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 responded to vascular endothelial growth factor (anti-VEGF) therapy experienced visual improvements without additional injections in the 6 months after treatment with gene therapy, explained Charles C. Wykoff, MD, PhD, director of research at Retina Consultants of Texas; Research Chair, Retina Consultants of America; and Vice Chair of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital.
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What is the latest data on RGX-314 in wet AMD to be presented at the 2023 Angiogenesis, Exudation, and Degeneration meeting?
RGX-314 is an intriguing gene therapy that has been studied for many years in both wet AMD and, more recently, diabetic retinopathy. And specifically, in this program, in this Phase 2 dataset, we are talking about the subretinal delivery of RGX-314 administered in the operating room during vitrectomy. In this context, these are patients with wet AMD. They are all patients who have responded to anti-VEGF therapy. They had multiple injections on average—an average of 22 injections previously and an average of 6 injections about the year prior to enrollment in this study.
The goal of this study was of course to examine anatomy, function and safety, but the actual core objective of this phase 2 study was to actually compare two different production methods for RGX-314. And the reason this is so important at this point is that RGX-314 has now been evaluated in multiple clinical trials and is now in pivotal trials with potential commercial access and potential FDA approval in the next few years aspire years. These pivotal studies will be included. Because of this, there has been a transition from a research and clinical process production style of RGX-314 to a much more scalable, consistent production method called the bioreactor process. This phase 2 pharmacodynamic study was truly designed to compare these two production processes [bioreactor and hyperstack] for RGX-314. That was sort of the core message of this study looking at the clinical outcomes and protein production of RGX-314 produced by these two methods.
The other learning we get from this phase 2 study is that the inclusion criteria, the follow-up criteria, and the surgical approach were all almost identical to what will be used in the pivotal study. It’s kind of a little taste of what we can expect from a safety, anatomical and functional result in the pivotal studies. But again, this is a phase 2 study that is really designed to compare 2 production methods.
To substantiate that a bit, RGX-314 is being made as a gene therapy to create a ranibizumab-like molecule. It’s an anti-VEGF protein that’s produced – it’s a Fab, which is very similar to ranibizumab. And RGX-314 has now been administered both suprachoroidally — a procedure used in the office to treat both diabetic retinopathy and wet AMD and ongoing Phase 2 programs — and then subretinally administered in the operating room in multiple studies.
I would say in this study that these are some of the most stubborn wet AMD eyes we have. And the reason I say that is to be eligible for the study you had to be anti-VEGF responsive and also have had prior anti-VEGF injections. So they were really looking for patients with persistent pathologic macular edema responsive to anti-VEGF injections to participate in this study. Once they responded to anti-VEGF, they were taken to the operating room, vitrectomy performed, and subretinal RGX-314 administered. From there, these patients were then observed monthly and withdrawn as necessary if disease activity recurred.
So far we have 6 month results for the high dose cohort. There were 4 cohorts in this study. The first looked at a high dose and the second 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 over 6 months for the first 2 cohorts: one is the bioreactor and the other is the hyperstack process for the high dose cohorts.
If we look at this data – just to go through this data at a high level – we see very strong results for visual acuity. We are actually seeing a vision gain in both arms that you might not expect in a previously treated population. But they gained 8.6 and 3.2 middle letters in the Bioreactor and Hyperstack cohorts. And then, from an anatomical point of view, we really see relative stability post-surgery with the central retinal thickness over time over 6 months. If we look at the percentage of patients who remained rescue injection-free, in the bioreactor and hyperstack processes, that percentage was 60% to 73%.
These are patients who received an average of about 6 injections on an annual basis in the previous year and now 60% to 73% of them will not receive any more injections in the next 6 months. It is a dramatic drop in treatment frequency for the vast majority of these patients. And perhaps more importantly, in a study of its size, the security was very reassuring.
The last point I want to make about the results is that the primary goal here was to assess the production of aqueous humor proteins. 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 to what you would expect based on the previous Phase 1/2 data and so far reassuring from an efficacy and safety perspective.