Animal studies indicate new approach for treating end-stage skin and kidney cancers

New Orleans, La., March 26, 2001 – Advanced skin and end-stage kidney cancer patients may have a better chance of survival with drugs developed from a new synthetic enzyme that significantly improves the effectiveness of existing interleukin-2 (IL-2) cancer therapy, based on research presented today at the American Association for Cancer Research 92nd Annual Meeting.

In animal studies conducted by researchers at the Huntsman Cancer Institute in Salt Lake City, UT, and MetaPhore Pharmaceuticals in St. Louis, MO, the synthetic enzyme M40403 showed an ability to reverse the extreme blood-pressure drop that is a common side effect of high-dosage IL-2 cancer therapy. The research also showed that the compound enhances the anti-cancer properties of IL-2 therapy.

IL-2 immunotherapy, which works by activating natural killer (NK) cells that have the ability to recognize and destroy many types of tumors, is an approved treatment for inoperable metastatic melanoma and metastatic renal cell carcinoma. About 80,000 cases of melanoma and renal cell carcinoma are diagnosed in the U.S. each year.

IL-2 use is limited, however, by potentially life threatening side effects, including hypotension, particularly at the high-dosage level indicated for these end-stage cancers. A majority of patients undergoing high-dosage IL-2 treatment currently either require intensive care unit (ICU) intervention and/or are unable to complete the full course of treatment.

Reseachers administered the synthetic enzyme, which mimics the action of a natural enzyme, superoxide dismutase (SOD), as a co-therapy with IL-2 in several animal models of advanced cancer. Previous studies have confirmed that the synthetic enzyme effectively reproduces the free-radical fighting properties of the natural SOD enzyme, which has been found to be deficient in cancer states.

When in excess, free radicals – particularly superoxide anions – have been shown to deactivate a class of molecules, called catecholamines, which aid the body’s natural blood pressure regulatory system. By reducing superoxide, the synthetic SOD enzyme restores the levels of catecholamines necessary to constrict blood vessels and reverse hypotension.

Moreover, superoxide also inhibits the activity of NK cells, hampering the anti-tumor effect of IL-2.

“By restoring the body’s natural vascular regulatory system, the synthetic SOD enzyme addresses a major limiting side effect of current IL-2 therapies. It also appears to work synergistically with IL-2’s anti-cancer properties,” said Dr. Wolfram Samlowski of the Huntsman Cancer Institute at the University of Utah.

In two separate animal models, as a co-therapy with IL-2, the synthetic SOD enzyme prevented the onset of IL-2 induced hypotension and enhanced IL-2’s ability to kill malignant cells. In an animal model of pulmonary metastasis, both the synthetic SOD enzyme and IL-2 appeared to have significant anti-tumor action, in combination and individually. In the aggressive Meth A fibrosarcoma tumor model, co-therapy with IL-2 and the synthetic SOD enzyme resulted in a 50 percent complete remission rate, which lasted more than 90 days following tumor implantation, while mice treated with IL-2 therapy alone lived an average of 21 days following implantation with no remissions.

“These studies demonstrate that the synthetic SOD enzyme may have tremendous potential as a co-therapy with IL-2 and related cytokine cancer therapies,” added Daniela Salvemini, MetaPhore’s Vice President and Director of Pharmacology and co-investigator in the study.

Other members of the research team include Ryan Petersen and John Robert McGregor of the Huntsman Cancer Institute.

Background

Production of superoxide, a free radical, results from cellular oxidative metabolism. However, when too much superoxide is produced in the body, various biomolecules, cell structures and even genes are damaged. Free-radical damage has been linked with a wide range of diseases and conditions, including autoimmune and neurodegenerative disorders, multiple types of cancer, complications of diabetes mellitus, strokes, reperfusion injury, as well as pain and inflammation. One of the body’s primary defense mechanisms against free-radical damage is the superoxide dismutase (SOD) family of enzymes. These enzymes typically regulate normal levels of superoxide by converting it into hydrogen peroxide and oxygen, also reducing production of related damaging free radicals, such as peroxynitrite.

MetaPhore is developing a proprietary family of drugs that mimic the catalytic activity of SOD to address the diseases and conditions resulting from excessive superoxide production. In pre-clinical models, the lead candidate from this family has suggested the potential to combat such diseases and conditions more effectively and with fewer side effects than existing treatments.

“Synthetic SOD enzymes have major medical potential, based on the growing body of anti-oxidant and disease research. For more than twenty years, we have understood the free-radical fighting power of the body’s natural SOD enzymes, but until recently, we have been unable to reproduce that beneficial effect in a stable and selective drug form,” said Dennis Riley, MetaPhore’s Senior Vice President of Research & Development.

MetaPhore’s synthetic SOD enzyme is well suited for use as a drug because it has a low molecular weight, is highly stable and does not appear to elicit an immune response in the body.

Animal studies published in journals such as Science and the Proceedings of the National Academy of Sciences during the past few years have confirmed the disease fighting potential of MetaPhore’s synthetic SOD enzymes. These studies have also demonstrated that MetaPhore’s synthetic SOD enzyme substantially reduces tissue damage due to inflammation and reperfusion injury – the latter involving the return of blood flow following removal of blockade, such as after an ischemic heart attack or stroke.

Statements in this press release that are not strictly historical are “forward looking” statements as defined in the Private Securities Litigation Reform Act of 1995. The actual results may differ from those projected in the forward looking statement due to risks and uncertainties that exist in the company’s operations, development efforts and business environment.