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Compound Interest

risk of litigation if a subsequent problem turns up—scare most drug companies away from developing chemopreventive agents.

Early on in the triterpenoid project, Sporn says he contacted every major pharmaceutical company in the U.S. and Europe to ask for support, but none of them were interested.

Despite the financial challenges, Sporn has kept the triterpenoid project going with several NIH grants, funds from private foundations, and gifts from the Dartmouth College Class of '34. He has also maintained a small and highly efficient lab staff. While many top cancer researchers, at Dartmouth and elsewhere, have multiple postdoctoral fellows and a stable of graduate and undergraduate students, Sporn has one postdoc, one doctoral student, and three technicians. And as hard a time as Sporn has had finding funding, he says it's even harder for young researchers interested in chemoprevention. "I'm able to stay afloat," he says, largely because of his long career and high profile in the field.

On February 16, 1998, the triterpenoid project hit a breakthrough. Honda created the most exciting compound the team had seen to date—triterpenoid 151, later named CDDO (for 2-cyano-3, 12- dioxooleana-1, 9-dien-28-oic acid). It was 10,000 times more potent than the 46th compound and close to a half-million times more potent than the original, natural triterpenoids.

When Sporn and his postdoctoral fellow at the time, Dr. Nanjoo Suh, tested CDDO in various cell lines and rodent models, they discovered it had an amazing combination of properties. CDDO inhibited the proliferation of many tumor cells, suppressed inflammation (which is linked to cancer and many other diseases), and, at the same time, protected healthy, noncancerous cells. And it did all this at extremely low concentrations—about a billionth of a gram—in cell cultures. Best of all, CDDO exhibited no negative side effects.

Over the next several years, Sporn's lab published dozens of papers in high-profile journals, such as Cancer Research, documenting CDDO's and its derivatives' anticancer, anti-inflammatory, and cyto-

As hard a time as Sporn has had finding funding, he says it's even harder for young researchers interested in chemoprevention. "I'm able to stay afloat," he says, largely because of his long career and high profile in the field.

protective properties in numerous animal models. The compounds wowed Sporn and his collaborators at Dartmouth, Johns Hopkins, Rutgers, and elsewhere, yet he still couldn't garner support from any major drug companies. But the work did attract the attention of a small and unusual company in Texas.

"We were immediately interested in the project," says Warren Huff, founding CEO and president of Reata Pharmaceuticals, which has licensed CDDO and derivatives CDDO-Me and CDDO-Im for development in clinical trials. Reata, formed in 2002 as a spin-off from the University of Texas system, specializes in moving promising drugs developed in academia into the marketplace. It focuses on the aspects of drug development that are difficult for academic institutions to handle, Huff explains, such as actually making the drugs, managing the clinical studies necessary to look for side effects and to gain FDA approval, and handling all of the regulatory issues. "We don't try to replicate [what the academic institutions] do best," adds Huff, such as figuring out how the drug works in the body. If the results of the early human trials with CDDOMe are any indication, Reata's investment in the triterpenoids is going to pay off.

CDDO-Me, the farthest along in the clinical testing pipeline, is in late Phase I trials at M.D. Anderson Cancer Center and Dana-Farber Cancer Institute; it's being used in patients with metastatic, late-stage solid tumors. (Phase I trials are small, include about 20-30 patients, and are designed to look at safety.) The results thus far have been "as good as it gets," says Huff. At very low doses, CDDO-Me seems to dramatically reduce a whole panel of immunoregulatory proteins that are markers for a poor prognosis—meaning the drug may help patients live longer. CDDO-Me, which is taken orally, also hasn't shown any negative side effects, according to Huff. Reata plans to begin Phase II trials by mid- 2007. (Phase II trials look at a drug's efficacy, in addition to its safety.)

If CDDO-Me shows a benefit in Phase II, "it would definitely be eligible for an accelerated approval," says Huff. The best-case scenario is that the drug could be approved and available by 2009.

If CDDO-Me is approved for treatment of patients with metastatic, late-stage solid tumors, Reata would then begin trying the drug in patients with earlier stages of cancer, in the hope of eventually conducting prevention trials. The company has already begun working with Sporn's lab on lung cancer and breast cancer prevention studies using CDDO- Me in animal models. Dr. Karen Liby, Sporn's current postdoctoral fellow, led three of these studies and presented the results in a press conference at the AACR chemoprevention meeting.

In the first study, Liby (pronounced "LIE- bee") tested whether CDDO-Me alone, as well as in combination with a drug called a rexinoid, prevents estrogen- receptor-negative (ER-) breast cancer—an especially difficult form of breast cancer to treat. She fed mice that had been engineered to develop ER- breast tumors either a control diet or one of three modified diets—containing CDDO-Me, the rexinoid, or both. By 40 weeks of age, 100% of the control mice had developed breast cancer. In contrast, Liby found tumors in only 12% of the mice fed CDDO-Me, 29% of the mice fed the rexinoid, and none in the mice fed the combo diet.

After an additional three months on the

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