Application of Translational Science to Clinical Development - Genomic Biomarkers for Pharmaceutical Development - page 3

into innovative therapeutics that extend and enhance the lives of patients with unmet medi-
cal needs.
We believe that judicious application of genomic analysis to develop greater understanding
of the molecular underpinnings of complex diseases such as cancer, rheumatic and respiratory
diseases will lead to novel targets and therapeutics that are tailored to subsets of these dis-
eases. Together with biomarkers that identify subsets of patients likely to benefit (or not) from
targeted therapies, such therapeutics are likely to have a greater PoS in clinical development
than those that target all-comers. In this chapter we describe current and emerging transla-
tional strategies to apply our expanding genomic knowledge to this end. For the purpose of
this discussion, we define 'translational science' as treating the 'right' patient with the 'right
drug' at the 'right dose'. Our objective here is to illustrate broad strategies for identifying the
right patient, the right drug and right dose using examples from the literature. We include in
our definition of the right patient not only those that will benefit from a novel therapeutic but
also those that are less likely to be harmed by it, and we end the chapter with a discussion
about adverse drug reactions.
1.2 TWO APPROACHES TO IDENTIFY PATIENT SUBSETS
THAT ARE LIKELY TO RESPOND TO INDIVIDUAL
THERAPEUTIC INTERVENTIONS
The current paradigm for drug development is to test a new drug candidate in a vari-
ety of diseases, such as different types of solid tumors including prostate, breast, colon
or hematologic malignancies. Depending on whether a positive signal in a small trial is
observed, a couple of indications are selected to conduct follow up larger registrational
trials. While this approach has been successful in the past, it is also a key contributor to
the ever-increasing cost of drug development; perhaps more importantly it exposes many
patients to therapies from which they are unlikely to benefit because the disease of inter-
est is not primarily driven by the targeted pathway in all patients. Viewed from a slightly
different perspective, this approach in effect uses the investigational drug to probe the
underlying disease in a given patient to assess whether it is amenable to the pathway that
is targeted by the drug.
An emerging approach, which is outlined in Fig. 1.3 , is to understand, using genomic
approaches (e.g., sequencing of tumors or gene expression analysis of relevant tissue), het-
erogeneity of disease first and thus identify subsets of patients in whom a biological path-
way is activated by mutation or by elevated expression of genes in the pathway. The disease
in such patients may, therefore, be causatively linked to a particular biological pathway and
thus be amenable to therapeutics targeted to the pathway.
Such patients - the right patients - are then targeted with a therapeutic that is tailored
to them - the right drug. Key to the success of this approach is a reliable way to identify
such patient subsets, i.e., a companion diagnostic to the tailored therapeutic that is economi-
cally viable and can be easily implemented in the clinic. We illustrate this approach using
the example of crizotinib (Xalkori®) from Pfizer, an ALK (anaplastic lymphoma kinase) and
ROS1 (c-ros oncogene1, receptor tyrosine kinase) inhibitor that was approved in 2011 for
patients with a particular kind of non-small cell lung cancer (NSCLC) [6] .