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Beating superbugs
January 7, 2002
By Laura Sivitz
lsivitz@washtech.com,
After years of research, phage therapy inches closer to
market
Two Maryland biotechnology companies and about 10 others
worldwide are aiming to defeat bacteria once thought conquered
by antibiotics. Applying the latest genetic technology to a
decades-old technique, these biotechs hope to put the first
modern phage therapy on pharmacy shelves. U.S. patients could
benefit as early as 2004, provided the companies can convince
reluctant investors to support an experimental drug still
unproven in this country.
"It's an area that has to bootstrap its way in," says Dr.
Carl R. Merril, one of the National Institutes of Health's
principal researchers in phage therapeutics.
Invented eight decades ago in the Soviet Union, phage therapy
deploys naturally occurring organisms that feed on bacteria.
About a hundred phages could lie end-to-end across the tip of a
hair. A phage injects its DNA into a bacterial cell, directing
the bacterium to make so many baby phages that the cell bursts.
The new phages invade more bacteria and destroy them.
The most near-term phage therapies aim to attack tenacious
bacteria that often infect patients in hospitals and long-term
care centers. Some 14,000 Americans die annually from
hospital-based infections by multidrug-resistant bacteria, and
doctors are clamoring for solutions.
The first phage drug could hit the U.S. market in three years
if all goes well for Exponential Biotherapies of Rockville. This
past spring, it became the first company to complete a human
clinical test of a phage drug in the United States, disproving
the skeptics who doubted it possible.
Exponential Biotherapies, its competitors and NIH scientists
use state-of-the-art gene sequencing and annotation to weed out
dangerous phages that code for toxins, antibiotic resistance or
other harmful qualities, eliminating problems that plagued phage
therapy in the past.
Exponential's drug is designed to fight a strain of bacteria
resistant to vancomycin, one of the most powerful antibiotics.
Scientists selected phages that stay in the bloodstream much
longer than normal, allowing for a 1000-fold smaller dose. "It's
always the goal in medicine to give the lowest possible dose,"
says Richard M. Carlton, the company's president and founder.
His firm holds the exclusive license on this technology for
long-circulating phages, which the company developed between
1995 and 1999 with Merril and another phage expert at NIH,
Sankar Adhya.
The drug was found safe for healthy volunteers during the
week-long test by Exponential, whose lab is in Rockville and
administrative office is in Port Washington, N.Y. Now, the
15-person company is improving the quality of its manufacturing
process for a bigger experiment to test the drug's efficacy in
100 to 500 patient volunteers. From the stage where
Exponential's drug is now, it takes seven years, on average, for
a biopharmaceutical to reach the market.
Though investors praise the idea of phage therapy, few have
put their money on it. Most prefer to hang back until a
precedent-setting phage drug overcomes the many regulatory
hurdles to FDA approval.
"Any time you have such an innovative product, you're talking
about huge risks," says venture capitalist Wei Wu He of Emerging
Technology Partners in Rockville. There are so few experimental
phage therapies in the United States that even the Food and Drug
Administration has no specific guidance to offer companies
wanting to pursue the technology.
But in theory, the lack of precedent wouldn't discourage
other venture capital firms like Oxford Biosciences of Boston.
"The growth of [antibiotic] resistance has been breathtaking, so
we're keenly interested in new technologies — we believe there's
a huge opportunity there," says Michael Lytton, a general
partner at the firm.
While antibiotics sweep through the body, wiping out a range
of bacteria both good and bad, phages are more finicky. Each
species of bacteriophage — as it's formally known — consumes
only a particular species of bacteria. Although a bacterial
strain can grow resistant to a phage attacker, nature constantly
invents new phages that overcome their prey.
Still, "It happens we've not looked at these companies"
pursuing phage therapy, Lytton says.
If the firm did, it would want a pharmaceutical company to
shoulder the capital investment of the biotech's clinical
trials, according to Lytton. For that reason, it would choose a
biotech that could partner well with a pharmaceutical company.
Intralytix, a young Baltimore biotech pursuing phage
therapies, knows venture capitalists' reticence well. The
company's biggest challenge? "Raising money," says CEO Torrey C.
Brown. A few venture capitalists have committed funds, he says,
but he still seeks a lead investor to close the round. His
competitor, Exponential Biotherapies, hasn't succeeded at wooing
any venture capitalists yet, either.
Both companies have a little money in the bank. Carlton says
$3 million remains from the $15 million he's raised from
individual investors since 1993, when he founded Exponential. He
expects another cash infusion from individual investors in the
near future.
Three-year-old Intralytix has raised $2 million to date. The
six-person company expects future revenue from phage
preparations it's being paid to develop by companies it declined
to name for fighting bacterial contamination in agricultural and
food products. The new preparations should hit the market next
year, says Alexander Sulakvelidze, an Intralytix co-founder and
chief scientist.
Those products' sales could partially support the company's
work on phage therapies for people. Intralytix applied in
September for government clearance to launch animal studies on
an anti-VRE phage ? the same bacteria targeted in Exponential's
human studies. The Baltimore company is developing another
treatment to combat a common, multi-drug-resistant bacterium
that infects as many as 80,000 people a year during hospital
stays: methicillin-resistant Staphylococcus aureus, or MRSA.
Sulakvelidze says Intralytix could start marketing its first
human therapeutic phage treatment as early as 2004 under the
best of circumstances. But biopharmaceuticals take 12 years, on
average, to progress through animal tests, human tests and the
FDA approval process.
Thirty to 40 scientists work for Intralytix on contract at
The Institute for Genomic Research in Rockville, the U.S.
Department of Agriculture, University of Maryland and elsewhere.
The company is applying to the National Institutes of Health
to fund and collaborate on clinical studies. NIH has two experts
on phage therapeutics, Merril and Sankar Adhya, who collaborated
with Carlton on the long-circulating phage technology he has
licensed.
Both Adhya and Merril have researched therapeutic phages for
decades. Currently, Merril's lab is developing phages to attack
VRE bacteria. Using some of the newest tools to unveil protein
structures and sequences, a scientist in the lab recently
identified a phage that can kill a broader range of bacterial
strains than most. Exponential accomplished a similar feat.
Intralytix hopes to set itself apart with an exclusive,
worldwide license on a wound-healing treatment developed by the
originators of phage therapy: the Eliava Institute in the former
Soviet republic of Georgia. The product, called PhagoBioDerm, is
a biodegradable polymer impregnated with a phage cocktail and
placed on the skin to treat poorly healing, infected ulcers or
to prevent ulcers from forming.
But the FDA wants more detail than is known now about the
phages in the cocktail, Sulakvelidze says, and the cocktail must
be purer.
Intralytix plans to apply for a small-business innovation
research grant from NIH to genetically analyze and purify the
phage mixture. PhagoBioDerm will reach the U.S. market in 2007
at the earliest, he says, although it's already sold in the
Republic of Georgia.
Published research has reported that bacteria have a harder
time evading phage attackers than antibiotics. Some executives,
like Brown and Sulakvelidze, say they believe phage therapies
will be faster and cheaper to make than antibiotics.
If the entrepreneurs can win funding and FDA approval for a
pioneer phage drug, Carlton expects genetically modified
versions will come next. "We can anticipate that genetically
engineered enhancements will help to realize the full [and vast]
potential of phages as antibacterial agents," he says.
© 2001 Post Newsweek Tech Media Group
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