Development of Pediatric Dosing for Mepolizumab in Severe Asthma Based on Extrapolation of Data From Adult Patients and a Phase II Open-Label Pediatric Trial.

The benefit-risk profile of mepolizumab in severe asthma was established through clinical trials in adults, leading to EU and US approvals in 2015. To support a pediatric indication (≥6 years), an extrapolation approach was implemented. This extrapolation and its validation were informed by data from Phase III trials in adults (N = 1841) and adolescents aged 12-17 years (N = 37) with severe asthma, an open-label trial in children aged 6-11 years (N = 36), and a trial in children aged 2-11 years (N = 32) and adolescents aged 12-17 years (N = 27) with eosinophilic esophagitis. Population pharmacokinetic and pharmacokinetic/pharmacodynamic meta-analyses demonstrated consistent mepolizumab pharmacokinetic and blood eosinophil reduction across age groups and diseases, with bodyweight the only covariate of exposure and absolute bioavailability also a covariate in children aged 6-11 years. Baseline blood eosinophil count and disease type were the only covariates of response. In severe asthma, mepolizumab reduced the annualized rate of clinically significant exacerbations by 40% in adolescents and 54% in adults versus placebo. Bootstrap resampling and Bayesian analyses supported similar efficacy between adolescents and adults, and responses in children aged 6-11 years were consistent with older groups. Safety evaluations revealed no unique safety concerns in pediatric patients with severe asthma. This extrapolation strategy, implemented as an innovative approach to pediatric clinical development of mepolizumab in severe asthma, was validated and provided the scientific basis for dosing recommendations and for EU regulatory approval in patients aged ≥6 years in 2018.