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Dr Charles Wykoff Highlights the Latest Data on the RGX-314 Gene Therapy for Wet AMD


Patients with wet age-related macular degeneration (AMD) who are responsive to anti–vascular endothelial growth factor (anti-VEGF) therapy experienced visual gains with no additional injections in the 6 months after treatment with the gene therapy.

Patients with wet age-related macular degeneration (AMD) who are responsive to anti–vascular endothelial growth factor (anti-VEGF) therapy experienced visual gains with no additional injections in the 6 months after treatment with the gene therapy, explained Charles C. Wykoff, MD, PhD, director of research at Retina Consultants of Texas; chair of research, Retina Consultants of America; and deputy chair of ophthalmology for the Blanton Eye Institute, Houston Methodist Hospital.


What is the latest data on RGX-314 in wet AMD being presented at the Angiogenesis, Exudation, and Degeneration 2023 meeting?

RGX-314 is a fascinating gene therapy that's been studied now for many years, in the context of both wet AMD, and more recently in diabetic retinopathy. And in particular, in this program in this phase 2 data set, what we're talking about is subretinal delivery of RGX-314 given in the operating room during vitrectomy. In that context, these are patients with wet AMD. They're all patients who have demonstrated anti-VEGF therapy responsiveness. They've had, on average, multiple injections—on average it was 22 injections previously, and, on average, 6 injections approximately in the year before enrollment in this trial.

The goal of this trial was, of course, to look at anatomy, function, and safety, but the real core goal of this phase 2 trial was to actually compare 2 different production methods for RGX-314. And the reason this is so important at this juncture, is that RGX-314 has been studied now in multiple clinical trials, and it's now in pivotal trials, which are looking at potentially getting commercial access, potential FDA approval, within the next couple of years. Those pivotal trials are enrolling. Because of that, there was a transition from sort of the research and clinical process production of RGX-314 to a much more scalable, consistent production method called a bioreactor process. This phase 2, pharmacodynamic study was really designed to compare those 2 production processes [bioreactor and hyperstack] for RGX-314. That was sort of the core message of this study was to look at the clinical outcomes and the protein production from RGX-314 produced using both of these methods.

Now, the other insight that we get from this phase 2 trial is that the inclusion criteria, the retreatment criteria, the surgical approach, were all almost identical to what's being used in the pivotal trial. It's sort of a sneak peek as to what we might expect to see from a safety, anatomic and functional outcome in the pivotal trials. But again, this is a phase 2 study designed really to compare 2 production methods.

Then, just to back up a little bit more on that, RGX-314 is produced as a gene therapy to produce a ranibizumab-like molecule. It's an anti-VEGF protein that's produced—it's a Fab very similar to ranibizumab. And RGX-314 has been delivered now both suprachoroidally—which is a procedure given in the office for both the treatment of diabetic retinopathy and wet AMD and ongoing phase 2 programs—and then in multiple trials given subretinally in the operating room.

I would say in this trial, these are some of the most recalcitrant wet AMD eyes that we have. And the reason I say that is to get into the trial, you had to have a responsiveness to anti-VEGF injections and have also received previous anti-VEGF injections. So, they were really looking for patients with persistent pathologic macular edema that was response to anti-VEGF injections to get into this study. Once they showed an anti-VEGF responsiveness, they were then taken to the operating room, a vitrectomy was performed and subretinal RGX-314 was delivered. Then from there, these patients were observed monthly and retreated as needed if there was a recurrence of disease activity.

So far, we have 6-month outcomes for the high-dose cohort. In this trial, there were 4 cohorts. The first one was looking at a high dose and the second one was looking at a lower dose. The high-dose cohort was 1.3 x 1011 genome copies per eye, and the lower dose was about half that at 6.4 x 1010. So far, we only have primary outcome data through 6 months for the first 2 cohorts: one being the bioreactor and the other being the hyperstack process for the high-dose cohorts.

When we look at that data—just to go over that data at a high level—we see very strong visual acuity outcomes. We actually see a gain of vision in both arms, which you may not expect in a previously treated population. But they gained 8.6 and 3.2 mean letters in the bioreactor and hyperstack cohorts. And then from an anatomic perspective, we really see relative stability after surgical intervention with the central retinal thickness over time through 6 months. If we look at the percentage of patients that remained rescue injection–free, that percentage was 60% to 73%, in the bioreactor and hyperstack processes.

These are patients that have received an average of about 6 injections in the previous year on an annualized basis, and now 60% to 73% of them are receiving no more injections in the next 6 months. It's a dramatic decrease in the treatment frequency for the large majority of these patients. Then maybe more importantly, in a study of the size, the safety was very reassuring.

Then the last point I'd make about the outcomes is that the primary objective here was to assess aqueous humor protein production. We saw similar levels between the bioreactor and hyperstack cohorts at 512 and 436 nanograms per milliliter in the two cohorts. So very similar protein levels from what you would anticipate based on the previous phase 1/2 data, and reassuring from an efficacy and safety perspective so far to date.

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