Review and Feature Article
The Relationship of Asthma Biologics to Remission for Asthma

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Asthma treatments have evolved from bronchodilators to interventions directed toward the regulation of airway inflammation. From these advances has come greater disease control and reduced morbidity. The addition of biologics directed toward specific pathways of inflammation has advanced the efficacy of asthma control. With these treatment advances, a renewed interest in achieving a remission in asthma has arisen. Although asthma remission has been considered to reflect a “cure,” new evaluations of this concept have proposed criteria for remission while on treatment. These criteria reflect a high level of disease control including absence of symptoms, optimization and stabilization of lung function, and absence of the use of systemic corticosteroids and have been proposed to indicate a remission of disease activity. Given the added efficacy found with biologics in asthma treatment for patients with moderate to severe disease, the question has arisen as to whether the use of biologics meets criteria for remission and may this change a component of underlying disease and risks. Biologics are highly effective in reducing exacerbations, diminishing symptoms, and improving lung function in well-defined asthma populations. At present, however, biologics achieve some, but in most cases not all criteria for a remission on treatment. However, the concept of promoting treatment efforts to achieve disease remission in asthma is important, potentially achievable, and merits consideration for future guideline-directed care approaches.

Introduction

Over the last 80 years, there have been significant advances in asthma therapy resulting from interactions between clinical care, broad-spectrum science efforts, and the pharmaceutical industry (Figure 1).1 Attention in the mid-1970s was directed toward relieving symptoms and airflow obstruction, with a therapeutic focus placed on β-adrenergic agonists.1 In the 1980s, airway inflammation was recognized as a critical and causative feature of asthma and that certain medications could block allergic reactions, leading to development of inhaled corticosteroid therapy.1 In the 1990s, inhaled corticosteroid therapy emerged as the cornerstone of asthma management, with bronchodilators serving as reliever therapy or supplementary therapy.1 A major limitation of inhaled corticosteroid therapy has been its failure to alter the natural history of asthma, including asthma progression.2 The early 2000s witnessed the introduction of asthma biologic therapies, initially with anti-IgE (omalizumab), followed 10 years later by the approval of antieosinophilic therapies (mepolizumab, benralizumab, reslizumab) and more recently anti-IL-4/-13–directed treatment (dupilumab).1 The latter agents have noteworthy properties of decreasing asthma exacerbations and oral corticosteroid exposure. Biologics in development against epithelial-derived cytokines hold great promise to fundamentally alter the airways inflammation that is driving asthma. It remains to be seen whether biologics can alter the course of asthma by inducing remission, preventing disease progression, or perhaps even blocking the onset of asthma. In managing populations of patients with asthma, for example, in a medical system, principles of individualized therapy based on biomarkers, genetics, and patient characteristics will be incorporated in selecting asthma medications.1

This review will consider current concepts of asthma remission, evaluate experience suggesting that biologic therapies may have the potential to induce remission, and review the steps necessary to determine how we could evaluate a medication's capability of inducing remission and how we might apply this methodology to current clinical management.

Section snippets

What does Remission Mean in Asthma?

The established paradigm of asthma management aims to improve asthma control, with any definition of asthma remission being of theoretical interest at best.3 Improved understanding of the pathophysiology of asthma, in combination with the development of targeted biologic therapies with improved control of disease, however, mandates the development of an asthma remission definition, because it may now, or soon, be an achievable treatment target and become a component of guideline-directed care.

Does the Use of Biologics Lead to a Remission in Asthma?

The use of biologics for severe asthma has provided therapeutic efficacy to achieve disease control when standard guideline-directed treatments are not effective. Five mAbs (Table I) are currently approved for use in severe asthma and target components of type 2 (T2) pathways of inflammation, including IL-4, IL-5, and IL-13, which are present in approximately 70% of patients with asthma.8,9 Given the added efficacy achieved when biologics are added to previous treatment that did not produce

Anticytokine Biologics

IL-4, IL-5, and IL-13 are the central mediators for T2 inflammation.12 MAbs directed against IL-5 and IL-4/IL-13 are approved for treatment of severe asthma (Table I). Collectively, but to varying degrees, T2 antagonists prevent asthma exacerbations, improve airflow obstruction, and reduce symptoms, all target features incorporated into the definition for remission. Furthermore, as will be reviewed, long-term observation periods with some monoclonals provide enriched insight into achievement of

Effect of Reductions of Systemic Corticosteroids With Biologic Treatment on Asthma Control

The need for systemic corticosteroid treatment to maintain disease control identifies patients with asthma with the most severe disease and greatest recalcitrance to current treatment approaches. In considering whether biologics may contribute to asthma remissions, an argument can be made that a reduction, or elimination, in systemic corticosteroids leads to a remission of a component of severe asthma. Evaluations of the effects of biologics in these patients are, we believe, important to

What are the Next Steps in Designing and Assessing Therapies to Induce Remission?

We can conclude, as a group, that current biologics are efficacious in achieving improved disease control in patients with severe disease with characteristics of T2 inflammation but do not meet criteria for remission in all treated subjects, or all the criteria for remission. The criteria for remissions most frequently achieved were a reduction in exacerbations. What is needed next is an analysis on the frequency of patients treated by available biologic treatments meet and criteria for a

Summary

Therefore, the future directions in asthma treatment to gain disease control, especially with asthma biologics, should determine whether they offer a unique feature beyond conventional therapy, including the establishment of a disease remission. It would be ideal if current or future medications could alter asthma progression and, perhaps, have the potential for early intervention to halt the onset of asthma and thus reflect disease remission. Asthma guidelines in the future should emphasize

References (26)

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Conflicts of interest: A. Menzies-Gow has attended advisory boards for GlaxoSmithKline, Novartis, AstraZeneca, Boehringer Ingelheim, Teva, and Sanofi; has received speaker fees from Novartis, AstraZeneca, Vectura, Boehringer Ingelheim, and Teva; has participated in research for which his host institution has been remunerated by AstraZeneca; has attended international conferences sponsored by Teva and Boehringer Ingelheim; and has consultancy agreements with AstraZeneca, Vectura, and Sanofi, outside the submitted work. S. J. Szefler has served as a consultant to Aerocrine, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Genentech, GlaxoSmithKline, Novartis, Propeller Health, Regeneron, Roche, Sanofi, and Teva, outside the submitted work. W. W. Busse reports personal fees from Boston Scientific, AstraZeneca, GlaxoSmithKline, Novartis, Sanofi/Genzyme-Regeneron, Genentech, Elsevier, and Medscape, outside the submitted work.

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