St. Louis, MO, December 12, 2001 – The estimated 1 to 2 million Americans suffering from inflammatory bowel disease may benefit from a potential new treatment, using small-molecule enzyme mimetics, based on research published in the European Journal of Pharmacology.
The preclinical study conducted by MetaPhore Pharmaceuticals, Inc.® of St. Louis, MO and the University of Messina (Italy) showed that a superoxide dismutase (SOD) enzyme mimetic significantly reduced the extent and severity of inflammation and tissue damage to the intestinal wall in an animal model of colitis. Researchers also observed a marked reduction in the diarrhea and body weight loss typical of this disease.
The SOD mimetic, M40403, was also shown to reduce elevated levels of two pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-á) and interleukin-1â (IL-1â), implicated in the development of inflammatory bowel disease. M40403 is one of a proprietary family of small-molecule SOD mimetics developed by MetaPhore that are designed to selectively remove superoxide, a free radical that, in excess, has been shown to contribute to inflammatory pathways and to regulate cytokine release.
In addition, M40403 reduced the production of adhesion molecules, intercellular adhesion molecule-1 (ICAM-1) and P-selectin, in the intestinal wall of the animals. These adhesion molecules appear to play a major role in the development and persistence of inflammatory bowel disease in humans by promoting infiltration of inflammatory cells (neutrophils) into the intestine wall.
Inflammatory bowel disease includes two specific disorders: Ulcerative colitis, which affects the inner lining of the lower colon, and Crohn’s disease, which extends into the deeper layers of the intestinal wall. In Crohn’s disease, the damage to the intestine can be so great that large openings, or fistulas, develop in the intestine. Because of difficulty diagnosing the disease, the estimated incidence of these disorders varies widely. Crohn’s disease, however, is now considered to be the second most common chronic inflammatory disorder, after rheumatoid arthritis.
In the study, researchers evaluated the effects of M40403 on inflammatory bowel disease and symptoms. Comparing treated animals to untreated animals:
§ Colonic tissue damage, as evaluated histologically, was substantially reduced.
§ Inflammation was reduced, as confirmed by a significant increase in both colon and spleen weights.
§ TNF-a and IL-1b levels were reduced to near normal.
§ Adhesion molecule expression in the intestinal wall was reduced.
§ Diarrhea and body weight loss were markedly reduced.
The results of this study echo those from another MetaPhore study – looking at rheumatoid arthritis – published this month in Arthritis & Rheumatism. In that study, an SOD mimetic was highly effective, not only at treating inflammation, but also preventing joint damage and reducing elevated cytokine levels to near normal in animal models of arthritis. “These preclinical findings bode well for the potential of SOD mimetics as clinical candidates for inflammatory bowel disease, including Crohn’s disease and ulcerative colitis,” said Daniela Salvemini, Ph.D., MetaPhore’s Vice President of Pharmacology and the principal investigator. “The protective effects observed in this model appear to be a result of the SOD mimetic’s ability to inhibit superoxide and cytokine production, consistent with earlier research and our recent positive preclinical outcomes in models of arthritis.”
In addition to Dr. Salvemini, other members of the research team included Dr. Dennis P. Riley with MetaPhore, and Drs. Salvatore Cuzzocrea, Emanuela Mazzon, Laura Dugo, and Achille P. Caputi with the University of Messina Medical School in Messina, Italy.
MetaPhore Pharmaceuticals has developed a fundamentally new approach to pharmaceutics – small-molecule mimics of an essential human enzyme. MetaPhore’s first clinical candidates from this approach target some of the most significant human medical needs. These include refractory hypotension, certain types of cancer, pain, and inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease.
As part of the body’s oxidative chemistry, SOD enzymes regulate normal levels of superoxide. Certain disease states, however, promote an overproduction of superoxide and the natural enzymes are overwhelmed. For example, in excess, superoxide has been shown to contribute to inflammatory processes, inhibit certain disease fighting mechanisms and affect mechanisms involved in regulating vascular pressure.
MetaPhore scientists pioneered the design and development of SOD mimetics. Previous attempts by the pharmaceutical industry to develop a naturally-derived SOD drug showed promise; however, use of the drug, a bovine form of SOD, was frustrated by the enzyme’s inherent instability and the immunologic response to the bovine protein.
The company’s SOD mimetics are promising drug candidates because they have a low molecular weight, are highly stable and do not appear to elicit an immune response in the body. Furthermore, the chemical structure of the metal-based compounds can be easily optimized for application to different diseases and conditions.
MetaPhore is developing its family of enzyme mimetics as drug candidates for refractory hypotension, pain, inflammation and cancer, as well as other diseases and conditions associated with free-radical damage. The first of MetaPhore's drug candidates began human clinical trials this year.
“SOD 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, Ph.D., Senior Vice President of Research & Development at MetaPhore.
MetaPhore Pharmaceuticals is a privately-held drug research and development company based in St. Louis, MO. For more information, please visit www.metaphore.com7.
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.
European Journal of Pharmacology