Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial

Abstract

Background: The p38 MAPK pathway seems to be involved in pathogenesis of chronic obstructive pulmonary disease (COPD). Losmapimod is a potent and selective inhibitor of p38 MAPK. We assessed the effect of losmapimod on exercise tolerance in patients with COPD.

Methods: We did this randomised, parallel-group, placebo-controlled trial at 46 secondary care centres in Argentina, Czech Republic, Estonia, Germany, Norway, South Korea, Ukraine, and USA between Nov 4, 2010, and Dec 22, 2011. We enrolled patients aged 40 years or older with moderate-to-severe COPD (6 min walking distance <350 m) who were current or previous smokers. Patients were randomly assigned (1:1:1:1) by a computer generated sequence to one of losmapimod 2·5 mg, 7·5 mg, or 15 mg, or placebo, twice daily for 24 weeks. Randomisation was stratified by country and exacerbation history (block size eight). Patients and investigators were masked to treatment assignment. The primary outcome was change in 6 min walking distance between baseline and week 24, assessed in the intention-to-treat population. This study is registered with ClinicalTrial.gov, number NCT01218126.

Findings: We screened 886 patients, of whom 602 were enrolled and received treatment. The difference between the placebo group and the losmapimod groups for mean change of 6 min walk distance was not significant: -6·7 m (95% CI -18·2 to 4·9) for losmapimod 2·5 mg, -4·7 m (-16·1 to 6·8) for losmapimod 7·5 mg, and -3·4 m (-15·1 to 8·2) for losmapimod 15 mg. The safety profile was much the same in each group, although drug-related adverse events were more common with losmapimod 7·5 mg (n=19, 13%) and losmapimod 15 mg (n=20, 13%) than with placebo (n=11, 7%) and losmapimod 2·5 mg (n=13, 9%). The most common serious adverse events were COPD exacerbation resulting in admission to hospital (eight patients [5%] taking placebo, six [4%] taking losmapimod 2·5 mg, two [1%] taking losmapimod 7·5 mg, and three [2%] taking losmapimod 15 mg) and pneumonia (four [3%] vs 0 [0%] vs 1 [1%] vs 4 [3%]).

Interpretation: Losmapimod did not cause an improvement in exercise tolerance or lung function, despite being well-tolerated in this COPD population.

Funding: GlaxoSmithKline.