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Asthma Drug Mepolizumab Shows Promise in Phase III Trials
A pivotal phase III study of mepolizumab (GlaxoSmithKline), an investigational interleukin-5 (IL-5) antagonist monoclonal antibody, has met its primary endpoint of a reduction in the frequency of exacerbations in patients with severe eosinophilic asthma.
Study MEA115588 was a 32-week, double-blind, double-dummy, placebo-controlled, parallel-group trial involving 576 patients with severe asthma who had experienced frequent exacerbations despite treatment with high-dose inhaled corticosteroids (ICS) plus at least one other controller medication. All of the patients were required to have a blood eosinophil count above a pre-specified threshold of ≥ 150 cells/mcL at the initiation of treatment or to have had blood eosinophils ≥ 300 cells/mcL during the previous 12 months.
The study evaluated the efficacy of two regimens of mepolizumab. Patients remained on their current asthma maintenance therapy throughout the study and were randomly assigned to receive either mepolizumab 75 mg intravenous (IV), mepolizumab 100 mg subcutaneous (SC), or placebo every 4 weeks.
For the primary endpoint, both mepolizumab treatment arms showed statistically significant reductions in the frequency of clinically significant exacerbations of asthma compared with placebo (75 mg IV, 47%, P P
Adverse events (AEs) were similar across all treatment groups. The most common AEs across all treatment groups were nasopharyngitis, headache, upper respiratory tract infection, and asthma. The frequency of AEs was 83% in the placebo group, 84% in the mepolizumab 75-mg IV group, and 78% in the mepolizumab 100-mg SC group. The frequency of serious AEs was 14% in the placebo group, 7% in the mepolizumab 75-mg IV group, and 8% in the mepolizumab 100-mg SC group.
In addition, a second phase III trial designed to evaluate the use of mepolizumab (100 mg SC every 4 weeks) in comparison with placebo in reducing daily oral corticosteroid use while maintaining asthma control met its primary endpoint.
Study MEA115575 was a 24-week double-blind, placebo-controlled, parallel-group trial involving 135 patients with severe asthma who were receiving regular treatment with oral corticosteroids, high-dose ICS, and an additional controller medication. As in the previous study, all of the patients were required to have a blood eosinophil count above a pre-specified threshold of ≥ 150 cells/mcL at the initiation of treatment or to have had blood eosinophils ≥ 300 cells/mcL during the previous 12 months.
The study showed that patients treated with mepolizumab 100 mg SC were able to achieve greater reductions in their maintenance oral corticosteroid dose during weeks 20 to 24 compared with patients given placebo (P = 0.008) while maintaining asthma control.
AEs were similar across treatment groups. The most common AEs in the two groups were headache, nasopharyngitis, bronchitis, sinusitis, fatigue, and asthma. The frequency of AEs was 92% in the placebo group and 84% in the mepolizumab group. The frequency of serious AEs was 18% in the placebo group and 1% in the mepolizumab group.
The presence of eosinophils may represent a subtype of severe asthma. Although asthma is a heterogeneous disease, it is often characterized by an accumulation of eosinophils in lung tissues. In general, increased eosinophils correlate with the severity and frequency of exacerbations. IL-5 is the main promoter of eosinophil growth, activation, and survival and provides an essential signal for the movement of eosinophils from the bone marrow into the lung.
Mepolizumab is an investigational fully humanized immunoglobulin G1 (IgG1) monoclonal antibody specific for IL-5. The drug binds to IL-5, stopping it from binding to its receptor on the surface of eosinophils. Inhibiting IL-5 binding in this way reduces blood, tissue, and sputum eosinophil levels.
Mepolizumab is in development for severe eosinophilic asthma in patients with exacerbated disease despite the use of high-dose oral or inhaled corticosteroids and an additional controller, such as a long-acting beta-2 agonist. In addition, mepolizumab is being investigated in patients with chronic obstructive pulmonary disease (COPD) and in patients with eosinophilic granulomatosis with polyangiitis (EGPA).
Mepolizumab is not approved anywhere in the world.
Source: GlaxoSmithKline; March 12, 2014.