FDA awards grant to metaphore pharmaceuticals to study septic shock in humans

November 01, 2000

MetaPhore and Saint Louis University researchers aim to explain perplexing blood pressure drop

St. Louis, MO, November 2, 2000 - The Food and Drug Administration (FDA) has awarded a six-month $100,000 Small Business and Innovation Research (SBIR) grant to MetaPhore Pharmaceuticals to study the dramatic and perplexing blood pressure drop that occurs during septic shock and leads to death in up to 50 percent of cases.

Researchers from MetaPhore and Saint Louis University School of Medicine will study the levels of two key biological markers, one of which directly affects blood pressure, to see if what happens among human subjects correlates with the phenomenon they observed in recent animal studies.

Findings of those studies, published in the Proceedings of the National Academy of Sciences in August, confirmed the role that oxygen free radicals, produced in excess during septic shock - particularly superoxide anions - play in deactivating the body's vascular regulation system.

Septic shock, a form of severe sepsis in which arterial blood pressure drops below safe levels, represents a life-threatening situation in which the body's immune system goes into overdrive and attacks an infection with all possible means. However, the large quantities of oxygen free radicals produced by the body during this internal fight also destroy catecholamines, the natural compounds that help to maintain blood pressure and oxygen delivery to critical organ systems. These compounds include dopamine and norepinephrine, which also are used as drugs to fight hypotension, i.e. low blood pressure, and are widely prescribed to treat this life-threatening aspect of sepsis.

"By studying the levels of catecholamines during septic shock, we hope to solve the question of why blood pressure most often continues to plummet in sepsis cases despite using pharmacological agents that should, in fact, increase and maintain vascular pressure and blood flow," said Dr. Daniela Salvemini, MetaPhore's Director of Biology and the Principal Investigator for the grant.

Dr. George M. Matuschak, Professor of Internal Medicine and Pharmacological and Physiological Science at Saint Louis University School of Medicine is the Co-Investigator of the study. Other members of the research team include Dr. Dennis Riley and Dr. Ronald Smith, both of MetaPhore.

The researchers will study blood samples from sepsis patients to confirm the link between free radicals and falling blood pressure. Because free radicals convert catecholamines into a second class of compounds, known as adrenochromes, the researchers expect to find increased levels of adrenochromes alongside decreased levels of catecholamines.

In the previous animal study, the researchers administered MetaPhore's developmental antioxidant compound that mimics a natural free-radical fighting enzyme called Superoxide Dismutase (SOD). In the study, the SOD mimetic was found to restore the ability of norepinephrine to constrict blood vessels and reverse hypotension.

Background on Free Radicals, SOD and MetaPhore's SOD Mimic The formation of free radicals is a naturally occurring process. An excess of these reactive oxygen-derived molecules damages cell structure and even genes -- much like oxidation causes metal to rust. This type of progressive damage has become increasingly linked to several diseases and conditions, particularly those associated with aging such as auto-immune disorders like Parkinson's and rheumatoid arthritis, multiple types of cancer, as well as pain and inflammation.

The SOD enzyme, which is an essential protein mapped in the body's DNA, removes free radicals by converting the undesirable superoxide molecules into hydrogen peroxide and oxygen. This product of SOD's catalytic action also has potential benefits that complement those of free radical removal. Hydrogen peroxide has been shown to be critical to the functioning of white blood cells in killing foreign bacteria.

"SOD mimetics have major medical potential, based on the growing body of antioxidant and disease research. For more than twenty years, we have understood the free radical fighting power of the body's natural SOD enzyme, but until recently, we have been unable to reproduce the beneficial effect in a stable and selective drug form," said Dennis Riley, MetaPhore's Vice President of Research & Development.

Just like the antioxidant vitamins E and C, MetaPhore's SOD mimetics remove free radicals. However, the metal-based mimetic compounds do so at a greatly enhanced rate (mopping up more than 20 million superoxide molecules per second) and in a very selective manner. Unlike naturally derived SOD enzyme, the metal-based mimetic is well suited for use as a drug because it has a much lower molecular weight, is much more stable, has a longer half-life, and does not appear to elicit an immune response in the body.

Attempts to use natural, bovine-derived SOD enzymes in clinical applications were frustrated by the natural form's inherent instability and the body's allergic reaction to its introduction. It also had a very short half-life, lasting intact in the body only about fifteen minutes.

Numerous animal studies over the last few years have confirmed the disease fighting potential of MetaPhore's SOD mimetics. The October 1999 issue of Science published research documenting that MetaPhore's SOD mimetic substantially reduced tissue damage due to inflammation and reperfusion - the latter involving the return of blood flow to an organ following removal of a blockage, such as after a heart attack.

MetaPhore recently announced that it has received an SBIR grant from the National Institutes of Health (NIH) to conduct Phase 1 studies aimed at developing potential new treatments for managing acute and chronic pain.

The company's first drug candidate is targeted at cancer, where it is proceeding toward an Investigational New Drug (IND) submission to the FDA by year-end. The second drug candidate, for acute and chronic pain, is expected to move into clinical trials in the first half of 2001.

Among the other areas where MetaPhore is moving its SOD mimetics program forward are dermatitis, rheumatoid arthritis and stroke. The company believes its novel approach could result in treatments with unmatched therapeutic value, either on their own or as adjunct therapy with existing medications, and with minimal side effects.

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.
MetaPhore Pharmaceuticals, Inc.
1910 Innerbelt Business Center Drive
St. Louis, MO 63114

Punnie Donohue
or 314-496-9620

Kupper Parker Communications

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