Associate Editor: J.S. Fedan
Drug development for severe asthma: What are the metrics?

https://doi.org/10.1016/j.pharmthera.2012.05.005Get rights and content

Abstract

Although reversible airway obstruction in part defines asthma, lung function as measured by spirometry alone inadequately predicts the value of new therapeutic agents in the treatment of severe asthma.

Our objectives are 1) to review whether pulmonary function and bronchodilator reversibility are endpoints for drug discovery and 2) to identify parameters that predict efficacy in drug development in severe asthma.

An English language literature search using MedLine and PubMed was conducted from 1997 to present concerning pathophysiology, diagnosis and therapy of severe asthma using the terms “severe asthma,” “irreversible asthma,” “difficult asthma,” “airway remodeling,” “fixed airway obstruction,” “reversibility” and “bronchodilator reversibility” as index terms. Eight studies were characterized that encompass 1424 subjects with asthma.

Our review identified the limitations of using bronchodilator reversibility as a predictor in drug development for severe asthma. Neither improvement in lung function nor bronchodilator reversibility characterized the benefit of new drugs in the treatment of severe asthma. Newly approved drugs in the treatment of severe asthma show decreased asthma exacerbations and improved quality of life associated with steroid-sparing benefits without altering bronchodilator responsiveness or improving lung function.

Although changes in lung function predict asthma control in mild/moderate asthma, lung function alone is inadequate to assess improvement in asthma control in severe asthma manifested by fixed airway obstruction. Endpoints that focus on asthma control, as defined by the Expert Panel Report 3 and GINA guidelines, may predict the value of new therapeutics in the management of severe asthma.

Introduction

Asthma, a syndrome characterized by airway hyperresponsiveness (AHR), obstruction and inflammation, remains a substantial financial burden globally due to increasing morbidity and mortality (GINA, National Asthma Education and Prevention Program, 2007). Despite considerable progress in understanding fundamental mechanisms inducing AHR and inflammation, therapeutic approaches to manage severe disease remain a significant unmet need (Jarjour et al., 2012). Disproportionately, patients with severe persistent asthma have profound decreases in quality of life and frequently require emergency department visits, hospitalizations and unscheduled physician visits (Jarjour et al., 2012). Further, patients with severe disease also manifest glucocorticoid insensitivity and irreversible airflow obstruction. International programs, such as the Global Initiative for Asthma (GINA) and the National Asthma Education Prevention (NAEP) Program, have focused attention on the characterization of severe asthma as shown in Table 1 (Jarjour et al., 2012). Compelling evidence suggests that patients with severe disease also represent a heterogeneous group that poses challenges in novel drug discovery (Lotvall et al., 2011, Jarjour et al., 2012). Despite attempts to clarify case definitions for severe asthma, few new therapeutics have been developed. The challenges in characterizing severe asthma and the use of metrics or clinical outcomes designed for less severe disease impede progress (Jarjour et al., 2012). The goals of this review are to summarize case definitions of severe asthma, review outcomes used recently in the approval of therapeutics in severe asthma and address new approaches to characterize the heterogeneity of these patients that may lead to composite metrics for drug discovery.

Section snippets

Current metrics for drug discovery in severe asthma

The World Health Organization, the Global Initiative for Asthma (GINA) and the National Asthma Education Prevention (NAEP) Program recognize that global asthma morbidity and mortality are increasing (GINA, National Asthma Education and Prevention Program, 2007). Despite progress in understanding asthma, there remains an unmet need to develop new therapeutics in the management of the disease. In less severe asthma, long-acting bronchodilators, inhaled corticosteroids (ICS) and leukotriene

Lessons learned

Since the formulation of improved case definitions of asthma by the World Health Organization, GINA and NAEP, therapeutic agents have recently been approved or reviewed by federal agencies in the treatment of severe asthma. Accordingly, we reviewed the publicly available English literature from 1997 and surveyed using search terms for “severe asthma,” “asthma pathophysiology,” “airway hyperresponsiveness,” “bronchodilator,” “irreversible asthma,” “fixed airway obstruction,” “difficult asthma,”

New approaches

Asthma remains a complex, heterogeneous syndrome whose pathogenesis likely encompasses different etiologies and pathophysiologies. Many phenotypes exist as defined by physiology, triggers and inflammatory parameters (Lotvall et al., 2011). The majority of patients with asthma are atopic; however, 30% to 40% are non-atopic patients who are often overrepresented in severe asthma (Arbes et al., 2007, Moore et al., 2007, Jarjour et al., 2012). Over the past five years, SARP demonstrated specific

Conclusions

Development of therapeutics in severe asthma has focused on inclusion of patients with bronchodilator reversibility and improvement in baseline pulmonary function. Until the Food and Drug Administration approval of omalizumab in 2003, the only approvable primary endpoint for asthma drugs in the US was change in FEV1. Other symptomatic endpoints could be co-primary endpoints but superiority of the active over placebo required improvement in the FEV1. Omalizumab was approved by showing a

References (34)

  • National Asthma Education and Prevention Program, N.-N. (2007). Expert Panel Report 3: Guidelines for the Diagnosis and...
  • Asthma Insight and Management
  • E.D. Bateman et al.

    Rate of response of individual asthma control measures varies and may overestimate asthma control: an analysis of the goal study

    J Asthma

    (2007)
  • L.P. Boulet et al.

    Evaluation of asthma control by physicians and patients: comparison with current guidelines

    Can Respir J

    (2002)
  • M. Castro et al.

    Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial

    Am J Respir Crit Care Med

    (2010)
  • K.R. Chapman et al.

    Suboptimal asthma control: prevalence, detection and consequences in general practice

    Eur Respir J

    (2008)
  • R. Djukanovic et al.

    Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma

    Am J Respir Crit Care Med

    (2004)
  • Cited by (0)

    This study was supported by grants from the National Institutes of Health: ES013508 and HL097796.

    View full text