Key wordsIntroduction

This communication provides the justification supporting the selection of the mepolizumab 300 mg subcutaneous (SC) dose in patients with eosinophilic granulomatosis with polyangiitis (EGPA) or hyper-eosinophilic syndrome (HES).

In rare diseases, the conduct of formal dose-ranging studies for determination of dosing recommendations is challenging due to limitations in access to the patient population. In such context, borrowing pharmacology information from other diseases that share a similar pathophysiology can be used to support dose selection for investigation, when the paucity of study patients requires innovative dose selection approaches. There are a number of common and rare diseases that are associated with elevated levels of blood and tissue eosinophils. Because reduction of blood eosinophils is the known pharmacologic effect of mepolizumab, blood eosinophil count data collected across multiple mepolizumab studies conducted in various eosinophilic diseases were leveraged to justify the dosing regimen proposed for investigation in the mepolizumab pivotal Phase III studies in patients with EGPA or HES. The aim was to select a mepolizumab dose that maximizes the pharmacologic effect to afford maximal efficacy in these rare diseases.

MethodsA dose–response meta-analysis of blood eosinophil data collected from 16 mepolizumab studies (GSK IDs, MHE100185, MHE100901, MEA112997, MEA115575, SB-240563/006, MEA115588, MEA115661, MEA115666, MEA114092, SB-240563/001, SB-240563/035, SB-240563/017, MEE103226, MEE103219, SB-240563/018, and MEA115705) was conducted by using SAS version 9.2 (SAS Institute, Inc, Cary, North Carolina). These studies encompassed various eosinophilic diseases (including asthma of varying severity, HES, and eosinophilic esophagitis) and healthy subjects. The end point for all studies was defined as the absolute blood eosinophil count 4 weeks after the last dose. All doses were converted to SC equivalent doses based on mepolizumab SC absolute bioavailability.1Pouliquen IJ Kornmann O Barton SV Price JA Ortega HG. Characterization of the relationship between dose and blood eosinophil response following subcutaneous administration of mepolizumab. Absolute blood eosinophil count was logarithmically transformed before analysis, and baseline blood eosinophil count was included as a covariate in the model. The best model was defined as the model with the lowest Bayesian information criteria.The nonlinear maximal response (Emax) model was of the form:

log(absolutebloodeosinophilcount)=β0+β1DosenDosen+(eβ2)n

where β0 is an intercept, β1 is the maximal response attributable to mepolizumab, and β2 is the logarithm of the dose providing half-maximal drug effect. Hill function slope, n, was fixed to unity for parsimony.

The final model was then inverted and used to represent the relationship between mepolizumab dose, D, and blood eosinophil count at baseline to achieve various absolute target counts.

Results

From the models tested, the model with the lowest Bayesian information criteria was a nonlinear Emax model with subject-level random effects (on β0 [intercept] and β1 [Emax]) and baseline blood eosinophil count included as a covariate on β1 (Emax) as well as on β2 (dose providing half-maximal drug effect).

The relationship between mepolizumab dose and blood eosinophil count at baseline for various absolute target counts derived from the final nonlinear Emax model is represented in the Figure 1. It clearly shows that the higher the baseline blood eosinophil count, the higher the mepolizumab dose required to achieve the same absolute target counts. For example, for a baseline count of 2000 cells/μL (or 2 giga [GI]/L), an SC dose of 100 mg is predicted to achieve a target absolute count of 300 cells/μL (or 0.3 GI/L), whereas an SC dose of 300 mg is predicted to achieve a target absolute count of 200 cells/μL (or 0.2 GI/L), affording a greater reduction. For a baseline count of 1000 cells/μL (or 1 GI/L), an SC dose of 100 mg is predicted to achieve a target absolute count of 150 cells/μL (or 0.15 GI/L).

Figure 1Mepolizumab dose (with 95% prediction interval) necessary to achieve a desired target blood eosinophil count as a function of baseline blood eosinophil count. GI = giga; SC = subcutaneous.

DiscussionIn the rare hypereosinophilic diseases EGPA and HES, characterized by elevated blood eosinophil counts at diagnosis (>1000 cells/μL [or 1 GI/L] and >1500 cells/μL [or 1.5 GI/L], respectively), the goal was to identify a dose that would maximize the reduction in blood eosinophil counts. The dose–response modeling exercise conducted provided evidence that blood eosinophil count at baseline is an important determinant of the overall mepolizumab pharmacologic response. The graphical representation of the mepolizumab dose required to achieve target absolute counts as a function of the baseline blood eosinophil count further illustrated that a higher mepolizumab dose is justified in eosinophilic diseases characterized by substantially higher blood eosinophil counts at diagnosis to maximize the pharmacology effect. Furthermore, exploration of mepolizumab pharmacology in a dose-ranging study conducted in subjects with severe eosinophilic asthma showed that the additional pharmacology benefit between a 250-mg intravenous dose (∼300 mg subcutaneously) and a 750-mg intravenous dose was marginal.2Pavord ID Korn S Howarth P Bleecker ER Buhl R Keene ON et al.Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. A dose of 300 mg subcutaneously was therefore selected for investigation in the pivotal Phase III EGPA and HES studies to ensure therapeutic benefit across the wide spectrum of blood eosinophils displayed by patients with EGPA and HES. Dose prediction from the modeling exercise was subsequently confirmed: in the pivotal Phase III studies conducted in EGPA3Wechsler ME Akuthota P Jayne D Khoury P Klion A Langford CA et al.Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. and HES,4Roufosse F Kahn JE Rothenberg ME Wardlaw AJ Klion AD Yun Kirby S et al.Efficacy and safety of mepolizumab in hypereosinophilic syndrome: a phase III, randomized, placebo-controlled trial. mepolizumab 300 mg SC every 4 weeks was found to be efficacious and well tolerated.Conclusions

A higher mepolizumab dose of 300 mg subcutaneously every 4 weeks is justified in eosinophilic diseases characterized by a substantially higher blood eosinophil count at diagnosis (compared with the therapeutic SC dose of 100 mg in severe asthma with an eosinophilic phenotype). This 300-mg SC dose allows maximal pharmacologic effect and ensures therapeutic benefit across the wide spectrum of blood eosinophils displayed in this patient population, with no substantial additional pharmacologic benefit afforded beyond this dose, regardless of the absolute count at baseline.

Declaration of Competing Interest

Dr. Pouliquen is a former employee of GSK who holds stocks/shares and is now an employee of AstraZeneca. Dr. Austin, Dr. Steinfeld, and Mr. Yancey are employees of GSK and hold stocks/shares. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

Acknowledgments

This analysis and the studies on which it was based were funded by GSK. The authors thank the investigators, their staff, and the patients for their participation in the studies included in this meta-analysis. Editorial support (in the form of minor editing, figure redrawing, and submission support) was provided by Laura Gardner, PhD, CMPP, at Fishawack Indicia Ltd, UK, and was funded by GSK.

Drs. Pouliquen and Austin contributed to the conception and analysis of this work. All authors contributed to the interpretation of the analysis and development of the manuscript, and all provided approval of the final draft to be published.

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J Allergy Clin Immunol. 146 (): 1397https://doi.org/10.1016/j.jaci.2020.08.037Article InfoPublication History

Published online: June 26, 2021

Accepted: May 25, 2021

Publication stageIn Press Corrected ProofIdentification

DOI: https://doi.org/10.1016/j.clinthera.2021.05.014

Copyright

© 2021 GlaxoSmithKline. Published by Elsevier Inc.

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