Betting on Nanotech Therapies
Brian Gormley
WSJ.Sep 12, 2007
Some venture capitalists are betting that tiny instruments will drive big
advances in cancer care.
Several investors are funding start-ups that use nanotechnology -- the
manipulation of matter on the scale of the nanometer, a billionth of a meter
-- to create therapies that destroy tumors and spare healthy cells.
By packaging drugs with nano-agents that home in on tumors directly,
several start-ups hope to knock out cancer cells while triggering relatively
few side effects. A number of these companies plan to begin clinical trials
shortly.
"There's an entire wave of important therapeutics [coming] using
nanotechnology," said Jim Matheson, general partner of Flagship
Ventures, Cambridge, Mass., which is contributing funding for one such
venture.
These companies' work represents some of the latest strategies in the long
quest to better target drugs with agents known as nanoparticles. A
milestone came in 1995 with the U.S. approval of Doxil, which
encapsulates the chemotherapy doxorubicin into a tiny fat bubble, or
liposome, and another layer of hair-like strands made from a type of
rubber.
Because Doxil liposomes are so small -- about 100 nanometers in
diameter -- and able to circulate for long periods, they penetrate the
vasculature, or arrangement of blood vessels, of tumors. Once they reach
the tumor tissue, they slowly release the medication, according to Ortho
Biotech Products LP, a unit of New Brunswick, N.J.-based Johnson &
Johnson, which sells Doxil in the U.S.
Doxil is used for certain multiple-myeloma and ovarian-cancer patients,
and also for AIDS-related Kaposi's sarcoma, a type of cancer
characterized by abnormal growth of blood vessels that develops into skin
lesions or occurs internally. Though at least 90% of the drug stays in the
liposome while it circulates in the blood, some may leak out and affect
normal tissue, according to Ortho Biotech.
Several venture-backed concerns are pursuing novel technologies outside
of liposomes that may enable them to attack tumors even more effectively.
Two of them, BIND Biosciences Inc. and Tempo Pharmaceuticals Inc., are
advancing research from Massachusetts Institute of Technology. The
Cambridge, Mass., companies share a board member, MIT professor
Robert Langer, and Polaris Venture Partners, Waltham, Mass., as an
investor, but their technologies are different.
BIND, which closed a $2.5 million first round of funding from Polaris and
Flagship in January, is developing a nanoparticle that enters tumors and
unleashes a payload of drugs.
BIND expects to put its first therapy in the clinic in mid-2009 for cancer or
cardiovascular disease, though Chief Executive Glenn Batchelder didn't
say which would be first. The company, which may be able to apply its
nanoparticles to a variety of medicines, will use an undisclosed drug that
has been cleared for use in the U.S. with the initial product that it expects
to begin testing in clinical trials in 2009.
Tempo, which raised a $12.1 million first round in May, also sees several
applications for its technology but will go after cancer first, said CEO Alan
Crane. Unlike BIND, Tempo doesn't use targeting agents to guide its
therapies. Since its Nanocell products are 180 to 200 nanometers in
diameter, they are small enough to slip through the pores of tumor blood
vessels.
As a result, its nanoparticle-based products accumulate in tumors, where
they release two drugs. The first collapses the tumor vasculature, trapping
the nanoparticle inside. Then, a chemotherapy is slowly released, and the
tumor is exposed to a steady, prolonged dose.
Tempo's first-round financing should carry it to the start of clinical trials, Mr.
Crane said, though he didn't say when those trials would begin or what
drugs Tempo intends to use with its initial product.
Avidimer Therapeutics Inc., which raised first-round funding in early August
from Flagship Ventures and North Coast Technology Investors LP, Ann
Arbor, Mich., also looks to hit tumors hard and foil their defenses, but
through other means.
The Ann Arbor, Mich., company, whose "dendrimer" agents are shaped
like tiny trees decorated with drugs, expects to begin testing one adorned
with the chemotherapy methotrexate in clinical studies next year.
One way tumors resist chemotherapies is by pumping them out. When
Avidimer's lead product enters a tumor, the methotrexate molecules
remain anchored to the dendrimer, which keeps them from being expelled,
said CEO Larry A. Sternson. Company research indicates that
methotrexate doesn't need to be set free to work, but Avidimer can make
dendrimers that release a drug if needed, he said.
In addition to making drugs more effective, nanotechnology might also
make it possible to apply certain drugs to new areas. Alta Partners, San
Francisco, and Frazier Healthcare Ventures, Seattle, Wash., saw this
potential last year when they co-led a $16 million first round of funding for
Palo Alto, Calif.-based Intradigm Corp., which hopes to bring a new kind of
medicine to cancer: RNA interference, a means of silencing disease
genes.
With RNA-interference therapy, small-interfering RNA, or siRNA,
molecules disrupt the cellular machinery for translating a target gene into a
protein. Though no siRNA drugs have reached market, Merck & Co.,
Whitehouse Station, N.J., saw enough potential in the approach to pay
$1.1 billion to acquire RNA-interference drug maker Sirna Therapeutics
Inc. last year.
Since RNA-interference molecules don't readily enter cells, most RNAinterference companies have focused on diseases where the drug can be
injected into a specific site, such as the eye for the treatment of agerelated macular degeneration. But localized delivery won't work for cancer
patients whose disease has spread throughout their body.
Intradigm packages siRNA molecules into its Nanoplex agents, which
search out tumors and penetrate them. Its first product will carry siRNA
molecules that silence two genes that tumors use to get an ample supply
of blood. To target its therapies, Intradigm attaches molecules that latch
onto receptors found on blood vessels feeding tumors.
Its Nanoplex drugs, about 100 nanometers in diameter, carry thousands of
siRNA molecules. In animal studies of colon and kidney cancer, they
shrunk tumors significantly, said CEO Mohammad Azab.
Of course, the next challenge for Intradigm and the others is to shrink
tumors in actual patients. While early research is reasonably predictive,
"the human system is much more complex than the animal systems we
use," Mr. Azab said. Intradigm intends to start human trials in mid-2008.
Some start-ups seek to improve diagnosis as well as treatment. One is St.
Louis-based Kereos Inc., backed with just more than $20 million from
RiverVest Venture Partners, St. Louis; Genentech Inc., South San
Francisco, Calif.; Triathlon Medical Ventures, Cincinnati; and others. Early
next year it plans to begin clinical testing of a molecular- imaging product
that delivers the contrast-agent gadolinium to the tumor by targeting its
growing vasculature. This enhances magnetic- resonance imaging, or MRI,
and could enable earlier detection of various solid tumors.
Eventually, Kereos intends to complement this product with one that
delivers the medication paclitaxel or another chemotherapeutic drug into
tumors. The company expects to raise an additional $25 million in 2008 to
progress its imaging agent through Phase II studies and to advance its
earlier-stage therapeutics for cancer and cardiovascular disease,
according to CEO Robert A. Beardsley.