Marshall Edwards, Inc.'s Investigational Drug Triphendiol (NV-196) Demonstrates Potent Activity Against Biliary Cancers
April 13 2008 - 4:00PM
Marketwired
SAN DIEGO, CA induces apoptosis in pancreatic and bile duct
cancer cell lines, and also retards tumor proliferation in animal
models of both indications. Of significance, triphendiol also
potently sensitizes pancreatic and bile duct cancer cell lines and
xenograft tumors to the standard of care drug, gemcitabine. These
data were presented by Ewan Tytler, PhD, Assistant Professor,
Division of General Surgery, Gastroinstestinal Section, University
of Alabama at Birmingham (UAB), as part of a "late breaking" poster
session.
"In laboratory studies, triphendiol is more potent at apoptosis
induction in pancreatic and bile duct cancer cells compared to
gemcitabine at up to ten-fold lower concentrations," said Dr.
Tytler.
There is an urgent need for new pancreatic cancer treatments
because fewer than 20 percent of patients are candidates for
surgery. Current treatment is limited to chemotherapy with
gemcitabine, to which most patients are resistant or acquire
resistance. This study assessed the potential of triphendiol as a
treatment for pancreatic adenocarcinoma using three representative
cell lines. Triphendiol-induced apoptosis (cell death) in all cell
lines and pre-treatment with triphendiol increased
gemcitabine-dependent apoptosis. Animal model studies showed that
triphendiol in combination with gemcitabine inhibits tumor growth
more effectively than each drug alone. Both triphendiol and
gemcitabine induce apoptosis via a mitochondrial pathway.
Structurally, triphendiol is an analogue of phenoxodiol, both of
which are investigational drugs that have been licensed by Novogen
to Marshall Edwards, Inc. Phenoxodiol is currently in Phase III
clinical development for patients with late stage ovarian cancer
under the OVATURE banner. Triphendiol has recently been granted
orphan drug status by the FDA for pancreatic cancer, bile duct
cancer and melanoma.
Like phenoxodiol, triphendiol is also able to induce apoptosis
however, triphendiol-induced cell death is thought to proceed via
both caspase-dependent and caspase-independent pathways. In
pancreatic cancer cells, triphendiol causes upregulation of p21
thereby arresting the cell cycle in G2M leading to apoptosis
induction. Integral to triphendiol-induced apoptosis induction is
mitochondrial depolarization due to transitory changes is Bcl-2 and
Bid expression. Like phenoxodiol, triphendiol also causes XIAP
degradation. In bile-duct cancer cells, triphendiol induces
apoptosis that is completely caspase-independent. Animal studies
using nude mice bearing human pancreatic and bile duct tumors,
demonstrated that oral triphendiol administration in combination
with gemcitabine resulted in a mean reduction in tumor volume by 62
percent and 81 percent respectively compared with untreated tumors
from control animals.
"With a lack of data from randomized Phase III studies, there is
no current evidence-based treatment recommendation for patients
with advanced pancreatic cancer that have failed first-line
gemcitabine," said Wasif Saif, MD, Associate Professor and
Director, Gastrointestinal Cancers Program, the Yale School of
Medicine. "The ability of triphendiol to sensitize pancreatic
cancer tumors to gemcitabine in animal studies justifies the
continued development of triphendiol as a pancreatic cancer
therapy, and would provide a welcome second-line therapeutic
contingency for late stage gemcitabine refractory pancreatic cancer
patients."
Professor Alan Husband, Group Director of Research for Marshall
Edwards, Inc., said, "The commercial potential of the flavonoid
technology platform from which these candidate molecules have been
derived is now becoming evident. Through continued refinement of
our proprietary molecular scaffold, we anticipate further
enrichment of our pipeline with analogues whose activity may be
directed against a diverse array of cancer targets."
About Phenoxodiol and Triphendiol
Phenoxodiol is being developed as a therapy for late-stage,
chemo-resistant prostate, ovarian and cervical cancers. It is a
novel-acting drug that inhibits key pro-survival signaling pathways
operating via sphingosine-1-phosphate and Akt. Inhibition of these
pathways leads to prevention of phosphorylation of key
anti-apoptotic proteins such as XIAP and FLIPs. Loss of activity of
these proteins restores the ability of chemoresistant tumor cells
to undergo apoptosis in response to chemotherapy. The molecular
target for phenoxodiol is an oxidase enzyme present on the surface
of cancer cells, accounting for the highly selective nature of the
drug.
Triphendiol is being developed as a therapy for late state
pancreatic and bile duct cancer and has recently been awarded
orphan drug status. Triphendiol-induced apoptosis is initiated by
mitochondrial depolarization due to transitory changes is Bcl-2 and
Bid expression. Like phenoxodiol, triphendiol also causes XIAP
degradation.
Multinational Trial Underway
Phenoxodiol in combination with carboplatin is currently being
studied in a multi-national Phase III clinical trial called the
OVATURE (OVArian TUmor REsponse) Trial, following positive findings
of previous trials conducted in Australia and at Yale-New Haven
Hospital. The OVATURE trial is taking place at over 70 clinical
sites in the United States, Europe, and Australia. For more
information on the trial, visit www.OVATUREtrial.com.
About Marshall Edwards, Inc.:
Marshall Edwards, Inc. (NASDAQ: MSHL) is a specialist oncology
company focused on the clinical development of novel anti-cancer
therapeutics. These derive from a flavonoid technology platform,
which has generated a number of novel compounds characterized by
broad ranging activity against a range of cancer cell types with
few side effects. The combination of anti-tumor cell activity and
low toxicity is believed to be a result of the ability of these
compounds to target an enzyme present on the surface of cancer
cells, thereby inhibiting the production of pro-survival proteins
within the cell. Marshall Edwards, Inc. has licensed rights from
Novogen Limited (NASDAQ: NVGN) to bring three oncology drugs --
phenoxodiol, triphendiol and NV-143 -- to market globally.
Marshall Edwards, Inc. is majority owned by Novogen, an
Australian biotechnology company that is specializing in the
development of therapeutics based on a flavonoid technology
platform. Novogen, based in Sydney, Australia, is developing a
range of therapeutics across the fields of oncology, cardiovascular
disease and inflammatory diseases. More information on phenoxodiol
and on the Novogen group of companies can be found at
www.marshalledwardsinc.com and www.novogen.com.
Under U.S. law, a new drug cannot be marketed until it has been
investigated in clinical trials and approved by the FDA as being
safe and effective for the intended use. Statements included in
this press release that are not historical in nature are
"forward-looking statements" within the meaning of the "safe
harbor" provisions of the Private Securities Litigation Reform Act
of 1995. You should be aware that our actual results could differ
materially from those contained in the forward-looking statements,
which are based on management's current expectations and are
subject to a number of risks and uncertainties, including, but not
limited to, our failure to successfully commercialize our product
candidates; costs and delays in the development and/or FDA
approval, or the failure to obtain such approval, of our product
candidates; uncertainties in clinical trial results; our inability
to maintain or enter into, and the risks resulting from our
dependence upon, collaboration or contractual arrangements
necessary for the development, manufacture, commercialization,
marketing, sales and distribution of any products; competitive
factors; our inability to protect our patents or proprietary rights
and obtain necessary rights to third party patents and intellectual
property to operate our business; our inability to operate our
business without infringing the patents and proprietary rights of
others; general economic conditions; the failure of any products to
gain market acceptance; our inability to obtain any additional
required financing; technological changes; government regulation;
changes in industry practice; and one-time events. We do not intend
to update any of these factors or to publicly announce the results
of any revisions to these forward-looking statements.
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