Corrections or additions?
This article was prepared by Michele Alperin for the May 18, 2005
issue of U.S. 1 Newspaper. All rights reserved.
New Combo for Coronary Health
Twenty years ago, the standard surgery for blocked arteries was the
coronary bypass. In the 1980s a less invasive procedure was introduced
– angioplasty with stents – mesh tubes, inserted with a
balloon-tipped catheter into a narrowed artery to keep it open.
The long-term effectiveness of stents increased dramatically two years
ago when Miami-based Cordis Corporation added a drug to its stent. The
role of the drug is to stop the growth of muscle cells that can
paradoxically re-close the artery – called restenosis in the medical
jargon. These drug-eluting stents (DES) – so named because the drug
seeps out at a slow rate over a specified time period – are now the
standard for surgeons in the United States. The number of bypass
surgeries dropped 30 percent. Two years ago, according to trade
magazine Managed Care, there were fewer than 400,000 bypass surgeries
performed in the U.S. compared to 1.2 million angioplasty operations
X-Cell Medical, which moved its laboratory from a Columbia University
incubator to Deer Park Drive last November, is a small "combination
product" company, which "combines" a medical device, the stent, with
new antirestenotic drugs, including a form of estrogen that it
believes will improve the healing process. X-Cell was founded in May,
2002, by Accelerated Technologies Inc., a company formed by
high-ranking cardiologists to locate and take over or form new
companies in interventional cardiology. With six employees at
Princeton Corporate Plaza on Deer Park Drive, the nearly
three-year-old company is hoping to break into a market dominated by
large medical device firms.
Here’s how a drug eluting stent works. Metal stents are coated with a
polymer that slowly releases an antirestenotic drug into the artery.
The perfect drug will accomplish two goals: The first is to prevent
re-closure of the artery by blocking the growth and migration of
smooth muscle cells. These cells may grow and move in response to
inflammation caused when the balloon stretches the artery. The second
purpose is to either promote the growth of the cells that line the
artery or, at the very least, not affect these cells.
The drugs currently on the market accomplish the first purpose, but
X-Cell has hopes that its estrogen drug, Estradiol, will accomplish
both. Estradiol had already been tested in humans once by the original
company, and, although the formulation was not optimal, the promise in
that early trial inspired X-Cell to license the drug.
X-Cell also hopes its DES will reduce the incidence of late
thrombosis, a rarer, but often fatal side effect of a stent, where a
blood clot forms at the site of the stent.
Drug-eluting stents entered the market in October 2002 when the FDA
approved, with recommended conditions, the Cypher Sirolimus-eluting
stent of Cordis Corporation, a Johnson & Johnson company. Clinical
results showed dramatic reductions in restenosis with drug-eluting
stents – 10 percent as compared to 30 percent with bare metal stents.
As a result, DES took over the market to such a degree that bare metal
stents have vanished from medical practice in the United States, and
randomized trials comparing stents with and without drugs are no
longer feasible here.
X-Cell has no intention of manufacturing either stents or the polymer
coatings that release the drug. Both are "commodities" that can be
purchased relatively cheaply from partners. "At X-Cell Medical the
drug side is the focus," says Oded Ben-Joseph, who came aboard as CEO
in May, 2003. "We offer an integrated full product through our
relationships with companies with good products. We don’t want to
reinvent the wheel, only to introduce innovation to the field."
The antirestenotic drugs on the market today, including Cordis’s
Rapamycin and its analogs and Boston Scientific’s Paclitaxel, focus
primarily on blocking the growth of smooth muscle cells. Although both
of these drugs are potent in terms of blocking restenosis, according
to CEO Ben-Joseph, both are fairly toxic and do not encourage the
healing process as much as possible. X-Cell, however, is moving toward
a second-generation DES with drugs that take a pro-healing approach.
To avoid infringing on Rapamycin’s patent area, X-Cell is looking at
drugs that attach to a different target than existing drugs.
Ben-Joseph believes that companies developing Rapamycin analogs are at
risk for legal action.
Although Ben-Joseph does expect to hire a few more people in the
coming months, he says his goal is "to keep the company lean and
mean." Two pivotal employees at X-Cell Medical are molecular biologist
William Baumbach, executive director of drug research and development,
and materials scientist and polymer expert Hari Shankar, executive
director of drug delivery and formulation.
Baumbach is responsible for screening compounds that have already
shown potential as antirestenotics. X-Cell typically licenses these
drugs from universities or from other companies.
During the drug discovery stage, X-Cell grows human coronary artery
cells in petri dishes, treats them with drugs, and then uses two
primary techniques to test these drugs’ antirestenotic properties. The
first approach is to analyze the drug’s effects with Cellomics. This
high content imaging system uses trays with 96 index-card-sized wells,
each containing about 10,000 cells. The system takes microscopic
pictures of the cells in each well, providing data on each individual
cell. The second approach is to put 100,000 cells in a fluorescence
reader that provides a single signal based on whatever property is
being measured. X-Cell has bolstered its competitive position, says
Baumbach, by having available these sophisticated technologies for
evaluating drug candidates.
One of X-Cell’s two lead candidates is XC-121, a form of Estradiol
that will commence human trials in the second half of this year.
X-Cell is currently optimizing formulations of XC-121 that will allow
it to be released from the stent into artery tissue in a controlled
manner. "The amount of drug per stent and the release characteristics
(fast/slow) are being analyzed initially in ongoing animal trials,"
explains Baumbach. "Our goal is to have the drug stay about one month,
but we are testing different formulations that would release the drugs
at different rates."
Shankar’s job is to get the product ready for preclinical and clinical
testing. He works closely with Orbus Medical Technologies Inc. in
Florida, which provides X-Cell with stents, catheters, and balloons,
and with SurModics in Minnesota, which supplies the polymer. More than
a million patients have been exposed to this polymer, in stents and
elsewhere, without serious side effects. Shankar formulates the drug
in the polymer so that it is delivered at the desired rate. Once the
drug and polymer mixture is applied to the stent, it is sent back to
Orbus where it is balloon-mounted, packaged, and sterilized for use in
Shankar got his bachelor’s degree in chemical engineering from the
University of Madras in 1975, and stayed in India three more years,
working in industry. Then he moved to Texas Tech University, where he
got a master’s degree and then a Ph.D in chemical engineering,
finishing in 1985. For an additional five years, he did academic
research at Texas Tech on vascular grafts used in bypass surgery – the
predecessors of stents. He moved to Enzon, a biotech, where he stayed
2 years, and then to J&J and Becton Dickinson in Franklin Lakes for 10
years before joining X-Cell in 2002.
Once the formulations are set, the drug candidates are tested in pigs,
which have hearts and arteries the same size as humans. Medical staff,
operating rooms, and other support items are also identical to those
that will be used in human trials. The disadvantage of the pig system
is that it is not very predictive of how the stent will work in
humans. "Once we have proved that a drug is safe in, typically, a
three-month study in pigs," concludes Baumbach, "it is routinely
tested in a small human trial."
X-Cell is currently preparing the first human trial to compare
formulated Estradiol stents with bare metal stents. To take place in
Brazil and Germany, its goal will be registration in the European
Union. Baumbach explains that it is standard practice for
interventionist, catheter-based cardiology to run the first trials
internationally: excellent heart centers are available where human
trials can move faster than in the United States, and the cost is
less. After a successful international trial, a major U.S. clinical
trial would compare Estradiol stents with those using Rapamycin and
The second lead candidate is XC-441, a platelet-derived growth factor
inhibitor that blocks smooth muscle cells but has no effect on the
cells lining the blood vessels. The drug has proven its feasibility in
an animal trial. A second large animal trial is scheduled in March for
Baumbach says that several other drugs are planned, but at too early a
stage to discuss in detail.
Baumbach graduated from Princeton University in 1975 with a degree in
biochemistry, but then spent several years working in ceramics and
pottery under Princeton artist Toshiku Takaezu. Shortly after he got
married in 1981, he returned to science at Princeton, graduating in
1987 with a Ph.D. in molecular biology. After 13 years in a large
pharmaceutical environment, at American Cyanamid, then Wyeth, in the
animal health area, he eventually moved to a smaller company,
Morphochem, as director of biology. With about 30 people in the U.S.
and 100 in Germany, he says, Morphochem "had a startup atmosphere and
a very interesting technology that they were trying to use in a
transatlantic scenario – in which most of the chemistry was in Germany
and the biology in New Jersey." When financial problems forced the
company to cut back at its U.S. site, with only a couple of people
remaining, he joined X-Cell.
Baumbach and his wife, an artist, live in Hopewell with their three
sons. He completely renovated their house, still does a little work in
Japanese-influenced stoneware, and is the chair for the Princeton
Class of 1975’s upcoming 30th reunion.
X-Cell moved to its new 2,000 square foot laboratory at Princeton
Corporate Plaza, says Ben-Joseph, "because we needed more space and
wanted to be part of a biotech complex," citing about 50 other such
companies at the new location. All of X-Cell’s employees live within a
half hour of the new site, except for Ben-Joseph, who spends two days
a week in Princeton and the rest in the Boston offices of X-Cell’s
lead investor, Oxford Bioscience Partners. In addition to Oxford and
ATI, X-Cell’s investors include ABN AMRO Capital/Life Sciences and
Giza Venture Capital.
Just as X-Cell Medical is a combination company, Ben-Joseph sees
himself as something of a mixed breed – someone who integrates science
and management. He started his career as a pure scientist, with a
degree in biochemistry from the Imperial College of Science and
Technology in London and then a Ph.D. in neurochemistry at the
University of Cambridge in 1988. His focus was on neurodegenerative
diseases, which he continued to study as an assistant professor at the
University of Michigan, Ann Arbor. "I’ve always been drawn to the most
intellectually challenging questions," he says. "As far as medicine, I
think the brain is still the final frontier, and the most interesting
side of biotechnology is neuroscience."
While in Ann Arbor he was a visiting scientist at Parke-Davis’s (now
Pfizer) R&D headquarters. "This was my first exposure to the more
industrial aspect of pharmaceuticals and biotechs," he says, adding
that he "always had an affinity for that sort of thing. I have a great
deal of respect for pure science, but at the end of the day I like to
see these things reach the patient."
Yet mundane corporate work was not what really excited him. He was
drawn to the complexities of the biotech world. "You have to be
multidisciplinary to be involved in biotech. It involves clinical,
legal, patent, financing, and strategic issues, which are extremely
gratifying and interesting," he says. "I thought that biotech
management was a convergence of many areas and disciplines, and I
wanted to be at that point."
But first he needed to move beyond his "scientific identity," break
into industry, and gain management experience. While consulting for
AMCOR, a large Israeli manufacturer of electrical appliances, he
developed a relationship with its "interesting CEO." When this man
decided to enter the healthcare arena via phototherapeutic medical
devices, Ben-Joseph saw an opening. He told the CEO that he would
"only help if you will spin off the company." That’s what happened,
and Ben-Joseph was cofounder and CEO of Biolight Phototherapy.
While at Biolight, he took the company to clinical trials and at the
same time completed an MBA at a branch of the University of Bradford
in Tel Aviv. But when Biolight was ready to start generating revenue,
Ben-Joseph was ready to move on. "To start a marketing infrastructure,
etc., is interesting, but not the field where I see myself," he
realized. "It was time to get a different personality type for CEO."
He says he is an entrepreneurial type, "best in the first two to three
years" of a new business. He also wanted to be close to the basic
science and was ready to go back to his first love, "biotech and
medical devices proper."
Ben-Joseph joined an Israeli venture capital firm, Medica Venture
Partners, and managed one of their portfolio companies, Ester
Neurosciences, from its inception. The company developed novel drugs
for neurodegenerative diseases like Alzheimer’s and Parkinson’s. After
about four years, the company had moved to Phase II testing in humans
of lead drug candidates, says Ben-Joseph, and "I was ready to move
back home, to the States."
Through Ester, he got to know Oxford Bioscience Partners, which he
dubs an American "Ivy League" healthcare venture-capital firm. Oxford
asked him to take the leadership of X-Cell Medical, where he has been
for about two years. He says he is pretty happy and optimistic – "as
much as one can be in this high-risk industry."
Ben-Joseph’s wife, Elana, is a pediatrician, and they have a preschool
"The market penetration of DES is 90 percent," continues Ben-Joseph.
"It is an amazing example in the history of medicine – a drug that has
penetrated so aggressively since it got FDA approval in April, 2003."
Some cardiac surgeons, nevertheless, point to the lack of data on the
success of using drug-eluting stents versus doing bypass surgery, and
they caution that procedures involving DES can actually cost more than
bypass surgery. "Patients with stents must be constantly restudied to
track the progression of the disease, and many must have repeat
procedures," says Bruno Cole, who has an office on Alexander Road and
is a cardiothoracic surgeon at RWJ University Hospital in New
Brunswick. "The cost for angioplasty plus stents works out to be the
same or more than the cost for bypass surgery," he claims.
Stents now cost about $2,500 each. At present the major players in the
DES market are Boston Scientific and Cordis; with little competition
there is no incentive to reduce prices.
Financially and scientifically, X-Cell Medical believes it is well
placed to enter the fray. Although now in the research and development
stage, the company projects that sometime between the beginning and
middle of next year, it will have generated data in humans and will be
ready to ally with a major company to take the product to market.
Ben-Joseph observes, "We are unlikely to do that on our own, although
we are open to that possibility in Europe, if we get the European
approval." He adds that many "pharmaceutical companies are very
interested in this highly lucrative market, which is now $7 billion
and still growing."
It is also in good shape, moneywise, to do what needs to be done. "We
are fully funded for the next couple of years," says Ben-Joseph, "and
through this funding we believe we can reach at least two first-in-man
clinical trials of our lead candidates."
– Michele Alperin
Monmouth Junction 08852. William R. Baumbach PhD, director, drug
research & development. 732-329-0297; fax, 732-329-0298.
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