Avastin (Bevacizumab)

General Information

Avastin is the first biologic to be approved in a new class of drugs know as angiogenesis inhibitors - drugs which work by blocking the growth of blood vessels, thus denying tumors blood, oxygen and other nutrients needed for growth. This approach to fighting cancer has been studied for three decades. It was approved in February 2004, and sells for $4,400 - $8,800.

Patent Number: 6,054,297 - Humanized antibodies and methods for making them
Filed: May 9, 1995
Granted: April 29, 2000
Inventors: Paul J. Carter and Leonard G. Presta
Patentee: Genentech

Pricing and Licensing

Notes on Government Funding of R&D

The NCI Fact Sheet on bevacizumab very briefly describes NIH involvement. The drug was based on a hypothesis of angiogenesis inhibitors published in 1971 by Judah Folkman, a professor at Harvard. The NCI has been involved in clinical development, and it has a CRADA with Genentech. Some of this was done through the Eastern Cooperative Oncology Group, which the NCI "primarily" funds. Without being specific about who paid for what, the NCI fact sheet includes this passage:

"By 1983, scientists had demonstrated that tumors secrete VEGF and by 1989, VEGF had been cloned for investigational purposes. The first clinical trials to examine the efficacy of anti-angiogenic agents for cancer patients began in the 1990s."

The NCI fact sheet says Genentech funded the phase III trial upon which FDA approval was based. For the clinical trials testing the drug for breast cancer, NCI is funding the doctors and Genentech is supplying the drug. For more info, see the following NCI press releases regarding bevacizumab research:

FDA Information on Clinical Trials

The original FDA prescribing information bases approval on two clinical studies involving 917 patients. The "Adverse Events" section of the prescribing information says that 1032 patients with cancer received avastin in"Genentech-sponsored clinical trials." The approval letter mentions specific ongoing trials (though it does not cite the number of patients in each). Further, post-marketing trials are demanded involving at least 4000 more patients.

History of Development

In 1971, a Harvard doctor named Judah Folkman published an article in the New England Journal of Medicine which identified the angiogenesis inhibition as a potential way to treat cancers. "He then embarked on a research career that identified the first factors that promote and inhibit angiogenesis, developed the crucial laboratory systems required to study their effects, and he guided the first efforts to translate antiangiogenic agents to clinical trial in human patients." (Source: Angiogenesis Foundation press release.)

In 1989, a Genetech scientist named Dr. Napoleone Ferrara discovered and cloned the Vascular Endothelial Growth Factor (VEGF) - the first evidence of a specific protein that acted as an angiogenic growth factor. In 1993, his team published an article in Nature showing how an antibody directed at VEGF could suppress angiogenesis in preclinical models. (http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/06-08-2004/0002189341&EDATE=)

In 1997, clinical trials of Avastin began. The main trial upon which FDA approval was based was a Phase III trial involving 813 patients. The results were first announced at the American Society of Clinical Oncology on June 1, 2003, and were then published in that month's NEJM. The lead investigator for this trial was Dr. Herbert Hurwitz of the Duke University Medical Center. This was the first Phase III trial of the drug (or any other angiogenesis inhibitor). According to the press release from the Duke Medical Center, this study was funded by Genetech.

Notes on People Involved

Napoleone Ferrara is not listed on the patent, but he and his team at Genentech seems to done much of the heavy lifting. They discovered and cloned the protein, and they showed it could fight tumors. He began working at Genentech in 1988, and he is still there, with the title of "Genentech Fellow."

""Over the last 14 years, I have engaged in extensive collaborations with scientists at Genentech as well as from many universities. These collaborations have played a major role in moving my various projects forward. Among the most gratifying have been my collaborations with Genentech colleagues in the humanization of an anti-VEGF antibody and with Kenneth Hillan in analyzing the morphology of knockouts and many other phenotypes."
Paul J Carter is one of the inventors listed on the patent. He joined Genentech around 1984. While at Genentech, he initiated the company's antibody humanization program and humanized three antibodies. Since then, he's worked for Amgen and a couple of small pharma companies. There's one grant in the CRISP database with his name on it, but it was given after Avastin's approval, and after he left the firm.

Leonard G. Presta's name comes up in a lot of scientific journals. As recently as 2004, he was still a staff scientist at Genentech.

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