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Like
many drug researchers doing biomarker discovery these
days, the scientists at Bristol-Myers Squibb (BMS)
were uncertain exactly what they would find or how
they would use it when they started looking for
markers of response to their cancer drug Sprycel (dasatinib).
The drug is a dual tyrosine SRC/ABL kinase inhibitor
— a new entrant in an increasingly competitive
field. Looking back, the marker work seems like a
smart move. Dasatinib was recently approved for two
types of leukemia. “Now we’d like to understand
better how dasatinib works in CML [chronic myelogenous
leukemia] and use that information to move it into
some solid tumors,” says Nicholas Dracopoli, vice
president of Clinical Discovery Technologies at BMS.
Dracopoli’s
division didn’t stop their biomarker work with
dasatinib. They are also looking for biomarkers that
will help them to commercially differentiate another
potential new cancer drug — Ixabepilone
(BMS-247550). This drug’s competitors include the
taxanes, which are now available as generics. In
addition, the BMS group is using biomarkers to unravel
the mechanisms underlying side effects from HAART,
which is the mainstay combination therapy for HIV
infection. All of these are instances where biomarkers
are poised to make a valuable contribution to a real
drug project. “The key point is to fit the biomarker
to the question being asked,” Dracopoli says.
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“Now
we’d like to understand better how dasatinib
works in CML [chronic myelogenous leukemia] and
use that information to move it into some solid
tumors,”
Nicholas Dracopoli, Bristol-Myers Squibb |
A
growing number of companies such as BMS are at least
experimenting with biomarkers in real projects. “I
think more pharmaceutical companies are getting on the
bandwagon and realizing that biomarkers can help them
from target identification through human trials,”
says Peter Maimonis, vice president of biological
research at Decision Biomarkers. “Before, all of
them thought that the only thing biomarkers would
accomplish is to reduce their market share.”
That
wasn’t the only hold up. Until recently, many
companies were still nervous about even doing
biomarker discovery. They wondered how FDA would view,
and then use, preliminary data from new genomic
technologies, such as DNA microarrays. FDA has eased
fears by making its position clearer, and companies
are gradually building up experience with the genomic
tools.
Choosing
a Workflow
Biomarker
discovery today sometimes involves looking at hundreds
of known analytes in something like a fishing
expedition. Companies such as Rules-Based Medicine
provide tools that are useful for that type of marker
prospecting. While it’s easy to find markers that
seem to work, the trickiest part is proving the
markers are robust. For that, specialized platforms
such as Decision Biomarkers’ benchtop Avantra Q400
Biomarker Workstation are coming into use. “Ours is
a quantitative assay,” explains Maimonis. “And
it’s fully automated with competitive throughput.”
Customers typically run panels of 8-16 markers on the
instrument. “When doing validation in particular,”
he says, “What they want are numbers they can
trust.”
“The
tricky part is the genomic tests,” says MDS Pharma
Services’ Robert Butz, vice president of Global
Regulatory Affairs. MDS has expertise in doing
immunoassay-based marker studies, but wanted to offer
its clients the option to include genomic tests in
their clinical trials as well. “We put together the
Biomarker Alliance around three general technologies
that were external to what we were already doing as a
large CRO,” explains Butz. One of these
collaborations is with
Massachusetts General
Hospital's Department of Radiology around imaging —
a hot spot for biomarker research. The other two are
for proteomics with Caprion Pharmaceuticals, and with
Gentris for pharmacogenomics, a field where many
robust markers already exist, but researchers are
pushing for more. “You can’t rely on a single
biomarker — you have to look broadly, and that’s
why we formed the
Alliance," Butz says.
Probably
the most popular, and most advanced, types of genomic
biomarkers today are those based on gene-expression
analysis. A few high-profile breast cancer genomic
signatures have even made it to the market, inspiring
the field. (See ““Tailoring Breast Cancer
Treatment,” July/August Pharma DD, p. 8.) The
challenge is not finding markers but validating them,
according to Dracopoli. “The key issue is having
sufficient numbers preclinically and clinically to
both identify a hypothesis and confirm it in
independent studies,” he says.
“A
common path is to find a gene signature using
microarrays, then look at a larger set of samples
using TaqMan to narrow the number of genes down to a
reliable set,” says Raymond Samaha of Applied
Biosystems (ABI). “Other people, who have a specific
gene set in mind, may go straight to the TaqMan.”
RT-PCR is cheaper on a per-sample basis, he says, and
is more accurate and less time consuming. Another
advantage is that it can be used with
paraffin-embedded tissues — the most common type of
samples available. Now, with ABI’s new TaqMan PreAmp
Master Mix, researchers can get even robust expression
signatures with very small amounts of sample
containing as little as 1 nanogram of cDNA.
Proteomics
is further behind gene expression analysis. “You
still need to run hundreds and hundreds of samples to
get anywhere, and different approaches are
possible,” according to Mary Lopez, head of
analytical proteomics at PerkinElmer. “People doing
biomarker discovery are often diving deep, and just
looking for signatures of proteins without identifying
the proteins,” she says. Meanwhile, those aiming to
create diagnostics are more interested in what the
proteins are. “If you take one approach and don’t
take the other into account, your research won’t
have the same clinical relevance,” she says.
Bright
Horizon?
Many
people still hope for a new generation of diagnostics
to spring from this explosion in biomarker research.
Journals are replete with articles about putative
biomarkers, but relatively few are getting anywhere
near the clinic. “From the diagnostic development
standpoint, the big question is who is going to pay
for it,” says Maimonis. Diagnostic companies have
such small margins, tackling tough problems is
prohibitive for them. “Biotechs can’t afford it
either, and the big pharmas just aren’t ready to
invest yet,” he adds.
Others,
however, feel that even if biomarkers simply ease the
often bumpy transition from preclinical to clinical
research, then that will help. “We think biomarkers
are the tool for translational medicine,” Butz says.
His clients, however, are carefully considering the
cost of doing these studies. Adding pharmacogenetic
testing to a Phase I trial, for example, can cost
around $300,000, he says.
In
this issue’s “Bench Notes,” we present two
approaches to such bridging biomarker strategies, from
companies that have pioneered this type of research.
As the field grows, Pharma DD will continue to
cover it in detail.
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