Intravitreal Gene Therapy for Wet AMD

Carl Regillo, MD: We can carry on with that theme of durability; the ultimate durable type of anti-VEGF treatment might be gene therapy. There is a lot of excitement. It’s only in phase 1, and while it’s moving along, the data we have are only from phase 1. Tell me, there are a couple of programs, can you tell me about gene therapy for wet AMD [age-related macular edema]?

Diana Do, MD: Gene therapy is a very exciting new field for retina. In wet AMD, the goal of gene therapy is not specifically to replace a defective gene, but the aim is to insert a viral vector that delivers a gene encoding for an antibody that could inhibit VEGF. The VEGF inhibitor is produced within the eye, and therefore would theoretically decrease the need for injections because the eye would be already producing an antibody to inhibit vascular endothelial growth factor. There are several programs underway in clinical trials. One of them is testing RGX-314 gene therapy. It’s being evaluated in phase 2 clinical trials, and it can be delivered either as a surgical subretinal injection, or it’s being evaluated as a clinic-based suprachoroidal injection. The clinical trials are evaluating the efficacy and safety of RGX-314.

Also recently, ADVM-022 is being evaluated as a gene therapy. This is unique because it’s an office-based intravitreal injection of this gene therapy. Although the early phase 1 clinical trials were quite promising, more recently there was a pause in their phase 2 clinical trial in patients with diabetic macular edema [DME] because in the highest dose of ADVM-022, a subject developed intraocular inflammation, low eye pressure, and decreased vision. That is being evaluated right now. I think gene therapy is exciting. It’s still in its infancy, and of course we will have to determine the long-term safety effects of gene therapy in wet AMD. Carl, what are your thoughts about gene therapy?

Carl Regillo, MD: It’s super exciting. It’s potentially “one and done” treatment for many of our patients, but in reality, 1 administration of gene therapy is not likely to eliminate all anti-VEGF injections. But it could potentially significantly reduce; there could be some patients who never need another injection, which the prospect of that is wonderful for our patients. That will certainly not only decrease burden but maximize the vision gains over time. They are 2 very different programs, and like you said they are looking really good coming out of phase 1 in terms of accomplishing that. Big reductions, and these are patients who have been getting frequent treatment injections and then gene therapy administered. This is maintenance phase, like the Port Delivery System trials. We saw some patients not even getting or needing another intravitreal anti-VEGF injection for a year or two, and that’s in both programs. They’re looking like they’re performing as we hope in that sense, disease control with very few supplemental intravitreal injections. 

Safety issues: a surgical approach with RGX, for example, can have complications. The suprachoroidal approach is really new, very interesting; it’s not something we do in practice but it has been done to deliver steroids in that way. We know it works in that regard, but how well it’s going to work as gene therapy we just don’t know. That’s in phase 2 testing. And the subretinal approach, the original approach with RGX, is now moving into phase 3. From 1 to 3, we’re speeding along, and that’s looking very promising to be able to do that. 

You mentioned ADVM-022, the intravitreal injection, that too in the optic neovascular AMD phase 1 study performed beautifully. The inflammation was common but not a major issue because it was very well controlled, typically mild, and steroid eye drops seem to be all that was necessary to keep it in check, and patients were doing really well. That very recent adverse event you’re referring to in the DME study was more than what we had been seeing in the wet AMD study, so we don’t know if it is unique to that disease or that particular patient. Time will tell, we’ll have that sorted out, but I think both approaches are looking really good. ADVM-022 is also looking into going to phase 3 for wet AMD within the next year. Those are really moving along. We used to think that was on a 4- or 5-year horizon, but it actually could be sooner.

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Transcript Edited for Clarity