Bevacizumab

From Wikipedia, the free encyclopedia

Bevacizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
TargetVEGF-A
Clinical data
Pronunciation/ˌbɛvəˈsɪzjʊmæb/[1]
Trade namesAvastin, others
Biosimilarsbevacizumab-adcd,[2] bevacizumab-awwb,[3] bevacizumab-bvzr,[4] bevacizumab-maly,[5] bevacizumab-tnjn, Abevmy,[6] Alymsys,[7][5] Avzivi, Aybintio,[8] Bambevi,[9] Bevacip,[10] Bevaciptin,[10] Equidacent,[11] Mvasi,[12] Onbevzi,[13][14] Oyavas,[15] Vegzelma,[2][16][17] Zirabev[18]
AHFS/Drugs.comMonograph
MedlinePlusa607001
License data
Pregnancy
category
Routes of
administration		Intravenous, intravitreal
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability100% (IV only)
Elimination half-life20 days (range: 11–50 days)
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC6638H10160N1720O2108S44
Molar mass149198.87 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Bevacizumab, sold under the brand name Avastin among others, is a monoclonal antibody medication used to treat a number of types of cancers and a specific eye disease.[28][26] For cancer, it is given by slow injection into a vein (intravenous) and used for colon cancer, lung cancer, ovarian cancer, glioblastoma, and renal-cell carcinoma.[29] In many of these diseases it is used as a first-line therapy.[28][26] For age-related macular degeneration it is given by injection into the eye (intravitreal).[28]

Common side effects when used for cancer include nose bleeds, headache, high blood pressure, and rash.[28] Other severe side effects include gastrointestinal perforation, bleeding, allergic reactions, blood clots, and an increased risk of infection.[28] When used for eye disease side effects can include vision loss and retinal detachment.[28] Bevacizumab is a monoclonal antibody that functions as an angiogenesis inhibitor.[28] It works by slowing the growth of new blood vessels by inhibiting vascular endothelial growth factor A (VEGF-A), in other words anti–VEGF therapy.[28]

Bevacizumab was approved for medical use in the United States in 2004.[30][28] It is on the World Health Organization's List of Essential Medicines[31][32][33] It is listed for its use in treating eye disease.[31][32]

Medical uses[edit]

Colorectal cancer[edit]

Bevacizumab was approved in the United States in February 2004, for use in metastatic colorectal cancer when used with standard chemotherapy treatment (as first-line treatment).[34] In June 2006, it was approved with 5-fluorouracil-based therapy for second-line metastatic colorectal cancer.[34]

It was approved by the European Medicines Agency (EMA) in January 2005, for use in colorectal cancer.[35][27]

Bevacizumab has also been examined as an add on to other chemotherapy drugs in people with non-metastatic colon cancer. The data from two large randomized studies showed no benefit in preventing the cancer from returning and a potential to cause harm in this setting.[36]

In the EU, bevacizumab in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of adults with metastatic carcinoma of the colon or rectum.[11]

Lung cancer[edit]

In 2006, the US Food and Drug Administration (FDA) approved bevacizumab for use in first-line advanced nonsquamous non-small cell lung cancer in combination with carboplatin/paclitaxel chemotherapy. The approval was based on the pivotal study E4599 (conducted by the Eastern Cooperative Oncology Group), which demonstrated a two-month improvement in overall survival in patients treated with bevacizumab (Sandler, et al. NEJM 2004).[citation needed] A preplanned analysis of histology in E4599 demonstrated a four-month median survival benefit with bevacizumab for people with adenocarcinoma (Sandler, et al. JTO 2010);[citation needed] adenocarcinoma represents approximately 85% of all non-squamous cell carcinomas of the lung.

A subsequent European clinical trial, AVAiL, was first reported in 2009 and confirmed the significant improvement in progression-free survival shown in E4599 (Reck, et al. Ann. Oncol. 2010).[citation needed] An overall survival benefit was not demonstrated in patients treated with bevacizumab; however, 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, Clin Colorectal Cancer, 2006).[citation needed] As an anti-angiogenic agent, there is no mechanistic rationale for stopping bevacizumab before disease progression. Stated another way, 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.

Another large European-based clinical trial with bevacizumab in lung cancer, AVAPERL, was reported in October 2011 (Barlesi, et al. ECCM 2011).[citation needed] First-line patients were treated with bevacizumab plus cisplatin/pemetrexed for four cycles, and then randomized to receive maintenance treatment with either bevacizumab/pemetrexed or bevacizumab alone until disease progression. Maintenance treatment with bevacizumab/pemetrexed demonstrated a 50% reduction in risk of progression vs bevacizumab alone (median PFS: 10.2 vs 6.6 months). Maintenance treatment with bevacizumab/pemetrexed did not confer a significant increase in overall survival vs bevacizumab alone on follow up analysis.[37]

The National Comprehensive Cancer Network recommends bevacizumab as standard first-line treatment in combination with any platinum-based chemotherapy, followed by maintenance bevacizumab until disease progression.[medical citation needed] Higher doses are usually given with carboplatin-based chemotherapy, whereas the lower dose is usually given with cisplatin-based chemotherapy.[medical citation needed]

In the EU, bevacizumab, in addition to platinum-based chemotherapy, is indicated for first-line treatment of adults with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology.[11] Bevacizumab, in combination with erlotinib, is indicated for first-line treatment of adults with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating mutations.[11]

Breast cancer[edit]

In December 2010, the US Food and Drug Administration (FDA) notified its intention to remove the breast cancer indication from bevacizumab, saying that it had not been shown to be safe and effective in breast cancer patients.[38][39] 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. This only prevented Genentech from marketing bevacizumab for breast cancer. Doctors are free to prescribe bevacizumab off label, although insurance companies are less likely to approve off-label treatments.[40][41] In June 2011, an FDA panel unanimously rejected an appeal by Roche. A panel of cancer experts ruled for a second time that Avastin should no longer be used in breast cancer patients, clearing the way for the US government to remove its endorsement from the drug. The June 2011 meeting of the FDA's oncologic drug advisory committee was the last step in an appeal by the drug's maker. The committee concluded that breast cancer clinical studies of patients taking Avastin have shown no advantage in survival rates, no improvement in quality of life, and significant side effects.[42]

On 11 October 2011, the FDA announced that the agency was revoking the agency's approval of the breast cancer indication for bevacizumab after concluding that the drug had not been shown to be safe and effective for that use.[citation needed]

In the EU, bevacizumab in combination with paclitaxel is indicated for first-line treatment of adults with metastatic breast cancer.[11] Bevacizumab in combination with capecitabine is indicated for first-line treatment of adults with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate.[11]

Renal cancers[edit]

In certain renal (kidney) cancers, bevacizumab improves the progression free survival time but not survival time. In 2009, the FDA approved bevacizumab for use in metastatic renal cell cancer (a form of kidney cancer).[43][44] following earlier reports of activity[45] EU approval was granted in 2007.[46]

In the EU, bevacizumab in combination with interferon alfa-2a is indicated for first-line treatment of adults with advanced and/or metastatic renal cell cancer.[11]

Brain cancers[edit]

Bevacizumab slows tumor growth but does not affect overall survival in people with glioblastoma.[47] The FDA granted accelerated approval for the treatment of recurrent glioblastoma multiforme in May 2009.[48][49] A 2018 Cochrane review deemed there to not be good evidence for its use in recurrences either.[47]

Eye disease[edit]

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.[50]

Bevacizumab has been used by ophthalmologists in an off-label use as an intravitreal agent in the treatment of proliferative (neovascular) eye diseases, particularly for choroidal neovascular membrane (CNV) in AMD. The injection of 1.25–2.5 mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity.[51] Many retina specialists have noted impressive results in the setting of CNV, proliferative diabetic retinopathy, neovascular glaucoma, diabetic macular edema, retinopathy of prematurity[52] and macular edema secondary to retinal vein occlusions.[50]

Several reviews concluded that similar results concerning effects and safety were obtained using either bevacizumab or ranibizumab.[53][54] The latter is an antibody fragment specifically designed and approved for the treatment of eye disease. Today there is no doubt that patients injected with bevacizumab intravitrealy died as a consequence of the treatment.[55][unreliable medical source] The risk to die is particularly high when the patients had a cardiovascular[56] 29429131 or cerebrovascular.[57] event before intravitreal bevacizumab treatment. In the years between 2006 and 2014 groups with higher and lower risk for thrombotic angiopathy were not defined before intravitreal injections of bevacizumab but was recommended later.[55]

Ovarian cancer[edit]

In 2018, the US Food and Drug Administration (FDA) approved bevacizumab in combination with chemotherapy for stage III or IV of ovarian cancer after initial surgical operation, followed by single-agent bevacizumab. The approval was based on a study of the addition of bevacizumab to carboplatin and paclitaxel.[58] Progression-free survival was increased to 18 months from 13 months.[58]

In the EU, bevacizumab, in combination with carboplatin and paclitaxel is indicated for the front-line treatment of adults with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages IIIB, IIIC and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer.[11] Bevacizumab, in combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel, is indicated for treatment of adults with first recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents.[11]

In May 2020, the FDA expanded the indication of olaparib to include its combination with bevacizumab for first-line maintenance treatment of adults with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability.[59]

Cervical cancer[edit]

In the EU, bevacizumab, in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in people who cannot receive platinum therapy, is indicated for the treatment of adults with persistent, recurrent, or metastatic carcinoma of the cervix.[11]

Administration[edit]

Bevacizumab is usually given intravenously every 14 days. In colon cancer, it is given in combination with the chemotherapy drug 5-FU (5-fluorouracil), leucovorin, and oxaliplatin or irinotecan.[medical citation needed] For treatment of eye diseases it is injected intravitreously.

Off-label use for age-related macular degeneration (AMD)[edit]

Dr Philip Rosenfeld developed off-label use of bevacizumab for age-related macular degeneration.[60][61] Bevacizumab is used off-label to treat neovascular AMD.[62]

Adverse effects[edit]

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.[63]

The main side effects are hypertension and heightened risk of bleeding. Bowel perforation has been reported.[64] Fatigue and infection are also common.[65]

In advanced lung cancer, less than half of patients qualify for treatment.[66][67] Nasal septum perforation and renal thrombotic microangiopathy have been reported.[68] In December 2010, the FDA warned of the risk of developing perforations in the body, including in the nose, stomach, and intestines.

In 2013, Hoffmann-La Roche announced that the drug was associated with 52 cases of necrotizing fasciitis from 1997 to 2012, of which 17 patients died.[69] About 2/3 of cases involved patients with colorectal cancer, or patients with gastrointestinal perforations or fistulas.

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.[citation needed]

Neurological adverse events include reversible posterior encephalopathy syndrome. Ischemic and hemorrhagic strokes are also possible.[70]

Protein in the urine occurs in approximately 20% of people. This does not require permanent discontinuation of the drug. Nonetheless, the presence of nephrotic syndrome necessitates permanent discontinuation of bevacizumab.[71]

Mechanism of action[edit]

Bevacizumab is a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A (VEGF-A).[72] VEGF-A is a growth factor protein that stimulates angiogenesis in a variety of diseases, especially in cancer. By binding VEGF-A, bevacizumab should act outside the cell, but in some cases (cervical and breast cancer) it is taken up by cells through constitutive endocytosis.[73] It also is taken up by retinal photoreceptor cells after intravitreal injection.[74]

Chemistry[edit]

Bevacizumab was originally derived from a mouse monoclonal antibody generated from mice immunized with the 165-residue form of recombinant human vascular endothelial growth factor. It was humanized by retaining the binding region and replacing the rest with a human full light chain and a human truncated IgG1 heavy chain, with some other substitutions. The resulting plasmid was transfected into Chinese hamster ovary cells which are grown in industrial fermentation systems.[35]: 4 

History[edit]

Bevacizumab is a recombinant humanized monoclonal antibody and in 2004, it became the first clinically used angiogenesis inhibitor.[75] Its development was based on the discovery of human vascular endothelial growth factor (VEGF), a protein that stimulated blood vessel growth, in the laboratory of Genentech scientist Napoleone Ferrara.[76][77][78] Ferrara later demonstrated that antibodies against VEGF inhibit tumor growth in mice.[79] His work validated the hypothesis of Judah Folkman, proposed in 1971, that stopping angiogenesis might be useful in controlling cancer growth.[78]

Approval[edit]

It received its first approval in the United States in 2004, for combination use with standard chemotherapy for metastatic colon cancer.[71] It has since been approved for use in certain lung cancers, renal cancers, ovarian cancers, and glioblastoma multiforme of the brain.[medical citation needed]

In 2008, bevacizumab was approved for breast cancer by the FDA, but the approval was revoked on 18 November 2011[80][81][82] because, although there was evidence that it slowed progression of metastatic breast cancer, there was no evidence that it extended life or improved quality of life, and it caused adverse effects including severe high blood pressure and hemorrhaging.[medical citation needed]

In 2008, the FDA gave bevacizumab provisional approval for metastatic breast cancer, subject to further studies. The FDA's advisory panel had recommended against approval.[83] In July 2010, after new studies failed to show a significant benefit, the FDA's advisory panel recommended against the indication for advanced breast cancer. Genentech requested a hearing, which was granted in June 2011. The FDA ruled to withdraw the breast cancer indication in November 2011. FDA approval is required for Genentech to market a drug for that indication. Doctors may sometimes prescribe it for that indication, although insurance companies are less likely to pay for it.[81]

The drug remains approved for breast cancer use in other countries, including Australia.[84] It has been funded by the English NHS Cancer Drugs Fund, but in January 2015 it was proposed to remove it from the approved list.[85] It remains on the Cancer Drugs Fund as of March 2023.[86]

Society and culture[edit]

Use for macular degeneration[edit]

In 2015, there was a fierce debate in the UK and other European countries concerning the choice of prescribing bevacizumab or ranibizumab (Lucentis) for wet AMD.[87] In the UK, part of the tension was between on the one hand, both the European Medicines Agency and the Medicines and Healthcare products Regulatory Agency which had approved Lucentis but not Avastin for wet AMD, and their interest in ensuring that doctors do not use medicines off-label when there are other, approved medications for the same indication, and on the other hand, NICE in the UK, which sets treatment guidelines, and has been unable so far to appraise Avastin as a first-line treatment, in order to save money for the National Health Service.[87] Novartis and Roche (which respectively have marketing rights and ownership rights for Avastin) had not conducted clinical trials to get approval for Avastin for wet AMD and had no intention of doing so.[87] Further, both companies lobbied against treatment guidelines that would make Avastin a first-line treatment, and when government-funded studies comparing the two drugs were published, they published papers emphasizing the risks of using Avastin for wet AMD.[87]

In March 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Lytenava, intended for treatment of neovascular (wet) age-related macular degeneration (nAMD).[88] The applicant for this medicinal product is Outlook Therapeutics Limited.[88]

Breast cancer approval[edit]

In March 2007, the European Commission approved bevacizumab in combination with paclitaxel for the first-line treatment of metastatic breast cancer.[89]

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. This 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.[83]

In 2010, before the FDA announcement, 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 in the treatment of metastatic breast cancer.[citation needed]

In 2011, the US Food and Drug Administration removed bevacizumab indication for metastatic breast cancer after concluding that the drug has not been shown to be safe and effective. The specific indication that was withdrawn was for the use of bevacizumab in metastatic breast cancer, with paclitaxel for the treatment of people who have not received chemotherapy for metastatic HER2-negative breast cancer.[citation needed]

Counterfeit[edit]

In February 2012, Roche and its US biotech unit Genentech announced that counterfeit Avastin had been distributed in the United States.[90] The investigation is ongoing, but differences in the outer packaging make identification of the bogus drugs simple for medical providers. Roche analyzed three bogus vials of Avastin and found they contained salt, starch, citrate, isopropanol, propanediol, t-butanol, benzoic acid, di-fluorinated benzene ring, acetone and phthalate moiety, but no active ingredients of the cancer drug. According to Roche, the levels of the chemicals were not consistent; whether the chemicals were at harmful concentrations could not therefore be determined. The counterfeit Avastin has been traced back to Egypt, and it entered legitimate supply chains via Europe to the United States.[91][92]

Biosimilars[edit]

See also: Biosimilars

In July 2014, two pharming companies, PlantForm and PharmaPraxis, announced plans to commercialize a biosimilar version of bevacizumab made using a tobacco expression system in collaboration with the Fraunhofer Center for Molecular Biology.[93][needs update]

In September 2017, the US FDA approved Amgen's biosimilar (generic name bevacizumab-awwb, product name Mvasi) for six cancer indications.[94][95][96]

In January 2018, Mvasi was approved for use in the European Union.[12]

In February 2019, Zirabev was approved for use in the European Union.[18] Zirabev was approved for medical use in the United States in June 2019,[97] and in Australia in November 2019.[10]

In June 2020, Mvasi was approved for medical use in Australia.[10]

In August 2020, Aybintio was approved for use in the European Union.[8]

In September 2020, Equidacent was approved for use in the European Union.[11]

In January 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Alymsys, intended for the treatment of carcinoma of the colon or rectum, breast cancer, non-small cell lung cancer, renal cell cancer, epithelial ovarian, fallopian tube or primary peritoneal cancer, and carcinoma of the cervix.[7] Alymsys was approved for medical use in the European Union in March 2021.[7]

In January 2021, Onbevzi was approved for medical use in the European Union.[13]

In June 2019, and June 2021, Zirabev was approved for medical use in Canada.[98][99]

Oyavas was approved for medical use in the European Union in March 2021.[15]

Abevmy was approved for medical use in the European Union in April 2021,[6] and in Australia in September 2021.[19][10]

In September 2021, Bambevi was approved for medical use in Canada.[9]

Bevacip and Bevaciptin were approved for medical use in Australia in November 2021.[10][100]

In November 2021, Abevmy and Aybintio were approved for medical use in Canada.[101][102]

In April 2022, bevacizumab-maly (Alymsys) was approved for medical use in the United States.[5]

In August 2022, Vegzelma was approved for medical use in the European Union.[16][103]

In September 2022, bevacizumab-adcd (Vegzelma) was approved for medical use in the United States.[2]

In June 2023, Enzene Biosciences launched its bevacizumab biosimilar in India.[104]

Bevacizumab-tnjn (Avzivi) was approved for medical use in the United States in December 2023.[105][106]

Research[edit]

A study released in April 2009, found that bevacizumab is not effective at preventing recurrences of non-metastatic colon cancer following surgery.[107]

Bevacizumab has been tested in ovarian cancer where it has shown improvement in progression-free survival but not in overall survival.[108] and glioblastoma multiforme where it failed to improve overall survival.[109][110]

Bevacizumab has been investigated as a possible treatment of pancreatic cancer, as an addition to chemotherapy, but studies have shown no improvement in survival.[111][112] It may also cause higher rates of high blood pressure, bleeding in the stomach and intestine, and intestinal perforations.[medical citation needed]

The drug has also undergone trials as an addition to established chemotherapy protocols and surgery in the treatment of pediatric osteosarcoma,[113] and other sarcomas, such as leiomyosarcoma.[114]

Bevacizumab has been studied as a treatment for cancers that grow from the nerve connecting the ear and the brain.[115]

References[edit]

  1. ^ "Bevacizumab Injection: MedlinePlus Drug Information". NLM.nih.gov. 28 February 2014. Archived from the original on 25 March 2014.
  2. ^ a b c d "Vegzelma- bevacizumab-adcd injection, solution". DailyMed. 23 November 2022. Archived from the original on 11 February 2023. Retrieved 11 February 2023.
  3. ^ a b "Mvasi- bevacizumab-awwb injection, solution". DailyMed. 25 June 2019. Archived from the original on 27 July 2020. Retrieved 18 March 2020.
  4. ^ a b "Zirabev- bevacizumab-bvzr injection, solution". DailyMed. 27 January 2020. Archived from the original on 27 July 2020. Retrieved 18 March 2020.
  5. ^ a b c d "Alymsys- bevacizumab-maly injection, solution". DailyMed. 13 April 2022. Archived from the original on 10 June 2022. Retrieved 20 April 2022.
  6. ^ a b c "Abevmy EPAR". European Medicines Agency (EMA). 24 February 2021. Archived from the original on 28 August 2021. Retrieved 27 August 2021.
  7. ^ a b c d "Alymsys EPAR". European Medicines Agency (EMA). 25 January 2021. Archived from the original on 8 October 2021. Retrieved 19 May 2021. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. ^ a b c "Aybintio EPAR". European Medicines Agency (EMA). 26 May 2020. Archived from the original on 29 December 2020. Retrieved 9 September 2020.
  9. ^ a b "Summary Basis of Decision (SBD) for Bambevi". Health Canada. 23 October 2014. Archived from the original on 29 May 2022. Retrieved 29 May 2022.
  10. ^ a b c d e f "Which biosimilar medicines are available in Australia?". Archived from the original on 30 December 2021. Retrieved 29 December 2021.
  11. ^ a b c d e f g h i j k l "Equidacent EPAR". European Medicines Agency (EMA). 20 July 2020. Archived from the original on 13 October 2020. Retrieved 12 October 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  12. ^ a b c "Mvasi EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 30 December 2019. Retrieved 2 April 2020.
  13. ^ a b c "Onbevzi EPAR". European Medicines Agency (EMA). 9 November 2020. Archived from the original on 5 November 2021. Retrieved 19 May 2021.
  14. ^ a b "Onbevzi APMDS". Therapeutic Goods Administration (TGA). 6 February 2024. Archived from the original on 8 February 2024. Retrieved 7 March 2024.
  15. ^ a b c "Oyavas EPAR". European Medicines Agency. 25 January 2021. Archived from the original on 8 October 2021. Retrieved 3 March 2023.
  16. ^ a b c "Vegzelma EPAR". European Medicines Agency (EMA). 20 June 2022. Archived from the original on 28 January 2023. Retrieved 3 March 2023.
  17. ^ a b c "Vegzelma APMDS". Therapeutic Goods Administration (TGA). 18 September 2023. Archived from the original on 2 January 2024. Retrieved 7 March 2024.
  18. ^ a b c "Zirabev EPAR". European Medicines Agency (EMA). 11 December 2018. Archived from the original on 30 December 2019. Retrieved 2 April 2020.
  19. ^ a b c "Abevmy". Therapeutic Goods Administration (TGA). 15 September 2021. Archived from the original on 16 September 2021. Retrieved 17 September 2021.
  20. ^ "Bevacizumab Use During Pregnancy". Drugs.com. 30 July 2019. Archived from the original on 18 March 2020. Retrieved 18 March 2020.
  21. ^ "AusPAR: Bevacizumab". Therapeutic Goods Administration (TGA). 2 February 2022. Archived from the original on 31 May 2022. Retrieved 12 June 2022.
  22. ^ https://www.tga.gov.au/resources/auspar/auspar-vegzelma
  23. ^ "Summary Basis of Decision for Vegzelma". Health Canada. 2 May 2023. Archived from the original on 10 March 2024. Retrieved 18 June 2023.
  24. ^ "Vegzelma Product information". Health Canada. 3 January 2023. Archived from the original on 10 March 2024. Retrieved 18 June 2023.
  25. ^ "Health product highlights 2021: Annexes of products approved in 2021". Health Canada. 3 August 2022. Retrieved 25 March 2024.
  26. ^ a b c "Avastin- bevacizumab injection, solution". DailyMed. 28 June 2019. Archived from the original on 27 July 2020. Retrieved 18 March 2020.
  27. ^ a b "Avastin EPAR". European Medicines Agency (EMA). 11 March 2020. Archived from the original on 18 March 2020. Retrieved 18 March 2020.
  28. ^ a b c d e f g h i "Bevacizumab". The American Society of Health-System Pharmacists. Archived from the original on 20 December 2016. Retrieved 8 December 2016.
  29. ^ "Bevacizumab". National Cancer Institute. 5 October 2006. Archived from the original on 10 April 2020. Retrieved 22 December 2023.
  30. ^ "Drug Approval Package: Avastin (Bevacizum) NDA #125085". U.S. Food and Drug Administration (FDA). 8 March 2005. Archived from the original on 8 April 2021. Retrieved 29 December 2021.
  31. ^ a b World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  32. ^ a b World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  33. ^ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
  34. ^ a b Cohen MH, Gootenberg J, Keegan P, Pazdur R (March 2007). "FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer". The Oncologist. 12 (3): 356–61. doi:10.1634/theoncologist.12-3-356. PMID 17405901. S2CID 21241228.
  35. ^ a b "Bevacizumab Scientific Discussion" (PDF). European Medicines Agency. 2005. Archived from the original (PDF) on 24 September 2015.
  36. ^ Van Cutsem E, Lambrechts D, Prenen H, Jain RK, Carmeliet P (January 2011). "Lessons from the adjuvant bevacizumab trial on colon cancer: what next?". Journal of Clinical Oncology. 29 (1): 1–4. doi:10.1200/JCO.2010.32.2701. PMID 21115866.
  37. ^ Barlesi F, Scherpereel A, Gorbunova V, Gervais R, Vikström A, Chouaid C, et al. (May 2014). "Maintenance bevacizumab-pemetrexed after first-line cisplatin-pemetrexed-bevacizumab for advanced nonsquamous nonsmall-cell lung cancer: updated survival analysis of the AVAPERL (MO22089) randomized phase III trial". Annals of Oncology. 25 (5): 1044–52. doi:10.1093/annonc/mdu098. PMID 24585722.
  38. ^ "Questions and Answers about Avastin". U.S. Food and Drug Administration (FDA). 16 December 2010. Archived from the original on 23 April 2020. Retrieved 22 April 2020.
  39. ^ "Avastin (bevacizumab) Information". U.S. Food and Drug Administration (FDA). 29 June 2011. Archived from the original on 23 April 2020. Retrieved 22 April 2020.
  40. ^ "FDA begins process to remove breast cancer indication from Avastin label" (Press release). U.S. Food and Drug Administration (FDA). 16 December 2010. Archived from the original on 16 December 2010. Retrieved 17 December 2010.
  41. ^ Andrew P (16 December 2010). "F.D.A. Rejects Use of Drug in Cases of Breast Cancer". The New York Times. Archived from the original on 11 November 2012. Retrieved 16 December 2010.
  42. ^ Couzin-Frankel J, Ogale Y (July 2011). "FDA. Once on 'fast track,' avastin now derailed". Science. 333 (6039): 143–4. doi:10.1126/science.333.6039.143. PMID 21737712.
  43. ^ "FDA clears Genentech drug for kidney cancer". San Francisco Chronicle. 2 August 2009. Archived from the original on 30 September 2010.
  44. ^ "FDA Gives Roche's Avastin the Go-Ahead for Metastatic Renal Carcinoma". GENNewsHighlights. Genetic Engineering & Biotechnology News. 3 August 2009. Archived from the original on 11 May 2020. Retrieved 13 August 2012.
  45. ^ Rini BI (February 2007). "Vascular endothelial growth factor-targeted therapy in renal cell carcinoma: current status and future directions". Clinical Cancer Research. 13 (4): 1098–106. doi:10.1158/1078-0432.CCR-06-1989. PMID 17317817.
  46. ^ European Medicines Agency (January 2008). "Avastin-H-C-582-II-0015 : EPAR - Assessment Report - Variation" (PDF). Archived (PDF) from the original on 30 January 2012.
  47. ^ a b Ameratunga M, Pavlakis N, Wheeler H, Grant R, Simes J, Khasraw M (November 2018). "Anti-angiogenic therapy for high-grade glioma". The Cochrane Database of Systematic Reviews. 2018 (11): CD008218. doi:10.1002/14651858.CD008218.pub4. PMC 6516839. PMID 30480778.
  48. ^ Richard P (May 2009). "FDA Approval for Bevacizumab". National Cancer Institute. Archived from the original on 10 January 2010. Retrieved 11 May 2010.
  49. ^ "FDA Grants Accelerated Approval of Avastin for Brain Cancer (Glioblastoma) That Has Progressed Following Prior Therapy". Drugs.com. 5 May 2009. Archived from the original on 26 July 2020. Retrieved 22 April 2020.
  50. ^ a b Fogli S, Del Re M, Rofi E, Posarelli C, Figus M, Danesi R (June 2018). "Clinical pharmacology of intravitreal anti-VEGF drugs". Eye. 32 (6): 1010–1020. doi:10.1038/s41433-018-0021-7. PMC 5997665. PMID 29398697.
  51. ^ Arevalo JF, Fromow-Guerra J, Sanchez JG, Maia M, Berrocal MH, Wu L, et al. (2008). "Primary intravitreal bevacizumab for subfoveal choroidal neovascularization in age-related macular degeneration: results of the Pan-American Collaborative Retina Study Group at 12 months follow-up". Retina. 28 (10): 1387–1394. doi:10.1097/IAE.0b013e3181884ff4. PMID 18827735. S2CID 8694305.
  52. ^ Azad R, Chandra P (2007). "Intravitreal bevacizumab in aggressive posterior retinopathy of prematurity". Indian Journal of Ophthalmology. 55 (4): 319, author reply 320. doi:10.4103/0301-4738.33057. PMID 17595491.
  53. ^ Scott LJ, Chakravarthy U, Reeves BC, Rogers CA (March 2015). "Systemic safety of anti-VEGF drugs: a commentary". Expert Opinion on Drug Safety. 14 (3): 379–88. doi:10.1517/14740338.2015.991712. PMID 25489638. S2CID 38910094.
  54. ^ Moja L, Lucenteforte E, Kwag KH, Bertele V, Campomori A, Chakravarthy U, et al. (September 2014). Moja L (ed.). "Systemic safety of bevacizumab versus ranibizumab for neovascular age-related macular degeneration". The Cochrane Database of Systematic Reviews. 9 (9): CD011230. doi:10.1002/14651858.CD011230.pub2. PMC 4262120. PMID 25220133.
  55. ^ a b Hanhart J, Comaneshter DS, Freier Dror Y, Vinker S (October 2017). "Mortality in patients treated with intravitreal bevacizumab for age-related macular degeneration". BMC Ophthalmology. 17 (1): 189. doi:10.1186/s12886-017-0586-0. PMC 5635499. PMID 29017506.
  56. ^ Hanhart J, Comaneshter DS, Freier-Dror Y, Vinker S (April 2018). "Mortality associated with bevacizumab intravitreal injections in age-related macular degeneration patients after acute myocardial infarct: a retrospective population-based survival analysis". Graefe's Archive for Clinical and Experimental Ophthalmology = Albrecht von Graefes Archiv Fur Klinische und Experimentelle Ophthalmologie. 256 (4): 651–663. doi:10.1007/s00417-018-3917-9. PMID 29429131. S2CID 3963177.
  57. ^ Hanhart J, Comaneshter DS, Vinker S (September 2018). "Mortality after a cerebrovascular event in age-related macular degeneration patients treated with bevacizumab ocular injections". Acta Ophthalmologica. 96 (6): e732–e739. doi:10.1111/aos.13731. PMID 29660843.
  58. ^ a b "FDA approves bevacizumab in combination with chemotherapy for ovarian cancer". U.S. Food and Drug Administration (FDA). 13 June 2018. Archived from the original on 18 March 2020. Retrieved 4 August 2018. Public Domain This article incorporates text from this source, which is in the public domain.
  59. ^ "FDA approves olaparib plus bevacizumab as maintenance treatment for ovarian, fallopian tube, or primary peritoneal cancers". U.S. Food and Drug Administration (FDA) (Press release). 8 May 2020. Archived from the original on 26 October 2020. Retrieved 12 October 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  60. ^ Rosenfeld PJ, Reichel E (May–June 2009). "The Path to Intravitreal Bevacizumab". Retina Today: 26–29. Archived from the original on 21 September 2021. Retrieved 21 September 2021.
  61. ^ Sun XD, Xu WQ, Rosenfeld PJ (March 2008). "[Therapeutic efficacy and safety of off-label use of Bevacizumab for the treatment of neovascular diseases of the eye]". [Zhonghua Yan Ke Za Zhi] Chinese Journal of Ophthalmology (in Chinese). 44 (3): 281–4. PMID 18785551.
  62. ^ ElSheikh RH, Chauhan MZ, Sallam AB (November 2022). "Current and Novel Therapeutic Approaches for Treatment of Neovascular Age-Related Macular Degeneration". Biomolecules. 12 (11): 1629. doi:10.3390/biom12111629. PMC 9688017. PMID 36358978.
  63. ^ Semenza GL (May 2008). "A new weapon for attacking tumor blood vessels". The New England Journal of Medicine. 358 (19): 2066–7. doi:10.1056/NEJMcibr0800272. PMID 18463385.
  64. ^ Sliesoraitis S, Tawfik B (July 2011). "Bevacizumab-induced bowel perforation". The Journal of the American Osteopathic Association. 111 (7): 437–41. PMID 21803880.
  65. ^ "AVASTIN (bevacizumab) injection, for intravenous use" (PDF). Genentech, Inc. Archived (PDF) from the original on 29 April 2016. Retrieved 2 June 2016.
  66. ^ Velcheti V, Viswanathan A, Govindan R (June 2006). "The proportion of patients with metastatic non-small cell lung cancer potentially eligible for treatment with bevacizumab: a single institutional survey". Journal of Thoracic Oncology. 1 (5): 501. doi:10.1097/01243894-200606000-00023. PMID 17409907.
  67. ^ Vaughn C, Zhang L, Schiff D (January 2008). "Reversible posterior leukoencephalopathy syndrome in cancer". Current Oncology Reports. 10 (1): 86–91. doi:10.1007/s11912-008-0013-z. PMID 18366965. S2CID 40332552.
  68. ^ Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, et al. (March 2008). "VEGF inhibition and renal thrombotic microangiopathy". The New England Journal of Medicine. 358 (11): 1129–36. doi:10.1056/NEJMoa0707330. PMC 3030578. PMID 18337603.
  69. ^ "Cancer drug Avastin tied to 2 cases of flesh-eating disease in Canada". CBC News. 2 May 2013. Archived from the original on 2 May 2013. Retrieved 2 May 2013.
  70. ^ Godfrey SE (May 1989). "Estrogen receptors". American Journal of Clinical Pathology. 91 (5): 629–30. doi:10.1215/15228517-2008-118. PMC 2718965. PMID 2718965.
  71. ^ a b "Avastin full Prescribing Information - Genentech" (PDF). Gene.com. 2011. Archived (PDF) from the original on 14 July 2011.
  72. ^ Los M, Roodhart JM, Voest EE (April 2007). "Target practice: lessons from phase III trials with bevacizumab and vatalanib in the treatment of advanced colorectal cancer". The Oncologist. 12 (4): 443–50. doi:10.1634/theoncologist.12-4-443. PMID 17470687.
  73. ^ Karpinska A, Magiera G, Kwapiszewska K, Hołyst R (2023). "Cellular Uptake of Bevacizumab in Cervical and Breast Cancer Cells Revealed by Single-Molecule Spectroscopy". Journal of Physical Chemistry Letters. 14 (5): 1272–1278. doi:10.1021/acs.jpclett.2c03590. PMC 9923738. PMID 36719904.
  74. ^ Heiduschka P, Fietz H, Hofmeister S, Schultheiss S, Mack AF, Peters S, et al. (June 2007). "Penetration of bevacizumab through the retina after intravitreal injection in the monkey". Investigative Ophthalmology & Visual Science. 48 (6): 2814–23. doi:10.1167/iovs.06-1171. PMID 17525217.
  75. ^ Pollack A (27 February 2004). "F.D.A. Approves Cancer Drug From Genentech". The New York Times. Archived from the original on 24 October 2016.
  76. ^ Palmer AM, Stephenson FA, Williams RJ (April 2007). "Society for Medicines Research: 40th anniversary symposium". Drug News & Perspectives. 20 (3): 191–6. PMID 17520096.
  77. ^ Ferrara N (2009). "Anti-angiogenic drugs to treat human disease: an interview with Napoleone Ferrara by Kristin H. Kain". Disease Models & Mechanisms. 2 (7–8): 324–5. doi:10.1242/dmm.002972. PMID 19553691. S2CID 22035397.
  78. ^ a b Ribatti D (2008). "Napoleone Ferrara and the saga of vascular endothelial growth factor". Endothelium. 15 (1): 1–8. doi:10.1080/10623320802092377. PMID 18568940.
  79. ^ Ferrara N (2011). "From the discovery of vascular endothelial growth factor to the introduction of avastin in clinical trials - an interview with Napoleone Ferrara by Domenico Ribatti". The International Journal of Developmental Biology. 55 (4–5): 383–8. doi:10.1387/ijdb.103216dr. PMID 21858763.
  80. ^ "Press Announcements - FDA Commissioner announces Avastin decision". U.S. Food and Drug Administration. 18 November 2011. Archived from the original on 15 December 2014. Retrieved 31 October 2014.
  81. ^ a b Pollack A (18 November 2011). "F.D.A. Revokes Approval of Avastin for Breast Cancer". The New York Times. Archived from the original on 21 November 2011.
  82. ^ "Cancer drug Avastin loses US approval". BBC News Online. 18 November 2011. Archived from the original on 19 November 2011.
  83. ^ a b "F.D.A. Approves Drug's Use for Breast Cancer". The New York Times. 22 February 2008. Archived from the original on 2 February 2017.
  84. ^ "Breast cancer drug 'still safe' for Aussie women". Australian Broadcasting Corporation. 22 July 2010. Archived from the original on 23 July 2010.
  85. ^ "David Cameron's flagship Cancer Drugs Fund 'is a waste of NHS cash'". The Guardian. 10 January 2015. Archived from the original on 15 January 2015. Retrieved 11 January 2015.
  86. ^ "NHS England » National Cancer Drugs Fund list". www.england.nhs.uk. Archived from the original on 9 March 2023. Retrieved 9 March 2023.
  87. ^ a b c d "Why have UK doctors been deterred from prescribing Avastin?". The British Medical Journal. 1 April 2015. Archived from the original on 4 April 2015. Retrieved 2 April 2015.
  88. ^ a b "Lytenava EPAR". European Medicines Agency. 21 March 2024. Retrieved 23 March 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  89. ^ Jasek W, ed. (2007). Austria-Codex (in German) (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 978-3-85200-181-4.[page needed]
  90. ^ "Counterfeits of cancer drug Avastin found in U.S". Reuters. 15 February 2012. Archived from the original on 24 September 2015.
  91. ^ Berkrot B (27 February 2012). "Fake Avastin had salt, starch, chemicals:Roche". Reuters. Archived from the original on 3 March 2012. Retrieved 28 February 2012.
  92. ^ Staton T (28 February 2012). "Phony Avastin vials contained chemicals, but no drugs". FiercePharma. Archived from the original on 1 March 2012. Retrieved 28 February 2012.
  93. ^ Brennan Z (23 July 2014). "Brazilian JV to tap plant-based manufacturing system for biosimilars". BioPharma-Reporter. Archived from the original on 10 January 2016. Retrieved 18 March 2020.
  94. ^ "FDA approves first biosimilar for the treatment of cancer". U.S. Food and Drug Administration (FDA) (Press release). 14 September 2017. Archived from the original on 5 November 2021. Retrieved 12 October 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  95. ^ "FDA approves first biosimilar for cancer treatment". U.S. Food and Drug Administration (FDA). 14 September 2017. Archived from the original on 21 September 2020. Retrieved 12 October 2020.
  96. ^ Gever J (14 September 2017). "Avastin Clone OK'd — Biosimilar for bevacizumab approved for various cancers". MedPage Today. Archived from the original on 16 September 2017. Retrieved 18 March 2020.
  97. ^ "Drug Approval Package: Zirabev". U.S. Food and Drug Administration (FDA). 14 August 2019. Archived from the original on 18 December 2019. Retrieved 29 December 2021.
  98. ^ "Summary Basis of Decision (SBD) for Zirabev". Health Canada. 23 October 2014. Archived from the original on 31 May 2022. Retrieved 29 May 2022.
  99. ^ "Summary Basis of Decision (SBD) for Zirabev". Health Canada. 23 October 2014. Archived from the original on 30 May 2022. Retrieved 29 May 2022.
  100. ^ "Bevacip/Bevaciptin". Therapeutic Goods Administration (TGA). 16 November 2021. Archived from the original on 30 December 2021. Retrieved 29 December 2021.
  101. ^ "Summary Basis of Decision (SBD) for Abevmy". Health Canada. 23 October 2014. Archived from the original on 29 May 2022. Retrieved 29 May 2022.
  102. ^ "Summary Basis of Decision (SBD) for Aybintio". Health Canada. 23 October 2014. Archived from the original on 29 May 2022. Retrieved 29 May 2022.
  103. ^ "Vegzelma Product information". Union Register of medicinal products. Archived from the original on 4 March 2023. Retrieved 3 March 2023.
  104. ^ Enzene Biosciences Launches Bevacizumab Archived 10 March 2024 at the Wayback Machine 29 June 2023
  105. ^ "Avzivi (bevacizumab-tnjn) injection, for intravenous use" (PDF). Bio-Thera Solutions, Ltd. U.S. Food and Drug Administration. 2020. Archived (PDF) from the original on 10 December 2023. Retrieved 10 December 2023.
  106. ^ "Biosimilar Drug Information". U.S. Food and Drug Administration. 8 December 2023. Archived from the original on 28 August 2021. Retrieved 10 December 2023.
  107. ^ Reed K (22 April 2009). "Roche drug Avastin fails cancer study, shares fall". Reuters. Archived from the original on 12 August 2009. Retrieved 22 April 2009.
  108. ^ Rossi L, Verrico M, Zaccarelli E, Papa A, Colonna M, Strudel M, et al. (February 2017). "Bevacizumab in ovarian cancer: A critical review of phase III studies". Oncotarget. 8 (7): 12389–12405. doi:10.18632/oncotarget.13310. PMC 5355353. PMID 27852039.
  109. ^ Diaz RJ, Ali S, Qadir MG, De La Fuente MI, Ivan ME, Komotar RJ (July 2017). "The role of bevacizumab in the treatment of glioblastoma". Journal of Neuro-Oncology. 133 (3): 455–467. doi:10.1007/s11060-017-2477-x. PMID 28527008. S2CID 4964000.
  110. ^ Kim MM, Umemura Y, Leung D (2018). "Bevacizumab and Glioblastoma: Past, Present, and Future Directions". Cancer Journal. 24 (4). Sudbury, Mass.: 180–186. doi:10.1097/PPO.0000000000000326. PMID 30119081. S2CID 52033623.
  111. ^ Rocha-Lima CM (June 2008). "New directions in the management of advanced pancreatic cancer: a review". Anti-Cancer Drugs. 19 (5): 435–46. doi:10.1097/CAD.0b013e3282fc9d11. PMID 18418211. S2CID 25507290.
  112. ^ Riess H (2008). "Antiangiogenic Strategies in Pancreatic Cancer". Pancreatic Cancer. Recent Results in Cancer Research. Vol. 177. pp. 123–9. doi:10.1007/978-3-540-71279-4_14. ISBN 978-3-540-71266-4. PMID 18084954.
  113. ^ Navid F, Santana VM, Neel M, McCarville MB, Shulkin BL, Wu J, et al. (October 2017). "A phase II trial evaluating the feasibility of adding bevacizumab to standard osteosarcoma therapy". International Journal of Cancer. 141 (7): 1469–1477. doi:10.1002/ijc.30841. PMC 5812455. PMID 28631382.
  114. ^ Bogani G, Ditto A, Martinelli F, Signorelli M, Chiappa V, Fonatella C, et al. (June 2018). "Role of bevacizumab in uterine leiomyosarcoma". Critical Reviews in Oncology/Hematology. 126: 45–51. doi:10.1016/j.critrevonc.2018.03.019. PMID 29759566. S2CID 46890425.
  115. ^ Plotkin SR, Merker VL, Halpin C, Jennings D, McKenna MJ, Harris GJ, et al. (August 2012). "Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: a retrospective review of 31 patients" (PDF). Otology & Neurotology. 33 (6): 1046–52. doi:10.1097/MAO.0b013e31825e73f5. PMID 22805104. S2CID 205755932. Archived (PDF) from the original on 10 March 2024. Retrieved 2 August 2019.

Further reading[edit]

External links[edit]

Retrieved from "https://en.wikipedia.org/w/index.php?title=Bevacizumab&oldid=1219347845"