The development of VEGF inhibitors for the treatment of neovascular age-related macular degeneration (AMD) ushered in a new era for the treatment of AMD. Wet AMD is associated with increased vascular permeability and the development of choroidal neovascularization (CNV). This increase in vascular permeability leads to abnormal fluid buildup within or below the retina; foveal involvement often results in serious visual deficits. Although no current US Food and Drug Administration (FDA)-approved treatment is likely to completely restore vision lost to the disease, some therapies may be able to preserve or even improve visual acuity. Over the past year, the treatment landscape for wet AMD has undergone a number of dramatic developments, including the release of the 1-year results from the CATT study, the suspension and then reinstatement of bevacizumab (Avastin, Genentech) as an off-label treatment option at US Department of Veterans Affairs (VA) hospitals, and, most recently, the FDA approval of aflibercept (Eylea, Regeneron). This month’s column reviews the history of treatment for wet AMD and breaks down the key players available for current treatment options.
Laser photocoagulation was the first treatment introduced in an effort to halt the progression of neovascular AMD. Unfortunately, a major drawback of laser photocoagulation is the laser-induced retinal lesions that result from the procedure. These lesions may cause permanent vision loss. Although laser photocoagulation may aid in stemming the course of wet AMD, the resulting side effects can be significant. For this reason, laser treatment is rarely used to treat wet AMD today. Fortunately for patients, treatments for neovascular AMD have improved significantly since the introduction of laser photocoagulation as a treatment option.
Photodynamic therapy (PDT) with verteporfin (Visudyne, QLT) was added to vitreoretinal specialists’ armamentarium in 2000. Unlike laser photocoagulation, PDT involves relatively selective photochemical damage to CNV, with less damage to the associated choroid and retina. During the PDT procedure, verteporfin, a lightsensitive drug, is injected into the arm. The drug enters the bloodstream and is absorbed by the abnormal blood vessels growing underneath the macula. A low-intensity, 689-nm laser is then directed at affected areas of the retina to activate verteporfin; photoactivation of the medication ultimately destroys abnormal vasculature and inhibits neovascularization. To date, verteporfin is the only FDA-approved PDT for wet AMD, although other light-sensitive drugs for wet AMD are being evaluated. Although laser photocoagulation and PDT with verteporfin were the first approved therapies for wet AMD treatment, researchers were already exploring antiangiogenic agents with the goals of inhibiting the growth and development of CNV, reducing the signs of exudation, and limiting or preventing fibrosis.
For decades, researchers have attempted to determine the underlying mechanism of neovascularization and vascular leakage in the eye. Modern angiogenesis research dates back to 1971, when Judah Folkman, MD, known today as the founder of the field of angiogenesis research, introduced the hypothesis that the growth of tumors is angiogenesis-dependent.
Therapy targeted against VEGF and its isoforms has revolutionized the treatment of neovascular AMD. In 2004, the FDA approved pegaptanib sodium injection (Macugen, Eyetech), the first anti-VEGF agent to target CNV. The approval of pegaptanib sodium also represents another milestone in drug development, as it was the first aptamer to be successfully developed as a therapeutic agent in humans. Aptamers are oligonucleotide ligands that are selected for high-affinity binding to molecular targets. Pegaptanib sodium is an RNA aptamer directed against VEGF165, the VEGF isoform primarily responsible for pathologic ocular neovascularization and vascular permeability. The VISION trials
In 2006, ranibizumab (Lucentis, Genentech), a humanized monoclonal antibody fragment targeting VEGF-A, was approved by the FDA for the treatment of neovascular AMD. Several phase 3 clinical trials have validated the use of ranibizumab in the treatment of all subtypes of choroidal neovascularization.
While awaiting FDA approval of ranibizumab, ophthalmologists began treating neovascular AMD with off-label use of bevacizumab. Approved in 2004 for intravenous treatment of metastatic colon cancer in combination with chemotherapy, bevacizumab garnered interest at the 2005 American Society of Retina Specialists meeting, where one case series described a favorable clinical experience with off-label bevacizumab for treating neovascular AMD.
With 2 effective, albeit 1 off-label, anti-VEGF options available, it became obvious that a direct, head-to-head comparison of ranibizumab and bevacizumab was needed. The CATT study was designed to evaluate the relative safety and efficacy of the 2 drugs used to treat neovascular AMD on visual acuity and to evaluate how frequently the drugs should be administered. CATT participants will complete a total of 24 monthly study visits for 2 years. In 2011, 1-year results from the CATT study found that, in each of the head-to-head comparisons of ranibizumab and bevacizumab, the drugs had equivalent effects on visual acuity at all time points.
In addition to determining which drug and dosing regimen is superior, another important aspect of CATT concerns the cost of these treatments.
Although price differences may be a great incentive for the off-label use of bevacizumab, the fact of the matter is that of the 2, only ranibizumab holds FDA approval for the treatment of wet AMD. This was highlighted in the recent stand-down instituted by the VA on all uses of bevacizumab for ophthalmic indications in September of 2011. According to the VA and an FDA alert, the Florida Department of Health notified the FDA of Streptococcus endophthalmitis infections in 3 clinics following intraocular injections of repackaged bevacizumab.
To date, the FDA is aware of at least 12 patients who were affected by repackaged bevacizumab. Although all of these patients had visual deficits prior to their injections, some of these patients lost all remaining vision in the treated eye due to endophthalmitis.
As the ranibizumab-bevacizumab saga carries on, the anti-VEGF marketplace continues to develop. On November 18, 2011, aflibercept was approved by the FDA for the treatment of neovascular AMD. In addition to inhibiting VEGF, aflibercept also blocks the formation of abnormal blood vessels by inhibiting placental growth factor. Two phase 3 trials (VIEW 1 and VIEW 2) found that all regimens of aflibercept successfully met the primary endpoint of statistical noninferiority compared with the current standard of care, ranibizumab 0.5 mg dosed every month, in the proportion of patients who maintained (or improved) vision over 52 weeks.
The primary difference between aflibercept and other macular degeneration treatments is the dosing regimen, as the recommended dose for aflibercept is 2 mg administered by intravitreal injection every 4 weeks for the first 12 weeks, followed by 2 mg once every 8 weeks. Aflibercept has a higher binding affinity to VEGF than ranibizumab or bevacizumab, which is believed to help reduce the dosing frequency. A second difference is that aflibercept costs approximately $1850. Priced just under ranibizumab, the differential may swing providers to prescribe aflibercept over the current standard of care. In fact, sales of aflibercept totaled between $24 million and $25 million in the fourth quarter of 2011, 5 times the anticipated sales and clear evidence of the drug’s impact on the anti-VEGF market.
The development of anti-VEGF agents for neovascular AMD provides a safe and effective treatment. For the millions of people affected by AMD, anti-VEGF therapy has resulted in unprecedented visual and anatomic outcomes far outpacing the performance of previously available treatments. Today, visual stabilization can be expected in most patients, and clinically significant visual improvement in many, especially if treatment begins early in the course of the disease.
Current research now focuses on increasing the durability of effect, reducing side effects, and facilitating delivery. Indeed, VEGF inhibitors in conjunction with other forms of therapy may be the next step in future treatments. It is no doubt that the bar for wet AMDtreatment has been set quite high, but we anticipate that further advances in therapy can be expected in the coming years.
Aron Shapiro is Vice President of Retina at Ora, Inc., in Andover, MA.
Ashley Lafond is a medical writer at Ora, Inc.