Anti–vascular endothelial growth factor therapy

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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

Anti–vascular endothelial growth factor therapy, also known as anti-VEGF therapy or anti-VEGF 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: lapatinib, sunitinib, sorafenib, axitinib, and pazopanib. (Some of these therapies target VEGF receptors rather than the VEGFs.)

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

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 suffering from 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[edit]

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]

Neovascular age-related macular degeneration[edit]

Ranibizumab, a monoclonal antibody fragment (Fab) derived from bevacizumab, has been developed by Genetech 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,[citation needed] 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[which?] 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. This study, called the Comparison of Age-Related Macular Degeneration Treatment Trials (CATT Study), will enroll about 1,200 patients with newly diagnosed wet AMD, randomly assigning the patients to different treatment groups.[citation needed]

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[edit]

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.[12]

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.[13] A 2017 review update found moderate evidence that in patients suffering from diabetic macular edema, aflibercept may have advantages in improving visual outcomes over bevacizumab and ranibizumab, after one year.[14]

References[edit]

  1. ^ Bergers G, Hanahan D (August 2008). "Modes of resistance to anti-angiogenic therapy". Nat. Rev. Cancer. 8 (8): 592–603. doi:10.1038/nrc2442. PMC 2874834. PMID 18650835.
  2. ^ Ebos, John; Christina R. Lee; William Cruz-Munoz; Georg A. Bjarnason; James G. Christensen; Robert S. Kerbel (March 2009). "Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis". Cancer Cell. 15 (3): 232–239. doi:10.1016/j.ccr.2009.01.021. PMID 19249681. Retrieved 22 October 2012.
  3. ^ Pàez-Ribes, Marta; Allen, Elizabeth; Hudock, James; Takeda, Takaaki; Okuyama, Hiroaki; Viñals, Francesc; Inoue, Masahiro; Bergers, Gabriele; Hanahan, Douglas; Casanovas, Oriol (March 2009). "Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis". Cancer Cell. 15 (3): 220–231. doi:10.1016/j.ccr.2009.01.027. PMC 2874829. PMID 19249680. Retrieved 22 October 2012.
  4. ^ Ledermann, Jonathan A; Embleton, Andrew C; Raja, Fharat; Perren, Timothy J; Jayson, Gordon C; Rustin, Gordon J S; Kaye, Stan B; Hirte, Hal; Eisenhauer, Elizabeth; Vaughan, Michelle; Friedlander, Michael; González-Martín, Antonio; Stark, Daniel; Clark, Elizabeth; Farrelly, Laura; Swart, Ann Marie; Cook, Adrian; Kaplan, Richard S; Parmar, Mahesh K B (2016). "Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial". The Lancet. 387 (10023): 1066–1074. doi:10.1016/S0140-6736(15)01167-8. ISSN 0140-6736. PMID 27025186.
  5. ^ a b Braithwaite, Tasanee; Nanji, Afshan A.; Lindsley, Kristina; Greenberg, Paul B. (2014-05-01). "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. ISSN 1469-493X. PMC 4292843. PMID 24788977.
  6. ^ Meadows, Kellen L.; Hurwitz, Herbert I. (October 2012). "Anti-VEGF Therapies in the Clinic". Cold Spring Harbor Perspectives in Medicine. 2 (10). doi:10.1101/cshperspect.a006577. ISSN 2157-1422. PMC 3475399.
  7. ^ "FDA Approves New Biologic Treatment for Wet Age-Related Macular Degeneration". FDA News & Events. June 30, 2006. Retrieved 17 April 2013.
  8. ^ Brown, David M.; Michels, Mark; Kaiser, Peter K.; Heier, Jeffrey S.; Sy, Judy P.; Ianchulev, Tsontcho; Anchor Study, Group (2009). "Ranibizumab versus Verteporfin Photodynamic Therapy for Neovascular Age-Related Macular Degeneration: Two-Year Results of the ANCHOR Study". Ophthalmology. 116 (1): 57–65. doi:10.1016/j.ophtha.2008.10.018. PMID 19118696.
  9. ^ Rosenfeld, Philip J.; Brown, David M.; Heier, Jeffrey S.; Boyer, David S.; Kaiser, Peter K.; Chung, Carol Y.; Kim, Robert Y.; Marina Study, Group (2006). "Ranibizumab for Neovascular Age-Related Macular Degeneration". New England Journal of Medicine. 355 (14): 1419–31. doi:10.1056/NEJMoa054481. PMID 17021318.
  10. ^ Raftery, J.; Clegg, A.; Jones, J.; Tan, S. C.; Lotery, A. (2007). "Ranibizumab (Lucentis) versus bevacizumab (Avastin): modelling cost effectiveness". 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. ^ 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". Fertil. Steril. 93 (6): 2042–7. doi:10.1016/j.fertnstert.2009.02.059. PMC 2847675. PMID 19342033.
  13. ^ Simha A, Braganza A, Abraham L, Samuel P, Lindsley K (2013). "Anti-vascular endothelial growth factor for neovascular glaucoma". Cochrane Database Syst Rev. 10: CD007920. doi:10.1002/14651858.CD007920.pub2. PMC 4261636. PMID 24089293.
  14. ^ Virgili G, Parravano M, Evans JR, Gordon I, Lucenteforte E (2017). "Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis". Cochrane Database Syst Rev. 6: CD007419. doi:10.1002/14651858.CD007419.pub5. PMID 28639415.