A Deeper Look at Three Emerging Areas in Neovascular AMD

Looking Forward to a Bright Treatment Future in AMD

Age-related macular degeneration (AMD) is a leading cause of vision loss worldwide and is the most common cause of blindness in the United States and Europe.^[1] It is a progressive disease whose prevalence increases with age, affecting about 25% of people by 80 years of age.^[2]

More than 90% of patients with AMD are diagnosed with its early or intermediate dry form, a chronic disease characterized by drusen and focal retinal pigment epithelial changes. Neovascular AMD is the most common form of AMD-associated blindness. It is defined by pathologic angiogenesis with abnormal blood vessel growth typically from the choroid into the neurosensory retina, thereby forming a choroidal neovascular membrane (CNVM), with secondary destructive vascular leakage, hemorrhaging, and scarring.^[3]

Since its introduction in the early 2000s, clinical blockade of the cytokine vascular endothelial growth factor A (VEGF) with one of three pharmaceuticals has revolutionized the management of wet AMD. Such treatments have dramatically altered incident cases of blindness on a population basis.^[4] Ranibizumab^[5,6] and aflibercept^[7] are approved by the US Food and Drug Administration (FDA) for the treatment of wet AMD, whereas bevacizumab^[8] is used in an off-label fashion.

The management of neovascular AMD has evolved dramatically over the past 15 years. However, much remains to be understood about this complex and chronic disease. The future is very bright, with many ongoing research endeavors being developed and honed alongside new and promising technologies. This article covers three key areas of innovation that will affect the field.

Pharmacologic Advances

Treatments for geographic atrophy. Besides CNVM, the second pathway leading to advanced AMD and blindness is the development of geographic atrophy, in which the photoreceptors and underlying retinal pigment epithelium degenerate. Although anti-VEGF agents have proven remarkably effective for AMD patients with CNVM, no approved treatment exists to reverse or slow the progression of geographic atrophy. Conversely, there is concern that anti-VEGF treatments themselves may accelerate macular atrophy.^[9]

Genetics accounts for > 50% of one's risk of developing AMD. Many of the implicated genes fall within the complement cascade,^[10] suggesting that chronic inflammation may underlie the pathogenesis of AMD. Although the complement pathway is complex with many potential therapeutic targets, blockage of the rate-limiting enzyme responsible for activation of the alternative complement cascade, complement factor D, has shown promise.

The monoclonal antibody lampalizumab inhibits complement factor D. At the 18-month primary endpoint of the phase 2 MAHALO study, monthly intravitreal injections of lampalizumab resulted in a 20.4% reduction in progression of geographic atrophy compared with sham-treated eyes (P < .2).^[11] The protective effect of lampalizumab was increased to 44% in monthly-treated patients who were positive for specific genotypes of complement factor I (P < .005). Given these promising phase 2 results, two large phase 3 trials, CHROMA^[12] and SPECTRI,^[13] are actively recruiting patients.

Novel agents for neovascular AMD. Current pharmacologic agents for neovascular AMD management focus on VEGF blockade. The relatively short intravitreal half-lives of these proteins, on the order of hours to days, often necessitates repeated administration—in many cases monthly—for maximal clinical effect and visual benefit.^[14,15]

The need for a longer anti-VEGF therapeutic window may be fulfilled in many ways. First, early-phase clinical trials are under way to assess the clinical value of a surgically implanted, refillable, sustained-delivery system for extended ranibizumab release.^[16] Second, pharmacologic agents with a longer duration of biological activity can be engineered, with such compounds as RTH258 (previously known as ESBA1008) and abicipar pegol (based on designed ankyrin repeat proteins, or DARPins) being actively assessed in phase 3^[17] and phase 2^[18] studies, respectively.

Third, gene therapy approaches may allow long-term sustained VEGF suppression. For example, a phase 1 trial of a viral vector expressing a soluble portion of a VEGF receptor intended to block VEGF (sFlt-1) revealed no safety concerns and appeared to demonstrate efficacy during evaluation.^[19] The viral vector is delivered during surgery as a single subretinal injection.

In addition, cytokine targets other than VEGF are being pursued. Aflibercept inhibits VEGF-B and placental growth factor.^[20] Many more therapeutic targets are conceivable in the pathologic angiogenesis cascade, including platelet-derived growth factor and tissue factor, both of which are being actively investigated in phase 3^[22] (EMERGE) studies, respectively.

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