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SAN FRANCISCO -- A form of gene therapy stabilized or improved diabetic retinopathy (DR) for up to a year, particularly in patients with nonproliferative (NP) DR, a small clinical study showed.

Overall, about 40% of patients had improved disease status, and another 30% had stable disease after a single injection of vascular endothelial growth factor (VEGF)-targeted RGX-314. In the subgroup of patients with NPDR, 29 of 30 had stable disease or improvement in the Diabetes Retinopathy Severity Scale (DRSS), including all patients treated with the higher dose.

The gene therapy was associated with a substantially reduced risk of vision-threatening events (VTEs), said Mark R. Barakat, MD, of Retinal Consultants of Arizona in Phoenix, at the American Academy of Ophthalmology (AAO) annual meeting.

"A one-time in-office injection showed clinically meaningful improvement in disease severity and a reduction in VTEs in patients with NPDR," said Barakat. "At [the higher dose level] and baseline NPDR, 100% of patients showed stable to improved disease severity. Only 4.2% of patients developed VTEs versus 37% in the control group, which represents an 89% reduction in those events."

During a discussion that followed the presentation, AAO session moderator Mark Humayun, MD, PhD, of the University of Southern California in Los Angeles, said the prospect of a one-and-done, in-office treatment "is provocative and could be a game changer. How would you incorporate this into your clinic?"

As long as the safety and efficacy profiles hold up, "it would be very tempting to treat a large majority of patients with diabetic retinopathy," said Barakat. "We all know that anti-VEGF treatment for diabetic retinopathy can have an effect. It's just a question of how often are you willing to treat. A single treatment in office makes sense."

Noting that the diabetes population tends to be younger, discussion panelist Gemmy Cheung, MBBS, of the Singapore National Eye Center, said that systemic control of diabetes can change over time.

"So, how do we mitigate a once and kind-of-forever kind of treatment that we can't turn off in these patients?" she asked.

The younger age of the population makes the patients an interesting group to target with the therapy, said Barakat.

"We know this is a chronic disease, and they'll need chronic treatment," he said. "The thought of doing monthly or even every-3-months injections is just not sustainable. Would you treat every patient with diabetic retinopathy who walks in the door? Probably not, but if someone comes in with moderately severe or severe nonproliferative diabetic retinopathy, I think it's simple and perfectly reasonable."

RGX-314 consists of an adeno-associated virus (AAV)8 vector carrying a gene that encodes for anti-VEGF antibody fragment (fab). Following suprachoroidal injection, the gene therapy induces ocular cells to produce anti-VEGF fab to reduce the formation of leaky blood vessels. The treatment has been investigated in a variety of retinal conditions, including diabetic macular edema (DME) and age-related macular edema.

Barakat reported findings from the phase II study involving patients with moderately severe or severe NPDR or mild PDR without active central-involved DME. The data included findings from 50 patients treated with one of two dose levels of RGX-314 and 10 patients in an observational control group. The primary endpoint was a ≥2-step improvement in the DRSS.

Baseline characteristics for all 60 patients showed 55% had moderately severe NPDR (DRSS 47) and 35% had mild PDR. Best corrected visual acuity was 81.3 letters, central subfoveal thickness (CST) averaged 270.4 µm, and three-fourths of the patients had phakic lens status. Duration of diabetic retinopathy averaged 2 years.

After a year of follow-up, one of 10 patients in the control group met the primary endpoint, one patient had a one-step improvement in DRSS, and three had stable disease.

Among 15 patients treated with the lower dose of RGX-314, two met the primary endpoint, two had a one-step improvement, and five had stable disease. In the higher-dose cohort, two of the 35 patients had a three-step improvement in DRSS, five had a two-step improvement, 12 had a one-step improvement, and 12 had stable disease.

An analysis limited to patients with NPDR showed a similar distribution of disease status at 12 months in the control group (n=8). Among six patients treated with the lower dose of RGX-314, two had a two-step improvement, two improved by one step, and one had stable disease. Among 24 patients in dose level two, five had a two-step improvement, 12 had a one-step improvement, and the remaining seven had stable disease.

The proportion of patients who had any level of improvement was 25% in the control group, 66.7% in dose level one of RGX-314, and 70.8% in dose level two, said Barakat.

The most common adverse events in patients treated with either dose of RGX-314 were conjunctival hyperemia (30%), conjunctival hemorrhage (14%), episcleritis (12%), intraocular pressure increase (8%), and intraocular inflammation (6%).

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