+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Biological effects of p38 MAPK inhibitor losmapimod does not translate to clinical benefits in COPD



Biological effects of p38 MAPK inhibitor losmapimod does not translate to clinical benefits in COPD



Respiratory Medicine 130: 20-26



p38 mitogen-activated protein kinase (MAPK) expression is increased in chronic inflammatory disease. Losmapimod, a p38 MAPK inhibitor, has been developed as a potential anti-inflammatory therapy in COPD. To evaluate the effect of losmapimod in reducing exacerbations in subjects with moderate-to-severe COPD. In this double-blind, parallel-group study, subjects at risk of COPD exacerbations and ?2% blood eosinophils at screening, were randomized 1:1 to losmapimod 15 mg or placebo (variable treatment duration: 26-52 weeks). The primary endpoint was the annualized rate of moderate/severe exacerbations. Using a Bayesian framework, treatment success was defined as >90% posterior probability that the true ratio of the losmapimod/placebo exacerbation rate was <1. Lung function and health status (St George's Respiratory Questionnaire (SGRQ)) were also assessed. A planned interim analysis resulted in early study termination due to the low probability of a successful study outcome; a total of 94 subjects were randomized to placebo and 90 to losmapimod 15 mg, and 14 and 10 subjects respectively completed the study. Losmapimod treatment was not associated with an improvement in the adjusted posterior median annualized exacerbation rate (losmapimod/placebo ratio: 1.04 (95% Cr I: 0.63, 1.73)). The posterior probability for the losmapimod/placebo annualized rate ratio being <1 was 0.44 (success criterion: >0.90). A statistically significant improvement in post-bronchodilator forced expiratory volume in 1 s was seen at Week 26, at the 5% significance level, with losmapimod treatment versus placebo (p = 0.007). Changes from baseline in SGRQ total score were similar in both groups. No new risks or safety signals were identified with losmapimod treatment. Losmapimod treatment did not reduce the rate of exacerbations in, subjects with COPD at high risk of exacerbation and ?2% blood eosinophils. These data do not support its use as a therapy in COPD in addition to standard of care.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 052193517

Download citation: RISBibTeXText

PMID: 29206629

DOI: 10.1016/j.rmed.2017.07.002


Related references

Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial. Lancet. Respiratory Medicine 2(1): 63-72, 2014

Hypothesis: atorvastatin has pleiotropic effects that translate into early clinical benefits on cardiovascular disease. Journal of Cardiovascular Pharmacology and Therapeutics 9(1): 61-63, 2004

Differential anti-inflammatory effects of budesonide and a p38 MAPK inhibitor AZD7624 on COPD pulmonary cells. International Journal of Chronic Obstructive Pulmonary Disease 13: 1279-1288, 2018

A randomized, placebo-controlled study of the effects of the p38 MAPK inhibitor SB-681323 on blood biomarkers of inflammation in COPD patients. Journal of Clinical Pharmacology 50(1): 94, 2010

A post-hoc subgroup analysis of data from a six month clinical trial comparing the efficacy and safety of losmapimod in moderate-severe COPD patients with ≤2% and >2% blood eosinophils. Respiratory Medicine 109(7): 860-869, 2015

Gene expression changes caused by the p38 MAPK inhibitor dilmapimod in COPD patients: analysis of blood and sputum samples from a randomized, placebo-controlled clinical trial. Pharmacology Research and Perspectives 3(1): E00094, 2015

Aripiprazole: does partial dopaminergic agonism translate into clinical benefits?. Annals of PharmacoTherapy 37(5): 738-740, 2003

Why clinical trial outcomes fail to translate into benefits for patients. Trials 18(1): 122, 2017

RV568, a narrow-spectrum kinase inhibitor with p38 MAPK-α and -γ selectivity, suppresses COPD inflammation. European Respiratory Journal 50(4):, 2017

Does the routine use of global coronary heart disease risk scores translate into clinical benefits or harms? A systematic review of the literature. Bmc Health Services Research 8: 60, 2008

COPD: more treatment will translate to better breathing. Will it?. Jornal Brasileiro de Pneumologia 45(1): E20190037, 2019

Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial. Lancet 384(9949): 1187-1195, 2014

Bortezomib (VELCADE) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits. Annals of Oncology 17(5): 813-817, 2006

Clinical Inquiry: what are the benefits and risks of inhaled corticosteroids for COPD?. Journal of Family Practice 63(5): 276-278, 2014

Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD. Plos one 11(9): E0163139, 2016