Degenerative vision loss significantly impacts a patient, but many find the treatment required to stabilize or improve vision — monthly injections into the eye — a huge turnoff. For that reason, a one-time gene therapy could change the course of the disease for many patients.
Regenxbio and pharma partner AbbVie are on their way to a potential solution with the retinal disease gene therapy candidate ABBV-RGX-314, designed to treat “wet” or neovascular age-related macular degeneration and diabetic retinopathy in one go. The companies recently published results from a phase 1/2a dose-escalation study in wet AMD patients, revealing most patients’ vision either improved or was stable after two years.
Wet AMD is a degenerative disease typically caused by leaking eye vessels that can lead to blindness, with about 200,000 new cases in the U.S. each year. While only about 10% of cases of AMD — which affects roughly 20 million people in the U.S. — are classified as “wet” versus “dry,” it accounts for 90% of legal blindness associated with the disease.
With ABBV-RGX-314, the companies hope to reverse wet AMD vision loss by producing an anti-vascular endothelial growth factor A (VEGF-A) protein response. They’re still enrolling patients across two pivotal trials — a U.S.-based Atmosphere trial and a global study called Ascent — and are shooting to start regulatory submissions in the U.S. and EU by late 2025.
"The big unmet need is to prevent patients from developing ... blinding complications."
Dr. Steve Pakola
Chief medical officer, Regenxbio
Although current treatments for wet AMD require patients to receive repeated injections, which many are unwilling to do, they’re still big business. One of the leading AMD anti-VEGF drugs, Regeneron’s Eylea, was approved in 2011 and reached sales of nearly $5.9 billion in 2023.
The gene therapy also holds potential for diabetic retinopathy, which can affect as many as a third of diabetics, Dr. Steve Pakola, chief medical officer at Regenxbio, said. Regenxbio is currently conducting a phase 2 study using minimally invasive delivery of ABBV-RGX-314 in diabetic retinopathy.
Regenxbio is hedging its bet that a one-time gene therapy producing a sustained anti-VEGF reaction will change the game in retinal diseases. Here, we caught up with Pakola, who is leading Regenxbio’s wet AMD and diabetic retinopathy program.
This interview has been edited for brevity and style.
PHARMAVOICE: What is the potential impact of the drug if it gets approved down the road? CEO Ken Mills called it a ‘multibillion-dollar’ opportunity.
DR. STEVE PAKOLA: The anti-VEGF market for treatment of VEGF-driven retinopathy, like wet AMD and diabetic retinopathy complications, like [diabetic macular edema] and another condition called retinal vascular occlusion, is over $10 billion, and is projected to keep growing to a $20 billion market. So clearly, there's a need for these anti-VEGF agents, and the unmet need is how you can make them more sustainable so the initial gains can be maintained — because of the unsustainability of repeated injections with the available therapies, patients then lose vision. We certainly believe from a business standpoint, as [Mills] has mentioned, this definitely fits the bucket of a multibillion-dollar opportunity. And we see validation of that because one of the biggest biopharmaceutical companies in the world [AbbVie] shares our enthusiasm and belief in both the subretinal route of administration as well as the suprachoroidal route.
Why are you looking at two routes for administration of ABBV-RGX-314?
The first route we evaluated was subretinal delivery, and we started with that route of administration because that's the most clinically validated. That has traditionally been the gold standard for achieving safe and effective transduction and expression in gene therapy for treatment of retinal diseases. We decided to start with the tried-and-true subretinal approach. We've seen very good results in our phase 1/2 study not only in the two-year followup but even in results out to the four-year follow-up since completion of the main portion of the study. That's what allowed us to advance that first route of administration into pivotal development, along with our Big Pharma partner AbbVie. This pivotal program is enrolling 1,200 patients with wet AMD around the world [and] is the largest clinical development program ever conducted for in vivo gene therapy.
One aspect of subretinal delivery is, although it's the most validated way to deliver gene therapy safely and effectively, it does involve a surgical procedure before you actually inject the gene therapy. Our view was to expand optionality — wouldn't it be great if you could have a one-time gene therapy [that you] actually could do in the clinic? We evaluated all the potential routes for non-surgical delivery approaches, and the two options available are either intravitreally or suprachoroidal administration. From a safety standpoint, we believe suprachoroidal delivery was a better route because similar to subretinal administration, the suprachoroidal space is compartmentalized. So you can keep the gene therapy localized to the target tissue, the retina, without having diffusion to off-target tissues.
What are some of the highlights of the Lancet study that have helped inform the pivotal study stage?
First and foremost, we saw excellent safety and tolerability, and we also saw a dose response in terms of pharmacokinetics. We could actually take fluid from the eye and measure the therapeutic protein [that] would show not only were we getting transduction, but we were getting efficient expression of the therapeutic protein within that increasing dose. For wet AMD, one of the nice things is you can assess for endpoints that show whether the drug is working, and actually be able to treat the patients in terms of retinal thickness, which is a way to measure disease activity. But also, we care about whether you can maintain disease control and stability of visual acuity. Can you do that without the need for these patients to continue to get frequent injections? The patients who were enrolled in the study were very difficult-to-treat wet AMD patients who were getting lots of injections into their eyes. What we were able to show in the Lancet publication was after two years of treatment, not only was it safe and effective and not only did we see a dose response in terms of PK measurement of therapeutic protein, but this was actually translating into achieving the results that we wanted to see at the end of two years.
What could be the impact of this drug on the diabetic retinopathy side?
What's garnered the most excitement in the retina community in the suprachoroidal delivery program has been the results that we've seen in the diabetic retinopathy study. What's exciting here is, similar to in wet AMD, we know that repeated anti-VEGF injections can successfully treat diabetic retinopathy and its complications like diabetic macular edema and proliferative diabetic retinopathy. And certainly once you develop those complications, patients are routinely treated with repeated anti-VEGF injections. The big unmet need is to prevent patients from developing those blinding complications. Repeated anti-VEGF injections into the eye can do that, but the problem is retina specialists and their patients are not signing up for this because of the significant treatment burden, to continue to get these injections indefinitely to stave off these complications.
Before you develop the vision threatening complications with the blinding complications, the patients are basically asymptomatic. So the only way to really fill this unmet need is to have a one-time in-office treatment that would allow you to have sustained anti-VEGF activity and not need to get the unsustainable, repeated injections.
