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Targanta is in the camp that believes
natural products will continue to be
the way forward, although it does keep
an eye on newer tools. The company
is devoting the bulk of its resources to
bringing oritavancin, a semisynthetic
glycopeptide licensed from Lilly, to
market. The Cambridge, Mass.-based
biotech filed a New Drug Application
with the Food & Drug Administration
in January and is expecting a response
by December so that the drug could
launch in 2009.
Even Targanta’s earlier-stage efforts
are focused on derivatives of natural
products. “The bugs are smarter than
the chemists,” Parr says. “I think there
is still great promise to find things by
looking to nature.” The challenge, he
adds, will be to accelerate the process of
sifting through natural products to find
useful molecules while figuring out how to
streamline the chemistry needed to turn
those molecules into drugs.
Meanwhile, Boston-based Paratek is
mining an older natural product class that
it believes has not been fully exploited.
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SHRINKING ARSENAL
Antibacterial drug approvals are on the
decline in the U.S.
Antibacterial drug approvals
20
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SOURCE: Infectious Diseases Society of America
The company’s lead molecule is a derivative
of tetracycline, an antibiotic that hit
the market in the 1950s. However, little
new chemistry has been introduced since
then to overcome resistance or other issues
with the drug. Paratek chemists made
thousands of tetracycline derivatives to try
to cut resistance while preserving antibac-
WWW.CEN-ONLINE.ORG 18 APRIL 14, 2008
terial activity. Eventually, they hit on
some promising compounds.
“This four-ring structure has a lot
going for it,” Levy says of tetracycline.
His team is now analyzing the data
from Phase II trials of PTK-0796, a
broad-spectrum derivative for intravenous
and oral use.
Optimer, meanwhile, is focused
on developing narrow, or at least
narrower, spectrum antibiotics that
take out just one or two pathogens;
broad-spectrum drugs, in contrast,
use brute force to wipe out a range of
bugs that may be causing an infection.
The narrower approach is not useful in
all settings, concedes Michael Chang,
Optimer’s president and CEO, particularly
in the absence of rapid diagnostics
to detect the specific bacteria infecting a
patient. But certain indications in patients
call for narrow-spectrum drugs, and with
fewer targets to hit, researchers could have
an easier time designing them.
The San Diego-based firm’s lead compound,
OPT-80, is an 18-membered macrocycle
that treats Clostridium difficile infection
(CDI), an infection in the lining of the colon
that is a prime candidate for a narrow-spectrum
drug. A broad-spectrum antibiotic like
vancomycin, currently the only approved
treatment for CDI, kills most of the flora in
the gut, but C. difficile protects itself by forming
spores. When antibiotic use is stopped,
the C. difficile grows again, and this time its
growth isn’t tempered by other bugs. “It
grows with a vengeance,” Chang says.
OPT-80 would be the first very-narrowspectrum
antibiotic on the market, Chang
says. The drug is currently in two Phase III
trials; results from the first trial are expected
in 2008 and from the second in the first
half of 2009. If all goes well with the trials
and regulatory authorities, the drug could
hit the market by 2010.
Replidyne is also exploring a narrowspectrum
approach as part of its overall
R&D strategy. The Louisville, Colo.-based
company identified a compound against C.
difficile from assets it licensed from Glaxo-
SmithKline. The compound blocks methionyl
transfer RNA synthetase, an enzyme
involved in synthesizing proteins. By halting
the production of toxic proteins, the
drug renders the bacteria harmless, says
Nebojsa Janjic, Replidyne’s chief scientific
officer. The company plans to file an Investigational
New Drug (IND) application
with FDA, the first step in initiating human
tests of the drug, by the end of the year.