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GEN,  Jun 1 2008 (Vol. 28, No. 11)
Development of Antibacterial Therapies Needs to Take a Front-Row Seat in the Research Arena
Sue Pearson, Ph.D.
At the recent “Superbugs and Superdrugs” conference in London, Nora Kaarela, CEO of Ipsat Therapies (www.ipsat-ther.com),
commented, “Hospital-acquired bacterial infections are a leading cause
of death in the U.S., and it costs between $16,000 and $100,000 per
patient to treat this largely preventable problem.”
Despite the
alarming rise in resistant bacteria, only a dozen or so new antibiotics
have been approved by the FDA in the past ten years compared to double
that number from 1988–1998, which begs the question: What’s behind the
steady decline in numbers of new antibiotics coming to market?
Jeff Alder, Ph.D., senior director, global clinical development, at Bayer Healthcare (www.bayerhealthcare.com)
observed, “A complex blend of properties is needed for an antibacterial
drug, it is much tougher than developing a cancer therapy. To beat
antibiotic resistance in bacteria we have to develop antibiotics that
act against multiple targets or products of multiple genes.
“These
targets have to be in the membrane or cell wall and they need to
contain genes that require multistep mutations to make the bacteria
resistant.
“For example, although rifampicin is 100 times more
potent than vancomycin, it is a poor antibiotic because it only
requires bacteria to have one point mutation to become resistant,
whereas vancomycin requires many.”
Another reason why fewer
antibiotics are coming to market might be due to the lack of approvals
of near-market antibiotics. According to Dr. Alder, the FDA is more
cautious about this drug class after Ketek™. The Sanofi-Aventis (www.sanofi-aventis.com)
antibiotic to treat sinusitis and lung infections caused a rare but
serious side effect, resulting in three deaths in 2006 from liver
damage.
Against such a backdrop, it’s easy to see why developing
novel antibacterial therapies is the road-less-travelled by big pharma
and biotechs firms. A few brave souls, however, have ventured in and
are showing some promising results.
Crystal Clear
Both New Haven-based Rib-X Pharmaceuticals (www.rib-x.com) and Prolysis (www.prolysis.com) in Oxford, U.K., presented novel approaches to designing new antibiotics.
“The
bacterial ribosome is a highly validated target for antibiotics,” said
Albert Collinson, Ph.D., CBO of Rib-X, “and we at Rib-X used an
approach of structure-driven drug design to build a substantial
database of 3-D information that enables an understanding of exactly
how old and new classes of antibiotics bind to and inhibit the
ribosome.
“Using this information in conjunction with the
company’s computational chemistry software, we are able to more rapidly
and efficiently design antibiotics that target the ribosome. Our
discovery process reduces the cost and time necessary for us to
identify new antibiotics that target the most resistant bacteria and
address unmet medical need.”
Rib-X has produced RX-1741, an
oxazolidinone antibiotic that exhibits activity against
methicillin-resistant Staphylococcus aureus (MRSA) and other
gram-positive organisms as well as Haemophilus influenzae and the
atypical pathogens such as Legionella that can cause respiratory tract
infections.
Dr. Collinson presented data from a Phase II study in
which RX-1741 was compared against market leading Zyvox® (linezolid) to
treat uncomplicated skin infections. The interim analysis showed that
of the 39 patients treated with RX-1741 orally, either once a day or
twice a day, all were cured and none experienced secondary lesion
formation.
“In our Phase II study,” added Dr. Collinson “the
predominant pathogen isolated was MRSA, against which RX-1741 is
fourfold more potent than linezolid.”
Furthermore, according to
Dr. Collinson, RX-1741 has been well tolerated in this study with only
minor gastrointestinal complaints reported. Rib-X plans to continue to
develop this compound and will look to identify a strategic partner to
assist in the development and commercialization of RX-1741.
Prolysis
has also used a structure-based approach by making crystals of the FtsZ
protein, which is located in a ring at the edge of the bacterial
septum. Inhibiting FtsZ’s activity prevents cell division.
Using
molecular docking, Prolysis identified a series of inhibitory
compounds, one of which, CDI-936, has shown promising activity against
S. aureus.
“With S. aureus, CDI-936 binds to FtsZ inhibiting
septum production during cell division, the cell balloons, and because
it cannot divide, it dies,” explained Lloyd Czaplewski, Ph.D., research
director for Prolysis. “One point mutation in FtsZ can confer
resistance to the compound series, but the frequency is low, and we are
working to reduce this. Therefore, we believe CDI-936 is still a good
candidate for further development.”
Revisiting Old Favorites
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The
production of b-lactamases to destroy b-lactam-based antibiotics has
long been used by bacteria to survive antibiotic attack. Two companies,
both spin-offs from big pharma, France’s Novexel (www.novexel.com), a sanofi-Aventis spin-off, and Swiss biotech Basilea Pharmaceutica (www.basilea.com), spun off from Roche, discussed their compounds to target b-lactamases.
Christine
Miossec, Ph.D., a senior scientist at Novexel said, “We identified
NXL104, a small molecule that inhibits serine b-lactamases. This
compound has shown good activity in mouse and rabbit models infected
with gram negatives including klebsiella that produce Class A and C
b-lactamases.” NXL104 had a good safety profile in its Phase I trial.
“We
have also used NXL104 in a Phase I study in combination with
ceftazidime, a third generation cephalosporin often compromised by
b-lactamases activity,” Dr. Miossec continued. “The data demonstrates a
high plasmatic bactericidal activity against enterobacter and
klebsiella producing b-lactamases, so we now plan to initiate Phase II
studies with the NXL104/ceftazidime combination to treat complicated
urinary tract infections. The ceftazidime/NXL104 combination could be
used as a front-line therapy for treating a broad spectrum of
gram-negative bacterial infections.”
Like Novexel, Basilea is
developing b-lactamase inhibitors to target gram-negative bacteria.
Malcolm Page, Ph.D., head of biology at Basilea explained why they are
targeting gram negatives. “In cancer patients the incidence of
gram-negative and -positive infections is about the same. In this
patient group, around 50 percent die from P. aeruginosa infections
because about 20 percent of the patients are multidrug resistant.”
The
company is developing the antibiotic BAL30376, which is a combination
of three compounds with both b-lactamase Class A and B inhibitory
activity. Dr. Page presented in vitro data that demonstrated that
BAL30376 has potent activity against acinetobacter, P. aeruginosa and
K. pneumoniae strains that were not susceptible to any other
antibiotics tested. “The promising activity of BAL30376 against
resistant stains shows that it is one of the few new drugs in
development that could overcome established resistance mechanisms,”
said Dr. Page.
Montreal-based, Biophage Pharma (www.biophagepharma.net)
and Ipsat Therapies presented two additional approaches to treating
bacterial infections in the form of phage and enzyme therapies.
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Prevention Rather Than Cure
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Beatrice
Allain, Ph.D., director of phage technologies at Biophage explained,
“We identified lytic phages specific to pathogenic bacteria. Lytic
phages did not integrate into the host DNA and lyze only bacterial
cells, not mammalian cells. When targeted pathogenic bacteria are not
present in the body, lytic phages are rapidly eliminated without toxic
effects, thus they could be safely used as antibacterial therapies or
as disinfectants.”
There have been no negative effects reported
with the use of lytic phages over the past 80 years, according to Dr.
Allain, and the FDA and EU have approved the use of phages as food
additives as well as the use of E. coli and Salmonella phages on live
animals.
The company was initially concentrating on E. coli and
Salmonella infections in swine and poultry and is now also focusing on
nosocomial infections and has phages for MRSA. “We have a codevelopment
program with Montreal Sacre Coeur Hospital where we hope to break the
transmission chain of MRSA. Several phages, that infect and destroy
MRSA strains found at the hospital yet do not infect nonpathogenic gut
E.coli have been identified.
“We will conduct proof of concept
studies using phages for equipment decontamination. We also believe
phages have massive potential as natural and ecological treatments
against superbugs,” said Dr. Allain.
Another novel strategy to
combat resistant infections is Ipsat Therapies’ idea of using a
b-lactamase enzyme in conjunction with a b-lactam-based antibiotic.
Kaarela
explained that “taking an antibiotic always changes patients’ gut
microflora and can lead to acquiring an additional infection or acting
as a reservoir to infect others. If we give b-lactamases at the same
time as a b-lactam antibiotic, it will inactivate any unused antibiotic
in the gastrointestinal tract, thus maintaining the gut microflora and
helping to prevent colonization by resistant or pathogenic bacteria.”
To
prove this theory, Kaarela presented data on five clinical studies of
its lead b-lactamase product, P1A, which showed that of 99 patients
treated with P1A and ampicillin, P1A did not produce serious adverse
events and did not change the clinical effectiveness of ampicillin.
In
a Phase IIb study of 112 patients treated with ampicillin for serious
respiratory infections, the 54 patients treated with ampicillin and P1A
had a 20% change in gut flora compared to 50% in those treated with
ampicillin alone.
There was also a 12% increase in
ampicillin-resistant coliforms in those treated with P1A and ampicillin
compared to an 80% increase in ampicillin resistant coliforms in those
treated with only ampicillin. “If we can reduce the number of secondary
infections from 10 to 3 percent using P1A with piperacillin/tazobactam
antibiotic, which the Phase II study is now targeting, we could
potentially reduce treatment costs of secondary infections by 50
percent,” concluded Kaarela.
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Time to Invest Again?
Speakers
at the “Superbugs and Superdrugs” conference agreed that the lack of
investment in antibiotic development is a cause for concern, which has
led to the unchecked rise of many resistant bacterial strains during
the 90s, both in hospitals and in the wider community.
“Big
pharma is producing less and less antibacterial therapies, so much so
that most real work in this area is now being done by underfunded
biotechs,” stated Dr. Page.
“Funding is being driven away from
antibiotics into areas such as obesity, erectile dysfunction, and male
pattern baldness,” Dr. Alder added. “Governments and investors are
favoring lifestyle drugs rather than those to treat desperately ill
people and as a result we have seen only two novel compounds come to
market since the 1970s.
“In nosocomial bacteria tested, over 50
percent of S.aureus are methicillin resistant, almost 30 percent of
Enterococci are vancomycin resistant, and over 30 percent of gram
negatives have quinolone resistance,” he warns. “The problem is that we
don’t have a lot in our bag of tricks to counter this, and it is
imperative that we start developing new drugs now. The alternative is
that we won’t be able to fight back the rising tide of bacterial
resistance.”
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Biophage in the press 