Irrefutable clinical and scientific data show that the best currently available for the treatment of neovascular age-related macular degeneration (AMD) is intravitreal ranibizumab (Lucentis, Genentech, Inc.) administered on a strict monthly basis. All other studies that have tried to decrease the frequency of injections, whether with a quarterly dosing regimen or an as-needed regimen, have proved disappointing.
A closer look at some of these studies, however, is valuable. For example, 20% of patients in the EXCITE study gained no vision, and 36% did not maintain vision, meaning 56% of patients did not either gain or maintain vision (Figure 1). In PIER, 34% of patients did not gain vision, and 39% of patients did not maintain vision, translating to a total of 73% of patients who did not either gain or maintain vision (Figure 2). Finally, in the SUSTAIN study, 26% of patients did not gain vision, and 21% of patients did not maintain vision; a total of 47% of patients did not gain or maintain vision (Figure 3).
TREATMENT GAPS WITH
MONOTHERAPY
Can we tell these patients apart from one
another anatomically? Currently, the answer
is no. In SUSTAIN, the optical coherence
tomography (OCT) scans of all three subgroups
were almost identical (Figure 4).
It is possible that the results from some of the earlier trials evaluating the efficacy and safety of ranibizumab foreshadowed this. In MARINA, despite strict monthly injections, at the 6-month mark, 70% of patients were still considered wet, and at the 12-month mark 56% of patients were still considered wet (Figure 5).
The reason for the treatment gap with our current monotherapy treatment model is not known; it may be the partial inhibition of the angiogenic cascade or it may be tachyphylaxis.1,2 Regardless of the reason, combination therapy may be the approach that fills these treatment gaps.
In any complicated physiologic process in medicine, such as angiogenesis, it is rare to find a process being treated with only one drug, but it is even more rare that that one drug should be aimed at a single factor in the disease process, such as vascular endothelial growth factor (VEGF). We know that there are hundreds, if not not thousands, of factors involved in angiogenesis, so it should come as no surprise that in many areas of medicine strong evidence exists to show that combination therapy is more effective than monotherapy.
ANTI-VEGF + RADIATION THERAPY
There are data from the field of oncology demonstrating
that combining anti-VEGF therapy and radiation is
highly effective in eliminating choroidal neovascularization
(CNV) tube formation when compared with either
treatment alone; triple combination of irradiation,
chemotherapy (pemetrexed), and VEGFR inhibition
(SU5416) was shown to be effective in human endothelial
and tumor cells.3
The downside to radiation is, of course, toxicity. Historically, radiation applied to the eye has been placed outside the eye, requiring a powerful ionizing radiation that is often in a toxic range.
EPIMACULAR BRACHYTHERAPY
A less toxic ionizing radiation, however, comes in the
form of beta radiation. Further, we now have new technology,
epimacular brachytherapy (Vidion ANV;
NeoVista, Newark, CA) that delivers strontium-90 beta
radiation in a targeted fashion to tissues within the eye.
The choice of radioactive source was a consideration when deciding on the design of the device in order to increase its safety. Brachytherapy, and particularly brachytherapy with strontium-90, was chosen based on its favorable characteristics for use in the intraocular compartment when treating the retina. Strontium-90 allows the delivery of a high dose of radiation. The high dose, however, is restricted to a small volume of tissue, outside of which the dose falls off rapidly. In comparing the 90% isotopes curve of x-ray delivery to brachytherapy, the overall size of the radiation field is similar, but the volume of tissue receiving the highest exposure is significantly smaller with brachytherapy (Figure 6). The smaller volume of tissue should translate into a lower threshold for damage to the retina.
EMERGING DATA
We have data from initial studies treating treatment-naïve
patients with anti-VEGF plus vitrectomy and epimacular
brachytherapy, but data are lacking for patients who,
despite numerous anti-VEGF injections, have persistent subretinal
fluid. These patients are presenting more frequently,
and not only are they difficult to treat from a clinical perspective,
but they also represent the unsustainable nature of
our current monotherapy treatment model for AMD.
The MERITAGE trial has been specifically designed to address this patient population. The sole aim of the MERITAGE study is to decrease the treatment burden by decreasing the number of injections while maintaining visual acuity. The baseline demographics are notable for the number of anti-VEGF injections required to enroll; some patients have received more than of 30 previous anti-VEGF injections, with a mean of 12.3 injections per patient. Additionally, visual acuity of the enrolled patients was good enough to either improve or deteriorate following epimacular brachytherapy.
Because we wanted to ensure that patients enrolled received the full effect of anti-VEGF, two phases were required prior to enrollment. The loading dose phase consisted of three consecutive monthly injections, and a maintenance phase consisted of either a minimum of five additional injections in the 12-month period preceding enrollment or a minimum of three additional injections in the 6 months preceding enrollment. The strict retreatment criteria included an increase in central retinal thickness by greater than 50 µm.
Although the study is still under way, initial results appear promising in terms of safety, visual outcomes, and importantly, in the reduction of number of injections required to maintain visual acuity gains and the reduction of the neovascular lesion size.
SUMMARY
In addition to MERITAGE, other studies evaluating epimacular
brachytherapy include the recently launched
GRAPE study, which is a genetic risk assessment of
patients in the MERITAGE trial, and the MERLOT trial.
MERLOT, an expansion study of MERITAGE, is being
sponsored in entirety by the National Health Service in
the United Kingdom.
Although it remains unclear what the best solution will be to address the unsustainable treatment model of monthly injections of anti-VEGF for AMD, the preliminary data for epimacular brachytherapy combined with anti-VEGF are promising, and definitive results are forthcoming.
Pravin U. Dugel, MD, is Managing Partner of Retinal Consultants of Arizona and Founding Member of the Spectra Eye Institute. Dr. Dugel states that he is a consultant to Alcon, Abbott Medical Optics, Macusight, Neovista, ArcticDx, Ora, and Regeneron, and is a minor shareholder in ArcticDx and Neovista. He is a Retina Today Editorial Board member. He can be reached via e-mail at pdugel@gmail.com.
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