Bevacizumab


Bevacizumab

drugbox
type = mab


source = Human
target = VEGF
CAS_number=216974-75-3
ATC_prefix=L01
ATC_suffix=XC07
PubChem=(none)
DrugBank=BTD00087
molecular_weight = approx. 149,000 kDa
bioavailability= 100% (IV only)
metabolism = ?
elimination_half-life= 20 days (range: 11–50 days)
excretion = ?
pregnancy_US = C
legal_status = Rx-only
routes_of_administration= Intravenous
licence_EU =Avastin
licence_US =Bevacizumab

Bevacizumab (Avastin, Genentech/Roche) is a monoclonal antibody against vascular endothelial growth factor (VEGF). It is used in the treatment of cancer, where it inhibits tumor growth by blocking the formation of new blood vessels (angiogenesis). Bevacizumab was the first clinically available angiogenesis inhibitor in the United States.

Bevacizumab has been approved by the U.S. Food and Drug Administration only for cancers that are metastatic (have spread to other parts of the body), although some doctors and patients want to use it for non-metastatic cancers. In 2004, it was approved for combination use with standard chemotherapy for metastatic colon cancer and non-small cell lung cancer [Avastin Prescribing Information, Genentech Inc., October 2006, www.clinicaltrials.gov ] . In 2008, it was approved by the FDA for use in breast cancer. This was against the recommendation of its advisory panel [http://www.nytimes.com/2008/02/22/business/apee-drug.html F.D.A. Approves Drug’s Use for Breast Cancer - New York Times, Feb. 22, 2008] , who objected because it only slowed tumor growth, but didn't extend the patient's life.

Clinical studies are underway in non-metastatic colon cancer, and metastatic breast cancer, renal cell carcinoma, glioblastoma multiforme, ovarian cancer, hormone-refractory prostate cancer, and metastatic or unresectable locally advanced pancreatic cancer.

Background

Bevacizumab is a humanized monoclonal antibody, and was the first commercially available angiogenesis inhibitor. 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.

The drug was first developed as a genetically engineered version of a mouse antibody that contains both human and mouse components. Genentech is able to produce the antibody in production-scale quantities.

Clinical use

Bevacizumab was approved by the Food and Drug Administration (FDA) in February 2004 for use in metastatic colorectal cancer when used with standard chemotherapy treatment. It was approved by the EMEA in January 2005 for use in colorectal cancer. Israel has also approved the use of bevacizumab.

In 2006, the FDA approved bevacizumab for use in lung cancer in combination with standard first-line chemotherapy. A study conducted by the Eastern Cooperative Oncology Group (ECOG) demonstrated a 2-month improvement in overall survival in patients with Stage IIIb/IV non-small cell lung cancer (NSCLC). Due to the observance of severe pulmonary hemorrhage in patients with NSCLC with squamous histology in an earlier study, patients with such histology were excluded from the pivotal ECOG trial.

In 2008, the FDA approved Bevacizumab for use in breast cancer. A panel of outside advisers voted 5 to 4 against approval, but their recommendations were overruled. 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 - two important benchmarks for late-stage cancer treatments. The clinical trial did show that bevacizumab reduced tumor volumes and showed an increase in progression free survival time. It was based on this data that the FDA chose to overrule the recommendation of the panel of advisers. The decision was lauded by patient advocacy groups and some oncologists. 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.

Bevacizumab is usually given intravenously through the arm every 14 days. In colon cancer, it is given in combination with the chemotherapy drug 5-FU (5-fluorouracil), leucovorin, and oxaliplatin or irinotecan.

Bevacizumab has also demonstrated activity in renal cell cancer and ovarian cancer when used as a single agent.

January 20, 2007: Researchers reported at the 2007 Gastrointestinal Cancers Symposium that a trial of bevacizumab as an addition to chemotherapy has shown no improvement in survival of patients with advanced pancreatic cancer. It may cause higher rates of high blood pressure, bleeding in the stomach and intestine, and intestinal perforations.

On December 5, 2007, the FDA voted 5-4 that bevacizumab's risks outweighed its benefits for women with advanced breast cancer. [ [http://money.cnn.com/2007/12/06/news/companies/simons_genentech.fortune/index.htm The silver lining behind Genentech's Avastin setback - Dec. 6, 2007 ] ]

Non oncologic uses

Many diseases of the eye, such as age-related macular degeneration (AMD) and diabetic retinopathy, damage the retina and cause blindness when blood vessels around the retina grow abnormally and leak fluid, causing the layers of the retina to separate. This abnormal growth is caused by VEGF, so bevacizumab has been successfully used to inhibit VEGF and slow this growth.

Bevacizumab has recently been used by ophthalmologists as an intravitreal agent in the treatment of proliferative (neovascular) eye diseases, particularly for choroidal neovascular membrane (CNV) in AMD. Although not currently approved by the FDA for such use, the injection of 1.25-2.5 mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity (although not studied in a contolled environment). Many retina specialists have noted impressive results in the setting of CNV, proliferative diabetic retinopathy, neovascular glaucoma, diabetic macular edema, retinopathy of prematurity [cite journal |author=Azad R, Chandra P |title=Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity |journal=Indian journal of ophthalmology |volume=55 |issue=4 |pages=319 |year=2007 |pmid=17595491 |doi=] and macular edema secondary to retinal vein occlusions.

Ranibizumab, a Fab fragment derived from the same parent molecule as bevacizumab, has been developed by Genentech (by the same scientist Napoleone Ferrara) for intraocular use. This drug, under the trade name Lucentis, now has FDA approval. It has undergone extensive clinical trials. Reports indicate substantially better outcomes in patients treated with inravitreal Lucentis than conventional treatments in people with choroidal neovascularization (wet age related macular degeneration). Most patients with choroidal neovascularization lose vision or at best maintain vision despite treatment with laser, photodynamic therapy or Macugen. A much larger proportion (up to 70%) gained vision with Lucentis. Lucentis is however very expensive ($1500&ndash;2000 per injection, - the studies were done with monthly intravitreal injections). Bevacizumab is significantly cheaper (<$100 a shot versus >$1500) it appears to be safe (at least in the short term) and many doctors have noticed improvements in vision and outcomes similar to those seen with Lucentis. As Genentech has developed both drugs it has little interest in seeing Bevacizumab use in the eye and it is likely to remain off label. Off-label use of this medication has created significant controversy in medical retina and vitreo-retinal surgery. On October 11, 2007, Genentech issued a [http://www.gene.com/gene/features/avastin/letter-to-physicians.jsp letter to Physicians] that they would no longer sell bevacizumab to compounding pharmacies. This will effectively stop its use for macular degeneration patients who have no insurance coverage for Ranibizumab (Lucentis) and for any patient who has other vision threatening conditions where Bevacizumab has been shown to work.

However, the ophthalmic community, led by the American Academy of Ophthalmology [http://www.aao.org/newsroom/release/20071012.cfm (AAO)] and the American Society of Retinal Specialists [http://www.asrs.org (ASRS)] , [http://www.patentdocs.net/patent_docs/2007/10/genentech-acts-.html fought back] and managed to get Gennentech to agree to continue providing bevacizumab to retinal surgeons, who in turn could get compounding pharmacies to "cut" the dosage to the appropriate ophthalmic dosage for continued use.

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. This study, called the Comparison of Age-Related Macular Degeneration Treatment Trials [http://irvaronsjournal.blogspot.com/2007/09/catt-study-update-3-avastin-vs-lucentis.html (CATT Study)] , will enroll about 1,200 patients with newly diagnosed wet AMD, randomly assigning the patients to one of four treatment groups:

(Group1) Lucentis with four-week dosing, and after one year, re-randomization to Lucentis every four weeks or variable dosing as required based on diagnostic findings;

(Group 2) Bevacizumab with four-week dosing, and after one year, re-randomization to bevacizumab every four weeks or variable dosing as required based on diagnostic findings;

(Group 3) Lucentis on a variable dosing schedule for 2 years; after initial treatment, with monthly evaluation and re-treatment based on signs of lesion activity; and

(Group 4) Bevacizumab on a variable dosing schedule for 2 years; after initial treatment, with monthly evaluation and re-treatment based on signs of lesion activity.

The [http://www.clinicaltrials.gov/ct2/show/NCT00593450 CATT Study] will be conducted at 47 clinical sites throughout the United States, which will follow the patients for two years and is expected to take four years to complete. Enrollment began on February 22, 2008, with [http://www.clinicaltrials.gov/ct2/show/locn/NCT00593450 fifteen sites] beginning recruiting. One-year follow-up data will be reported in 2009.

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.

ide effects

Bevacizumab inhibits the growth of blood vessels, which is part of the body's normal healing and maintenance. The body grows new blood vessels in wound healing, and as collateral circulation around blocked or atherosclerotic blood vessels. One concern is that bevacizumab will interfere with these normal processes, and worsen conditions like coronary artery disease or peripheral artery disease. [New England Journal of Medicine, 8 May 2008, 358(19):2066, Clinical Implications of Basic Research: A New Weapon for Attacking Tumor Blood Vessels, Gregg L. Semenza.]

The main side effects are hypertension and heightened risk of bleeding. Bowel perforation has been reported. In advanced lung cancer, less than half of patients qualify for treatment. [cite journal |author=Vamsidhar Velcheti, Avinash Viswanathan, Ramaswamy Govindan |title=The Proportion of Patients with Metastatic Non-small Cell Lung Cancer Potentially Eligible for Treatment with Bevacizumab: A Single Institutional Survey|journal=Journal of Thoracic Oncology |volume=1|issue=5 |pages=501 |year= 2006 | pmid = 17409907 |doi=10.1097/01243894-200606000-00023 [http://www.jto.org/pt/re/jto/fulltext.01243894-200606000-00023.htm;jsessionid=GWxGsvQ1f7mhFZP1k1MvwGvdnpC4HWvnYlGWH6DBZGtjV0Jx37KD!-680354521!-949856145!8091!-1 Full text] ] Brain capillary leak syndrome, nasal septum perforation, and renal thrombotic microangiopathy have been reported. [cite journal |author=Vera Eremina, J.Ashley Jefferson et al. |title=VEGF Inhibition and Renal Thrombotic Microangiopathy|journal=The New England Journal of Medicine |volume=358|issue=11 |pages=1129 |year= 2008 | pmid = 18337603|doi=10.1056/NEJMoa0707330 [http://content.nejm.org/cgi/content/short/358/11/1129?query=TOC Full text] ]

Costs

Bevacizumab is one of the most expensive drugs widely marketed. Doctors and editorials have criticized the high cost, for a drug that doesn't cure cancer but only prolongs life. In the U.S., insurance companies have refused to pay for all or part of the costs of bevacizumab, and in countries with national health care systems, such as the UK and Canada, the health care systems have restricted its use because of the low ratio of benefits to cost. Genentech argues that the benefit is worth the cost, and the high cost pays for the expensive and risky research needed to develop new drugs. Genentech has adjusted the price for patients in certain circumstances.

For colorectal cancer, Meyer wrote in the New England Journal of Medicine that bevacizumab extended life by 4.7 months (20.3 months vs. 15.6 months) in the initial study, at a cost of $42,800 to $55,000 [ [http://content.nejm.org/cgi/content/full/350/23/2406 Two Steps Forward in the Treatment of Colorectal Cancer,] Robert J. Mayer, N Engl J Med, 350:2406-2408 June 3, 2004]

The addition of bevacizumab to standard treatment can prolong the lives of breast and lung cancer patients by several months, at a cost of $100,000 a year. [ [http://www.nytimes.com/2006/02/15/business/15drug.html A Cancer Drug Shows Promise, at a Price That Many Can't Pay,] By ALEX BERENSON, New York Times, February 15, 2006]

References

External links

* [http://www.avastin.com Avastin.com]
* [http://www.amdsupport.ca/articles/55/1/Off-Label-Uses-of-Avastin-as-a-Treatment-for-Macular-Degeneration/Page1.html Off Label Uses of Avastin for AMD]
* [http://www.avastin-info.com Avastin-info.com Information for healthcare professionals outside of the US]
* [http://www.nytimes.com/2006/02/15/business/15drug.html?ex=1297659600&en=62aabaec5acffa8c&ei=5090&partner=rssuserland&emc=rss A Cancer Drug Shows Promise, at a Price That Many Can't Pay] "New York Times", February 15, 2006, Alex Berenson
* [http://www.cancer.gov/cancertopics/druginfo/bevacizumab NCI Drug Information Summary on Bevacizumab for Patients]
* [http://www.cancer.gov/Templates/drugdictionary.aspx?CdrID=43234 NCI Drug Dictionary Definition for Bevacizumab]
* [http://www.clinicaltrials.gov/ct/show/NCT00222469?order=1 Phase II Clinical Trial of Bevacizumab for Adenocarcinoma of the Pancreas]
* [http://irvaronsjournal.blogspot.com/2007/09/catt-study-update-3-avastin-vs-lucentis.html CATT Study Update 3: Avastin vs. Lucentis -- To Get Underway by Year's End!]
* [http://www.clinicaltrials.gov/ct2/show/NCT00593450 Comparison of Age-Related Macular Degeneration Treatments Trials: Lucentis-Avastin Trial]


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