By Mary Welch

Staff Writer

Funded from small business innovation research grants and later from "angel investors," MetaPhore Pharmaceuticals Inc. is designing metal-based therapeutics and hopes to enter Phase I trials next year.

"It's pretty unusual," said Denis Forster, executive vice president, said of the company's technology, which is protected by 24 U.S. and foreign patents.

Founded in 1995, MetaPhore's platform in rational drug design and metal-based therapeutics has been used to produce mimetics of superoxide dismutase (SOD), a powerful antioxidant.

Although oxygen is basic to life, it also produces undesirable free radicals that can harm cells. The body fights oxygen overproduction through SODs, the body's radical-fighting enzyme. In a disease state, such as inflammation, the native SOD enzyme is overwhelmed, resulting in radical damage.

"The body uses lots of metals but most of the drugs try to block or inhibit enzymes and their receptors," Forster said. "We think that certain enzymes are very, very good and that the body sometimes needs more. There are two forms of SODs that are designed to prevent free radical damage."

The 13-person company set out to "mimic one of the enzymes and we have extensive patent coverage in many disease states to protect our approach," Forster said.

MetaPhore's SOD mimetic is a much smaller, less complex and more stable molecule but can perform the same job of transforming superoxide to oxygen. In addition, it can be delivered specifically to provide therapeutic results with a high degree of effectiveness.

The St. Louis-based company is working with Johns Hopkins University researchers, who can detect in vivo free radicals and have studied them in heart disease. When the drug is put into place, the free radicals are gone, Forster said.

So far, the company's SOD mimics have shown activity against a wide range of animal models of disease including pain, arthritis, pleuritis and inflammatory bowel disease.

Its first drug candidate is scheduled to enter Phase I trials in the second half of next year.

Forster didn't disclose any more details about the project, but a colleague, Dennis Riley, vice president of research, presented a paper about a new anti-inflammatory drug that could help reduce the body's rejection of artificial implants.

Speaking at the Royal Society of Chemistry's annual conference in Edinburgh, Scotland, Riley noted that when the immune system is invaded by foreign bodies (such as a man-made implant), it produces white blood cells that attack the invaders. These white blood cells produce a byproduct, superoxide, that damages tissues and produces an inflammatory reaction. When dealing with an implant, the reaction could eventually lead to the body's rejection of it. In response, the body produces an enzyme - SOD - that converts the superoxide back into hydrogen peroxide, a less toxic chemical, and ultimately into water through another enzyme.

When animals exposed to an irritating chemical that creates an inflammatory response were treated with MetaPhore's SOD mimic, the inflammation was dramatically reduced.

"The company was founded on trying to find therapeutics for iron overload, but in the past nine months we have significantly shifted our interests into SODs," Forster said.

Spurring that "shift" is a co-exclusive agreement with St. Louis-based Monsanto Co. Nine months ago the two companies signed an agreement under which Monsanto gets right of first offer for anything MetaPhore develops in exchange for an equity investment of about $1 million. MetaPhore, which already has a potential partner in place, received the rights to Monsanto's SOD technology in return.

"We can't file an IND without first discussing it with Monsanto," Forster said. "However, if they're not interested we are free to look elsewhere for a partner or continue the development ourselves."

Monsanto played an important role in the company's development. Three of its executives came from that company. Forster was a distinguished fellow and director of chemical sciences in corporate research and Riley a senior research fellow working on catalysis. Riley's work on the small molecular weight SOD mimic is the cornerstone of MetaPhore's initial technology platform. The third Monsanto veteran is Daniela Salvermini, director of biology, who was a senior pharmacologist researching novel anti-inflammatory therapeutics and analgesics.

The lone company executive without a Monsanto background is the company's president and chief scientific officer, Garland Marshall. Marshall is the director of the Center for Molecular Design and a professor of molecular biology and pharmacology and of biochemistry and molecular biophysics at Washington University in St. Louis. Marshall founded Tripos Inc., also based in St. Louis.

Although the company raised $7 million this year from non-institutional "angel investors," which should take the compound into Phase I, Forster said the company is "always looking for future funding. You can never stop. We are in active discussions."