RGX-314 Could Lessen Treatment Burden for Wet AMD

If it passes clinical testing, the gene therapy RGX-314 could help to alleviate the overall treatment burden for patients with wet age-related macular degeneration (AMD) via a one-time subretinal injection, according to a presentation at the 2017 American Society of Retina Specialists Annual Meeting.

An open-label phase I study is now enrolling to explore RGX-314 in patients with wet AMD. The trial plans to recruit 18 participants with previously treated wet AMD who were responsive to prior anti-VEGF therapy. RGX-314 with be administered at 3 exploratory doses and the primary outcome measures are focused on safety and tolerability at 24 weeks.

"Gene therapy for neovascular AMD offers the potential to alleviate treatment burden," Jeffrey S. Heier, MD, co-president and medical director at the Ophthalmic Consultants of Boston, said during a presentation at the meeting. "In terms of other gene therapies, both intravitreal and subretinal approaches have been studied, and each of these has had limited success. This may be due to a variety of reasons but the most important is believed to be inadequate expression."

To overcome the lack of expression seen with other gene therapies, RGX-314 was designed to deliver a gene encoding for an anti-VEGF monoclonal antibody fragment protein using adeno-associated virus 8 (AAV8). Previous studies primarily used AAV2. In studies looking at various viral vectors in non-human primates, AAV8 appeared superior to AAV2 at delivering a therapeutic transgene to cells of the retinal pigment epithelium leading to higher levels of protein expression.

"Studies to date have had issues with protein expression, and it's our hope that RGX-314 will allow us to overcome this," said Heier. "This proprietary gene platform is believed to lead to higher and longer expression with lower immune response."

In addition to advantages inherent to AAV8, investigators also explored other means of administration to help facilitate transduction. Although intravitreal delivery is an easier method, it is 100 to 1000 times less efficient for gene therapy than subretinal delivery, according to Heier. The lower efficacy for intravitreal treatment could be related to pre-existing AAV neutralizing antibodies, which are present for 30% to 50% for AAV8 and up to 70% for AAV2.

Although it is more invasive, the subretinal space is immune privileged and neutralizing antibodies do not block transduction, Heier noted. However, surgery is required, complicating the development of a clinical trial for wet AMD, which is traditionally a medically treated disease.

"Designing a surgical trial for a medical disease is challenging," said Heier. "Standardization and reproducibility of the procedure is critical."

The RGX-314 administration procedure, which is carried out under local anesthesia, begins with a standard small gauge vitrectomy followed by automated delivery using the MedOne subretinal cannula. The gene therapy is injected at 250 µl into a single bleb superior to the superotemporal arcade vessel or outside the arcades and away from the fovea. At the end of the procedure, there is an air fluid exchange and sub-conjunctival steroids.

The phase I study continues to enroll patients 50 years and older. The estimated primary completion date for determining results is August 2018 (NCT03066258). The study is being conducted by Regenxbio.

Heier JS, Campochiaro P, Ho A, et al. RGX-314 Gene Therapy Subretinal Delivery for the Treatment of Neovascular Age-Related Macular Degeneration (nAMD). Presented at: 35th Annual Meeting of the American Society of Retina Specialists; August 11-15, 2017; Boston, Massachusetts.