Fueling a Revolution in Retinal Care

AMD TherapyIn the 1990s, the 2014 Champalimaud Award Laureates worked in parallel and in collaboration to identify vascular endothelial growth factor (VEGF) as the major trigger for angiogenesis in the eye. In 1993, they showed that the human retina synthesizes VEGF, and subsequently demonstrated that VEGF expression is induced in low-oxygen conditions. In 1994, the team correlated VEGF with ocular angiogenesis in primates (American Journal of Pathology), which was the first in vivo demonstration of VEGF’s role in ocular neovascularization. That same year, the team published two separate studies (New England Journal of Medicine, American Journal of Ophthalmology) both demonstrating increased VEGF in the vitreous of patients with proliferative diabetic retinopathy. A subsequent study describing a mouse model of retinopathy of prematurity and other oxygen-induced retinal disorders became the most-cited article in the journal Investigative Ophthalmology and Visual Science. In a series of studies published between 1995 and 1996, the investigators demonstrated that VEGF inhibitors could block ocular neovascularization in preclinical models. This cumulative work provided the scientific foundation for the development of anti-VEGF therapies – now the gold standard for treating neovascular AMD, diabetic macular edema and retinal vein occlusion. VEGF inhibitors hold potential for a growing list of indications, including neovascular glaucoma and retinopathy of prematurity.

2000 Visudyne®
As the first treatment for neovascular AMD, photodynamic therapy with verteporfin (Visudyne) is approved by the FDA and international drug regulatory agencies, opening the pharmacologic era of retinal disease therapy.

2004 Macugen®

Following results from a large multicenter clinical trial published in New England Journal of Medicine, pegaptanib (Macugen) becomes the first FDA-approved anti-VEGF therapy for
neovascular AMD.

2004 Avastin®

Bevacizumab (Avastin) – originally FDA-approved 2004 as an anti-VEGF drug for cancer – is successfully administered off-label via intravitreal injection to treat neovascular AMD. By early 2006, Avastin is widely used off-label for neovascular AMD.

2006 Lucentis®

Ranibizumab (Lucentis) receives FDA approval for the treatment of AMD. This was hailed as one of the top ten breakthroughs of 2006 by the journal Science.

2010 Lucentis®

Ranibizumab receives FDA approval for the treatment of macula edema following retinal vein occlusion.

2011 Avastin® and Lucentis®

Bevacizumab (Avastin) is shown to have similar efficacy as ranibizumab when administered according to the same schedule in the Comparison of AMD Treatments Trials (CATT) by the National Institutes of Health (NIH). Bevacizumab is a cost-effective alternative to ranibizumab and the most widely used off-label treatment today for neovascular AMD. Bevacizumab is also used to treat diabetic macular edema and retinal vein occlusion. A study also estimated that two years of Lucentis treatment reduces visual impairment in neovascular AMD by 37 percent and legal blindness by 72 percent.

2011 Eyelea®

The most recent FDA- approved anti-VEGF therapy, aflibercept (Eylea) requires fewer intraocular injections than other anti-VEGF therapies and has become the predominant FDA-approved therapy for treating neovascular AMD.

2012 Lucentis®

Ranibizumab receives FDA approval for the treatment of diabetic macular edema.

Should Genetic Testing Guide AREDS Recommendations?

VitaminsTwo studies provide different recommendations regarding whether genetic testing should be used to guide Age-Related Eye Disease Study (AREDS) supplemental recommendations. “This is one of the hottest debates at present regarding treatment for AMD. At some level, both studies may be right,” noted Joan W. Miller, MD, FARVO, Chair of the HMS Department of Ophthalmology and Chief of Ophthalmology at Mass. Eye and Ear and Mass General Hospital. “AREDS2 recommendations are reasonable to follow at present. When we have a new and better treatment for early AMD, it is quite possible that genetic testing will be used to select the “best” treatment for an individual."

Improving Anti-VEGF Treatment for AMD

Developing more patient-friendly, less burdensome treatments for patients with neovascular disease is an important goal of ongoing research efforts. Approved by the FDA in 2011 for treating neovascular AMD, aflibercept (Eylea) has an alternative mechanism of VEGF blockade that has been shown to have higher binding affinities compared to ranibizumab and bevacizumab. Mass. Eye and Ear investigators conducted a study exploring the short-term visual and anatomic outcomes of patients with refractory or recurrent neovascular AMD who were converted from bevacizumab and/or ranibizumab to aflibercept. They also examined whether aflibercept conversion could extend the injection intervals to decrease injection burden. The data suggest that converting patients with chronic neovascular AMD to aflibercept resulted in stabilized vision and improved anatomic outcomes, allowing a less frequent dosing schedule of every 8 weeks after 3 initial monthly injections. Further studies are warranted to determine whether the conversion benefits to aflibercept are sustained. Looking ahead, pharmacogenomic technology may  play a role in guiding treatment for personalized medicine. Researchers are working toward developing better methods of phenotyping using improved imaging techniques,  metabolomics, and genetic animal models.

Multiple Treatment Options

Given the multiple treatment options for neovascular AMD, the selection of medication and treatment modality depends on the type of lesion, as well as the patient’s systemic health, social circumstances, and economic considerations. Having multiple options has been particularly helpful in treating difficult cases. For example, switching from one anti-VEGF medication to another has been shown to be effective in recurrent and refractory choroidal neovascularization. Photodynamic therapy (PDT) with verteporfin is still an effective method of treating refractory cases. Moreover, a multicenter, randomized controlled trial has shown that combination therapy (PDT with an anti-VEGF agent) may be an effective approach for treating polypoidal choroidal vasculopathy (PCV), while a retrospective review demonstrated promising results using triple therapy (PDT with an anti-VEGF agent plus a steroid) for PCV.

Clinical Resources

  • Miller JW. Age-related macular degeneration revisited–piecing the puzzle: the LXIX Edward Jackson memorial lecture. Am J Ophthalmol 2013 Jan;155(1):1-35.e13. doi: 10.1016/j.ajo.2012.10.018.
  • Yonekawa Y, Andreoli C, Miller JB, Loewenstein JI, Sobrin L, Eliott D, Vavvas DG, Miller JW, Kim IK. Conversion to aflibercept for chronic refractory or recurrent neovascular age-related macular degeneration. Am J Ophthalmol 2013;156:29-35.e22.
  • Yonekawa Y, Kim IK. Clinical characteristics and current treatment of age-related macular degeneration. Cold Spring Harb Perspect Med 2014 Oct 3. pii: a017178. doi: 0.1101/cshperspect.a017178.