In this post hoc meta-analysis of the MENSA and MUSCA studies, the licensed dose of mepolizumab (100 mg SC) showed consistent improvements versus placebo in exacerbation rate, HRQoL and asthma control, independent of patients’ body weight or BMI. These data demonstrate comparable efficacy of mepolizumab in patients with either high or low body weight/BMI, and confirm that dose-weight adjustments with mepolizumab are not required, thereby addressing queries regarding the need for higher mepolizumab doses in patients with high body weight/BMI. Our findings reinforce the suitability of a simple, fixed-dose regimen across all ranges of body weight/BMI in eligible patients.
Several novel biologic treatments approved for use in patients with differing severe asthma phenotypes have demonstrated reduced efficacy in patients who are obese. For example, a recent retrospective study in patients with severe asthma (N = 340) found that obesity may reduce the effectiveness of the anti-immunoglobulin E mAb omalizumab, independent of other asthma-influencing factors . In addition, a post hoc pooled analysis of the Phase 3 SIROCCO and CALIMA trials demonstrated that the effects of the anti-IL-5 receptor mAb benralizumab on the annual rate of exacerbations and lung function in patients with severe eosinophilic asthma were less robust in obese individuals than in those who were of normal weight . It is important to note that the DREAM study, which was a double-blind, placebo-controlled trial assessing mepolizumab in patients with severe eosinophilic asthma, showed no dosing effect over a 10-fold dose range of mepolizumab on exacerbation rate and other outcomes . For this reason it was important to further investigate whether there was any relationship between mepolizumab efficacy and body weight/BMI in patients with severe eosinophilic asthma.
To date, the effect of mepolizumab 100 mg SC in patients with high body weight/BMI has not been extensively investigated. However, a post hoc analysis of the DREAM study suggested that mepolizumab remains efficacious in these individuals [18, 19]. In this analysis responder subgroups were identified using cluster analysis; the cluster demonstrating greatest response to mepolizumab was an obese, eosinophilic group with airway reversibility . Moreover, a post hoc analysis of the MENSA and DREAM studies showed that treatment with mepolizumab (doses of 75, 250 or 750 mg IV or 100 mg SC) resulted in similar exacerbation rate reductions across weight categories of ≤60 kg, > 60–≤75 kg, > 75–≤90 kg and > 90 kg, with no discernible trend noted in exacerbation reductions with the 250 mg and 750 mg IV doses of mepolizumab, even at the higher weight categories (Additional file 1: Table S1) . In the current analysis, mepolizumab treatment was associated with reduced exacerbation rates across all body weight and BMI categories, versus placebo. In addition, mepolizumab induced an increase from baseline in pre-bronchodilator FEV1 versus placebo in all body weight categories except > 90 kg. A similar trend was observed in the BMI categories. This is consistent with results from post hoc analyses of data from Phase 3 trials of benralizumab [16, 21]. For example, it has been shown that the increase in pre-bronchodilator FEV1 following benralizumab treatment was lower in patients with extremely high body weight (≥115 kg) compared with those with a body weight < 115 kg . It is possible that mechanical factors causing airway restriction may be responsible for a reduced treatment response in obese patients , although it should also be noted that low patient numbers in the highest body weight category may have contributed to this observation in our analysis.
Consistent improvements in both SGRQ total score and ACQ-5 score were also seen with mepolizumab versus placebo across all body weight and BMI categories, including patients with body weight > 90 kg. Although the effects of mepolizumab on measures of HRQoL and asthma control have been reported several times previously in populations with severe eosinophilic asthma [7, 8], this is the first analysis to demonstrate a consistent effect on these parameters across all body weight and BMI categories. Given the particularly poor QoL and reduced asthma control in patients with asthma and comorbid obesity , this is a clinically important finding.
Also of clinical relevance is the consistent and sustained reduction in blood eosinophil count with mepolizumab versus placebo shown in this study, regardless of body weight/BMI. This finding builds upon a substantial body of evidence demonstrating mepolizumab-induced reductions in blood eosinophil levels and a correlation between reduced blood eosinophils and improvements in clinical parameters such as exacerbations and lung function [7, 8]. Of particular importance in this analysis, obesity was previously thought to be associated with a non-eosinophilic asthma phenotype that is typically unresponsive to steroids and therefore not considered to be eligible for treatment with mepolizumab . However, more recently, elevated sputum IL-5 and submucosal and sputum eosinophils have been reported in obese patients with asthma [18, 23, 24]. The baseline patient characteristics in the current study are in line with this finding, with no obvious trend for lower blood eosinophil counts in patients with higher body weight or BMI, albeit in a population of patients who satisfied inclusion criteria pertaining to eosinophilic asthma. Together, these data suggest that patients with high body weight/BMI can have raised blood eosinophil levels and therefore be eligible for mepolizumab treatment, and further, that mepolizumab 100 mg SC can be efficacious in this population. One important consideration is the evidence that inflammatory biomarkers, including blood eosinophils, may be less predictive of airway eosinophilia in obese patients . Nonetheless, the current analysis has demonstrated improvements in a range of clinical parameters in a population of patients with severe eosinophilic asthma across body weight and BMI categories.
Body weight typically influences the exposure of biologics . However, whether this exposure difference translates into a meaningful efficacy difference also depends on the drug-to-target ratio. For omalizumab to adequately neutralise immunoglobulin E levels, a weight-based dosing strategy was deemed necessary . By contrast, neutralisation of IL-5 levels with a fixed-dose regimen of mepolizumab 100 mg SC was found to be efficacious and sufficient over the expected body weight/BMI range in adults and adolescents. A previously reported analysis showed that the efficacy dose–response was consistent with that of the well-defined pharmacological dose–response, in which the half-maximal effect was estimated at 11 mg SC , which is well below the licensed dose of 100 mg SC. Unlike mepolizumab, the clinical development programme for reslizumab only investigated a mg/kg dosing regimen and reslizumab is therefore dosed according to body weight .
Combining data from two large randomised, controlled trials in the current analysis provided a large sample in which to determine the effect of mepolizumab across a range of body compositions. However, there are several limitations that should be considered. First, the post hoc nature of the analysis should be considered when interpreting the findings. In addition, the number of patients varied substantially between subgroups, with smaller patient numbers in the highest body weight and BMI subgroups. We also did not investigate whether there were any differences in safety findings between the subgroups, although previous studies have demonstrated that mepolizumab is well tolerated with minimal immunogenic potential [6,7,8]. Despite these limitations, our findings provide valuable insights into the use of mepolizumab in patients with severe eosinophilic asthma.