Learning from Angiogenesis Trial Failures

Although targeting angiogenesis is a promising anticancer approach, the recent spate of Phase III trial failures has bashed some scientists' hopes for success. According to industry insiders, however, the 12 recent failures involving five trials are symptoms of a young field, of clinical trial design that requires unconventional endpoints, and of improper delivery systems, rather than a condemnation of the general approach. Moreover, because drug development takes such a long time, researchers had less information when plans were originally made than they have now. "About 40 papers a week are coming out [on angiogenesis]; it is a very fast-moving field," says Judah Folkman, professor of pediatric surgery and cell biology at Children's Hospital in Boston. "Ten years ago, people thought all new capillaries were the same, but now we know they're not." Revisiting the Strategy Similar to cutting off army supply lines to cripple the foe, scientists believe that cutting off a tumor's supply lines (the blood vessels) is the way to stop it in its tracks. However, last month's failure of Pharmacia's SU5416, the 12th Phase III trial failure of an angiogenesis inhibitor (AI) since 1999 and a failure of a new AI class, has investigators revisiting prior research and learning to incorporate new information. According to Laura Shawver, president of Sugen, the company that initially developed SU5416 and was later acquired by Pharmacia, "[Angiogenesis] wasn't studied from the drug development perspective until the '90s." SU5416 targets the vascular endothelial growth factor (VEGF) receptor. When VEGF was discovered in 1989, it was the first factor known to be specifically involved in the proliferation and migration of blood vessel precursor cells. Subsequently, labs began focusing on VEGF inhibition. However, at that time, it was less understood that as tumors progress, they express an increasingly broad array of pro-angiogenic growth factors. "In the first generation of angiogenesis inhibitors that were developed, we didn't know enough about the best way to develop drugs against these new molecular targets," Shawver says. "As we go forward, we'll dissect out which targets are more adequate ... and which ones are not appropriate. Now we're taking an approach where our drugs are more broad-acting." Claude Hariton, vice president of clinical and regulatory affairs at Aeterna Laboratories Inc., Quebec, whose company has a broadly acting angiogenesis inhibitor currently in Phase III trials, agrees with Shawver. "Multimodality is definitely the future in angiogenesis and antiangiogenic drug development because there is a dependency of several complex processes in angiogenesis. Shutting one door won't allow the drug to solve the problem. You have to shut, if possible, all the doors by which the vessels will grow around the tumor," he explains. An additional factor that may have contributed to the past failures of angiogenesis inhibitors is that they are expected to stabilize tumors rather then eradicate them. Thus, if the agents' efficacy is measured using traditional cancer trial endpoints such as tumor shrinkage, one could almost predict they would fail. "Chemotherapy guidelines which have been used for the past 50 years are not as useful in antiangiogenic therapy," says Folkman. Shawver adds, "Preclinically, we see that angiogenesis inhibitors are most effective in early disease and minimal residual disease, but ... the Food and Drug Administration requires that early testing is done in late-stage disease. If you want to test in early-stage disease, you have to add your drug [into a] standard of care, and then that is another level of difficulty because much of the standard of care is chemotherapy that brings toxicity." However, an FDA spokesperson counters that, "for relatively nontoxic drugs, the FDA does not require initial testing in patients with advanced disease." Learning on the Job Companies and regulatory agencies are becoming more aware of the issues that surround clinical trial design, and as a result protocols and regulations are evolving. "A lot of the study design is now incorporating these kinds of things," says Hal Hirte, head of medical oncology at the Hamilton Regional Cancer Center, in Ontario, and one of the lead investigators on a previous Phase III AI trial. "In Canada, through the National Cancer Institute of Canada, we've incorporated measures of disease stabilization along with shrinkage as endpoints in the early phase trials. However, only time will tell us whether these are appropriate endpoints." The FDA spokesperson adds that the endpoints for early studies are generally left to the investigator's discretion; the FDA expects the endpoints for new drug-approval trials to be clinically meaningful and adequately evaluated. Formulation and dosing issues have also been a factor in previous AI trial failures, and companies with products still in development are making great strides in this area. "SU5416 [was] administered with a twice-weekly IV infusion, and we learned over the course of development that we probably weren't keeping the receptor in the 'off' position for long enough to maximally inhibit the receptor. That's why our new generation of candidates are given daily," explains Shawver. EntreMed, a company developing angiogenesis inhibitors, has also overcome formulation problems with the Phase II drug Endostatin. At first the company could not solubilize the molecule in high concentrations, says John Holaday, EntreMed's CEO. "Since then, we've found a way to concentrate [the dose] more than 15-fold and to freeze-dry it. When it is reconstituted, you can get less than 100 mg in less than 1cc." Folkman, for one, has retained his optimism. "A lot of this will probably be known next year," he says. "The fact that one of the angiogenesis inhibitors failed doesn't mean much. There will be many that fail, but some of them will get through; and understanding why they fail is very educational." Mignon Fogarty (mignon@welltopia.com) is a freelance writer in Santa Cruz, Calif. Supplemental Materials Angiogenesis Inhibitors that Failed Phase III Trials

Learning from Angiogenesis Trial Failures

Revisiting the Strategy

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