Molecular Heterogeneity, Biomarker Discovery, and Targeted Therapy in Asthma - Genomic Biomarkers for Pharmaceutical Development - page 87

study subjects. Regulations in different countries may be variable. In the European Union, for
example, though diagnostic tests can be placed on the market in a more simplified manner by
seeking a Conformité Européenne (CE) mark to self-declare that the product meets regula-
tory requirements, there is a mechanism for early consultation with the European Medicines
Agency's Scientific Advisory Group on Diagnostics (SAG-D), which can be requested by the
Committee for Medicinal Products for Human Use (CHMP) to review scientific and technical
aspects of a proposed companion diagnostic program and provide advice to the companies
sponsoring the combined development of the drug and device.
Although most companion diagnostic tests approved thus far have been tissue-based
assays for oncology or infectious disease indications, some examples of serum protein-
based diagnostics for use in inflammatory disorders like asthma are also now under devel-
opment. Each platform and situation has its own challenges. As detailed in this chapter,
we have worked on the development of a serum test for the measurement of periostin, a
protein whose expression is linked to the presence of IL13, which has been implicated in
asthma pathogenesis. Serum periostin levels were used in a pre-specified retrospective
analysis of a Phase II trial to predict the clinical response of patients with asthma to leb-
rikizumab, an anti-IL13 biological therapy [72] . We spent many years collecting supportive
data in small pilot studies without lebrikizumab to try to understand periostin biology and
what a relevant threshold for a 'normal' level of periostin might be. Despite these efforts,
it was recognized from the beginning that until the clinical experiment with the drug had
been conducted and repeated to confirm the previous findings, the relationships between
the biomarker, the drug target, the disease, and the drug would be incompletely understood
at best. Though it has been challenging to provide a wealth of information about the peri-
ostin biology in health and disease in a relatively compressed timeframe to allow it to be
used in an informed manner by the lebrikizumab drug development program, the lessons
learned from these studies will advance the field toward better understanding a segment of
asthma pathophysiology, and may redefine how we approach the treatment of patients with
asthma.
4.5 OUTLOOK FOR THE FUTURE
As more clinical experience is accrued with novel asthma therapeutics and biomarkers,
several key issues will need to be addressed to increase the chances of success for personal-
ized health care in asthma. First, a clearer consensus on how asthma heterogeneity should
be defined is needed, not least to foster recognition on the part of regulatory authorities that
asthma is a heterogeneous disorder and that asthma heterogeneity has a molecular basis.
Second, as discussed above, the promising initial findings in proof-of-concept clinical stud-
ies must be replicated and extended in larger pivotal studies. These studies will be instru-
mental in defining effect sizes and biomarker cutoffs more precisely. Third, as a corollary
to the first two points, clinical outcome measures and biomarker assays should be stand-
ardized to the extent possible to enable better comparisons between clinical trials. Fourth,
the gradients, as opposed to sharp demarcations, between asthma subtypes need to be bet-
ter appreciated in the context of interventional studies. Thus far, most biomarkers used
to define asthma 'subtypes' exhibit continuous rather than multimodal distributions. As