Associate Editor: J.S. FedanDrug development for severe asthma: What are the metrics?☆
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)
- et al.
Asthma cases attributable to atopy: results from the third National Health and Nutrition Examination Survey
J Allergy Clin Immunol
(2007) - et al.
Targeting TNF-alpha: a novel therapeutic approach for asthma
J Allergy Clin Immunol
(2008) - et al.
Airway remodeling and lack of bronchodilator response in steroid-resistant asthma
J Allergy Clin Immunol
(2007) Pathophysiology of asthma: what has our current understanding taught us about new therapeutic approaches?
J Allergy Clin Immunol
(2011)- et al.
Understanding the pathophysiology of severe asthma to generate new therapeutic opportunities
J Allergy Clin Immunol
(2006) - et al.
Identifying ‘well-controlled’ and ‘not well-controlled’ asthma using the Asthma Control Questionnaire
Respir Med
(2006) - et al.
Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome
J Allergy Clin Immunol
(2011) - et al.
Recent asthma exacerbations: a key predictor of future exacerbations
Respir Med
(2007) - et al.
Characterization of the severe asthma phenotype by the National Heart, Lung, and Blood Institute's Severe Asthma Research Program
J Allergy Clin Immunol
(2007) - et al.
Development of the asthma control test: a survey for assessing asthma control
J Allergy Clin Immunol
(2004)