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Bevacizumab ?
Monoclonal antibody Type Source Target Whole antibody Humanized (from mouse) VEGF-A Clinical data Trade names AHFS/ Licence data Pregnancy cat. Legal status Routes Avastin monograph EMA:Link, US FDA:link C(US) ℞ Prescription only Intravenous Pharmacokinetic data Bioavailability Half-life 100% (IV only) 20 days (range: 11–50 days) Identifiers CAS number ATC code DrugBank UNII KEGG ChEMBL 216974-75-3 L01XC07 BTD00087 2S9ZZM9Q9V D06409 CHEMBL1201583 Chemical data Formula Mol. mass C6638H10160N1720O2108S44 approx. 149 kDa (what is this?) (verify)

especially in cancer. the growth of new blood vessels.[5] In July 2010. the FDA gave bevacizumab provisional approval for metastatic breast cancer.S. and it caused adverse effects including severe high blood pressure and hemorrhaging.[citation needed] Bevacizumab was approved by the U. Doctors can still prescribe it for that indication. FDA approval is only required for Genentech to market a drug for that indication.[3] The drug is still approved for use in Australia. because although there was evidence that it slowed progression of metastatic breast cancer.1 Colorectal cancer o 2. In 2008. The FDA's advisory panel had recommended against approval. although insurance companies are less likely to pay for it. it received FDA approval for treatment of recurring glioblastoma multiforme. the FDA's advisory panel again recommended against the indication for advanced breast cancer. there was no evidence that it extended life. breast. Genentech requested a hearing.2 Lung cancer o 2. Food and Drug Administration (FDA) for certain metastatic cancers. lung. while treatment for initial growth is still in phase III clinical trial. the approval was revoked on 18 November 2011.4 Other cancers o 2. which was granted in June 2011. Bevacizumab was the first clinically available angiogenesis inhibitor in the United States.Bevacizumab (trade name Avastin.[8] Contents [hide]   1 Background 2 Indications o 2.5 Drug administration . kidney. Genentech/Roche) is a drug that blocks angiogenesis.3 Breast cancer  2. after new studies. or improved quality of life. subject to further studies.[7] In May 2009.[3][4] The approval for breast cancer was controversial. and glioblastomas.[1] VEGF-A is a chemical signal that stimulates angiogenesis in a variety of diseases.[2] While at one point approved for breast cancer by the FDA. including colorectal. The FDA finally ruled to withdraw the breast cancer indication in November 2011. Bevacizumab is a humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A).[6] In the curative setting (adjuvant therapy).3. clinical studies are still underway in breast cancer and lung cancer. A study released in April 2009 found that bevacizumab is not effective at preventing recurrences of non-metastatic colon cancer following surgery. It is commonly used to treat various cancers.1 History relating to breast cancer o 2. It received its first approval in 2004 for combination use with standard chemotherapy for metastatic colon cancer.

This recommendation was based on E3200 trial . A preplanned analysis of histology in E4599 demonstrated a 4-month median survival benefit with bevacizumab for patients with adenocarcinoma (Sandler. A subsequent European clinical trial. adenocarcinoma represents approximately 85% of all nonsquamous carcinomas of the lung. It stops tumor growth by preventing the formation of new blood vessels by targeting and inhibiting the function of a natural protein called vascular endothelial growth factor (VEGF) that stimulates new blood vessel formation. et al. Ann. 2010). which demonstrated a 2-month improvement in overall survival in patients treated with bevacizumab (Sandler. was first reported in 2009 and confirmed the significant improvement in progression-free survival shown in E4599 (Reck. The approval was based on the pivotal study E4599 (conducted by the Eastern Cooperative Oncology Group). An overall survival benefit was not demonstrated in patients treated with bevacizumab. NEJM 2004). Genentech is able to produce the antibody in production-scale quantities.1 Adverse effects o 3. the FDA approved bevacizumab for use in first-line advanced nonsquamous non-small cell lung cancer in combination with carboplatin/paclitaxel chemotherapy. It was approved by the EMEA in January 2005 for use in colorectal cancer.addition of bevacizumab to oxaliplatin/5-FU/leucovorin (FOLFOX4) therapy.[citation needed] [edit] Lung cancer In 2006.6 Investigational 2. and was the first commercially available angiogenesis inhibitor.[citation needed] [edit] Indications [edit] Colorectal cancer Bevacizumab was approved by the FDA in February 2004 for use in metastatic colorectal cancer when used with standard chemotherapy treatment (as first-line treatment) and with 5fluorouracil-based therapy for second-line metastatic colorectal cancer.7 Uses in eye disease 3 Concerns o 3. JTO 2010).[citation needed] The drug was first developed as a genetically engineered version of a mouse antibody that contains both human and mouse components. Oncol.    2.2 Costs 4 See also 5 References 6 External links o o [edit] Background Bevacizumab is a humanized monoclonal antibody. et al. et al. . AVAiL.

an FDA panel unanimously rejected an appeal by Roche. Stated another way. drugmaker Roche could lose up to $1 billion in revenue for its best-selling product. a year's treatment of Avastin can cost over $90. Clin Colorectal Cancer. lung. ECCM 2011).however.000. Maintenance treatment with bevacizumab/pemetrexed demonstrated a 50% reduction in risk of progression vs bevacizumab alone (median PFS: 10. whereas the lower dose is usually given with cisplatin-based chemotherapy. there is no mechanistic rationale for stopping bevacizumab before disease progression. As an antiangiogenic agent. which are not part of the debate. and significant side effects.S. no improvement in quality of life. saying that it had not been shown to be safe and effective in breast cancer patients. Bevacizumab is given as an intravenous infusion every three weeks at the dose of either 15mg/kg or 7. et al. clearing the way for the U. government to remove its endorsement from the drug.5mg/kg. This only prevented Genentech from marketing bevacizumab for breast cancer. Doctors are free to prescribe bevacizumab off label. which generates over $6 billion per year. The higher dose is usually given with carboplatin-based chemotherapy. The National Comprehensive Cancer Network recommends bevacizumab as standard first-line treatment in combination with any platinum-based chemotherapy. [edit] Breast cancer In December 2010. The June 2011 meeting of the FDA's oncologic drug advisory committee was the last step in an appeal by the drug's maker. and then randomized to receive maintenance treatment with either bevacizumab/pemetrexed or bevacizumab alone until disease progression. First-line patients were treated with bevacizumab plus cisplatin/pemetrexed for four cycles. kidney and brain cancer. this may be due to the more limited use of bevacizumab as maintenance treatment in AVAiL versus E4599 (this differential effect is also apparent in the European vs US trials of bevacizumab in colorectal cancer: Tyagi and Grothey.50. should no longer be used in breast cancer patients. When administration fees are included.[11] Assuming the FDA follows through on the withdrawal.[9][10] In June 2011. p<0. HR 0.[citation needed] Avastin is FDA-approved for various types of colon. Patient support groups were disappointed by the committee's decision. though insurers may not pay for it. The committee concluded that breast cancer clinical studies of patients taking Avastin have shown no advantage in survival rates. followed by maintenance bevacizumab until disease progression. The combined data from four different clinical trials showed that bevacizumab neither prolonged overall survival nor slowed disease progression sufficiently to outweigh the risk it presents to patients. AVAPERL. Another large European-based clinical trial with bevacizumab in lung cancer.2 vs 6.6 months. the best-selling cancer drug in the world.[11] . 2006).001). A panel of cancer experts has ruled for a second time that Avastin. although insurance companies are less likely to approve offlabel treatments. the survival benefits achieved with bevacizumab can only be expected when used in accordance with the clinical evidence: continued until disease progression or treatment-limiting side effects. Doctors will still be allowed to prescribe Avastin for breast cancer. the FDA removed the breast cancer indication from bevacizumab. was reported in October 2011 (Barlesi.

lung.[18] Avastin may also be useful in the treatment of radiation necrosis. the European Commission approved bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer. The panel expressed concern that data from the clinical trial did not show any increase in quality of life or prolonging of life for patients . Avastin will still remain on the market as an approved treatment for certain types of colon. an FDA advisory committee unanimously recommended Bevacizumab for treatment of glioblastoma multiforme.[17] In the September 2009 issue of the Journal of Clinical Oncology.[13] [edit] Other cancers In certain renal (kidney) cancers. 2011 the U. since it reduces edema and mass effect and diminishes blood-brain-barrier leakage. The National Comprehensive Cancer Network (NCCN) updated the NCCN Clinical Practice Guidelines for Oncology (NCCN Guidelines) for Breast Cancer to affirm the recommendation regarding the use of bevacizumab (Avastin. Other oncologists felt that granting approval for late-stage cancer therapies that did not prolong or increase the quality of life for patients would give license to pharmaceutical companies to ignore these important benchmarks when developing new late-stage cancer therapies. before the FDA announcement. Food and Drug Administration (FDA) announced that the agency is revoking the agency’s approval of the breast cancer indication for Avastin (bevacizumab) after concluding that the drug has not been shown to be safe and effective for that use. Also in 2009. a type of brain cancer. Genentech/Roche) in the treatment of metastatic breast cancer. In 2009. kidney and brain cancer (glioblastoma multiforme).[15] following earlier reports of activity[16] and EU approval in 2007. the FDA approved Bevacizumab for use in breast cancer. Bevacizumab did not meet its primary endpoint of extending overall survival (OS) in a recent phase III trial in unresectable gastric cancer (in combination with paclitaxel / Taxol).On October 11.[citation needed] . It was based on this data that the FDA chose to overrule the recommendation of the panel of advisers. but their recommendations were overruled. The clinical trial did show that bevacizumab reduced tumor volumes and showed an increase in progression free survival time. This decision was lauded by patient advocacy groups and some oncologists. UCLA researchers reported that Avastin improves response and survival in patients with recurrent glioblastoma in comparison to historical controls.two important benchmarks for late-stage cancer treatments. the FDA approved Bevacizumab for use in metastatic renal cell cancer (a form of kidney cancer) [14] .[5] On March 28. [12] [edit] History relating to breast cancer In 2010. but it did demonstrate a positive result in treatment of ovarian cancer.[citation needed] In 2008. 2007.S. Bevacizumab improves the progression free survival time but not survival time. A panel of outside advisers voted 5 to 4 against approval.

[22] In 2010 two phase III trials showed a 27% and 54% increase in progression-free survival in ovarian cancer. The drug is also undergoing initial trials as an addition to established chemotherapy protocols and surgery in the treatment of pediatric osteosarcoma. damage the retina and cause blindness when blood vessels around the retina grow abnormally and leak fluid. This drug. under the trade name Lucentis. particularly for choroidal neovascular membrane (CNV) in AMD. it is given in combination with the chemotherapy drug 5-FU (5-fluorouracil). bleeding in the stomach and intestine. Reports indicate substantially better outcomes in patients treated with intravitreal Lucentis than conventional treatments in people with choroidal neovascularization (wet age related macular degeneration). now has FDA approval. Bevacizumab has recently been used by ophthalmologists as an intravitreal agent in the treatment of proliferative (neovascular) eye diseases.252. Ranibizumab. This abnormal growth is caused by VEGF.[24][25][26] It may also cause higher rates of high blood pressure. the injection of 1. has been developed by Genentech (by the same scientist Napoleone Ferrara) for intraocular use.[21] a type of brain tumour. leucovorin. when used as a single agent. so bevacizumab has been successfully used to inhibit VEGF and slow this growth.[27] [edit] Uses in eye disease Many diseases of the eye. It has undergone extensive clinical trials. retinopathy of prematurity[28] and macular edema secondary to retinal vein occlusions. but studies have shown no improvement in survival.[edit] Drug administration Bevacizumab is usually given intravenously every 14 days. proliferative diabetic retinopathy. In colon cancer. The FDA granted accelerated approval of Avastin for the treatment of recurrent glioblastoma multiforme in May 2009. Most patients with choroidal neovascularization lose vision or at best .[citation needed] [edit] Investigational Bevacizumab has also demonstrated activity in ovarian cancer. and oxaliplatin or irinotecan.[19][20] and glioblastoma multiforme. diabetic macular edema.5 mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity[citation needed] Many retina specialists have noted impressive results in the setting of CNV. such as age-related macular degeneration (AMD) and diabetic retinopathy.[23] Bevacizumab has been investigated as a possible treatment of pancreatic cancer. as an addition to chemotherapy. Although not currently approved by the FDA for such use. neovascular glaucoma. and intestinal perforations. a Fab fragment derived from the same parent molecule as bevacizumab. causing the layers of the retina to separate.

[34] One-year follow-up data will be reported in 2009.200 patients with newly diagnosed wet AMD.[citation needed] Results of the study were released on April 29.[29][30] The National Eye Institute (NEI) of the National Institutes of Health (NIH) announced in October 2006 that it would fund a comparative study trial of ranibizumab (Lucentis) and bevacizumab (Avastin) to assess the relative safety and effectiveness in treating AMD.[31] This study. (Group 2) Bevacizumab with four-week dosing. New York.maintain vision despite treatment with laser. 2011. and after one year. re-randomization to bevacizumab every four weeks or variable dosing as required based on diagnostic findings. and will follow the patients for two years and is expected to take four years to complete. only tiny and relatively inexpensive doses (compared to amounts used in colon and other cancers) are required. after initial treatment. Avastin is being used successfully in a case study of Familial Exudative Vitreoretinopathy in Buffalo. randomly assigning the patients to one of four treatment groups:[32] (Group1) Lucentis with four-week dosing.[citation needed] When bevacizumab is used in the treatment of macular degeneration.593 a dose. and (Group 4) Bevacizumab on a variable dosing schedule for 2 years. re-randomization to Lucentis every four weeks or variable dosing as required based on diagnostic findings. This has a significant impact because the price difference between the two medications means insurance providers and Medicare will fund treatment with Avastin in preference to the higher priced Lucentis. with monthly evaluation and re-treatment based on signs of lesion activity. The primary goals of the study are to better understand the safety and efficacy of intravitreal bevacizumab and to develop better dosing and re-treatment guidelines for both bevacizumab and Lucentis. 2008. Some investigators believe that bevacizumab at a cost of around $42 a dose is as effective as ranibizumab at a cost of over $1. photodynamic therapy or Macugen. and after one year. (Group 3) Lucentis on a variable dosing schedule for 2 years. A much larger proportion (up to 70%) gained vision with Lucentis. The benefits of both Avastin and Lucentis are essentially identical after one year. with fifteen sites beginning recruiting.[citation needed] As of July 2010. The CATT Study will be conducted at 47 clinical sites throughout the United States. called the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT Study). after initial treatment. enrolled about 1.[citation needed] [edit] Concerns .[33] Enrollment began on February 22. with monthly evaluation and re-treatment based on signs of lesion activity.

3 months vs. Bowel perforation has been reported.[43] . many insurance companies have refused to pay for all or part of the costs of bevacizumab. Mayer wrote in the New England Journal of Medicine that bevacizumab extended life by 4. which is part of the body's normal healing and maintenance. 15. Robert J.[39]In 2006 the Scottish Medicines Consortium recommended against the NHS funding Avastin.000 per Quality-adjusted life year (QALY).[41] For colorectal cancer.[citation needed] Genentech continues to insist that the benefit is worth the cost. and worsen conditions like coronary artery disease or peripheral artery disease. at a cost of $100.S. less than half of patients qualify for treatment.6 months) in the initial study.[38] In December 2010.000 per patient but has only limited usage in cancer treatment because it merely extends life rather than providing a cure. and renal thrombotic microangiopathy have been reported.[citation needed] [edit] Costs The media have criticized the high cost of a drug that doesn't cure cancer[citation needed] but only prolongs life[citation needed]. and intestines. in the U. at a cost of $42.[35] The main side effects are hypertension and heightened risk of bleeding. In advanced lung cancer.800 to $55. the National Institute for Health and Clinical Excellence has taken the public position that bevacizumab should not be funded by the NHS because it costs nearly £21. The body grows new blood vessels in wound healing.. in Canada it is reported to cost $40. and as collateral circulation around blocked or atherosclerotic blood vessels.7 months (20.000 CAD per year. stomach.000 to £93.[edit] Adverse effects Bevacizumab inhibits the growth of blood vessels. for first-line treatment of metastatic carcinoma of the colon or rectum.[40] Though Genentech has adjusted the price for patients in certain situations. One concern is that bevacizumab will interfere with these normal processes. the FDA warned of the risk of developing perforations in the body. In the U..[36][37]Nasal septum perforation. for example.[42] Costs in other countries vary. The addition of bevacizumab to standard treatment can prolong the lives of breast and lung cancer patients by several months.000 a year in the United States. including in the nose.000. These effects are largely avoided in ophthalmological use since the drug is introduced directly into the eye thus minimizing any effects on the rest of the body. and the medication's high cost helps cover the cost of the expensive and risky research needed to develop new drugs.K. In countries with national health care systems (such as the UK and Canada). due to estimated costs of £24. many of those national health services have restricted on the basis of cost-benefit calculations.

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