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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