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February 19,
2008 |
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Plexxikon Inc. today announced the publication of data from
studies of Plexxikon’s targeted cancer compound published in
The Proceedings of the National Academy of Sciences
by a team of scientists from Plexxikon and the Wistar
Institute. Plexxikon’s novel anti-cancer compound
selectively destroys tumor cells which contain the B-RafV600E
cancer-causing mutation, a defect present in most melanomas
and thyroid tumors and a large number of colorectal and
other cancers. Patients with the B-RafV600E
gene may have particularly aggressive tumors often resulting
in much poorer survival outcomes.
Using its
proprietary Scaffold-Based Drug Discovery™ platform,
Plexxikon has identified a portfolio of unique anti-cancer
compounds that selectively kill cells with the B-RafV600E
mutation, leaving healthy cells unharmed since the mutation
only occurs in tumor cells. The co-crystallography platform
enabled scientists at Plexxikon to determine the exact
location where such inhibitors selectively bind to the
cancer-causing enzyme.
Plexxikon is
conducting a Phase 1 clinical trial utilizing PLX4032, one
of Plexxikon’s selective B-RafV600E
inhibitors, in collaboration with Roche. Separately,
Plexxikon and Roche Molecular Diagnostics collaborated to develop a test to identify patients who carry
the tumor mutations and for whom a selective B-RafV600E
inhibitor may have the greatest therapeutic benefit.
“Through
a series of in vivo and in vitro studies, we
demonstrated that our B-RafV600E inhibitor
selectively destroys BRAF-oncogene driven tumors,
supporting the development of a B-Raf inhibitor as a
personalized medicine for patients with this mutation,” said
Gideon Bollag, Ph.D., vice president of discovery biology
for Plexxikon.
Plexxikon’s family of B-RafV600E
kinase inhibitors selectively target a unique binding site
of the protein, minimizing the common side effects seen from
other less selective kinase inhibitors. In several different
cancer cell lines, Plexxikon’s B-RafV600E
inhibitor induces cell cycle arrest and cell death
(apoptosis) exclusively in B-RafV600E-positive
cells, with no damage to the healthy cells. These results
were confirmed in tumor-bearing mice, which show tumor
regression and delayed tumor growth in animals treated with
the B-RafV600E inhibitor. The
comprehensive findings from Plexxikon and the Wistar
Institute, a National Cancer Institute-Designated Cancer
Center, are contained in an article entitled “Discovery of a
selective inhibitor of oncogenic B-Raf kinase with potent
antimelanoma activity” in the February 19, 2008 Early
Edition and the February 26, 2008 Print Edition of The
Proceedings of the National Academy of Sciences.
www.pnas.org/cgi/content/full/0711741105.
“Our kinase inhibitor can bind and act in an extremely
selective way, providing a wide safety window not seen so
far with other compounds in this category. With the
Plexxikon approach, we have opened the door to the
possibility of using kinase drugs not only for more
effective cancer therapies, but also for the treatment of
other chronic diseases like rheumatoid arthritis, pain and
polycystic kidney disease,” said K. Peter Hirth, Ph.D.,
chief executive officer of Plexxikon. “Designing highly
selective drug candidates is a hallmark of Plexxikon’s
discovery platform for a number of different classes of
targets, including kinases, nuclear receptors,
phosphodiesterases and more recently, proteases.”
Plexxikon is conducting a Phase 1 clinical trial in
collaboration with Roche to evaluate PLX4032/R7204, an
orally available anti-cancer agent designed to specifically
inhibit the B-RafV600E protein. Enrollment
is complete for the dose escalation phase of the trial,
which is being conducted in cancer patients. The next phase
of this trial will test efficacy of the drug only in
melanoma patients who have the B-RafV600E
mutation, and will include radiologic imaging studies such
as positron emission tomography (PET) scans and CT scans to
assess anti-tumor activity. Patients will be selected for
this study using an investigational diagnostic test
developed by Roche Molecular Diagnostics in collaboration
with Plexxikon for this purpose. Enrollment for this trial
is expected to be completed by the end of 2008. To date,
PLX4032 has been safe and well tolerated even at the highest
doses administered.
"Later this year, we anticipate the further expansion of our growing clinical stage portfolio as we plan to file an IND for a novel pain agent, and move multiple compounds from our Fms franchise into pre-development and IND-enabling studies, targeting rheumatoid arthritis and bone metastases in breast cancer," commented Kathleen Sereda Glaub, president of Plexxikon Inc.
Plexxikon Profile
Plexxikon is a leader in structure-guided discovery and
development of novel small molecule pharmaceuticals to treat
human disease. The company’s clinical stage programs include
PLX204 for the treatment of diabetes, and PLX4032 for the
treatment of melanoma and colorectal cancer. Preclinical
development programs include a kinase inhibitor for the
treatment of pain, and a portfolio of kinase inhibitors for
the treatment of kidney disease, rheumatoid arthritis and
metastatic breast cancer.
Plexxikon’s proprietary
Scaffold-Based Drug Discovery™ platform is being applied to
build a pipeline of diverse product opportunities for the
treatment of metabolic and cardiovascular disease,
inflammation, oncology and CNS disorders. This discovery
process integrates a number of state-of-the-art
technologies, including structural screening as one key
component that provides a significant competitive advantage
over other drug discovery approaches. To date, the company
has discovered a portfolio of clinical and preclinical stage
compounds in multiple disease areas addressing significant
unmet needs in each therapeutic category. Plexxikon is
seeking pharmaceutical and biotechnology partners for select
collaboration opportunities. For more information, please
visit www.plexxikon.com.
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