Conceptually, giving anti-VEGF injections to a high-risk nonexudative AMD patient to prevent progression to wet AMD makes intuitive sense. One would expect that there would be no way for choroidal neovascularization (CNV) to develop or, at worst, this would lead to better visual outcomes in the long run, if CNV did develop. Unfortunately, to date, no study of a prevention therapy has been successful. Proponents of the approach would argue that these studies were not done without true antiangiogenic agents.

Enter the PRO-CON study, a prospective, single-masked, randomized, investigator-sponsored study investigating prophylactic quarterly intravitreal aflibercept (Eylea; Regeneron) vs sham injection to prevent conversion to wet AMD in high-risk dry AMD eyes. Interim results showed a conversion rate of 9% in the sham arm, and 6% in the aflibercept arm for a 33% risk reduction. In this issue, we discuss the 2-year results presented at the American Society of Retina Specialists (ASRS) meeting in Chicago by Jeffrey Heier, MD. Unfortunately, the results did not show an increasing delta over time. Moreover, the P value was P=.98, with no shift in the Kaplan Meier curves to indicate that results would improve over an even longer time.

In the PREVENT study that investigated sham vs q3-month ranibizumab (Lucentis; Genentech), the results were identical, with a 9% conversion rate for sham and 7% for quarterly ranibizumab. And quarterly treatment with either drug did not drastically reduce conversion rates. Also, even my patients with wet AMD do not want to come in for monthly or bimonthly injections, so to ask a patient with 20/20 visual acuity to come in more frequently is foolish and not cost effective. Moreover, we know that the second eye does better from a visual acuity standpoint.

As chair of the DRCR Retina Network, Dan Martin, MD, forecasted these results. The DRCR Retina Network looked very carefully at the power calculations required to perform a prevention study using an anti-VEGF agent. Their CNV prevention calculations indicate that 95% of patients would have 20/40 or better vision with no preventive treatment, and 98.8% would be better than 20/40 with a 75% prophylaxis rate. This would mean that preventing 1 eye from being worse than 20/40 would cost $350,000 if using quarterly aflibercept (an Institute for Clinical and Economic Review assessment of $1.3 million) — simply not feasible.

This does not mean we will never have a way to prevent CNV conversion. There are several therapies in clinical trials currently, including Genentech’s Port Delivery System, Kodiak Sciences’ KSI-301, Adverum’s intravitreal gene therapy with aflibercept, and Regenxbio’s gene therapy with an anti-VEGF monoclonal antibody fragment. If they work, these long-acting anti-VEGF systems may offer advantages for prevention. It is also possible that anti-VEGF agents are simply permeability drugs and not truly antiangiogenic, or that VEGF is not critical to the development of CNV. In this scenario, we need to come up with a different pathway to uncover the holy grail of preventing wet AMD. RP

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