Molecular Heterogeneity, Biomarker Discovery, and Targeted Therapy in Asthma - Genomic Biomarkers for Pharmaceutical Development - page 88

such, any cutoffs applied to enable treatment decisions will necessarily require a tradeoff
between the magnitude of treatment benefit and the size of the treatment-eligible popula-
tion. Further complicating this issue is the possibility that different biomarker cutoffs may
be optimal for different outcome measures with regard to a particular intervention. Even in
the case of pharmacogenomic biomarkers defined by specific polymorphisms, it is clear that
no single genetic variant will cleanly delineate asthma phenotypes; rather it is likely that
many polymorphisms, each with a small effect size, contribute to the genetic component of
asthma. Finally, more precise and physiologically direct outcome measures are needed to
link therapeutic targets and clinical outcome measures: while FEV1 and exacerbations are
valid and approvable outcomes for asthma trials, the physiological mechanisms whereby
specific molecular pathways contribute to lung function in human asthma are unclear.
High-resolution imaging technologies, bronchoscopies before and after treatment, and sur-
rogate biomarkers of specific physiological processes may help to explain the molecular,
cellular, and physiological mechanisms linking targets to clinical endpoints in better detail.
Fortunately, the proliferation of novel agents targeting specific mediators and pathways, if
rigorously examined in well designed clinical studies, will generate data to test the hypoth-
eses underlying asthma 'endotypes', as successful therapeutic intervention in a particular
pathway is necessary to confirm that pathway as a key mediator of disease.
Acknowledgments
We wish to thank Ted Rigl and Heleen Scheerens for critical review and helpful comments on the manuscript.
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