M
AY
2005
BioExeutive International
25
at the University of Wisconsin in
Madison, Peltz started focusing in
post-transcriptional control mecha-
nisms in 1983
1
.
To date, the area
is still virtually unexploited in drug
discovery. Athough some products on
the market specifically target PTCMs
(such as the antibiotic gentamicin or
the immunosuppressive rapamycin),
they were not discovered through
efforts focused directly on those mech-
anisms, but subsequently deciphered
by mechanism-of-action studies.
"I realized early on that these
mechanisms are critical to controlling
protein levels, and that if you could
modulate these processes you could
correct the problem," says Peltz. "We
believe we can achieve with small
molecules the same type of results
that have been seen with protein or
antibody products. There are lots of
advantages to small-molecule drugs,
especially the fact that you can pop a
pill versus inject a protein."
The genetic disorders program
was just the beginning. Peltz believed
there were multiple ways to target the
mechanisms--that "one could turn up
or down the amount of protein gener-
ated by modulating how long the RNA
lives in the cell or how well the RNA
is used." While advancing the genetic
disorders program, Peltz assembled
a team of biologists and chemists to
work on optimizing that approach.
GEMS is the result of those efforts.
"The business questions were how
broadly to apply this technology,
how much time to invest, to partner
or not to partner?" Peltz says.
PTC started in Peltz's lab at the
University of Medicine and Dentistry
of New Jersey (UMDNJ) in 1998.
Peltz and his long-time mentor,
Allan Jacobson, PhD (University
of Massachusetts Medical School),
decided that the science they had
explored through their careers begged
for application in drug discovery, and
that only a business enterprise could
make that happen. Jacobson had previ-
ously founded Applied Biotechnology.
In 1998, they sought out and received
seed investments from Tularik,
Genentech founder Robert Swanson,
and Peter Svennilson of Three Crowns
Capital. Tularik and its former chair-
man Swanson chipped in a few million
dollars, and PTC Therapeutics was
born.
That has been the company's con-
sistent plan ever since. Thus, PTC's
core strategy sets it well apart from
either big pharma, or the specialty/
biopharma model of licensing in
later-stage compounds regardless of
a company's original technology plat-
form. Instead, after assembling its own
compound library and high-
throughput screening facility, PTC
screened for molecules that fit pre-
cisely into key points along a cellular
mechanism elucidated in a systems-
biology framework. Biologists and
chemists worked hand-in-hand to
accomplish the goal.
Pre-
Processing
mRNA
mRNA
A S
TRING
OF
B
EADS
that we have to come up, with models
and tested models to explain how they
work. But there's fluidity in nature. That's
why biologists don't often go back to
manuscripts in 1950, where chemists
will go back to 1900. We're learning
more all the time, and it is more fluid,
and more complicated.
Chemistry's much more like
engineering. Here's a molecule; here's
how I want to build it. In biology, and
you look at nature, there are a thousand
different ways to do the same thing.
So with safety and toxicology, you do
the best you can to move something
forward. And we tend to think of it in a
riskbenefit profile, that's what you have
to do. With a common pain reliever, the
riskbenefit bar is that much higher
because it's not a life threatening
situation. But with conditions that are
serious and life threatening, you're
willing to take a risk.
With the projects that we're developing
here, the riskbenefit profile is quite
high, We're doing oncology, genetic
disorders, where there's a great medical
need. We need to take on the risk
because the benefit could be so high.
What do you think of the idea of
personalized medicine as reducing some
of that safety risk even for life threatening
diseases, but selecting . . .
Patient populations? We're much
farther ahead in being able to
accrue information than to use that
information. Our PTC124 is probably
one the first examples of using a
treatment based on the nucleic acid
sequence of the patient. The Cystic
Fibrosis Foundation has been very
good about ensuring the genotyping
of patients. But this will be the first
example of a drug that will be tested
based on the genotyping of a patient.
So PTC124 is a good example of what
personalized medicine is going to be.
Even blockbuster drugs in, say,
oncology, might extend life only a
month to five months. And second
of all, they all work on a small subset
of the population. But an interesting
question, and what you're getting to
is, why does it work on that population
and not on others? If you could define
the population it works on, and only
treat those patients, you'd go from a
15% rate of treatment, to probably a
90% rate. But it's that gap that we don't
understand most of the time.
DIALOGUE,
CONTINUED
