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The Challenge.
Cancer is the number two killer in the U.S.,
with 1,437,180 cases and 565,650 deaths projected for 2008, according to the
American Cancer Society. Thanks to improvements in diagnosis and treatment,
and a reduction in the incidence of cancers such as lung cancer with poor
5-year prognoses, overall 5-year survival rates for newly diagnosed cancer
patients have improved significantly during recent years.
However, the overall 5-year rate of survival for patients diagnosed between
2000 and 2005 was still only 60 percent - better than the data 25 years ago
when mean 5-year survival was only 50 percent - but still indicating that
more than a third of all newly diagnosed cancer patients will die within 5
years. Furthermore, for certain cancers, 5-year survival remains
significantly below the mean and has barely improved over the last 25 years.
For example, pancreatic cancer
survival has improved
from 3 to 4 percent over those years, and lung and bronchus cancer from 13
to 15 percent over those years.
There is clearly room for improved therapies for these devastating diseases,
and these challenges are the focus of AmpliMed's drug development program.
Many cancers do not respond well to drug therapy, in part because the cancer
cells can become resistant to many of the most frequently used drugs. Also
the use of high doses or combinations of these drugs is limited by their
toxicity. Specifically, many widely used drugs suppress the number of new
blood cells produced by the bone marrow (known as myelosuppression), thereby
reducing the amount of cells in the blood (the blood counts), which can lead
to an increased risk of infection and bleeding. They may also produce other
irreversible toxicities, such as damage to the peripheral nerves.
New drugs with new mechanisms of action which are better tolerated by
patients are urgently needed. AmpliMed's portfolio of more than 100
compounds has been designed to address this challenge.
AmpliMed's
Insight.
Our anticancer drugs exhibit novel mechanisms
of action that overcome some of the limitations frequently encountered with
current cancer therapy. In particular, our first drug to enter the clinic,
Amplimexon® (imexon, inj.), is only minimally myelosuppressive (suppressing
blood cell counts) at the highest doses and circumvents the multi-drug
resistance (MDR) mechanism by which cancer cells avoid the effects of
anticancer drugs.
The unique anticancer properties of Amplimexon® were discovered by our
founding scientists in the laboratories of the Arizona Cancer Center at the
Univesity of Arizona in Tucson, Arizona. Through an extensive program of
experimental studies, they defined the drug's mechanism of action, developed
manufacturing and formulation methods, confirmed that the drug was safe for
use in human trials and introduced the product into clinical studies in
September of 2003. Phase I studies to define the safety and tolerability of
the drug have been completed. Phase Ib/II trials to determine effectiveness
in defined patient populations are underway or have been completed in
several different types of cancer including pancreas cancer, malignant
melanoma, and lung, breast and prostate cancer. Results from these studies
have enabled us to determine which cancer types (indications) will be
studied in our next set of efficacy studies, which have begun in 2008.
Cancer patients may have their physicians contact the company at
520-529-1000 to check on their eligibility for one of AmpliMed's trials.
Unique Mechanism of Action -
Unique Advantages.
Research carried out at the Arizona Cancer
Center in Tucson has revealed that Amplimexon® is effective at killing
cancer cells as a result of unique mechanisms of action. Amplimexon® causes
toxic substances, called reactive oxygen species, to build up inside cancer
cells exposed to the drug. Ultimately this leads to the cell undergoing a
process known as apoptosis, or programmed cell death.
Cells which divide rapidly generate toxic substances known as reactive
oxygen species (or ROS), which can accumulate inside the cell. Cancer cells
are particularly susceptible to this problem, because they are in a phase of
rapid, uncontrolled division. In order to protect themselves against the
buildup of ROS, cancer cells produce compounds containing chemical groups
known as thiols. These compounds "neutralize" the toxins. One of these thiol
compounds that is commonly produced by cancer cells is glutathione (GSH).
When cancer cells are exposed to Amplimexon®, the levels of GSH and other
thiols in the cells are significantly reduced. As a result, the toxic ROS
levels in the cell are increased, the cells become damaged and undergo
apoptosis, ultimately leading to cell death.
Other chemotherapeutic drugs also target rapidly dividing cells. However,
this often leads to damage to tissues such as bone marrow and the lining of
the gastrointestinal tract, which contain cells which are normally dividing
rapidly. However, our preliminary clinical data suggest that these cells are
better able to tolerate imexon than are cancer cells, so that at doses of
Amplimexon® which appear to be effective at killing cancer cells, there is
relatively less damage to normal cells in the body. This limits the
side-effects of Amplimexon® and, while it may cause nausea, vomiting,
constipation, or diarrhea, these side-effects can be managed well with
standard preventive treatment, leading to acceptable patient tolerance.
Furthermore, it is only at the highest doses that the drug significantly
suppresses the activity of the bone marrow (myelosuppression), resulting in
a reduction in blood counts.
Unique Synergy.
Amplimexon® appears to be very effective
against certain types of cancer cells by itself. However, typical cancer
chemotherapy involves the use of combinations of drugs which each kills by a
different mechanism. The effects of these combinations can be additive
(simply the combined impact of each individual drug) or synergistic (their
combined effect on cancer cells is greater than the sum of the individual
effects of each drug alone). However, the use of combinations is often
compromised because the toxicities are also usually additive or synergistic.
Thus, many promising combinations are poorly tolerated by patients. However,
because effective doses of Amplimexon® generally do not result in a
significant reduction in blood counts or cause many of the toxicities seen
with other cancer drugs, the drug is a particularly useful candidate for
combination therapy.
Even more exciting, our preclinical studies have shown that Amplimexon® can
re-sensitize cancer cells which have become resistant to drugs which are
routinely used to treat certain types of cancer.
There are several characteristics of Amplimexon® which seem to be important
for this synergy. For example, cancer cells develop resistance mechanisms
that involve the rapid efflux of toxic cancer drugs from the cell, thereby
reducing their effectiveness. These are called multi-drug resistance
mechanisms or MDR. These excretion mechanisms are dependent on GSH, and high
GSH concentrations inside cancer cells makes them more resistant to certain
cancer drugs. By reducing intracellular GSH concentrations, we believe that
Amplimexon® makes cancer cells more sensitive to these drugs. Furthermore,
Amplimexon® itself is not a target of the MDR mechanism.
In addition, we have determined that Amplimexon® has the ability to increase
the amount of an important chemotherapy drug gemcitabine, that is
incorporated into the DNA of cancer cells (thereby preventing the DNA from
replicating). It also targets an enzyme critical for DNA synthesis in a
complementary way to gemcitabine. This is the basis for AmpliMed's pancreas
cancer treatment regimen.
Our preclinical studies showing this potential have now been confirmed in
the clinic. We have shown that full doses of Amplimexon® can be combined
with full doses of the standard, FDA-approved cancer drugs, including DTIC®
(dacarbazine), Gemzar® (gemcitabine) and Taxotere® (docetaxel). This
suggests that full dose combinations will hold true for all toxic anticancer
drugs with Amplimexon®.
Clinical Program
AmpliMed has completed 3
Phase I studies of Amplimexon® in patients with various cancers, has
completed one Phase I/II study of Amplimexon® plus DTIC® in melanoma, and is
completing 2 other combination chemotherapy trials in patients with
pancreas, breast, lung and prostate cancer. Preliminary evidence for
activity has been seen in several different cancers. These findings will now
be tested and hopefully confirmed in a series of larger clinical trials.
In summary, Amplimexon® is unique. It has shown evidence of being well
tolerated in humans as a single agent and in combination with standard
chemotherapy. It has a novel mechanism of action. It appears to be
well-tolerated at doses that are effective in preclinical studies. It has
exhibited exciting evidence of synergy with other cancer drugs. Its activity
may be useful in targeting cancer types for which better therapy is needed.
It can restore the efficacy of drugs to which the tumor has become
resistant. At AmpliMed we are committed to exploring the potential for
Amplimexon® to impact the management of several common but poorly treated
types of cancer.
