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


RESULTS
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%]).


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


BACKGROUND
GlaxoSmithKline.
Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Centre North, German Centre for Lung Research, Grosshansdorf, Germany. Electronic address: h.watz@pulmoresearch.de.
Henrik
H
Watz
Respiratory Clinical Research Department, GlaxoSmithKline, Stockley Park, London, UK.
Helen
H
Barnacle
Clinical Statistics Department, GlaxoSmithKline, Stockley Park, London, UK.
Benjamin F
BF
Hartley
Respiratory Clinical Research Department, GlaxoSmithKline, Stockley Park, London, UK.
Robert
R
Chan
D000208:Acute Disease; D000328:Adult; D000368:Aged; D003521:Cyclopropanes / Q000627:therapeutic use*; D004311:Double-Blind Method; D017079:Exercise Tolerance / Q000187:drug effects; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D011725:Pyridines / Q000627:therapeutic use*; D016896:Treatment Outcome; D014797:Vital Capacity / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D003521:Cyclopropanes; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases