Wet AMD gene therapy shows promise

RGX-314 is one of a number of gene therapy candidates targeting retinal diseases, but where the bulk of these agents target inherited retinal disease, RGX-314 is unique in that it’s one of the few gene therapies that targets wet age-related macular degeneration. REGENXBIO, the company developing RGX-314, says the goal is to have a one-time subretinal treatment for wet AMD.

RGX-314 includes a vector of adeno-associated virus serotype 8 (AAV8). Because this serotype shows a greater affinity for liver transduction than other serotypes, it is the preferred vector for hemophilia A and familial hypercholesterolemia.¹ More recent research in retinal diseases has implicated AAV8 in inducing immune responses in primate retinas² and, more specifically, in suppressing vascular endothelial growth factor.³

REGENXBIO has developed RGX-314 based on a proprietary platform called NAV. RGX-314 contains a gene that encodes for a monoclonal antibody fragment that binds to and neutralizes VEGF activity.

Phase I/IIa dose-escalation trial
A Phase I/IIa dose-escalation trial is currently evaluating four doses of RGX-314: 3E9 GC/eye; 1E10 GC/eye; 6E10 GC/eye; and 1.6E11 GC/eye. At last report, 30 subjects have been dosed in the trial. The trial is also now recruiting an additional cohort of 12 patients at a dose of 2.5E11 GC/eye.

These trial results will be used to help design the Phase IIb trial, which principal investigator Jeffrey S. Heier, MD, says is scheduled to begin by the end of the year.

Here, Dr. Heier, director of the vitreoretinal service at Ophthalmic Consultants of Boston, answers questions about the Phase I/IIa trial.

Q: What can you tell us about the mechanism of action of RGX-314?

A: RGX-314 utilizes an AAV8 viral vector that carries a gene encoding for an anti-VEGF protein. The vector is taken up preferentially by retinal cells. In essence, it uses the patient’s cells to produce high levels of the therapeutic protein.

Q: How is RGX-314 administered?

 A: It’s administered subretinally. The procedure used to place the vector involves a conventional three-port, small- gauge core vitrectomy and, if not already present, a posterior vitreous detachment is induced. Then, using a small-gauge, subretinal cannula, the gene therapy product is introduced into the subretinal space. A bleb is created by injecting 250-μl of the gene therapy product adjacent to, but not in, the macula. This is similar to the procedure used for other retinal gene therapies, such as voretigene neparvovecrzyl (Luxturna, Spark Therapeutics).

Q: What are the potential advantages of subretinal delivery?

A: The hypothesis is that subretinal delivery will provide broader retinal coverage, higher protein expression and reduced sensitivity to neutralizing antibodies than intravitreal delivery. This will potentially lead to higher and longer gene expression.

Q: What have the Phase I/IIa results shown so far?

A: The Phase I/IIa study is designed primarily to evaluate safety, but it is also designed to show long-term protein expression after administering RGX-314. In each cohort we have seen increasing levels of protein expression as measured by anterior chamber taps. Fifty percent of the patients in cohort 3 (6E10 GC/eye) haven’t received any rescue injections out to nine months. Patients in cohort 4 (1.6E11 GC/eye), which is still recruiting, had continued evidence of dose-dependent protein expression.