PGx7669: an exploratory pharmacogenetic efficacy investigation of steroid reduction in subjects with severe asthma treated with mepolizumab in 115575 and 115661

Trial description: Mepolizumab, SB-240563, is a humanized anti-interleukin5 (anti-IL5) antibody that binds to and inactivates IL-5, a cytokine that recruits and promotes activation and persistence of eosinophils in asthma exacerbations. Blocking IL-5 with mepolizumab has a positive effect in reducing the frequency of asthma exacerbations and eosinophilic inflammation in subjects with severe refractory asthma who are dependent on maintenance steroid to treat their asthma. This results in reduction in steroid use for many subjects.The objective for eTrack study ID 207390 is to assess evidence of the influence of candidate genetic variants and genome-wide variation with oral corticosteroid reduction in mepolizumab-treated subjects using data from studies MEA115575 and MEA115661.The co-primary objectives are1) to determine evidence for association between genetic variation and percent reduction of oral corticosteroid (OCS) dose in mepolizumab-treated subjects from study MEA115575. Ordered logistic regression of percent reduction in OCS from Baseline in the Genetics mepolizumab group will be conducted. This endpoint will also be analyzed in the Genetics placebo group to aid in interpretation of results from the Genetics mepolizumab group. Estimation of genotype by treatment interactions using appropriate contrasts of linear combinations of the genetic effect size estimates obtained within the treatment arms will be conducted.2) to determine evidence for association between genetic variation and percent reduction of oral corticosteroid (OCS) dose after combining evidence from a) mepolizumab-treated subjects in MEA115575 and b) previously placebo-treated (PPG) subjects from MEA115575 enrolled and treated with mepolizumab in the open label extension study MEA115661. A meta-analysis combining the effect estimates from Genetics mepolizumab and Genetics PPG groups for percent reduction in OCS from Baseline. These groups will be analyzed individually using ordered logistic regression, and meta-analysis will be used to combine effect estimates from each group.The secondary objectives are1) to determine evidence for association between genetic variation and proportion of subjects achieving an OCS reduction of 50% or greater in mepolizumab-treated subjects from study MEA115575. Logistic regression of percent reduction in OCS from Baseline in the Genetics mepolizumab group will be conducted. This endpoint will also be analyzed in the Genetics placebo group to aid in interpretation of results from the Genetics mepolizumab group. Estimation of genotype by treatment interactions using appropriate contrasts of linear combinations of the genetic effect size estimates obtained within the treatment arms will be conducted.2) to determine evidence for association between genetic variation and proportion of subjects achieving an OCS reduction of 50% or greater after combining evidence from a) mepolizumab-treated subjects in MEA115575 and b) PPG subjects from MEA115575 enrolled and treated with mepolizumab in the open label extension study MEA115661. A meta-analysis combining the effect estimates from Genetics mepolizumab and Genetics PPG groups for percent reduction in OCS from Baseline. These groups will be analyzed individually using logistic regression, and meta-analysis will be used to combine effect estimates from each group.