Pneumologie 2017; 71(S 01): S1-S125
DOI: 10.1055/s-0037-1598375
Posterbegehung – Sektion Klinische Pneumologie
Asthma bronchiale – Stephanie Korn/Mainz, Christian Geßner/Leipzig
Georg Thieme Verlag KG Stuttgart · New York

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

I Pouliquen
1   Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park
,
D Austin
1   Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park
,
N Gunsoy
2   Clinical Statistics, GlaxoSmithKline, Stockley Park
,
SW Yancey
3   Respiratory Therapeutic Area, GlaxoSmithKline, Research Triangle Park
› Author Affiliations
Further Information

Publication History

Publication Date:
23 February 2017 (online)

 
 

    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


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    No conflict of interest has been declared by the author(s).