Safety and tolerability of the inhaled phosphodiesterase 4 inhibitor GSK256066 in moderate COPD.

BACKGROUND

Inhibition of phosphodiesterase 4 (PDE4) represents an approach to anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). GSK256066 is a potent and selective inhaled PDE4 inhibitor. The aim of this study was to investigate the safety and tolerability of 28 days repeat inhaled dosing with GSK256066 in moderate COPD.

METHODS

This was a Phase IIa, multicenter, parallel-group, double-blind, three-arm, placebo-controlled, four-week, randomized study with two doses of GSK256066 (25 μg, 87.5 μg). The primary endpoint was safety and tolerability. Secondary endpoints included changes in inflammatory markers in induced sputum and blood, lung function (spirometry, body plethysmography, impulse oscillometry), and pharmacokinetics.

RESULTS

104 patients were randomized and 94 patients completed the study. The incidence and intensity of treatment-related adverse events were similar between treatment groups. The most frequent adverse event was nasopharyngitis and there were no serious adverse events in patients receiving GSK256066. The overall incidence of gastrointestinal adverse events was low in all treatment groups. There were no statistically significant changes in inflammatory markers in induced sputum and blood following treatment with GSK256066. Analysis of sputum mRNA suggested engagement of pharmacology, based on increased expression of cAMP-dependent genes including amphiregulin and CREM in subjects receiving GSK256066. There was a trend for an increase in post-bronchodilator FEV1 for both doses of GSK256066; in addition, for the 87.5 μg group, there was a mean reduction in residual volume of 0.367 L (95% confidence interval: 0.112, 0.622 L) relative to placebo.

CONCLUSIONS

Administration of inhaled GSK256066 was well-tolerated in patients with moderate COPD. Further studies would be required to confirm the favorable safety profile and to demonstrate clinical efficacy of this compound. (ClinicalTrials.gov identifier: NCT00549679).