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 - 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 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 University 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 humans and introduced Amplimexon®  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 pancreatic cancer, malignant melanoma, lung, breast and prostate cancer. Results from these studies have enabled us to determine which cancer types (indications) to study in our next set of efficacy studies, which began 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, (or ROS) to build up inside cancer cells. Ultimately this leads to the cell undergoing a process known as apoptosis, or programmed cell death.

Cells which divide rapidly generate 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 thiols "neutralize" the ROS. One of the 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, and the cells become damaged and undergo apoptosis and die

Other chemotherapeutic drugs also target rapidly dividing cells. 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 Amplimexon® 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 in combination therapy.

In addition, we have determined that Amplimexon® has the ability to synergize with the chemotherapy drug gemcitabine, that is incorporated into the DNA of cancer cells (thereby preventing the DNA from replicating). It significantly enhances the anti-tumor effect of gomcitabine in mice bearing human pancreas

Our preclinical studies showing this potential for synergy 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 conducted 6 studies of Amplimexon® in over 300 patients with various cancers, and one Phase I/II study of Amplimexon® plus DTIC® in melanoma.  These clinical trials are summarized in table 1 with pancreatic, 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.


Publications
Concerning Amplimexon and Amplizone