ENCORE: A weight-based exacerbation dose response analysis of mepolizumab in severe asthma with eosinophilic phenotype

Introduction/background:

Despite careful design of dose ranging studies, full characterisation of dose response for clinical endpoints is not always achieved. The absence of a dose response for reduction in clinically significant exacerbations with mepolizumab in the primary analysis led to a meta-analysis using individualized weight-based measures of dose to take advantage of the known effect of bodyweight on mepolizumab exposure.

Aims/objectives:

Evaluate weight-based measures of mepolizumab dose-response for reduction in annualized exacerbation rate.

Methods:

Inclusion of exacerbation data with dose and bodyweight information from two GSK funded mepolizumab severe asthma pivotal studies (DREAM, NCT01000506 and MENSA, NCT01000506). Intravenous doses were converted to subcutaneous-equivalent dose using absolute bioavailability of 80 and 70% and normalized by individual body weight, body mass index and body surface area at baseline.

Results:

Description of the dose response showed that although the maximal treatment effect was well-estimated, location of half-maximal efficacious dose (ED50) was poor. Using a Bayesian analysis with informative priors for ED50 (away from the pharmacological ED50 (blood eosinophil reduction) [11 mg]), convergence was achieved. Posterior ED50 distributions showed a shift in prior belief towards the pharmacological ED50 with narrower credibility interval. The largest effects were noted for bodyweight-adjusted dose response.

Conclusions:

Exacerbation data from studies DREAM and MENSA did not show a dose response by conventional analysis unlike with Bayesian analysis which also showed consistency between the efficacy dose response and the well-defined dose response for pharmacology, with an ED50 of approximately 0.17 mg/kg or 12 mg.

Abstract previously presented at ERS 2016, PA4106