St. Louis, MO, – The painful inflammation and debilitating joint damage characteristic of rheumatoid arthritis may be reduced or prevented with a new approach using small-molecule ‘enzyme mimetics,’ described in research published today in the journal Arthritis & Rheumatism.
The preclinical study conducted by researchers at MetaPhore Pharmaceuticals, Inc.® and the University of Messina (Italy) showed that a superoxide dismutase (SOD) mimetic substantially reduced the erosion of cartilage and bone – as well as the chronic inflammation – in a standard animal model. The SOD mimetic also was shown to markedly reduce elevated levels of two pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-á) and interleukin-1â (IL-1â), involved in the development of arthritis in humans.
Rheumatoid arthritis, the most common chronic inflammatory disease, affects more than 2 million Americans. It is also an autoimmune disease, where elements of the body’s immune system attack specific points in the body itself (the joints). These pro-inflammatory immune response factors include TNF-á, IL-1â, and superoxide, a free radical that, in excess, is a significant mediator of tissue and cell damage and regulates cytokine release.
To evaluate the potential of selective removal of superoxide in treating rheumatoid arthritis, researchers tested the SOD mimetic M40403. M40403 is one of a proprietary family of small-molecule SOD mimetics developed by MetaPhore that are designed to replicate the action of natural SOD enzymes, and selectively remove excess superoxide.
In the study, researchers evaluated the effects of daily doses of M40403 on the development and progression of arthritis in rats. Comparing animals treated with M40403 to untreated animals:
- Inflammation – as evaluated by the swelling of the affected hind paw – was reduced by up to 56%
- Joint erosion – as evaluated both histologically and radiographically – was reduced by at least 70%
- TNF-a and IL-1b levels were reduced, at two of the doses tested, to those typical of normal, non-arthritic rats.
“The findings of this study suggest a potentially novel therapeutic for rheumatoid arthritis, combining anti-inflammatory and disease-modifying properties into a single drug,” said Daniela Salvemini, Ph.D., MetaPhore’s Vice President of Pharmacology and the principal investigator. “The SOD mimetic possesses both of these properties because superoxide plays a dual role, in acting both as a direct inflammatory molecule as well as stimulating the release of the inflammatory cytokines, TNF-á and IL-1â. This contrasts with the current generation of disease-modifying arthritis drugs which attempt to control the cytokines after their release.”
In addition to Dr. Salvemini, other member of the research team included Drs. Emanuela Mazzon, Laura Dugo, Ivana Sarraino, Angela De Sarro, Achille P. Caputi, and Salvatore Cuzzocrea, all with the University of Messina Medical School in Messina, Italy.
Background
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.
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 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.
Journal
Arthritis & Rheumatism