Historical Highlights

1787: British surgeon Dr. John Hunter first uses the term “angiogenesis” (new blood vessel growth) to describe blood vessels growing in the reindeer antler.

1935: Boston pathologist Dr. Arthur Tremain Hertig describes angiogenesis in the placenta of pregnant monkeys.

1971: Surgeon Judah Folkman hypothesizes that tumor growth is dependent upon angiogenesis. His theory, published in the New England Journal of Medicine, is initially regarded as heresy by leading physicians and scientists.

1975: The first angiogenesis inhibitor is discovered in cartilage by Dr. Henry Brem and Dr. Judah Folkman.

1984: The first angiogenic factor (basic fibroblast growth factor, bFGF) is purified by Yuen Shing and Michael Klagsbrun at Harvard Medical School.

1989: One of the most important angiogenic factors, vascular endothelial growth factor (VEGF), is discovered Dr. Napoleone Ferrara. It turns out to be identical to a molecule called Vascular Permeability Factor (VPF) discovered in 1983 by Dr. Harold Dvorak.

1989: The first successful treatment of an angiogenesis-dependent benign tumor (pulmonary hemangioma) using interferon alfa2a is reported by Dr. Carl White, a pediatric radiologist in Denver.

1992: The first clinical trial of an antiangiogenic drug (TNP-470) begins in cancer patients.

1994: The Angiogenesis Foundation is founded to improve global efforts by facilitating the development and application of angiogenesis-based medicines.

1997: The first angiogenesis-stimulating drug (becaplermin, Regranex) is FDA-approved for treatment of diabetic foot ulcers.

1997: Dr. Michael O’Reilly publishes research findings in the journal Nature, showing complete regression of cancerous tumors following repeated cycles of antiangiogenic therapy using angiostatin and endostatin.

1998: The first angiogenesis-stimulating laser is FDA-approved for the treatment of severe, end-stage coronary disease.

1999: The first vascular targeting therapy is FDA-approved for treatment of age-related macular degeneration.

1999: Massive wave of antiangiogenic drugs enter clinical trials: 46 antiangiogenic drugs for cancer patients; 5 drugs for macular degeneration; 1 drug for diabetic retinopathy; 4 drugs for psoriasis.

1999: Massive wave of angiogenesis-stimulating drugs enter clinical trials: 5 drugs for coronary artery disease; 5 drugs for peripheral vascular disease; 1 drug for stroke; 10 drugs for wound healing.

1999: Laboratory research led by Dr. Robert Kerbel and Dr. Judah Folkman shows that some traditional cytotoxic chemotherapies may inhibit tumor angiogenesis when given at low-doses.

1999: Dr. Richard Klausner, Director of the U.S. National Cancer Institute, designates the development of antiangiogenic therapies for cancer as a national priority.

2003: The monoclonal antibody drug Avastin (Bevacizumab) becomes the first antiangiogenic drug to demonstrate in large-scale clinical trials that inhibiting tumor blood vessel growth can prolong survival in cancer patients.

2004: A pivotal phase 3 trial published in the New England Journal of Medicine shows that the addition of bevacizumab (Avastin), an anti-VEGF monoclonal antibody, to chemotherapy significantly improves survival in patients with metastatic colorectal cancer.

2004: Bevacizumab is FDA approved for the treatment of advanced colorectal cancer. At the time of bevacizumab’s approval, FDA Commissioner Mark McClellan declares antiangiogenic therapy “the fourth modality for cancer treatment.”

2004: Pegaptanib (Macugen), an anti-VEGF aptamer, becomes the first anti-VEGF drug to be FDA approved for the treatment of age-related macular degeneration.

2005: Endostatin (Endostar), an agent that inhibits metastasis and angiogenesis by downregulating multiple proangiogenic growth factors, is approved in China for the treatment of advanced lung cancer.

2005: Sorafenib (Nexavar), a multi-tyrosine kinase inhibitor, demonstrates significantly longer progression-free survival vs. placebo in patients with advanced renal cancer in a randomized phase 3 trial.

2005: Sorafenib is FDA approved as second-line therapy for advanced renal cancer.

2005: Lenalidomide (Revlimid), an agent with both immumomodulatory and antiangiogenic properties, is FDA approved for treatment of myelodysplastic syndrome.

2006: Sunitinib (Sutent), a multi-tyrosine kinase inhibitor, receives FDA approval as first-line therapy for advanced renal cancer and gastrointestinal stromal tumor (GIST).

2006: Ranibizumab (Lucentis), a fragment of the bevacizumab molecule, is FDA approved for the treatment of age-related macular degeneration.

2006: Bevacizumab in combination with paclitaxel and carboplatin is shown to significantly improve progression-free survival, overall survival, and response rates in treatment-naïve patients with advanced NSCLC. This is the first time an antiangiogenic agent plus chemotherapy has been shown to prolong survival in NSCLC patients.

2007: Results from a randomized phase 3 trial published in the New England Journal of Medicine show a significant survival benefit for sorafenib vs. placebo in patients with advanced renal cancer who fail first-line therapy.

2007: Temsirolimus (Torisel), an inhibitor of mTOR, is approved for the treatment of advanced renal cancer after a pivotal phase 3 trial published in the New England Journal of Medicine shows significantly improved progression-free survival in previously untreated mRCC patients with poor prognosis.

2007: Results from a randomized phase 3 trial published in the New England Journal of Medicine show that sunitinib doubles progression-free survival in previously untreated patients with metastatic renal cancer.

2007: Results announced at ASCO 2007 from a randomized phase 3 study show that sorafenib extends overall survival by 44% vs. placebo in patients with advanced liver cancer. Based on these findings, in November the FDA approved sorafenib to treat unresectable advanced hepatocellular carcinoma. Sorafenib is the first systemic agent to show efficacy for advanced liver cancer.

2008: Angiogenesis pioneer Dr. Judah Folkman passes away suddenly on January 14 while traveling to a conference. At the time of Dr. Folkman’s death, an estimated 1.2 million patients had been treated with antiangiogenic therapy, a concept he first conceived of almost 4 decades prior. Dr. Folkman is widely recognized as one of the most important figures in modern medicine.

2008: In February, bevacizumab (Avastin) becomes the first antiangiogenic agent approved to treat breast cancer. The approval is based on phase 3 trial results in which BV/paclitaxel doubled median progression free survival versus paclitaxel alone (PFS: 11.8 mo. vs. 5.9 mo., P<0.0001) in women with locally recurrent or metastatic breast cancer. 2009: In March, the FDA granted approval for the use of the anti-angiogenic agent everolimus (Afinitor), an mTOR inhibitor, for the treatment of adult patients with advanced renal cell carcinoma (RCC) whose disease was resistant to sunitinib or sorafenib. 2009: In May, the FDA granted accelerated approval to bevacizumab injection (Avastin) as a single agent for patients with glioblastoma, with progressive disease following prior therapy. The approval was based on demonstration of durable objective response rates observed in two single-arm trials, AVF3708g and NCI 06-C-0064E. 2009: In July, the FDA granted approval for the use of anti-angiogenic agent bevacizumab (Avastin) in combination with interferon alfa for the treatment of patients with metastatic renal cell carcinoma. The approval was based on results from the BO17705 trial, which demonstrated a 5-month improvement in median progression-free survival (PFS) in patients treated with bevacizumab. 2009: In October, the FDA granted approval to pazopanib hydrochloride tablets (Votrient) for the treatment of patients with advanced renal cell carcinoma. 2010: In October, the FDA granted accelerated approval to everolimus (Afinitor), an mTOR inhibitor, for patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) who require therapy but are not candidates for surgical resection. Afinitor was originally approved in March 2009 for the treatment of adult patients with advanced renal cell carcinoma (RCC) whose disease was resistant to sunitinib or sorafenib. 2011: In April, the FDA approved vandetanib tablets (Vandetanib), a kinase inhibitor, for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable, locally advanced, or metastatic disease. 2011: In May, the FDA approved two anti-angiogenic agents for the treatment of progressive neuroendocrine tumors of pancreatic origin (PNET) in patients with unresectable, locally advanced or metastatic disease: everolimus (Afinitor) and sunitinib (Sutent). 2011: In June, ranibizumab (Lucentis) was further approved by the FDA for treatment of macular edema following retinal vein occlusion (RVO), in addition to its previous approval for neovascular macular degeneration. Ranibizumab is a recombinant humanized IgG1 kappa monoclonal antibody fragment that binds vascular endothelial growth factor-A (VEGF-A) and cleavage products, and prevents their interaction with VEGF receptors (VEGFR-1 and VEGFR-2), thereby inhibiting endothelial cell proliferation, angiogenesis, and vascular leakage in the retina and choroidal layers. 2011: In November, the FDA approved aflibercept (Eylea), a fusion protein that functions as an inhibitor of vascular endothelial growth factor, for “wet” age-related macular degeneration. The approval was based on three phase III studies in which the drug was given by intraocular injection monthly for three months followed by injections every two months for a total of one year. 2011: In December, the European Commission approved bevacizumab (Avastin) for the treatment of advanced, newly diagnosed ovarian cancer in Europe. The approval was based on two clinical studies that found that women with newly diagnosed, advanced ovarian cancer who used Avastin and chemotherapy, and then continued on just Avastin, lived longer without their disease getting worse compared to those who received only chemotherapy. 2012: In September, the FDA approved regorafenib (Stivarga) to treat patients with metastatic colorectal cancer that has progressed after treatment. This approval was based on the study of 760 patients with previously treated metastatic colorectal cancer, conducted under the FDA’s priority review program for drugs that could provide major advances in treatment, or provide treatments in diseases areas with few options. 2012: In January, the FDA approved axitinib (Inlyta) for renal cell carcinoma after failure of one prior systemic therapy. 2012: The FDA further approved pazopanib hydrochloride tablets (Votrient) for patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy. 2012: In July, the FDA further approved ranibizumab (Lucentis) for diabetic macular edema (DME). 2012: In August, the FDA approved the use of ziv-aflibercept (ZALTRAP) in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin containing regimen. 2012: In September, the FDA further approved afilbercept (EYLEA) for macular edema following Central Retinal Vein Occlusion (CRVO). 2012: The FDA further approved the mTOR inhibitor everolimus (Afinitorr), for: adults with renal angiomyolipoma, associated with tuberous sclerosis complex (TSC), who do not require immediate surgery (April); postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole (July); and pediatric and adult patients with TSC who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected (August). 2012: In December, the FDA approved cabozantinib (Cometriq), a small molecule tyrosine kinase inhibitor of c-Met and VEGFR2, for progressive, metastatic medullary thyroid cancer. 2013: In November, the FDA approved a supplemental New Drug Application for the oral multi-kinase inhibitor sorafenib (NEXAVAR®) for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment. The FDA approval is based on the results of the DECISION (stuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine refractory thyrOid caNcer) trial– an international, multicenter, placebo-controlled study.