First Angiogenesis Inhibitor Approved

The first product that works by preventing angiogenesis, called Avastin (bevacizumab) has been cleared by the U.S. Food and Drug Administration (FDA) as a first-line treatment for patients with metastatic colorectal cancer.

In trials, Avastin was shown to extend the lives of patients by about five months. The drug is given intravenously in combination with intravenous 5-Fluouracil-based chemotherapy (IFL) for colon cancer. Avastin is a genetically engineered version of a mouse antibody that contains both human and mouse components. Scientists say the new monoclonal antibody works by targeting and inhibiting the function of vascular endothelial growth factor (VEGF), which stimulates new blood vessel formation.

Safety and efficacy of the new drug were shown in a randomized, double-blind clinical trial of more than 800 patients with metastatic colorectal cancer, designed to discover if Avastin could extend the lives of the patients. About half of the patients received IFL while the other half received Avastin once every two weeks in addition to IFL. Overall, patients given Avastin in combination with IFL survived about five months longer, and the average time before tumors started regrowing or new tumors appeared was four months longer than patients given IFL alone. The overall response rate to the treatment was 45% compared to 35% for the control arm of the trial. The survival and progression-free survival results observed in the trial are the longest ever reported in a randomized, phase III study of patients with metastatic colorectal cancer.

The most serious but uncommon side-effects in the trial that occurred in the patients receiving Avastin include gastrointestinal perforations generally requiring surgery, impaired wound-healing, and bleeding from the lungs or internally. More common side-effects were high blood pressure, tiredness, blood clots, diarrhea, decreased white blood cells, headache, appetite loss, and mouth sores.

VEGF was discovered in 1989 by Napoleone Ferrara, M.D., a staff scientist at Genentech (South San Francisco, CA, USA). Dr. Ferrara and his team cloned VEGF, providing some of the first evidence that a specific angiogenic growth factor existed. Dr. Ferrara then created a mouse antibody to this protein. In 1993, he and his team at Genentech demonstrated that the antibody directed against VEGF could suppress angiogenesis and tumor growth in preclinical models, providing evidence that VEGF could play a critical role in tumor growth. Clinical studies with a humanized version of the antibody, called Avastin, began in 1997.

"Dr. Ferrara's scientific accomplishments and the approval of Avastin mark a turning point in science as it proves the long-pursued angiogenic hypothesis and, through an elegantly designed clinical trial, has turned a theory into a treatment for metastatic colorectal cancer patients,” said Judah Folkman, M.D., professor of pediatric surgery at Children's Hospital and Harvard Medical School (Boston, MA, USA.), and another pioneer in the field of angiogenesis.




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