Anti-VEGF

Anti–vascular endothelial growth factor therapy, also known as anti-VEGF (/vɛdʒˈɛf/) therapy or medication, is the use of medications that block vascular endothelial growth factor. This is done in the treatment of certain cancers and in age-related macular degeneration. They can involve monoclonal antibodies such as bevacizumab, antibody derivatives such as ranibizumab (Lucentis), or orally-available small molecules that inhibit the tyrosine kinases stimulated by VEGF: sunitinib, sorafenib, axitinib, and pazopanib (some of these therapies target VEGF receptors rather than the VEGFs).

Anti-VEGF
Specialtyoncology

Both antibody-based compounds and the first three orally available compounds are commercialized. The latter two, axitinib and pazopanib, are in clinical trials.

Bergers and Hanahan concluded in 2008 that anti-VEGF drugs can show therapeutic efficacy in mouse models of cancer and in an increasing number of human cancers. But, "the benefits are at best transitory and are followed by a restoration of tumour growth and progression."[1]

Later studies into the consequences of VEGF inhibitor use have shown that, although they can reduce the growth of primary tumours, VEGF inhibitors can concomitantly promote invasiveness and metastasis of tumours.[2][3]

AZ2171 (cediranib), a multi-targeted tyrosine kinase inhibitor has been shown to have anti-edema effects by reducing the permeability and aiding in vascular normalization.[4]

A 2014 Cochrane Systematic Review studied the effectiveness of ranibizumab and pegaptanib, on patients who have macular edema caused by central retinal vein occlusion.[5] Participants in both treatment groups showed improvement in visual acuity measures and a reduction in macular edema symptoms over six months.[5]

Cancer
Approved anti-VEGF drugs
Drug Use
axitinib cancer
bevacizumab cancer, AMD
cabozantinib cancer
lapatinib cancer
lenvatinib cancer
pazopanib cancer
ponatinib cancer
ramucirumab cancer
ranibizumab AMD
regorafenib cancer
sorafenib cancer
sunitinib cancer
vandetanib cancer

The most common indication for anti-VEGF therapy is cancer, and they are FDA and EMA approved for many forms of cancer. These medications are one of the most used forms of targeted therapy and are typically used in combination with other medications.[6]

Ranibizumab, a monoclonal antibody fragment (Fab) derived from bevacizumab, has been developed by Genentech for intraocular use. In 2006, FDA approved the drug for the treatment of neovascular age-related macular degeneration (wet AMD). The drug had undergone three successful clinical trials by then.[7]

In the October 2006 issue of the New England Journal of Medicine (NEJM), Rosenfield, et al. reported that monthly intravitreal injection of ranibizumab led to significant increase in the level of mean visual acuity compared to that of sham injection. It was concluded from the two-year, phase III study that ranibizumab is very effective in the treatment of minimally classic (MC) or occult wet AMD (age-related macular degeneration) with low rates of ocular adverse effects.[8]

Another study published in the January 2009 issue of Ophthalmology provides the evidence for the efficacy of ranibizumab. Brown, et al. reported that monthly intravitreal injection of ranibizumab led to significant increase in the level of mean visual acuity compared to that of photodynamic therapy with verteporfin. It was concluded from the two year, phase III study that ranibizumab was superior to photodynamic therapy with verteporfin in the treatment of predominantly classic (PC) Wet AMD with low rates of ocular adverse effects.[9]

Although the efficacy of ranibizumab is well-supported by extensive clinical trials, the cost effectiveness of the drug is questioned. Since the drug merely stabilizes patient conditions, ranibizumab must be administered monthly. At a cost of $2,000.00 per injection, the cost to treat wet AMD patients in the United States is greater than $10.00 billion per year. Due to high cost, many ophthalmologists have turned to bevacizumab as the alternative intravitreal agent in the treatment of wet AMD.

In 2007, Raftery, et al. reported in the British Journal of Ophthalmology that, unless ranibizumab is 2.5 times more effective the bevacizumab, ranibizumab is not cost-effective. It was concluded that the price of ranibizumab would have to be drastically reduced for the drug to be cost-effective.[10]

Off-label use of intravitreal bevacizumab has become a widespread treatment for neovascular age-related macular degeneration.[11] Although the drug is not FDA-approved for non-oncologic uses, some studies suggest that bevacizumab is effective in increasing visual acuity with low rates of ocular adverse effects. However, due to small sample size and lack of randomized control trial, the result is not conclusive.

In October 2006, the National Eye Institute (NEI) of the National Institutes of Health (NIH) announced that it would fund a comparative study trial of ranibizumab and bevacizumab to assess the relative efficacy and ocular adversity in treating wet AMD. In 2008, this study, called the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT Study), enrolled about 1,200 patients with newly diagnosed wet AMD. The patients were assigned randomly to different treatment groups, and the data was collected from 2008 to 2009. So far, the result has been at least 41 papers and 10 editorials/commentaries published in major medical journals. An additional paper is in press and work proceeds on 10 more. The overall conclusions demonstrated no statistical difference between the treatment groups outcomes after eight years [12]

By May 2012, anti-VEGF treatment with Avastin has been accepted by Medicare, is quite reasonably priced, and effective. Lucentis has a similar but smaller molecular structure to Avastin, and is FDA-approved (2006) for treating MacD, yet remains more costly, as is the more recent (approved in 2011) aflibercept (Eylea). Tests on these treatments are ongoing relative to the efficacy of one over another.

Research

VEGF is also inhibited by thiazolidinediones (used for diabetes mellitus type 2 and related disease), and this effect on granulosa cells gives the potential of thiazolidinediones to be used in ovarian hyperstimulation syndrome.[13]

A Cochrane Review seeking to determine the effectiveness of anti-VEGF agents such as ranibizumab and bevacizumab on lowering intraocular pressure in patients with neovascular glaucoma was inconclusive, as more research is needed to compare anti-VEGF treatments with conventional treatments.[14] A 2017 review update found moderate evidence that in patients with diabetic macular edema, aflibercept may have advantages in improving visual outcomes over bevacizumab and ranibizumab, after one year.[15]

Anti‐VEGF subconjunctival injections have been proposed as a means of controlling wound healing during glaucoma surgery, however the evidence for or against this therapeutic approach is limited and several studies are ongoing.[16]

References
  1. Bergers G, Hanahan D (August 2008). "Modes of resistance to anti-angiogenic therapy". Nature Reviews. Cancer. 8 (8): 592–603. doi:10.1038/nrc2442. PMC 2874834. PMID 18650835.
  2. Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS (March 2009). "Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis". Cancer Cell. 15 (3): 232–9. doi:10.1016/j.ccr.2009.01.021. PMC 4540346. PMID 19249681.
  3. Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, Casanovas O (March 2009). "Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis". Cancer Cell. 15 (3): 220–31. doi:10.1016/j.ccr.2009.01.027. PMC 2874829. PMID 19249680.
  4. Ledermann JA, Embleton AC, Raja F, Perren TJ, Jayson GC, Rustin GJ, Kaye SB, Hirte H, Eisenhauer E, Vaughan M, Friedlander M, González-Martín A, Stark D, Clark E, Farrelly L, Swart AM, Cook A, Kaplan RS, Parmar MK (March 2016). "Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial". Lancet. 387 (10023): 1066–1074. doi:10.1016/S0140-6736(15)01167-8. PMID 27025186.
  5. Braithwaite T, Nanji AA, Lindsley K, Greenberg PB (May 2014). "Anti-vascular endothelial growth factor for macular oedema secondary to central retinal vein occlusion". The Cochrane Database of Systematic Reviews (5): CD007325. doi:10.1002/14651858.CD007325.pub3. PMC 4292843. PMID 24788977.
  6. Meadows KL, Hurwitz HI (October 2012). "Anti-VEGF therapies in the clinic". Cold Spring Harbor Perspectives in Medicine. 2 (10): a006577. doi:10.1101/cshperspect.a006577. PMC 3475399. PMID 23028128.
  7. "FDA Approves New Biologic Treatment for Wet Age-Related Macular Degeneration". FDA News & Events. June 30, 2006. Retrieved 17 April 2013.
  8. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T (January 2009). "Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study". Ophthalmology. 116 (1): 57–65.e5. doi:10.1016/j.ophtha.2008.10.018. PMID 19118696.
  9. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, Kim RY (October 2006). "Ranibizumab for neovascular age-related macular degeneration". The New England Journal of Medicine. 355 (14): 1419–31. doi:10.1056/NEJMoa054481. PMID 17021318. S2CID 13505353.
  10. Raftery J, Clegg A, Jones J, Tan SC, Lotery A (September 2007). "Ranibizumab (Lucentis) versus bevacizumab (Avastin): modelling cost effectiveness". The British Journal of Ophthalmology. 91 (9): 1244–6. doi:10.1136/bjo.2007.116616. PMC 1954941. PMID 17431015.
  11. Patent Docs: Genentech Acts to Halt Off-label Use of Avastin® for Age-related Macular Degeneration
  12. https://www.med.upenn.edu/cpob/catt.html | Date=January 2022
  13. Shah DK, Menon KM, Cabrera LM, Vahratian A, Kavoussi SK, Lebovic DI (April 2010). "Thiazolidinediones decrease vascular endothelial growth factor (VEGF) production by human luteinized granulosa cells in vitro". Fertility and Sterility. 93 (6): 2042–7. doi:10.1016/j.fertnstert.2009.02.059. PMC 2847675. PMID 19342033.
  14. Simha, Arathi; Aziz, Kanza; Braganza, Andrew; Abraham, Lekha; Samuel, Prasanna; Lindsley, Kristina B. (6 February 2020). "Anti-vascular endothelial growth factor for neovascular glaucoma". The Cochrane Database of Systematic Reviews. 2020 (2): CD007920. doi:10.1002/14651858.CD007920.pub3. ISSN 1469-493X. PMC 7003996. PMID 32027392.
  15. Virgili G, Parravano M, Evans JR, Gordon I, Lucenteforte E (October 2018). "Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis". The Cochrane Database of Systematic Reviews. 10: CD007419. doi:10.1002/14651858.CD007419.pub6. PMC 6517135. PMID 30325017.
  16. Cheng, Jin-Wei; Cheng, Shi-Wei; Wei, Rui-Li; Lu, Guo-Cai (2016-01-15). Cochrane Eyes and Vision Group (ed.). "Anti-vascular endothelial growth factor for control of wound healing in glaucoma surgery". Cochrane Database of Systematic Reviews. 2016 (1): CD009782. doi:10.1002/14651858.CD009782.pub2. PMC 8742906. PMID 26769010.
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