Elsevier

Biochemical Pharmacology

Volume 179, September 2020, 113978
Biochemical Pharmacology

Review
Prediction of response to biological treatment with monoclonal antibodies in severe asthma

https://doi.org/10.1016/j.bcp.2020.113978Get rights and content

Abstract

In recent years, major developments have occurred in severe asthma management. Different asthma phenotypes and subgroups have been identified and new treatment options have become available. A total of five monoclonal antibodies are currently approved in severe asthma treatment: omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab. These drugs have been shown to reduce exacerbations and to have an oral corticosteroid-sparing effect in many severe asthma patients. However, biological treatment is not successful in all patients and should be discontinued in non-responsive patients. Treating the right patient with the right biologic, and therefore biologic response prediction, has become a major point of interest in severe asthma management. A variety of response outcomes is utilized in the different clinical trials, as well as a huge range of potential predicting factors. Also, regarding the timing of the response evaluation, there are considerable differences between studies. This review summarizes the results from studies on predicting responses and responders to biological treatment in severe asthma, taking into account clinical, functional and inflammatory parameters assessed prior to the start of treatment as well as following a few months of therapy. In addition, future perspectives are discussed, highlighting the need for more research to improve patient identification and treatment responses in the field of biological treatment in severe asthma.

Introduction

Patients with severe asthma require high-dose inhalation therapy to control their disease. These patients experience frequent exacerbations, and they often depend on the chronic use of oral corticosteroids (OCS) with associated serious adverse effects.[1] In recent years, major developments occurred in severe asthma management. Different asthma phenotypes and subgroups were identified [2] and new treatment options have become available in the form of monoclonal antibodies (MABs).[3] Although these novel biological agents have shown promising results in many patients with asthma, it is evident that not all patients respond equally well. This difference in treatment response may be multifactorial and related to the heterogeneity of the severe asthma population or the different underlying molecular pathways, but also drug and treatment strategy related factors may play a role. Optimal use of biologics, both in terms of costs and prevention of unnecessary patient exposure, is of the utmost importance. A Dutch cost estimation indicates the drug costs per patient per year in the Netherlands at €15.000,-.[4] Unfortunately, it is not yet clear which patients will respond to which biologic. Therefore, biologic response prediction has become a major point of interest in severe asthma management.

The present article shortly describes asthma phenotypes, and inflammatory mechanisms and pathobiologic features leading to severe asthma. Furthermore, the pharmacological mechanism of action and clinical outcomes of the currently available biologics for severe asthma are summarized. Then, we thoroughly review predictors of response to the currently registered biologics and, finally, discuss recent developments and future perspectives in response prediction.

Section snippets

Asthma subtypes and pathobiology

Asthma is a heterogeneous, inflammatory airway disease in which different phenotypes have been identified based on clinical, functional or inflammatory parameters.[2] Late-onset eosinophilic asthma is currently one of the most well-defined asthma phenotypes with a clearly different clinical profile from that seen in classic childhood-onset allergic asthma.[5] Patients with late-onset eosinophilic asthma show eosinophilic inflammation in blood as well as sputum and frequently report absence of

Predictors of response

The main objective of phase I-III clinical trials is the assessment of efficacy and safety. Knowing which patient will respond in real-life is a different objective and usually not established at the moment of market approval of the biologic. Prediction of treatment responses is not easy and has to deal with various problems: e.g. how to define a response or responder, what are clinically relevant outcome measures [51], and what should be the timing of the evaluation of response. Since

Future perspectives

New perspectives in response prediction of the MABs used in severe asthma may present themselves in the near future. Four possible aspects will be highlighted below.

Conclusion

This article summarizes the current state of knowledge on response prediction of biological treatment in severe asthma. Studies that explore the predictability of biologic efficacy are mainly based on post-hoc analyses of the large registration trials or small exploratory studies with a limited number of patients. Although these studies provide some insight, there are still several issues that require further evidence. For example, what is the best timing to assess biologic response or when can

CRediT authorship contribution statement

J.A. Kroes: Investigation, Formal analysis, Writing - original draft, Writing - review & editing. S.W. Zielhuis: Conceptualization, Writing - review & editing, Supervision, Funding acquisition. E.N. van Roon: Writing - review & editing, Supervision. A. ten Brinke: Conceptualization, Writing - review & editing, Supervision.

Declaration of Competing Interest

JA Kroes: No conflicts of interest to disclose.

A ten Brinke: Unrestricted research grants GSK, TEVA. Research advisory boards GSK, Novartis, AstraZeneca, Boehringer Ingelheim, Chiesi, Sanofi. Honoraria lectures GSK, Novartis, Teva, Boehringer Ingelheim.

SW Zielhuis: Advisory boards Novartis, AstraZeneca, Sanofi. Honoraria lectures MSD. Until 2007 employed at Teva NL, but no involvement since then.

EN van Roon: No conflicts of interest to disclose.

Acknowledgements

This article was supported by funding of the Medical Centre Leeuwarden Science Fund, the Netherlands.

The authors would like to thank Olga van Dijk and colleagues from the MCL Academy for the reference acquisition for this study.

References. (131)

  • C.E. Jia et al.

    The Asthma Control Test and Asthma Control Questionnaire for assessing asthma control: Systematic review and meta-analysis

    J. Allergy Clin. Immunol.

    (2013)
  • E.F. Juniper et al.

    Validation of a standardized version of the Asthma Quality of Life Questionnaire

    Chest

    (1999)
  • M. Suzukawa et al.

    Baseline serum CXCL10 and IL-12 levels may predict severe asthmatics' responsiveness to omalizumab

    Respir. Med.

    (2018)
  • J. Bousquet et al.

    Predicting and evaluating response to omalizumab in patients with severe allergic asthma

    Respir. Med.

    (2007)
  • I.D. Pavord et al.

    Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial

    Lancet

    (2012)
  • J. Silver et al.

    Baseline percent predicted fev1 does not predict a response to mepolizumab in patients with severe eosinophilic asthma: meta-analysis from two phase 3 trials

    Chest

    (2019)
  • G.L. Chupp et al.

    Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial

    Lancet Respir. Med.

    (2017)
  • H.G. Ortega et al.

    Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies

    Lancet Respir. Med.

    (2016)
  • F.C. Albers et al.

    Baseline blood eosinophil count as a predictor of treatment response to the licensed dose of mepolizumab in severe eosinophilic asthma

    Respir. Med.

    (2019)
  • S.W. Yancey et al.

    Biomarkers for severe eosinophilic asthma

    J. Allergy Clin. Immunol.

    (2017)
  • S. Arakawa et al.

    Expression of Siglec-8 is regulated by interleukin-5, and serum levels of soluble Siglec-8 may predict responsiveness of severe eosinophilic asthma to mepolizumab

    Allergol. Int.

    (2018)
  • L. Condreay et al.

    No genetic association detected with mepolizumab efficacy in severe asthma

    Respir. Med.

    (2017)
  • G. Brusselle et al.

    Reslizumab in patients with inadequately controlled late-onset asthma and elevated blood eosinophils

    Pulm. Pharmacol. Ther.

    (2017)
  • J. Corren et al.

    Phase 3 Study of Reslizumab in Patients With Poorly Controlled Asthma: Effects Across a Broad Range of Eosinophil Counts

    Chest

    (2016)
  • J.M. FitzGerald et al.

    Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies

    Lancet Respir. Med.

    (2018)
  • K.F. Chung et al.

    International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

    Eur. Respir. J.

    (2014)
  • E.H. Bel

    Clinical phenotypes of asthma

    Curr. Opin. Pulm. Med.

    (2004)
  • Horizonscangeneesmiddelen mepolizumab....
  • de Groot JC, Ten Brinke A, Bel EH. Management of the patient with eosinophilic asthma: a new era begins. ERJ Open Res....
  • Jantina C. de Groot et al.

    Clinical profile of patients with adult-onset eosinophilic asthma

    ERJ Open Res

    (2016)
  • E. Israel et al.

    Severe and Difficult-to-Treat Asthma in Adults. N.Engl

    J. Med.

    (2017)
  • P. Haldar et al.

    Cluster analysis and clinical asthma phenotypes

    Am. J. Respir. Crit. Care Med.

    (2008)
  • B.N. Lambrecht et al.

    The immunology of asthma

    Nat. Immunol.

    (2015)
  • C.M. Lloyd et al.

    Functions of T cells in asthma: more than just T(H)2 cells

    Nat. Rev. Immunol.

    (2010)
  • B. Kim et al.

    Fundamental role of dendritic cells in inducing Th2 responses

    Korean J. Intern. Med.

    (2018)
  • D.K. Chu et al.

    Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo

    J. Exp. Med.

    (2014)
  • A. Kato et al.

    TLR3- and Th2 cytokine-dependent production of thymic stromal lymphopoietin in human airway epithelial cells

    J. Immunol.

    (2007)
  • C.S. Klose et al.

    Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis

    Nat. Immunol.

    (2016)
  • J. Zhu

    GATA3 Regulates the Development and Functions of Innate Lymphoid Cell Subsets at Multiple Stages

    Front. Immunol.

    (2017)
  • R. Yagi et al.

    An updated view on transcription factor GATA3-mediated regulation of Th1 and Th2 cell differentiation

    Int. Immunol.

    (2011)
  • D.B. Corry et al.

    Requirements for allergen-induced airway hyperreactivity in T and B cell-deficient mice

    Mol. Med.

    (1998)
  • L.K. Poulsen et al.

    Triggers of IgE class switching and allergy development

    Ann. Med.

    (2007)
  • J.P. Kinet

    The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology

    Annu. Rev. Immunol.

    (1999)
  • C.E. Brightling et al.

    Mast-cell infiltration of airway smooth muscle in asthma. N.Engl

    J. Med.

    (2002)
  • C.N. McBrien et al.

    The Biology of Eosinophils and Their Role in Asthma

    Front. Med. (Lausanne)

    (2017)
  • Z. Zhu et al.

    Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production

    J. Clin. Invest.

    (1999)
  • Hershey GK. IL-13 receptors and signaling pathways: an evolving web. J.Allergy Clin.Immunol. 2003;111:677,90; quiz...
  • G. Aversa et al.

    An interleukin 4 (IL-4) mutant protein inhibits both IL-4 or IL-13-induced human immunoglobulin G4 (IgG4) and IgE synthesis and B cell proliferation: support for a common component shared by IL-4 and IL-13 receptors

    J. Exp. Med.

    (1993)
  • Omalizumab Drugbank information....
  • Mepolizumab Drugbank information....
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