Chronic obstructive pulmonary disease (COPD) is a common lung disease leading to progressive decline in lung function. Inhibition of release of inflammatory mediators by p38 inhibitors may be a useful treatment for chronic inflammation of the airways thought to underlie the pathogenesis of the disease.

To evaluate the efficacy and safety of PH-797804, a potent and selective p38 inhibitor, in adults with moderate to severe COPD (Global Initiative for Chronic Obstructive Lung Disease stage II/III).

This was a randomised, adaptive design, double-blind, placebo-controlled, parallel-group, multicentre trial. Patients were initially randomised to placebo, 0.5, 3, 6 or 10 mg PH-797804 once daily and treated for 6 weeks following a 2-week run-in.

The primary endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV₁) compared with placebo after 6 weeks of treatment. Secondary endpoints included other spirometric parameters, transition dyspnoea index, rescue mediation use, high sensitivity C-reactive protein and symptoms. A total of 230 patients were assigned to treatment; placebo (n=45), 0.5 mg (n=20), 3 mg (n=47), 6 mg (n=70) and 10 mg (n=48). PH-797804 showed a statistically significant improvement in trough FEV₁ at week 6 compared with placebo of 0.086 litre (95% Bayesian CI 0.008 to 0.164) and 0.093 litre (95% CI 0.018 to 0·166) at 3 and 6 mg PH-797804, respectively. PH-797804 3 mg and 6 mg showed an improvement in the baseline dyspnoea index/transition dyspnoea index total focal score at week 6. PH-797804 was well tolerated at all doses studied.

PH-797804 demonstrated improvements over placebo in lung function parameters and dyspnoea in patients with moderate to severe COPD.

The nature of inflammation varies greatly between COPD patients, leading to heterogeneity in clinical manifestations. For example, emphysema is severe in some patients but minimal in others.1 The varied nature of COPD inflammation means that a novel anti-inflammatory drug is unlikely to be effective in all patients. This is certainly true for established anti-inflammatory therapies such as inhaled corticosteroids, which are most effective in the subgroup of patients with a history of exacerbations,2 and also those with evidence of increased sputum eosinophils.3 The PDE4 inhibitor, roflumilast, also shows greater efficacy in a COPD subgroup; those with chronic bronchitis and a history of exacerbations.4

The p38 mitogen activated protein kinase (MAPK) signalling pathway promotes inflammation by enhancing inflammatory gene transcription, stabilising mRNAs and increasing protein translation.5 p38 MAPK signalling is activated by different extracellular stimuli that are relevant to...