation Tests; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058988:Phosphodiesterase 4 Inhibitors; D013450:Sulfones / Q000008:administration & dosage*; D016896:Treatment Outcome; D055815:Young Adult
C549469:6-((3-((dimethylamino)carbonyl)phenyl)sulfonyl)-8-methyl-4-((3-methyloxyphenyl)amino)-3-quinolinecarboxamide; D000634:Aminoquinolines; D058988:Phosphodiesterase 4 Inhibitors; D013450:Sulfones