Molecular Heterogeneity, Biomarker Discovery, and Targeted Therapy in Asthma - Genomic Biomarkers for Pharmaceutical Development - page 70

CHAPTER
4
Molecular Heterogeneity,
Biomarker Discovery, and
Target ed Therapy in A sthma
Joseph R. Arron, Jeffrey M. Harris
Genentech, Inc., South San Francisco, California
4. 1 INTRODUCTION: ASTHMA HETEROGENEIT Y
Asthma has been described as a heterogeneous disorder on multiple clinical levels, includ-
ing family history, age of onset, sex, body habitus, environmental triggers, symptoms, comor-
bidities, and responsiveness to specific interventions [1-6] . While in a broad sense some
of these features align across populations of patients, there is no consensus on clinically
defined asthma phenotypes. The concept of 'endotypes' in asthma has recently gained trac-
tion [7] : endotyping refers to an attempt to define specific subtypes of a disorder in terms of
pathophysiologic mechanisms that may be amenable to targeted therapeutic interventions.
However, to prove that a putative pathophysiologic mechanism 'drives' disease in a subset of
asthma patients, successful intervention with therapeutics targeting that mechanism must be
demonstrated.
While it has long been recognized that eosinophilic airway inflammation is a feature of
asthma, a large and growing body of more recent evidence has shown that not all asthma
patients have eosinophilic airway inflammation, and that asthma patients with variable lev-
els of eosinophilia respond differently to anti-inflammatory therapies [3,6-13] . In particular,
inhaled corticosteroids (ICS), the standard of care for most asthma patients, do not confer
benefit to all asthmatics [14] . In several studies, ICS show greater efficacy in patients defined
as having 'eosinophilic' disease than in 'noneosinophilic' patients. ICS treatment gener-
ally reduces the amount of airway inflammation as measured by sputum or tissue eosino-
phils or Fractional exhaled nitric oxide (FeNO) [11,15-17] . Furthermore, in ICS-responsive
patients, titrating steroid dose to the level of airway eosinophilia or FeNO has been shown
to reduce the rate of exacerbations and/or improve asthma control more effectively than