Molecular Heterogeneity, Biomarker Discovery, and Targeted Therapy in Asthma - Genomic Biomarkers for Pharmaceutical Development - page 71

clinical guideline-based ICS dosing [18-20] . However, a subset of approximately 10% of
asthma patients does not achieve adequate disease control even on high doses of ICS; this
'ICS-refractory' subset consumes a disproportionate share of health care expenditure and
represents the most significant unmet medical need in asthma [21,22] . There are several
non-mutually exclusive reasons why a given asthma patient may not achieve adequate dis-
ease control on ICS. These include poor adherence to prescribed therapy [17,23] , intrinsic or
acquired resistance to the molecular mechanism of action of steroids [24,25] , or pathophysiol-
ogy that is not inherently responsive to the effects of steroids. Development of new, molecu-
larly targeted asthma therapies has been directed at the ICS-refractory population [26-28] , but
this population exhibits substantial heterogeneity [6] , [29,30] . Thus, to interrogate whether a
particular therapeutic candidate has the potential to show efficacy, it is important to assess the
intervention in the patients most likely to have activity of the targeted pathway.
In this chapter we will describe our efforts, in collaboration with numerous colleagues in
academia and industry, to define asthma heterogeneity in molecular terms and use that infor-
mation to develop biomarkers that define asthma subsets and a novel therapy targeted at
a subset of asthma patients. We will consider our findings in the context of recent publica-
tions of proof-of-concept clinical studies of candidate asthma therapeutics and an emerging
appreciation of the challenges inherent in developing companion diagnostic tests alongside
novel therapeutics. This is a rapidly evolving field and as of this writing, the therapeutic can-
didates and biomarkers discussed here had not yet been validated in pivotal clinical trials
nor approved for the treatment of asthma. It should also be acknowledged that the issues
and recommendations we raise with respect to the development of personalized therapies
for asthma reflect our own experience and opinions and have not been formally endorsed by
any regulatory authorities for any specific asthma therapies or biomarkers.
4 .2 MOLECULAR HETEROGENEITY IN ASTHMA
4.2.1 Gene Expression Studies in the Asthmatic Airway
Although many studies have used genomic technologies to identify patterns that differ-
entiate a given disease from other diseases or healthy controls, relatively few studies have
used genomic technologies to characterize heterogeneity within a clinically defined non-
neoplastic disorder such as asthma. One of the first studies to examine gene expression in
airway tissues from asthma patients was conducted by Woodruff et al. [31] , in which bron-
chial epithelial brushings from 42 mild-moderate asthma patients and 28 non-asthmatic
controls were assessed by genome-wide expression microarrays. In this study, gene expres-
sion was compared between healthy controls and all asthmatics taken together. Using a
fairly conservative analytical approach with Bonferroni correction for multiple testing,
only 22 probesets achieved genome-wide significance for being significantly differentially
expressed between asthma and control. Thirteen were expressed at higher levels and nine
were expressed at lower levels in asthmatics than in control subjects. Given the considerable
clinical and physiological differences in airway function between the asthma patients and
controls in this study, one might have expected a greater number of differentially expressed