Is There a Place for Combination Therapy in Neovascular AMD?

Richard F. Spaide, MD

Vitreous, Retina, Macula Consultants of New York

Certain types of choroidal neovascularization (CNV), such as that seen in inflammatory diseases like multifocal choroiditis and panuveitis, virtually require combination therapy of some type. The neovascular component can be addressed with anti-VEGF therapy, but the underlying inflammatory disease driving the neovascularization also requires treatment. It is common to use corticosteroids in treating multifocal choroiditis, and the corticosteroids not only decrease inflammation but also help reduce the angiogenesis as well.

In CNV secondary to AMD, there is evidence of inflammation. Histopathologic examination of excised CNV shows inflammatory infiltrate, with the amount of VEGF, which colocalizes with macrophages, present in direct proportion to the number of macrophages present.^1-4 Abnormalities in the complement system have been found in a large proportion of patients with late AMD.^5-7 VEGF has a number of pro-inflammatory effects, including macrophage recruitment,⁸ so reducing VEGF can be expected to reduce inflammation in CNV.

Anti-VEGF therapy with ranibizumab is associated with visual acuity improvement in 25% to 33% of patients.⁹ This is much better than any other published treatment evaluated by randomized trial. However, is this all there is? If we had a cancer treatment where 25% to 33% of patients got better (not cured!) would we be happy? Maybe, at first, but the search would be on for something better. In a similar fashion, we shouldn’t sit back and believe that anti-VEGF therapy is the final answer for CNV secondary to AMD. Maybe it is, but the history of medicine is such that almost every treatment ever developed in the past has been improved with progress.

The invasion of CNV is not just the infiltration of blood vessels; there are inflammatory cells, fibroblast, myofibroblasts, and RPE cells as well.⁹ All of this seems to be triggered via a number of interconnected stimuli.¹⁰ At present we don’t have a way to stop these stimuli and, if started, there may be a number of other mechanisms recruited in the final pathway of neovascularization. As such, we will probably not have a single magic bullet. We will have to combine therapies to target processes involved in the formation and maintenance of CNV. Anti-VEGF drugs are an important part of our armamentarium, but many other targets, like platelet-derived growth factor, tissue necrosis factor alpha, and fibroblastic derived growth factor to name a few, may also be important. Non-specific drugs like corticosteroids may block these factors, but corticosteroids have a number of side-effects. Specific targeting molecules are available or under development and offer possibilities for combination treatments in CNV secondary to AMD.

Another approach to combination therapy would be to add photodynamic therapy (PDT) to an anti-VEGF regimen. We don’t have any information at present to suggest this may be worthwhile in terms of visual acuity outcomes, but there are anecdotal reports of a decreased frequency of anti-VEGF injections needed in patients treated with concurrent PDT.  There are several reasons to consider combination treatments: 1) improvement in visual acuity outcomes, 2) decreased treatment frequency, and 3) the possibility of decreased total risk or side-effects. The targeting of additional growth factors may help in improving visual function over what anti-VEGF agents can achieve in isolation. The addition of PDT to anti-VEGF agents may help in realizing goal number 2—that is, reducing the number or frequency of treatments. To date, combination therapies appear to have the summation of the risks associated with the component treatments (not fewer risks), making goal number 3 elusive at present.

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