AbbVie and Regenxbio bet on one-time gene therapy, aiming at a 'multi-billion dollar opportunity' in the field of vision loss
The gene therapy ABBV-RGX-314, co-developed by Regenxbio and AbbVie, aims to address wet age-related macular degeneration (wet AMD) and diabetic retinopathy through a one-time treatment. Latest data from the Phase 1/2a study show that vision improved or stabilized in most patients after two years. If approved, the therapy could disrupt the existing anti-VEGF drug market, which already generates annual sales exceeding ten billion dollars.
Degenerative vision loss profoundly impacts patients, yet many are deterred by the treatment required to stabilize or improve vision—monthly injections into the eye. Therefore, a one-time gene therapy has the potential to alter the disease course for many patients.
Regenxbio and its pharmaceutical partner AbbVie are moving toward a potential solution with their retinal disease gene therapy candidate, ABBV-RGX-314. The treatment is designed as a one-time therapy for "wet" (neovascular) age-related macular degeneration (wet AMD) and diabetic retinopathy. The companies recently announced results from a Phase 1/2a dose-escalation study in patients with wet AMD, showing that most patients experienced improved or stable vision after two years.
Wet AMD is a degenerative disease, often caused by leaking blood vessels in the eye, that can lead to blindness. In the U.S., there are approximately200,000 new caseseach year. Although only about 10% of AMD cases (affecting approximately 20 million people in the U.S.) are classified as "wet" rather than "dry," it accounts for90% of legal blindness。
ThroughABBV-RGX-314, the companies aim to reverse vision loss in wet AMD by generating a protein response against vascular endothelial growth factor A (VEGF-A). They are still enrolling patients in two pivotal trials—one is the U.S.-based Atmosphere trial, and the other is a global study called Ascent—and plan to initiate regulatory submissions in the U.S. and EU by the end of 2025.
"The biggest unmet need is preventing patients from developing... blinding complications."
Dr. Steve Pakola
Chief Medical Officer, Regenxbio
Although current treatments for wet AMD require patients to undergo repeated injections, which many are reluctant to accept, these treatments remain a massive business. One of the leading anti-VEGF drugs for AMD—Regeneron's Eylea, approved in 2011—generated nearly$5.9 billion。
in sales in 2023. The gene therapy also holds potential in diabetic retinopathy, a condition that can affect up to one-third of people with diabetes, said Dr. Steve Pakola, Chief Medical Officer of Regenxbio. Regenxbio is currently conducting a Phase 2 study using aminimally invasiveapproach to deliver ABBV-RGX-314 for diabetic retinopathy.
Regenxbio is betting that a one-time gene therapy producing a sustained anti-VEGF response will transform the retinal disease landscape. Here, we spoke with Pakola, who leads Regenxbio's wet AMD and diabetic retinopathy programs.
This interview has been edited for length and style.
PHARMAVOICE: If this drug is approved in the future, what is its potential impact? CEO Ken Mills has called it a "multi-billion dollar" opportunity.
DR. STEVE PAKOLA:The anti-VEGF market for VEGF-driven retinal diseases, such as wet AMD and complications of diabetic retinopathy like diabetic macular edema and retinal vein occlusion, has exceeded $10 billion and is expected to continue growing toward a $20 billion market. So, the need for anti-VEGF agents is clear, and the unmet need lies in making these agents more sustainable so that the initial efficacy can be maintained—patients subsequently lose vision because current therapies require repeated injections that are not sustainable. We certainly believe that, from a commercial standpoint, as Mills mentioned, this falls squarely within the multi-billion dollar opportunity. We see validation of this because one of the largest biopharmaceutical companies in the world (AbbVie) shares our enthusiasm and confidence in both the suprachoroidal and subretinal delivery routes.
Why consider two delivery routes for ABBV-RGX-314?
The first route we evaluated is subretinal delivery, and we started with this route because it is the most clinically validated. Traditionally, it has been the gold standard for achieving safe and effective transduction and expression in gene therapy for retinal diseases. We decided to start with the validated subretinal route. We saw very good results in the Phase 1/2 study, not only at the two-year follow-up but even at the four-year follow-up after the main part of the study was completed. This allowed us to advance this first delivery route into pivotal development, in collaboration with our pharma giant partner AbbVie. This pivotal program is enrolling 1,200 patients with wet AMD globally and is the largest in-vivo gene therapy clinical development program to date.
One aspect of subretinal delivery is that, although it is the most validated route for safely and effectively delivering gene therapy, it requires a surgical procedure before the gene therapy is actually injected. Our perspective was to expand the options—wouldn't it be better if there were a one-time gene therapy that could actually be done in the clinic? We evaluated all potential options for non-surgical delivery routes, and the two available choices were intravitreal or suprachoroidal administration. From a safety standpoint, we believe suprachoroidal delivery is the better route because, similar to subretinal administration, the suprachoroidal space is compartmentalized. Therefore, the gene therapy can be confined to the target tissue (the retina) without spreading to non-target tissues.
How do some of the highlights from The Lancet study inform the pivotal phase?
First, we saw excellent safety and tolerability, and we observed a dose response in pharmacokinetics. We were actually able to take fluid from the eye and measure the therapeutic protein, which not only showed that we achieved transduction, but also that as the dose increased, the expression of the therapeutic protein was efficient. For wet AMD, one advantage is that you can assess endpoints showing whether the drug is working and be able to treat patients based on retinal thickness, a measure of disease activity. Additionally, we were concerned about whether we could maintain disease control and visual stability. Could we do this without requiring patients to continue frequent injections? The patients in the study were very refractory wet AMD patients who had received numerous intraocular injections. In our study published in The Lancet, we were able to demonstrate that after two years of treatment, it was not only safe and effective, not only showing a dose response of the therapeutic protein in PK measurements, but that this actually translated into achieving the outcomes we wanted at the end of two years.
What impact could the drug have in diabetic retinopathy?
In the retina community, the most exciting results from the suprachoroidal delivery program come from our findings in the diabetic retinopathy study. What's exciting is that, similar to wet AMD, we know that repeated anti-VEGF injections can successfully treat diabetic retinopathy and its complications, such as diabetic macular edema and proliferative diabetic retinopathy. Once these complications develop, patients are typically treated with repeated anti-VEGF injections. The biggest unmet need is preventing patients from developing those blinding complications. Repeated intraocular anti-VEGF injections can do this, but the problem is that retina specialists and their patients are reluctant to accept them because of the heavy treatment burden, requiring indefinite ongoing injections to delay these complications.
Before vision-threatening complications develop, patients are essentially asymptomatic. Therefore, the only way to truly address this unmet need is to provide a one-time, in-office treatment that can produce sustained anti-VEGF activity without subjecting patients to unsustainable repeated injections.