NEW YORK – An experimental gene therapy that Regenxbio and AbbVie are developing as a treatment for multiple retinal diseases continues to advance within wet age-related macular degeneration (AMD), and the companies say they could begin seeking regulatory approval within two years.
Wet AMD is a late-stage eye disorder marked by severe and rapid vision loss due to the abnormal growth of blood vessels in the retina, stimulated by an excess of vascular endothelial growth factor (VEGF) proteins. The condition is known as "wet" AMD because the blood vessels leak fluid and blood within the eye, damaging it and leading to vision issues. Wet AMD always starts as the more common and less severe form of the disease, dry AMD.
The gene therapy candidate, ABBV-RGX-314, aims to deliver a gene that encodes a therapeutic protein that counteracts VEGF, explained Steve Pakola, chief medical officer at Regenxbio.
"That approach allows you to address major patient populations, like wet AMD and diabetic retinopathy," he said, referring to a diabetes complication in which VEGF also has a role.
Regenxbio and AbbVie are developing ABBV-RGX-314 as a potential treatment for chronic retinal conditions within a development and commercialization agreement they inked in 2021. In addition to wet AMD, the gene therapy is also being tested in a Phase II trial for diabetic retinopathy, and the companies expect to initiate a pivotal trial in that setting next year.
Within wet AMD, investigators are enrolling patients into two Phase III pivotal trials, ATMOSPHERE and ASCENT. The companies expect data from these clinical trials to support regulatory applications with the US Food and Drug Administration and the European Medicines Agency in the first half of 2026.
Under the 2021 deal, AbbVie paid Regenxbio $370 million upfront. AbbVie is leading global clinical development of the gene therapy, which was then known as RGX-314, and is the sponsor of the two Phase III pivotal trials. AbbVie and Regenxbio will share equally in profits from net sales of a potentially commercialized product in the US, and Regenxbio will participate in US commercialization efforts. AbbVie will pay Regenxbio tiered royalties on net sales outside of the US.
Regenxbio may receive up to $1.4 billion in additional payments tied to potential development, regulatory, and commercial milestones.
Rockville, Maryland-headquartered Regenxbio has focused on the US and doesn't have commercialized products yet, although it does have other candidates in later stage clinical development, including a gene therapy for mucopolysaccharidosis type II, for which it plans to submit a biologics license application to the FDA this year. AbbVie made sense as a partner on the retinal disease gene therapy program because of its late-stage clinical development and commercialization experience and its global footprint, Pakola said.
"Our goal as a company who has traditionally focused on executing in the US was to really find a partner who could accelerate and broaden the reach that [ABBV-RGX-]314 could have," he said. For example, AbbVie set up ASCENT as a pivotal trial with international sites in Canada as well as in the US.
In the randomized, controlled Phase IIb/III ATMOSPHERE and Phase III ASCENT trials, patients receive one of two dose levels of ABBV-RGX-314, which Regenxbio has said is a potential one-time treatment for wet AMD.
Patients in the control arms receive standard care of anti-VEGF injections every few weeks that aim to stop the growth of new blood vessels. In ATMOSPHERE, the control group receives Genentech's Lucentis (ranibizumab) every 28 days, while in ASCENT, the control group receives Regeneron Pharmaceuticals' Eylea (aflibercept) monthly for three months, and then every eight weeks. Both of these drugs are administered using an intravitreal injection in an office setting.
The companies plan to enroll 1,200 patients across the two trials, according to Pakola, and are measuring average change in best-corrected visual acuity (BCVA) after about a year.
"The goal is to show non-inferiority to these very intensive on-label, frequent dosing regimens," Pakola said. He added that although standard care does improve vision — and likely will show improvements within a controlled clinical trial — it requires frequent injections and doesn't stop patients' vision from deteriorating in the long term if they stop treatment.
However, a gene therapy might be able to after only a single injection.
"No one wants to get their eyeball injected over and over again," Pakola said. "That's really what existing therapies require."
ABBV-RGX-314, injected underneath the retina, uses an adeno-associated virus serotype 8 vector to deliver a transgene that encodes an antibody fragment that expresses a protein designed to bind to and neutralize VEGF-A, a specific protein that plays a role in wet AMD and is encoded by the VEGFA gene. This is expected to inhibit growth of the leaky blood vessels.
While the two pivotal trials are testing a version of ABBV-RGX-314 that's injected subretinally, the gene therapy is also being developed in a suprachoroidal formulation, which is delivered between the layers of the eye, in a Phase II trial.
Subretinal injection has the most precedent as a route of delivery for a retinal disease treatment, Pakola said. However, it requires an outpatient surgical procedure to administer.
By contrast, a suprachoroidal injection could be delivered within an office setting.
"We've seen excellent safety to date, and we've seen proof of concept across a range of doses," Pakola said of the suprachoroidal formulation. In interim results from the Phase II AAVIATE trial, which Regenxbio shared earlier this year, the suprachoroidal version of the gene therapy has been tolerated well in more than 100 patients who received one of three doses without any drug-related serious adverse events.
There are other drugmakers nearing late-stage clinical development of their own wet AMD gene therapies that could be delivered within an office setting. 4D Molecular Therapeutics, for example, plans to kick off a pivotal Phase III trial of its intravitreal gene therapy for wet AMD, 4D-150, early next year and is also preparing for a Phase I trial of 4D-175, an intravitreal gene therapy for another advanced form of AMD known as geographic atrophy. Adverum Biotechnologies is testing ixoberogene soroparvovec as an intravitreal gene therapy treatment for wet AMD in a Phase II trial and has said it expects to share details about a pivotal Phase III trial design this year.
Further, PulseSight Therapeutics earlier this year launched as a gene therapy company focused on severe retinal diseases, with two candidates in investigational new drug (IND)-enabling studies: PST-809 for wet AMD and PST-611 for geographic atrophy.
Results for Regenxbio and AbbVie's subretinally administered ABBV-RGX-314 have been promising so far. Data from the first-in-human open-label Phase I/IIa trial, sponsored by Regenxbio, were published in the Lancet in the spring, and investigators found that patients who received the gene therapy had stable or improved vision for up to two years after treatment, as measured by BCVA, which measures the highest level of vision a patient achieves with corrective lenses.
For the study, 42 patients with wet AMD received a single dose of the gene therapy at one of five dose levels in just one eye. The average age for participants was 80 years old.
After treatment, patients returned for follow-up visits one day and one week after receiving the gene therapy, and then monthly for two years. During these visits, physicians could administer standard-of-care anti-VEGF drugs to patients as needed, for example, if their visual acuity declined due to the accumulation of fluid in the eye.
Investigators observed that patients who received the third-highest dose or higher had stable or improved BCVA, including patients who did not receive supplemental anti-VEGF injections during the last year of the study. Most patients in the three highest dose cohorts had few or no supplemental anti-VEGF injections and experienced a "striking reduction" in anti-VEGF injections when comparing the years before and after they received the gene therapy, the study authors wrote.
These patients also experienced stable or improved central retinal thickness and sustained levels of the anti-VEGF protein expressed by the gene therapy.
Improvements were maintained for up to four years, Pakola noted. Although the study ran for two years, investigators in a follow-up study continue to monitor patients through five years post-treatment.
The gene therapy was generally tolerated well, according to the study authors. Every participant experienced at least one treatment-emergent adverse event; however, most were mild. The most common of these adverse events were post-procedure conjunctival hemorrhage and retinal pigmentary changes.
There were 20 serious adverse events across 13 of the 42 participants, one of which was possibly attributed to the gene therapy: pigmentary changes with severe vision reduction a year after treatment with the highest dose. Retinal pigmentary changes were observed in 27 other patients who received lower treatment doses but at levels determined to be mild or moderate, without symptoms or reduced visual acuity.
"The pathogenesis of the dose-related retinal pigmentary changes that were observed is not completely understood," the study authors wrote, "but increased incidence with increased RGX-314 dose suggests a drug or vector association."
Two participants died during the study, but investigators determined the deaths were unrelated to the treatment.
AbbVie also launched an open-label study in which patients who received ABBV-RGX-314 in one eye during the Phase I/IIa trial can receive the gene therapy in their other eye. Investigators will monitor safety, immune responses, and efficacy of the gene therapy during this study to support inclusion of bilateral use in a potential product label. Most patients with wet AMD have it in both eyes, though the level of disease severity may differ.
Pakola said they are hoping that ABBV-RGX-314 can be a one-time treatment. However, more evidence is needed on the durability of the gene therapy for various patient groups to understand whether additional treatment will be needed and if re-dosing in the same eye is possible. The clinical trial evaluating the gene therapy in a second eye will provide some early insight into whether a second dose to the same patient is possible, albeit in a different eye.
"The big unmet need is a sustainable treatment option," Pakola said, "where you don't need to give the injections into the eye nearly as frequently."