MetaPhore Pharmaceuticals completes Phase I clinical trial first enzyme mimetic tested in humans, Phase II cancer co-therapy trial planned

July 12, 2001

St. Louis, Mo., - MetaPhore Pharmaceuticals today announced that initial human clinical studies of the first candidate from its proprietary family of free-radical fighting enzyme mimetics have shown the drug to be safe and well tolerated. The studies are also significant because they represent the first time that a small molecule drug developed to mimic an enzyme's activity has been tested in humans, based on published reports.

The Phase I, double-blind, placebo-controlled clinical trial involved single, escalating doses of the enzyme mimetic drug M40403 administered intravenously in a total of 36 normal, healthy human subjects. No dose-limiting side effects were observed or reported.

MetaPhore now intends to proceed shortly with a Phase II trial to assess the efficacy of M40403 as a co-therapy with interleukin-2 (IL-2) in small groups of patients with advanced skin and end-stage kidney cancers.

MetaPhore's enzyme mimetics work by replicating the catalytic activity of the natural enzyme, superoxide dismutase (SOD), the body's natural defense against free radical damage to tissues and cells. The natural regulation of superoxide free radicals by SOD, however, is unbalanced in certain disease states, including cancer, when the body's immune system prompts an overproduction of superoxide and the natural SOD enzymes become overwhelmed.

"The successful completion of the first clinical trial with a member of our family of enzyme mimetic compounds is a major step for MetaPhore and our SOD program, said Denis Forster, Chief Executive Officer of MetaPhore. "It also opens the door for a new therapeutic approach to many areas of significant medical need.

Promoting or duplicating an enzyme's activity is known to be difficult, which is why most drugs today that target enzymatic pathways take a blocking, or antagonist, approach. SOD enzyme mimetics have been shown to effectively replicate the catalytic activity of the natural enzyme, and now the first drug candidate from this group has been shown safe and tolerable in healthy human subjects."

Pre-clinical efficacy studies in models of cancer have shown that the enzyme mimetic significantly improves the effectiveness of IL-2 by addressing the dose-limiting side effects, primarily severe hypotension, of IL-2, and also appears to work synergistically with IL-2's anti-tumor effect.

IL-2, a cytokine-based immunotherapy, is currently an approved treatment for advanced, inoperable forms of melanoma and renal cell carcinoma. Approximately 80,000 cases of these two cancers are diagnosed in the U.S. each year. The immunotherapy works by activating natural killer (NK) cells that have the ability to recognize and destroy many types of tumors.

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

In pre-clinical studies conducted by researchers with MetaPhore and the Huntsman Cancer Institute at the University of Utah, the enzyme mimetic showed an ability to reverse and prevent the onset of an IL-2 induced blood pressure drop. The studies also showed that the enzyme mimetic enhances the direct anti-tumor properties of IL-2 therapy.

"Based on these results, SOD enzyme mimetics may offer improved therapeutic options for end-stage cancer patients, with a greatly reduced side-effect profile," said Daniela Salvemini, MetaPhore's Vice President and Director of Pharmacology. "Moreover, these studies also indicate the drug may hold wider potential with other cytokine-based cancer therapies."

Additional pre-clinical studies conducted by MetaPhore researchers and others indicate that SOD enzyme mimetics hold extensive potential for a wide array of diseases and conditions associated with free-radical damage, including pain and inflammation, stroke, heart attack as well as certain types of cancers. These studies, conducted in a range of disease models, indicate that the compounds have significant anti-inflammatory properties as well as contributing to the maintenance of vascular pressure.

In addition to cancer, MetaPhore is developing drug candidates for pain and other diseases and conditions associated with free-radical damage to tissue and cells.
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Background

MetaPhore scientists pioneered the design and development of SOD mimetic compounds. Previous attempts by the pharmaceutical industry to develop a naturally derived SOD drug showed promise; however, use of the drug, which was the bovine form of SOD enzyme, was frustrated by the natural form's inherent instability and the body's reaction to its introduction.

MetaPhore's SOD mimetics are promising drug candidates because they have a low molecular weight, are highly stable and do not elicit an immune response in the body. Furthermore, the chemical structure of the metal-based compounds can easily be optimized for application to different diseases and conditions.

In a study published earlier this year in the journal Inorganic Chemistry, MetaPhore researchers reported the development of a 'superactive' mimetic compound, achieving the highest catalytic rate for reducing superoxide free radicals of any known synthetic compound and exceeding the rate of the natural SOD enzymes. The researchers also reported that the improved SOD mimetic, consistent with its higher catalytic rate, exhibited protective effects in pre-clinical models of reperfusion injury and septic shock at significantly lower dosage levels.

"SOD enzyme mimetics have major medical potential, based on the growing body of research that links free radical-induced damage to numerous diseases and conditions. We can effectively replicate the beneficial action of the SOD enzyme in a stable and selective drug form, and also tailor specific mimetic compounds for each disease state," said Dennis Riley, Senior Vice President of Research & Development at MetaPhore.

For more information, please visit http://www.metaphore.com

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.

Kupper Parker Communications

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