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Biological effects of p38 MAPK inhibitor losmapimod does not translate to clinical benefits in COPD
Steven Pascoe1, Maria Costa2, Joanna Marks-Konczalik2
1GlaxoSmithKline, Research Triangle Park, NC, USA.
Rationale:
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.
Objectives:
To evaluate the effect of losmapimod in reducing exacerbations in subjects with moderate-to-severe COPD.
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Losmapimod did not reduce exacerbations in COPD patients. The study found no significant benefit for this p38 MAPK inhibitor in managing COPD exacerbations.
Area of Science:
- Pharmacology
- Respiratory Medicine
- Inflammation Research
Background:
- p38 mitogen-activated protein kinase (MAPK) is upregulated in chronic inflammatory conditions.
- Losmapimod is a p38 MAPK inhibitor investigated for treating chronic obstructive pulmonary disease (COPD).
Purpose of the Study:
- To assess the efficacy of losmapimod in decreasing exacerbation rates in moderate-to-severe COPD patients.
- To evaluate losmapimod's impact on lung function and health status in COPD.
Main Methods:
- A double-blind, parallel-group study randomized 184 subjects with COPD at risk of exacerbations to losmapimod 15 mg or placebo.
- The primary endpoint was the annualized rate of moderate/severe exacerbations, analyzed using a Bayesian framework.
- Lung function (FEV1) and St George's Respiratory Questionnaire (SGRQ) scores were secondary endpoints.
Main Results:
- The study was terminated early due to a low probability of success; 90 subjects received losmapimod and 94 received placebo.
- Losmapimod did not significantly reduce the annualized exacerbation rate (losmapimod/placebo ratio: 1.04; posterior probability <1: 0.44).
- A significant improvement in FEV1 was observed with losmapimod at Week 26 (p=0.007), but SGRQ scores were similar between groups. No new safety concerns were identified.
Conclusions:
- Losmapimod treatment failed to demonstrate a reduction in exacerbation rates for COPD patients with high exacerbation risk and >=2% blood eosinophils.
- Current data do not support the use of losmapimod as an add-on therapy for COPD management.
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