24 BioExecutive International
M
AY
2005
into mRNA and then into proteins.
Nonsense mutations in specific codons
along the mRNA chain, signaling a
"false stop," may interrupt the transla-
tion and result in truncated proteins.
(See "String of Beads.")
Two interesting ramifications spring
from PTC's approach to genetic disor-
ders: patients can be identified by the
presence of a testable mutation; and
the same mutation in the relevant gene
for the disease plays a role in numer-
ous conditions, making it possible for
PTC124 to be applied beyond the first
indications being sought (CF
and DMD).
The antibiotic gentamicin has been
shown to read through nonsense
mutations when administered in high
concentrations, and a study published
at the New England Journal of Medicine
validates the concept that reading-
through the nonsense mutations
allows a functional protein to be made.
Gentamicin is not considered a viable
therapy because of its toxicity profile
when given in high doses, and because
it is not very potent in reading through
nonsense mutations. PTC124 was
developed specifically to read though
those mutations, and it has been opti-
mized for pharmaceutical properties.
Small molecules may correct muta-
tions at the cellular level, much as a
process fix can boost a fermenting
tank's output at the industrial level.
Rather than replicate and replace the
protein from the outside, the result-
ing therapy potentiates its production
from the inside, using the patient's
own cells as the protein factory.
Following PTC124 is a full pipeline
of programs across therapeutic areas.
(See "PTC Pipeline.")
PTC has a unique niche in how it
searches for its compounds; though it
focuses on biological processes, it does
so through chemistry. PTC targets the
multiple processes involved in translat-
ing genetic instructions into proteins:
"post-transcriptional control mecha-
nisms." Such mechanisms regulate
the rate and timing of cellular protein
production.
In 2000, when PTC first occu-
pied its laboratory space, Peltz says
it seemed almost impossible to meet
the goal of selecting one development
candidate a year. Even so, he stood in
front of his board and investors and
told them that was PTC's goal. PTC
selected PTC124, in 2003, and in 2004
it selected PTC299 as the development
candidate in its oncology anti-angio-
genesis program. In 2005, the company
expects to identify a development can-
didate in its hepatitis C program.
D
ERIVING
C
ONCEPT
Stu Peltz takes everyone by surprise.
A dandruff-collared professor and
researcher, he succeeds by deliver-
ing serious scientific and business
ideas with Tom Sawyer-like charisma.
When he laughs, it appears as much in
delight as in humor. Insights, not one-
liners, tickle his fancy. In conversation,
his enthusiasm for the subject at hand
quickly becomes contagious.
Everything at PTC starts with this
big idea: developing small-molecule
therapies that target the post-tran-
scriptional control mechanisms in
diseased cells. As a graduate student
PTC Pipeline
Focusing on post-transcriptional control mechanisms allows PTC
to rapidly launch programs across targets and disease areas.
Bio Meets Pharma at PTC: The
following is an edited excerpt from our
interview with Stuart W. Peltz, PhD,
President and CEO of PTC Therapeutics.
Equally enthusiastic about the science
and business his company is exploring,
Peltz speaks about the fast-paced growth
experience of his unique enterprise.
BEI: How would you explain your
company's technology--small molecules
that target post-transcriptional control
mechanisms?
Peltz: We focus on post-transcriptional
control. The goal is to modulate how
much protein the cell makes. All the
instructions of how to make a protein
come from DNA. When you want to
make a protein, you copy the region
of DNA that encodes the protein.
That copy is called a transient copy,
or messenger-RNA. Then, the RNA
undergoes multiple events that allow
it to be used by ribosomes to make
protein. The RNA encodes instructions
of how to assemble the protein and
also how much protein to make. When
a "nonsense mutation" in that code
interrupts the string of instructions,
the ribosomes make proteins in the
wrong shapes and amounts. Our small
molecules allow the ribosomes to
skip over the interruption and resume
producing the protein correctly.
Is there also some possible disadvantage
in your small-molecule theory? There was
a perfectly good theory behind Vioxx.
Sure, but that can also be true for
antibodies and proteins--if you were to
give too much TNF-alpha, for example.
What you're alluding to is not about
efficacy, it's about safety. So what we
tend to do is to measure risk versus
benefit.
I was thinking not so much about fault,
but that sometimes you just don't know
what will happen in large populations,
even though the theory is solid. Does that
have to do with a gap between biology
and chemistry?
Actually, the interesting thing about
biology versus chemistry or physics is
the biological theory isn't always solid,
it's fluid (laughs). You know, that's why
chemists and biologists often don't get
along: Biology, if you think about it, is
all sort of invented theory based on
our ability to measure certain things,
right? There's always some kind of a fog
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