Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial
Florence Roufosse, Jean-Emmanuel Kahn, Marc E Rothenberg, Andrew J Wardlaw, Amy D Klion, Suyong Yun Kirby, Martyn J Gilson, Jane H Bentley, Eric S Bradford, Steven W Yancey, Jonathan Steinfeld, Gerald J Gleich, HES Mepolizumab study group, Florence Roufosse, Jean-Emmanuel Kahn, Marc E Rothenberg, Andrew J Wardlaw, Amy D Klion, Suyong Yun Kirby, Martyn J Gilson, Jane H Bentley, Eric S Bradford, Steven W Yancey, Jonathan Steinfeld, Gerald J Gleich, HES Mepolizumab study group
Abstract
Background: Anti-IL-5 therapy is a potential treatment for patients with hypereosinophilic syndrome (HES), although its clinical efficacy is unclear.
Objective: We sought to investigate the clinical efficacy and safety of mepolizumab versus placebo in patients with HES.
Methods: This randomized, multicenter, double-blind, placebo-controlled, phase III trial was conducted across 39 centers in 13 countries. Eligible patients had FIP1L1-PDGFRA-negative HES, experienced 2 or more flares (worsening of HES-related symptoms or blood eosinophil count requiring therapeutic escalation) in the previous 12 months, and had a screening blood eosinophil count greater than or equal to 1000 cells/μL. Patients were randomized (1:1) to subcutaneous mepolizumab (300 mg) or placebo every 4 weeks for 32 weeks, plus existing HES therapy. The primary outcome was the proportion of patients with 1 or more flares (worsening of HES-related symptoms necessitating therapy escalation or ≥2 courses of blinded rescue oral corticosteroids) during the study; in addition, patients who withdrew early from the study were counted as having a flare. Safety end points were also assessed.
Results: The proportion of patients experiencing 1 or more flares/withdrawing from the study was 50% lower with mepolizumab versus placebo (15 of 54 [28%] vs 30 of 54 [56%]; P = .002). Logistic regression analysis was consistent with the primary analysis (odds ratio, 0.28; 95% CI, 0.12-0.64; P = .003). Similar proportions of patients in the mepolizumab and placebo groups experienced on-treatment adverse events (48 of 54 [89%] vs 47 of 54 [87%]).
Conclusions: Compared with placebo, mepolizumab significantly reduced the occurrence of flares in patients with HES, with no new safety signals identified.
Trial registration: ClinicalTrials.gov NCT02836496.
Keywords: Hypereosinophilic syndrome; efficacy; flare; mepolizumab; safety.
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Figures
References
- Curtis C, Ogbogu P. Hypereosinophilic syndrome. Clin Rev Allergy Immunol 2016;50:240–51.
- Ogbogu PU, Bochner BS, Butterfield JH, Gleich GJ, Huss-Marp J, Kahn JE, et al. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol 2009;124: 1319–25.e3.
- Shomali W, Gotlib J. World Health Organization-defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management. Am J Hematol 2019;94:1149–67.
- Whitehouse MW. Anti-inflammatory glucocorticoid drugs: reflections after 60 years. Inflammopharmacology 2011;19:1–19.
- Kahn JE, Groh M, Lefevre G. (A critical appraisal of) classification of hypereosinophilic disorders. Front Med (Lausanne) 2017;4:216.
- Menzella F, Lusuardi M, Galeone C, Taddei S, Zucchi L. Profile of anti-IL-5 mAb mepolizumab in the treatment of severe refractory asthma and hypereosinophilic diseases. J Asthma Allergy 2015;8:105–14.
- Mepolizumab (NUCALA) highlights of prescribing information. 2019. Available at: . Accessed February 24, 2020.
- Mepolizumab (NUCALA) summary of product characteristics. 2019. Available at: . Accessed February 24, 2020.
- Plotz SG, Simon HU, Darsow U, Simon D, Vassina E, Yousefi S, et al. Use of an anti-interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic dermatitis. N Engl J Med 2003;349:2334–9.
- Garrett JK, Jameson SC, Thomson B, Collins MH, Wagoner LE, Freese DK, et al. Anti-interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes. J Allergy Clin Immunol 2004;113:115–9.
- Rothenberg ME, Klion AD, Roufosse FE, Kahn JE, Weller PF, Simon HU, et al. Treatment of patients with the hypereosinophilic syndrome with mepolizumab. N Engl J Med 2008;358:1215–28.
- Stein ML, Villanueva JM, Buckmeier BK, Yamada Y, Filipovich AH, Assa’ad AH, et al. Anti-IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL-5 and IL-5 receptor levels. J Allergy Clin Immunol 2008;121:1473–83, 483. e1–4.
- Roufosse F, de Lavareille A, Schandene L, Cogan E, Georgelas A, Wagner L, et al. Mepolizumab as a corticosteroid-sparing agent in lymphocytic variant hypereosinophilic syndrome. J Allergy Clin Immunol 2010;126:828–35.e3.
- Roufosse FE, Kahn JE, Gleich GJ, Schwartz LB, Singh AD, Rosenwasser LJ, et al. Long-term safety of mepolizumab for the treatment of hypereosinophilic syndromes. J Allergy Clin Immunol 2013;131:461–7.e1-5.
- GSK Clinical Studies Register 2020. Available at: . Accessed January 17, 2020.
- Valent P, Klion AD, Horny HP, Roufosse F, Gotlib J, Weller PF, et al. Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes. J Allergy Clin Immunol 2012;130: 607–12.e9.
- Mendoza TR, Wang XS, Cleeland CS, Morrissey M, Johnson BA, Wendt JK, et al. The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer 1999;85:1186–96.
- Kieser M, Friede T. Simple procedures for blinded sample size adjustment that do not affect the type I error rate. Stat Med 2003;22:3571–81.
- Pavord 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. Lancet 2012;380:651–9.
- Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med 2017;376:1921–32.
- Duncan EA, Ortega H, Gleich G, Price R, Yancey S, Klion A. Observational experience describing the use of mepolizumab in patients with hypereosinophilic syndrome. Am J Respir Crit Care 2015;191:A1365.
Source: PubMed