Disclosures: Singh reports he is a consultant to Alcon, Carl Zeiss Meditec, Genentech/Roche, Novartis and Regeneron. Do reports she is a consultant to Boehringer Ingelheim, Genentech/Roche, Kodiak Sciences, Novartis and Regeneron.
September 22, 2020
3 min read

What safety concerns relate to the gene therapy approach to vascular retinal diseases?

Disclosures: Singh reports he is a consultant to Alcon, Carl Zeiss Meditec, Genentech/Roche, Novartis and Regeneron. Do reports she is a consultant to Boehringer Ingelheim, Genentech/Roche, Kodiak Sciences, Novartis and Regeneron.
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Click here to read the Cover Story, "Strategies for sustained anti-VEGF delivery aimed at consistent dosing, durability."


Gene therapy cannot be switched off or modulated

There are long-term concerns about gene therapy for a number of reasons.

First, across the disease stages, there are various levels of anti-VEGF needed. Although age-related macular degeneration appears to be a chronic condition, a small percentage but significant number of patients do not need chronic therapy and can be managed with a low number of injections.

Rishi P. Singh, MD
Rishi P. Singh

In the CATT trial, 14% of patients on average received one or two injections over a 2-year period, and other studies confirm these findings. Imagine if those patients had undergone a surgical intervention to provide sustained VEGF inhibition; wouldn’t there be a concern about unnecessary overtreatment? In the diabetic population, patients are usually treated intensively over 2 or 3 years. However, the 5-year data of Protocol I and some other studies showed that there is little anti-VEGF use in years 4 and 5. Essentially, with gene therapy, you would be suppressing VEGF in those patients for no benefit and with the risk for causing adverse events.

Second, we are not clear about the systemic bioavailability of this drug. Acutely, you are treating the vitreous cavity, but chronically, you are affecting the circulation system, while normal vasculogenesis or angiogenesis is needed for various conditions. In the event of a stroke or a heart condition, vasculogenesis is a lifesaving mechanism that creates collateral vessels to maintain blood flow.

Gene therapy cannot be switched off or modulated, and we do not know what the risk for adverse events is in that population of patients 3, 4 or 5 years down the road. From the local level of the macula, we suspect that chronic anti-VEGF therapy leads to macular atrophy, and macular atrophy is even worse than neovascular AMD because there is no treatment. Most patients who are on chronic anti-VEGF therapy have lost more vision because of macular atrophy than because of uncontrolled neovascular AMD. A major risk of gene therapy is that we could have a population of patients that get a lot of macular atrophy and decline of vision over time.

One final consideration is in relation to socioeconomic factors. Our current anti-VEGF therapy is highly beneficial and cost-effective, especially if we take into account the bevacizumab population. Gene therapy has a much higher cost, with not necessarily an incremental benefit. Luxturna (voretigene neparvovec-rzyl, Spark Therapeutics) treats a rare condition at the cost of $1 million per dose. For sure, we cannot expect to spend that amount on our vast AMD population. No health care system, even in the most developed countries, could provide access and coverage for such an expensive treatment in a large population that needs long-term chronic therapy.

Rishi P. Singh, MD, is an OSN Retina/Vitreous Board Member.


Safety analyses are ongoing

Wouldn’t it be terrific if we had a treatment for chronic retinal vascular diseases such as neovascular age-related macular degeneration that could provide sustained VEGF inhibition and prevent undertreatment of this vision-threatening eye disease?

Diana V. Do, MD
Diana V. Do

What if this treatment could be administered only once, yet still provide effective control of the ocular disease? Ocular gene therapy has the potential of positively changing the management landscape for neovascular AMD and other chronic retinal vascular diseases.

Published studies have shown that the high treatment burden of neovascular AMD, including frequent injections and office visits, means there are challenges to achieving optimal outcomes. Frequent monitoring and chronic treatment with anti-VEGF agents are significant challenges for older patients. Often, they cannot adhere to frequent visit and treatment schedules, and this results in suboptimal visual acuity gains compared with those achieved in clinical trials. It makes sense to evaluate new technology that can provide sustained levels of a therapeutic medicine inside the eye.

Gene therapy is an exciting new approach. The key principle of gene therapy is to put corrective genetic material into cells to treat genetic disease or deliver a gene that allows the body to produce a therapeutic protein to treat a specific disease. In inherited retinal diseases, gene therapy has been an effective, safe and game-changing treatment for RPE65-mediated retinal dystrophy. For neovascular AMD, the gene therapy approach involves administering a viral vector to constantly produce the therapeutic protein, a monoclonal antibody fragment that inhibits VEGF. The expressed antibody protein neutralizes VEGF activity, thereby reducing leakage from abnormal blood vessels. Early-stage clinical trials of candidate agent RGX-314 (Regenxbio) using a novel AAV8 vector has demonstrated that RGX-314 is well tolerated in more than 40 subjects with reduction in anti-VEGF injection burden in cohorts 4 and 5. Ongoing safety data are being analyzed, and an additional phase 2b study using an office-based suprachoroidal injection technique is underway. In addition, ADVM-022 (Adverum Biotechnologies) is an intravitreal administration of recombinant AAV to inhibit VEGF. The initial phase 1 study has shown bioactivity with no patients needing rescue injections of anti-VEGF agents. There have been reports of mild to moderate ocular inflammation that has been controlled with topical corticosteroids. Additional clinical trials are being planned to evaluate safety and efficacy.

If the clinical trials for gene therapy candidates demonstrate efficacy and long-term safety, ocular gene therapy could be a viable treatment option for patients with neovascular AMD and prevent undertreatment of this prevalent condition.

Diana V. Do, MD, is from Byers Eye Institute, Stanford University School of Medicine.