A review of preclinical studies, medical literature, and clinical trials of the Food and Drug Administration (FDA)-approved anti-vascular endothelial growth factor (VEGF) drug aflibercept (Eylea, VEGF Trap-Eye) confirms that the drug promises to deliver excellent visual outcomes for patients with exudative age-related macular degeneration (AMD).
"Trial results indicate that patients undergo fewer injections of aflibercept than they would with ranibizumab," says Michael W. Stewart, M.D., with the Department of Ophthalmology at Mayo Clinic in Florida and a co-author of the review article "With a Wholesale Cost of $1,850 per Dose, the Cost per Patient for Aflibercept Treatment Also Promises to be Lower Than Ranibizumab."
Early anti-VEGF agents
Common indications for intraocular anti-VEGF injections
The most common indications for intraocular anti-vascular endothelial growth factor (VEGF) injections include exudative age-related macular degeneration, background and proliferative diabetic retinopathy, branch and central retinal vein occlusions, and retinopathy of prematurity. Intraocular anti-VEGF drugs generally work through two mechanisms: 1. Decreasing vascular permeability allows absorption of edema. 2. Decreasing neovascularization prevents hemorrhages and tissue distortion caused by fibrous proliferation. RPE indicates retinal pigment epithelium. From Dr. Stewart's article "The expanding role of vascular endothelial growth factor inhibitors in ophthalmology" which was published in Mayo Clinic Proceedings in 2012, Vol. 87 No. 1, pages 77-88. This graphic is used with permission.
Anti-VEGF drugs introduced since 2005 have revolutionized the treatment of exudative AMD by stabilizing and, in many cases, reversing vision loss. Surgeons were enthusiastic about ophthalmologic applications for the 3 FDA-approved anti-VEGF drugs, bevacizumab, pegaptanib, and ranibizumab.
Bevacizumab, a full-length antibody against VEGF, has been used extensively since 2005 for exudative AMD, diabetic retinopathy, retinal vein occlusions, retinopathy of prematurity, and other chorioretinal vascular disorders. Pegaptanib and ranibizumab were developed specifically for intraocular use. After intraocular injection, these drugs reach the systemic circulation in concentrations sufficient to decrease baseline VEGF levels. Clinical results for all three drugs, however, have been mixed and regulatory hurdles, particularly those regarding off-label use of bevacizumab, have been challenging.
Unlike the earlier drugs that were created with antibody technology and bind only to isoforms of VEGF-A, aflibercept is a fusion protein with binding domains from native VEGF receptors that binds VEGF-A, VEGF-B, and placental growth factors 1 and 2 with high affinity. Preclinical ophthalmologic studies demonstrated that aflibercept suppressed choroidal neovascularization in several animal models.
The phase 3 Vascular Endothelial Growth Factor (VEGF) Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration 1 and 2 trials showed that monthly and bimonthly aflibercept treatments were noninferior to monthly ranibizumab at preventing vision loss (<15-letter loss), with comparable vision gains and safety. Year 2 treatment involved monthly pro re nata injections with required injections every three months and maintained vision gains from the first year, with an average of 4.2 injections of aflibercept and 4.7 injections of ranibizumab.
The FDA approved aflibercept for the treatment of subfoveal choroidal neovascularization due to AMD in November 2011. "Trial results showed excellent short-term suppression of choroidal neovascularization in patients with exudative AMD and suggest that aflibercept provides more durable outcomes for patients than other anti-VEGF drugs," says Dr. Stewart. "Aflibercept seems to offer the effectiveness of the other anti-VEGF agents with less frequent injections and monitoring — a great benefit for patients."
Dr. Stewart has received research support from and is on the advisory board of Regeneron Pharmaceuticals, Inc.
For more information
Browning DJ, et al. Aflibercept for age-related macular degeneration: A game-changer or quiet addition? American Journal of Ophthalmology 2012;154:222. Accessed Dec. 6, 2012.
Stewart MW. Aflibercept (VEGF trap-eye): The newest anti-VEGF drug. British Journal of Ophthalmology. Accessed Dec. 6, 2012.
Stewart MW, et al. Aflibercept. Nature Reviews Drug Discovery. 2012;11:269. Accessed Dec. 6, 2012.
Points to remember
- Aflibercept is a fusion protein with binding domains from native VEGF receptors that binds VEGF-A, VEGF-B and placental growth factors 1 and 2 with high affinity.
- Aflibercept suppresses choroidal neovascularization in several animal models and was approved by the FDA in November 2011 for the treatment of subfoveal choroidal neovascularization due to AMD.
- Trials showed that monthly and bimonthly aflibercept treatments were noninferior to monthly ranibizumab at preventing vision loss, with comparable vision gains and safety.