Results published in the New England Journal of Medicine ( NEJM ) and presented at the European Respiratory Society ( ERS ) congress provide further data from the two pivotal Phase III asthma studies of Mepolizumab, an investigational IL-5 antagonist monoclonal antibody: MENSA ( MEpolizumab as adjunctive therapy iN patients with Severe Asthma ); SIRIUS ( The SteroId ReductIon with MepolizUmab Study ).
The objective of these pivotal studies was to evaluate the impact of Mepolizumab on a number of key endpoints. Both studies met their primary endpoints, with patients receiving Mepolizumab achieving a statistically significant reduction in the frequency of clinically significant asthma exacerbations compared to placebo in MENSA, and a statistically significant reduction of daily oral corticosteroid ( OCS ) dose during weeks 20-24 compared to the dose determined during the optimisation phase in SIRIUS.
Treatment with Mepolizumab also enabled patients in the studies to experience improved quality of life and improved asthma control.
Mepolizumab is an investigational humanised IgG1 monoclonal antibody specific for IL-5, which 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 being investigated as a potential treatment for a sub-group of severe asthma patients who have high eosinophil levels defined as greater than or equal to 150cells/mcL at screening or greater than or equal to 300 cells per mcL within 12 months prior to screening, who exacerbate despite high-dose oral or inhaled corticosteroids and an additional controller such as long-acting beta-2 agonist.
Currently the World Health Organization ( WHO ) estimates that as many as 235 million people are living with asthma worldwide. For many of these patients, use of inhaled therapies can provide some or adequate control of their symptoms, however there are as many as 10% of asthma patients who live with severe asthma and cannot achieve control with inhaled therapies and require additional anti-inflammatory medicines, including the use of regular doses of systemic corticosteroids. Whilst this additional treatment may help these difficult-to-treat patients achieve a level of symptom control, frequent use can result in serious and often irreversible effects, such as weight gain, diabetes mellitus, hypertension and glaucoma.
Although asthma is a heterogeneous disease it is often characterised by an accumulation of eosinophils in lung tissues and, in general, raised eosinophils correlate with severity and frequency of exacerbations. Interleukin-5 (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.
Study MEA115588 was a 32-week double-blind, double-dummy, placebo-controlled, parallel group multicentre study that randomised and treated 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 patients were also required to have a blood eosinophil count above a pre-specified threshold of greater than or equal to 150 cells/mcl at initiation of treatment or who have had blood eosinophils greater than or equal to 300 cells/mcl in the past 12 months to be eligible for the study.
Patients remained on their current asthma maintenance therapy throughout the study and were randomised to receive either Mepolizumab 75mg intravenous ( IV ), 100mg subcutaneous ( SC ), or placebo every four weeks.
For the primary endpoint of reduction in exacerbations, defined as worsening of asthma requiring use of systemic corticosteroids and/or hospitalisation, both Mepolizumab treatment arms showed a statistically significant reduction in the frequency of clinically significant asthma exacerbations compared to placebo ( 75mg IV, 47%, p less than 0.001; 100mg SC, 53%, p less than 0.001 ).
For the endpoints of lung function, measured by FEV1, quality of life, measured by the St George’s Respiratory Questionnaire ( SGRQ ), and asthma control, measured by Asthma Control Questionnaire ( ACQ ), both Mepolizumab arms generated improvements across all measures compared to placebo.
In addition, patients receiving Mepolizumab had a significant reduction in their blood eosinophil count ( 83% reduction for IV and 86% for SC ) which was maintained from week 12 for the duration of the study.
Results from a pre-specified subgroup analysis of time to first exacerbation showed that patients receiving Mepolizumab IV or SC compared to placebo significantly reduced their risk of exacerbations at week 16 ( probability of an exacerbation, 28%, 24%, 45%, respectively ) and also week 32 ( 37%, 33%, 56% respectively ).
In addition, patients receiving Mepolizumab SC had a statistically significant reduction in hospitalisation compared to placebo and a relative reduction of 61% ( p=0.015 ).
An even greater reduction in all endpoints was seen in patients with a blood eosinophil level of greater than or equal to 500 cells/mcL, who received Mepolizumab. In this sub-group of patients, those receiving Mepolizumab 75mg IV and 100mg SC achieved a 74% and 80% reduction in exacerbations respectively.
Adverse events reported in the study were similar across all treatment groups. The most common reported adverse events across all treatment groups were nasopharyngitis, headache, upper respiratory tract infection and asthma. The frequency of adverse events was 83% in the placebo group, 84% in the Mepolizumab 75mg IV and 78% in the Mepolizumab 100mg SC group. The frequency of serious adverse events was 14% in the placebo group, 7% in the Mepolizumab 75mg IV and 8% in the Mepolizumab 100mg SC group.
Study MEA115575 was a 24-week double-blind, placebo-controlled, parallel group multicentre study to evaluate the use of Mepolizumab 100mg SC, every 4 weeks in comparison to placebo in reducing daily oral corticosteroid use while maintaining asthma control.
A total of 135 patients with severe asthma who were on treatment with oral corticosteroid, high dose inhaled corticosteroids ( ICS ) plus an additional controller medication, were enrolled.
All patients were required to have a blood eosinophil count above a pre-specified threshold of greater than or equal to 150 cells/mcl at initiation of treatment or who have had blood eosinophils greater than or equal to 300 cells/mcl in the past 12 months to be eligible for the study.
Prior to randomisation, an oral corticosteroid optimisation phase was undertaken to ensure that patients genuinely needed oral corticosteroid to control their asthma and establish the lowest optimal dose.
Patients were then initiated onto therapy ( week 0-4 ), and between week 4-20 oral corticosteroid reduction was undertaken in patients with stable disease, followed by a maintenance period ( week 20-24 ).
The primary efficacy endpoint was the percentage reduction of daily oral corticosteroid dose during weeks 20-24 compared to the dose determined during the optimisation phase.
Mepolizumab was effective in reducing oral corticosteroid while maintaining control [ OR=2.39 ( 95% CI, 1.25-4.56 ), p=0.008 ].
The median overall reduction from baseline in oral corticosteroid dose was 50% for patients treated with Mepolizumab compared to 0% with placebo ( p=0.007 ).
Patients receiving Mepolizumab also reported a significant improvement ( 0.52 points, p=0.004 ) in their asthma control ( ACQ-5 score ) and their quality of life, measured by the SGRQ ( 5.8 points, p=0.019 ).
For the secondary endpoint of total cessation of daily oral glucocorticoids, this was achieved by 14% of patients receiving Mepolizumab compared to 8% on placebo, which was not statistically significant ( p=0.41 ).
Patients receiving Mepolizumab also had a significant reduction ( p less than 0.001 ) in their eosinophil count throughout the duration of the study.
In this study adverse events were similar across treatment groups. The most common reported adverse events were headache, nasopharyngitis, bronchitis, sinusitis, fatigue and asthma.
The frequency of adverse events was 92% in the placebo and 84% in the Mepolizumab treatment group. Frequency of serious adverse events was 18% in the placebo group and 1% in the Mepolizumab group. ( Xagena )
Source: Glaxo-Smith Kline ( GSK ), 2014