Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Applying Pharmacogenomics in Drug Discovery and Development
85
data to guide patient selection during subsequent stages of drug development and
to establish guidelines for usage after the drug has been approved. 65,66 This strategy
helps streamline the clinical trial process and reduce the number of patients
needed for each phase; more patients are likely to respond to the drug and fewer are
likely to drop from the study due to the reduced risk of developing ADRs. The collected
pharmacogenomic data can also be used to identify biomarkers that predict
whether patients could respond well to the drug.
Targeted therapies should be used only for patients who express the target of
interest and/or have altered expression levels of the target. Because most diseases
have multiple causes and because not all patients could harbor the target of interest,
testing of the target is necessary. Pharmacogenomic testing can be used to determine
whether the patient harbors the target and thereby predict whether the patient
is likely to benefit from the drug. The codevelopment of pharmacogenomic tests is
becoming increasingly common, particularly for anticancer drugs. This is undoubtedly
related to the high cost, toxicity profiles, and the fact that many anticancer drugs
are targeted therapies. An example is crizotinib, an ATP competitive kinase inhibitor
that targets c-Met, ALK, ROS, and is used to treat NSCLC. A pharmacogenomic
test (the Vysis ALK Break Apart FISH Probe Kit; Abbott Molecular; www.abbottmolecular.com),
which detects genetic rearrangements involving the ALK gene, was
codeveloped with crizotinib, and allowed for its rapid development and approval.
The lead drug was developed in 2005, and, based on data from a phase III study that
showed 88% clinical benefit, crizotinib received FDA approval in 2011. 67 As only
6% of NSCLC patients harbor ALK gene fusions, 68 it is essential that patients are
screened for this target prior to prescription of crizotinib. The test was developed
during preclinical studies (cell line and animal studies) based on the target kinase
profiles in the molecularly defined target population; during these studies, ALK was
identified as a predictive marker and a test developed that allowed for selection of
patients in subsequent clinical studies. 68 Clearly, in this particular case, codevelopment
of a pharmacogenomic test has proved to be hugely beneficial to both patients
and the drug company.
Pharmacogenomic testing is also used to screen patients to be enrolled in
phase I and II clinical trials for polymorphisms and other genetic alterations that
have been shown to affect metabolism and/or efficacy of the drug in preclinical
studies. 69 Patients should be excluded from clinical trials or have dose adjustments
if they harbor polymorphisms that are more likely to place them at risk of developing
treatment-related toxicity, or, in the case of prodrugs, harbor polymorphisms
that affect drug efficacy. A number of tests are available to detect CYP450 enzyme
polymorphisms: for example, the Roche AmpliChip Cytochrome P450 genotyping
test (www.roche.com). 39,70,71
To date, over 80 FDA-approved drugs contain information regarding pharmacogenomic
testing within their drug label (Table 4.1). 72 Ideally, pharmacogenomic
tests should be codeveloped with the drug, beginning in preclinical studies. Such
testing can allow clinical trials to be streamlined and benefit both patients and
drug companies; fewer patients are needed for a clinical trial if the anticipated
effect size is larger and patient drop rate is lower. The reality is that the majority
of tests are developed and/or recommended post approval after severe ADRs have