Marshall Edwards, Inc.'s NV-128, a Novel mTOR Inhibitor, Demonstrates Good Safety Profile and High Anti-Cancer Activity In Vivo
September 29 2009 - 8:30AM
Marketwired
Marshall Edwards, Inc. (NASDAQ: MSHL), a pharmaceutical company
specializing in clinical development of oncology drugs, today
released data demonstrating that the efficacy of NV-128 in animal
xenograft models is achieved without apparent toxicity.
NV-128 is a novel flavonoid small molecule mTOR inhibitor,
capable of inhibiting both mTORC1 and mTORC2 pathways which are
central to the aberrant proliferative capacity of both mature
cancer cells and cancer stem cells.
The data demonstrated that NV-128 has much greater safety than
some other mTOR inhibitors in mice bearing human ovarian cancer
xenografts.
Most of the current compounds acting on this pathway are analogs
of rapamycin, known as rapalogs. Rapamycin and its analogs are
regarded as the archetypal inhibitors of mammalian target of
rapamycin or mTOR. In addition to their reported toxicities,
rapalogs have been shown to contribute to the development of drug
resistant tumors and ultimately reduced effectiveness over time due
to their inability to efficiently inhibit mTORC2, a complex of mTOR
with "rictor" (rapamycin-insensitive companion of mTOR).
NV-128 administered daily resulted in a reduction in tumor
volume of 51 per cent relative to untreated control animals after
15 days, compared to a 50 per cent reduction in mice given
rapamycin every other day. However, whereas rapamycin treated mice
lost 8 per cent of body weight over this period, NV-128 treated
mice gained weight, finishing at 6 per cent above their starting
weight after the 15 day period. This is a significant indicator of
lack of toxicity for NV-128, whereas the weight loss in the
rapamycin-treated mice was judged to be a reflection of the well
documented toxicity of rapamycin in both animal and human studies.
After 21 days the tumors were removed and weighed. In NV-128
treated mice, tumor mass was reduced by 41 per cent compared to
vehicle controls, an effect equivalent to rapamycin treated animals
in which tumor mass was reduced by 44 per cent.
In additional data released today by Marshall Edwards Inc., the
Company reported that NV-128 was judged to be without cardiac
toxicity, further indicating the likely safety of NV-128 in
clinical use.
One limitation of many drugs in clinical application, including
some mTOR inhibitors, is their interference with heart function
causing the interval between heart beats to increase (known as the
QTc interval). In carefully controlled studies undertaken by an
independent contract laboratory, using guinea pigs attached to
recording devices to monitor heart function (electrocardiograms),
NV-128 administration was shown to have no impact on the QTc
interval and was judged therefore to be devoid of cardiac
toxicity.
"The combined findings of high level efficacy and good safety
profile, including a lack of interference with heart functioning,
is a significant step forward in the search for safe and effective
cancer drugs that target mTOR," said Professor Alan Husband, Group
Director of Research for Marshall Edwards, Inc.
"mTOR inhibitors have been given a high priority by many
pharmaceutical companies working in the oncology field in recent
times but none have been able to produce clinical efficacy in the
absence of toxicities. We are encouraged that the novel mTOR
inhibitor, NV-128, has great potential in human cancer management
and we are moving as rapidly as possible to obtain approvals for
human clinical trials to commence," Professor Husband said.
The Marshall Edwards cancer biology group, headed by Dr. David
Brown, is currently also exploring the utility of NV-128 in
non-small cell lung cancer (NSCLC) models.
"While broadly acting against most cancer cell lines, of all the
cell lines we have tested with NV-128, NSCLC lines appear to be the
most sensitive to the anti-cancer effects of the drug," said Dr.
Brown.
"More recently we have also obtained evidence of the anti-cancer
effect of NV-128 in vivo in mice bearing human NSCLC xenografts.
Since lung cancer is one of the most prevalent forms of human
cancer, we are excited at the prospect in due course of taking the
compound into the clinic to evaluate it as a treatment option for
this priority target indication," Dr. Brown said.
About NV-128:
Structurally, NV-128 is an analog of triphendiol and
phenoxodiol, both of which are investigational drugs that have been
licensed by Novogen Limited to Marshall Edwards, Inc. Phenoxodiol
is in development for ovarian and prostate cancer and triphendiol
has been granted orphan drug status by the FDA for pancreatic and
bile duct cancers, and late stage melanoma.
In contrast to phenoxodiol and triphendiol, NV-128 has been
shown to induce caspase-independent DNA degradation and cancer cell
death. It appears that in conjunction with autophagy induction,
NV-128 induces caspase independent cell death via the AKT-mTOR
pathway resulting in beclin sequestration of Bcl-2, Bax
up-regulation and mitochondrial depolarization. As a consequence,
endonuclease G translocates to the nucleus where it initiates DNA
degradation and cell death. This offers an opportunity for use as a
monotherapy in chemoresistant cancers and enhanced efficacy against
cancer targets less susceptible to phenoxodiol. The option for
co-administration of combinations of these drugs is also under
investigation to extend the potential therapeutic range of this
unique class of oncology compounds.
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. Marshall Edwards, Inc. has licensed rights from
Novogen Limited (ASX: NRT) (NASDAQ: NVGN) to bring four oncology
drugs -- phenoxodiol, triphendiol, NV-143 and NV-128 -- to market
globally.
Marshall Edwards, Inc. is majority owned by Novogen Limited, an
Australian biotechnology company that is specializing in the
development of therapeutics based on a flavonoid technology
platform. Novogen is developing a range of therapeutics across the
fields of oncology, cardiovascular disease and inflammatory
diseases. More information 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 arty 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.
Contact: Warren Lancaster +1-203-966-2556 (USA) Email Contact
Alan Husband +61 2 9878 0088 (Australia) Email Contact
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