93Role of Biomarkers in Development of Personalized Drugs
In addition to personalizing the use of existing drugs, the development of new
personalized drugs should start at the discovery stage. One example of this is phar-
macogenetics/pharmacogenomics-based monoclonal antibody (MAb) drug devel-
opment in oncology. Another example of the usefulness of biomarkers in
development of personalized medicine is biomarkers for Huntington’s disease
(HD). Genome-wide gene expression profi les from blood samples of HD patients
have identifi ed changes in blood mRNAs that clearly distinguish HD patients from
controls. The elevated mRNAs is signifi cantly reduced in HD patients involved in a
dose-fi nding study of the histone deacetylase inhibitor sodium phenylbutyrate.
These alterations in mRNA expression correlate with disease progression and
response to experimental treatment. Such biomarkers may provide clues to the state
of HD and may be of predictive value in clinical trials.
The advantage of applying biomarkers to early drug development is that they
might aid in preclinical and early clinical decisions such as dose ranging, defi nition
of treatment regimen, or even a preview of effi cacy. Later in the clinic trials, bio-
markers could be used to facilitate patient stratifi cation, selection and the descrip-
tion of surrogate endpoints. Information derived from biomarkers should result in a
better understanding of preclinical and clinical data, which ultimately benefi ts
patients and drug developers. If the promise of biomarkers is realized, they will
become a routine component of drug development and companions to newly dis-
covered therapies.
Drug Rescue by Biomarker-Based Personalized Medicine
Biomarkers can rescue drugs by identifying the patients that respond to them.
Herceptin, approved in 1998, emerged as a $480 million-per-year winner only a
decade after clinical trials showed little or no effi cacy. Only when the 20–30 % of
women with breast cancer whose tumors overexpress HER2 were singled out, was
the drug’s effi cacy indisputable. In the pivotal clinical trial of patients with meta-
static breast cancer, tumor-response rates to Herceptin plus chemotherapy were
45 %, compared to 29 % for chemotherapy alone.
But response is not wholly predictable. Reported response rates for HER2-
positive cancers vary from <20 % to >75 %. HER2-positive cells that do not respond
to Herceptin may have more active forms of the kinase Akt, whereas HER2 belongs
to a receptor family that can be activated by 11 different soluble proteins and com-
binations thereof. Investigation of the biology behind the biomarker is likely to
improve treatment of breast cancer. Similarly, the lung-cancer drug Iressa (gefi tinib)
could be rescued by a diagnostic based on a biomarker. Unfavorable clinical trial
results were disappointing, but fi nding the patients most likely to benefi t improved
the outlook. Various studies found that patients that responded to Iressa had
mutations in the gene for EGFR.
Drug Rescue by Biomarker-Based Personalized Medicine