When the FDA approved Spark Therapeutics’ Luxturna in December 2017, gene therapy became a household concept. Chatter about gene therapy curing blindness became hot fodder at dinner tables and watering holes nationwide. While more gene therapies have been approved in the past six to seven years, there has been little movement in the eye disease space using this therapeutic modality. 

REGENXBIO and their eye care program partner, AbbVie, have published two-year data from their first-in-human gene therapy study in patients with neovascular age-related macular degeneration (nAMD), better known as wet AMD. Published in The Lancet, the Phase I/IIa trial (NCT03066258) data shows safety and efficacy for subretinal injection of ABBV-RGX-314—an AAV vector containing a gene encoding for a monoclonal anti-VEGF antibody fragment.  

Steve Pakola
Steve Pakola, MD, chief medical officer at REGENXBIO

“This data was strong enough and ticked up the key boxes to allow us to proceed into [Phase III] pivotal development,” Steve Pakola, MD, chief medical officer for REGENXBIO, told GEN Edge 

“Based on this data, we created a global strategic collaboration with AbbVie to start a 1,200-patient pivotal program. This is the largest in vivo gene therapy program ever conducted. And, with AbbVie’s help, we’ve gone global—we’re enrolling patients worldwide. Everything is lined up for BLA and European submissions in late 2025 and early 2026.” 

The study was led by Peter Anthony Campochiaro, MD, director of the retinal cell and molecular laboratory and professor of ophthalmology at Johns Hopkins Medicine. This one-time gene therapy treatment has the potential to become the new standard of care for nAMD—the largest indication for gene therapy to date, which has enormous market implications. AbbVie paid $370 million for rights to the candidate, ABBV-RGX-314, in 2021. 

Sight for sore eyes 

Over the past couple of decades, repeated anti-VEGF injections have been transformational in treating patients with AMD. But after the initial excitement over the therapy, Pakola said the celebration died down when both providers and patients came face-to-face with the reality of repeated eye injections, which typically require the patient (and sometimes a caregiver) to take repeated time away from work due to the procedure. 

“No matter how good the results are in clinical trials, that’s not what is happening in the real world,” said Pakola. “In a clinical trial setting, you pick the best patients; they’re followed super close, and if they don’t show up, you follow up with them because you don’t want to lose patients—they don’t miss those injections. But suppose you speak to clinicians in the real world and even the large studies that have been done of follow-up of these patients after they leave that trial or patients who have been treated in commercial databases in the real world. In that case, patients aren’t getting anything close to the number of anti-VEGF injections that they need, and so they’re losing vision.” 

REGENXBIO created RGX-314 as a one-time gene therapy for long-term anti-VEGF production to lower the treatment burden, slow disease progression, and prevent blindness.    

Durable (aqueous) humor levels 

From May 2017 to May 2019, 42 participants received a single RGX-314 injection and were followed for two years. REGENXBIO reported one serious adverse event that was possibly related to RGX-314: a patient with pigmentary changes in the macula with severe vision reduction 12 months after injection. Besides that, they reported asymptomatic pigmentary changes and no clinically determined immune responses or inflammation beyond that expected.

In the Phase I/IIa trial, RGX-314 showed safety and tolerability across a range of doses and good treatment outcomes, including improved visual acuity. Measurements of anti-VEGF levels in the patients’ aqueous humor—the fluid in the front of the eyes—have shown the apparent durability of RGX-314, which excites Pakola particularly. 

“We proved that we’re getting transduction and expression of the therapeutic protein, and we also measured this over time, showing that the protein expression is sustained,” said Pakola. “This isn’t in the publication (because the main study was two years), but in any gene therapy, patients are rolled over into long-term follow-up studies for safety, which, in our setting, allows us to see if there is continued durability. We’re seeing patients in the therapeutic dose range who maintain this benefit of stability to improve vision through four years so far and maintain the dramatic reduction in treatment burden.”  

Digging deeper  

While there has been much movement in the genome engineering field toward using nonviral delivery methods for genes, many of the approved gene therapies rely on viral vectors, particularly adeno-associated virus (AAV). While LUXTURNA and Zolgensma used AAV2 and AAV9, respectively, REGENXBIO chose to use AAV8 for RGX-314. Pakola said that the publication of their study in The Lancet is “strong clinical validation” for REGENXBIO’s proprietary AAV vectors. 

Like Luxturna, RGX-314 is delivered to the retina by subretinal injection. While subretinal injections offer improvements compared to intravitrial injections, which invariably lead to inflammation and the transduction of unintended eye structures, the efficacy of transduction into the retina is limited. Injections into the suprachoroidal space, which sits posterior to the subretinal space, have been shown to provide increased transduction efficacy throughout the retina. Also, suprachoroidal administration could enable physicians to administer the gene therapy in their offices rather than requiring patients to go to operating rooms. 

As RGX-314 worked well in the subretinal space, REGENXBIO is confident in the potential for suprachoroidal injections for both nAMD and diabetic retinopathy at the same time, which are in Phase I/II stages of clinical investigation. Earlier this year, REGENXBIO reported interim data for their clinical trials with suprachoroidal injections, demonstrating successful safety and tolerability.  

With the market for currently approved drugs for nAMD already in the billions, barring any major derailment, RGX-314 looks like a blockbuster. 

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