- Editor’s Page: What's New on EyetubeOD?
- The Crucial Role of Optometry in State-of-the-Art Glaucoma Care
- Implantable Miniature Telescope Offers Hope to Patients With Advanced AMD
- A Clinician’s Overview of Anti-VEGF Therapies
- Protocol T 2-Year Data Released
- Nutrition and AMD: What We Know Now
- Complement Inhibition in Geographic Atrophy
- State of the Science in Ocular Allergies
- Allergy is More Than the Itch
- Ocular Allergy Testing: A Simple Solution to a Diagnostic Dilemma
- Important Developments in Ocular Allergy
- The Low Vision Tsumami
- How to Deliver, Part 2
- The ABCs of SEO and SEM
- Unilateral Retinitis Pigmentosa
Vascular endothelial growth factor (VEGF) is a protein growth factor that stimulates the processes of vasculogenesis and angiogenesis. In normal concentrations, VEGF contributes to the development and healing of blood vessels in the circulatory system. However, overproduction of VEGF is a signal of tissue distress found in disease processes.1
In 1989, Ferrara and colleagues at Genentech first isolated and cloned VEGF. In 1993, after investigations of the biochemistry and molecular biology of VEGF, Ferrara reported that certain monoclonal antibodies inhibited VEGF-induced angiogenesis.2 The inhibitory effect of these monoclonal antibodies caused growth suppression in a variety of tumors. These findings led to development of the first anti-VEGF monoclonal antibody, bevacizumab (Avastin; Genentech), in 1997.2
Today, anti-VEGF therapies are used off label in the treatment of numerous medical and ophthalmic conditions.
ANTI-VEGF THERAPY IN CANCERS
The formation of new blood vessels, or angiogenesis, is crucial for tumor growth. VEGF is the primary stimulant of vascularization in solid tumors. Furthermore, VEGF-A, the most important form of VEGF, is the primary tumor angiogenesis factor. Thus, VEGF-mediated angiogenesis plays a key role in tumor growth and metastasis.3
Over the years, anti-VEGF therapies have been investigated as anticancer treatments. Studies have revealed that anti-VEGF monoclonal antibodies can neutralize the VEGF receptor, thereby inhibiting VEGF function. VEGF inhibitors suppress the process of angiogenesis, thereby suppressing tumor growth.4
In 2004, bevacizumab was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic renal and colorectal cancer, non-small cell lung cancer, and glioblastoma. Bevacizumab can be used as an alternative or as an adjunct to chemotherapy or radiotherapy in the treatment of any of these malignancies.5
Anti-VEGF treatments were not without controversies. In 2011, following various reported cases of life-threatening side effects of bevacizumab in breast cancer patients, its use for the treatment of breast cancer was revoked by the FDA.
ANTI-VEGF THERAPY IN EYE DISEASES
In the past decade, anti-VEGF therapy has become the cornerstone of managing numerous eye diseases. Anti-VEGF therapy has a continually expanding role in ophthalmology, and it is used in the treatment of several eye diseases.
A decade’s worth of clinical trials and clinical experience has revealed that anti-VEGF monoclonal antibodies can restore the integrity of the blood-retina barrier and improve visual acuity by resolving macular edema.6 Repeated intravitreal injections of pegaptanib sodium (Macugen; Bausch + Lomb), ranibizumab (Lucentis; Genentech), and aflibercept (Eylea; Regeneron), as well as bevacizumab, can effectively treat diabetic macular edema (DME). Of these drugs, ranibizumab and aflibercept have received FDA approval for use in the treatment of DME. 7,8
Research has shown that anti-VEGF therapy is beneficial for the treatment of proliferative diabetic retinopathy (PDR), especially in cases of neovascular glaucoma or persistent vitreous hemorrhage, and as an aid before vitrectomy.9
In the Western world, retinal vein occlusion (RVO) is the second most common cause of visual loss. Two anti-VEGF agents, ranibizumab and aflibercept, have been approved by the FDA and the European Medicines Agency for the treatment of RVO.
Mintz-Hittner and Kuffel found that intravitreal injections of bevacizumab were effective in the treatment of moderate to severe stage 3 retinopathy of prematurity in infants. Anti-VEGF therapy was most effective in treating zone 1 and posterior zone 2 retinopathy of prematurity.10
Anti-VEGF agents have also been administered topically to address corneal diseases. Dastjerdi et al reported that treatment of corneal neovascularization with topical bevacizumab 1% for 3 weeks was well-tolerated and effective.11 Yoeruek et al found that bevacizumab eye drops were effective in treating alkali burns, significantly reducing corneal damage.12 Wu et al reported regression of pterygium after administration of bevacizumab eye drops four times daily for 3 weeks.13
ANTI-VEGF THERAPY IN AMD
Perhaps the most thoroughly studied and most frequently used ophthalmic application of anti-VEGF therapy is in age-related macular degeneration (AMD). AMD is a leading cause of irreversible blindness in the elderly population around the world. It is well known that VEGF plays a critical role in the pathogenesis of AMD. In this ocular disease, VEGF overproduction leads to choroidal neovascularization, a characteristic pathologic sign in the wet form of AMD.14
Three anti-VEGF agents have been approved by the FDA for the treatment of AMD: pegaptanib, ranibizumab, and aflibercept.15 The first to be approved was pegaptanib sodium. It is an effective drug for the treatment of AMD, but it acts only on one form of the VEGF protein, VEGF-165. It is administered by injection every 6 weeks.16
The second anti-VEGF drug to be approved by the FDA for treatment of AMD was ranibizumab. This drug binds and neutralizes all active forms of the VEGF protein. Ranibizumab has been shown to significantly slow the rate of vision loss in AMD and to inhibit disease progression for up to 3 years in patients. The current recommended dosage of ranibizumab is 0.5 mg monthly.17
Most recently, the FDA approved aflibercept for the treatment of wet AMD. The current recommended dosage is 2 mg every 4 weeks for 3 months, followed by 2 mg every 8 weeks.7
Of these three anti-VEGF agents, ranibizumab has been the most widely studied in the treatment of AMD. Ranibizumab is a recombinant monoclonal antibody fragment that binds to the VEGF-A protein. This protein is believed to be the key component in angiogenesis and in the hyperpermeability of blood vessels in macular degeneration. Ranibizumab binds to the receptor binding sites on the active forms of the VEGF-A protein. This binding prevents interaction between VEGF-A and its receptors, VEGFR-1 and VEGFR-2, on the surface of endothelial cells. This reduces endothelial cell proliferation, vascular leakage, and angiogenesis.17
Several large clinical trials have demonstrated the efficacy of ranibizumab in the treatment of AMD. Rosenfeld et al studied the effects of intravitreal injections of ranibizumab in AMD patients with choroidal neovascularization. The patients received monthly injections of ranibizumab 0.3 mg or 0.5 mg for 2 years. In this landmark study, ranibizumab prevented vision loss and improved visual acuity. The drug was found to be effective in the treatment of minimally classic or occult wet AMD with low rates of ocular adverse effects.17
Brown et al compared the effects of intravitreal ranibizumab to photodynamic therapy with verteporfin (Visudyne; Bausch + Lomb). They concluded that ranibizumab improved mean visual acuity and was superior to photodynamic therapy.18 Rothenbueler et al found that ranibizumab 0.5 mg, given with a variable dosage regimen for 24 months, improved visual acuity, prevented further loss of vision, and improved central macular thickness.17
Bevacizumab is not approved by the FDA for any ophthalmic application, but studies have found it to be safe and effective in ophthalmic clinical practice. To be used for treatment of eye diseases such as wet AMD, DME, and RVO, bevacizumab must be pharmacologically compounded. When this is done, bevacizumab is repackaged from large, glass vials into multiple smaller single-use plastic prefilled syringes. The repackaged bevacizumab is much less expensive than ranibizumab. The current recommended dosage of bevacizumab is 1.25 to 2.5 mg monthly.19
There are no doubts that one of the biggest developments in eye care in the past decade has been the introduction of VEGF inhibitors and their evolution as an important option in the management of multiple retinal disorders. Use of anti-VEGF agents has been a major clinical advance in the management of PDR and AMD.
Although photocoagulation is still the standard of care for long-term management of PDR, with further development and improvements in drug delivery methods, there is no question that this class of medications will play a major role in managing patients with high-risk retinal vascular diseases in the future. n
1. Brekken RA, Huang X, King SW, Thorpe PE. Vascular endothelial growth factor as a marker of tumor endothelium. Cancer Res. 1998;58(9):1952-1959.
2. Ferrara N. From the discovery of vascular endothelial growth factor to the introduction of Avastin in clinical trials—an interview with Napoleone Ferrara. Int J Dev Biol. 2011;55(4-5):383-388.
3. Sitohy B, Nagy JA, Dvorak HF. Anti-VEGF/VEGFR therapy for cancer: reassessing the target. Cancer Res. 2012;72(8):1909-1914.
4. Palmer JM, Amoaku WM, Kamali F. Quality of bevacizumab compounded for intravitreal administration. Eye (Lond). 2013;27:1090-1097.
5. Stewart MW. Anti-VEGF therapy for diabetic macular edema. Curr Diab Rep. 2014;14(8):510.
6. Shikari H, Samant P. Intravitreal injections: a review of pharmacological agents and techniques. J Clin Ophthalmol Res. 2016:1(4):51-59.
7. FDA News release. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm439838.htm. Accessed March 2, 2016.
8. FDA News release. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm315130.htm Accessed March 2, 2016 .
9. Osaadon P, Fagan XJ, Lifshitz T, Levy J. A review of anti-VEGF agents for proliferative diabetic retinopathy. Eye (Lond). 2014;28(5):510-520.
10. Mintz-Hittner HA, Kuffel RR Jr. Intravitreal injection of bevacizumab (avastin) for treatment of stage 3 retinopathy of prematurity in zone I or posterior zone II. Retina. 2008;28(6):831-838.
11. Dastjerdi MH, Al-Arfaj KM, Nallasamy N, et al. Topical bevacizumab in the treatment of corneal neovascularization: results of a prospective, open-label, noncomparative study. Arch Ophthalmol. 2009;127(4):381-389.
12. Yoeruek E, Ziemssen F, Henke-Fahle S, et al; Tübingen Bevacizumab Study Group. Safety, penetration and efficacy of topically applied bevacizumab: evaluation of eyedrops in corneal neovascularization after chemical burn. Acta Ophthalmol. 2008;86(3):322-328.
13. Wu PC, Kuo HK, Tai MH, Shin SJ. Topical bevacizumab eyedrops for limbal-conjunctival neovascularization in impending recurrent pterygium. Cornea. 2009;28(1):103-104.
14. Campa C, Harding SP. Anti-VEGF compounds in the treatment of neovascular age related macular degeneration. Curr Drug Targets. 2011;12(2):173-181.
15. Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1419-1431.
16. Palmer JM, Amoaku WM, Kamali F. Quality of bevacizumab compounded for intravitreal administration. Eye. 2013;27:1090-1097.
17. Rothenbuehler SP, Waeber D, Brinkmann CK, et al. Effects of ranibizumab in patients with subfoveal choroidal neovascularization attributable to age-related macular degeneration. Am J Ophthalmol. 2009;147(5):831-837.
18. Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.
19. Ventrice P, Leporini C, Aloe JF, et al. Anti-vascular endothelial growth factor drugs safety and efficacy in ophthalmic diseases. J Pharmacol Pharmacother. 2013;4(suppl 1):S38-42.
Agustin L. Gonzalez, OD
• Optometric glaucoma specialist and therapeutic optometrist in practice at Eye & Vision in Richardson, Texas
• Financial disclosure: consultant to Allergan, Shire, and Valeant