Neparvovec yields durable visual function improvements in inherited retinal disease

Gene-augmentation therapy with voretigene neparvovec (VN) appears to be safe and confers visual function benefits that persist up to 4 years in patients with biallelic RPE65 mutation-associated inherited retinal disease, as shown in an open-label phase III study.

“Improvements included stable gains in ambulatory navigation and light sensitivity, the endpoints most representative of the overall impact of RPE65-mediated inherited retinal disease on daily life,” according to the investigators. “The safety profile was consistent with previous results of the clinical trials of VN, and no deleterious immune responses occurred.” [Lancet 2017;390:849-860; Ophthalmology 2019;126:1273-1285]

The analysis included 29 patients who were randomized to receive bilateral subretinal VN injections (intervention; n=20) or to wait a year before receiving VN injections (wait-list control; n=9). All patients had a confirmed genetic diagnosis of biallelic RPE65 gene mutations, visual acuity of 20/60 or worse, visual field of <20° in any meridian, sufficient viable retinal cells, and had failed the multiluminance mobility test (MLMT) at 1 lux.

The improvements in visual field and functional vision parameters initially observed at years 1 and 2 were preserved. Mean bilateral MLMT change scores were 1.7 at year 4 in the intervention group and 2.4 at year 3 in the control group, with 71 percent of the patients who attended the year-3 visit being able to pass MLMT at the lowest light level. [Ophthalmology 2021;128:1460-1468]

Full-field light sensitivity threshold white light, averaged over both eyes, remained low relative to baseline, with a mean reduction of 1.90 log₁₀(cd.s/m²) at year 4 in the intervention group and 2.91 log₁₀(cd.s/m²) at year 3 in the control group. The mean change in Goldmann kinetic VF III4e sum total degrees was 197.7 and 157.9 in the respective groups, while the mean change in visual acuity (Holladay scale) was –0.003 and −0.06 logMAR.

There was a single patient in the intervention group who experienced retinal detachment by year 4, and this incidence affected visual acuity overall in the intervention group. None of the patients had VN-related treatment-emergent adverse events that occurred beyond year 1.

“RPE65 is an all-trans-retinyl ester isomerase expressed in the retinal pigment epithelium encoded by the RPE65 gene. The expression product of the RPE65 gene is responsible for rod and cone functioning because of its essential role in the biochemical recycling of chromophore in the retinoid cycle,” the investigators explained. [Ophthalmic Genet 2009;30:57-62; Int J Ophthalmol 2017;10:480-484]

Among the common clinical findings associated with biallelic mutations in the RPE65 gene are reduced light sensitivity (commonly called night blindness), progressive loss of visual field, and eventual profound loss of visual acuity. Patients with reduced visual field and light sensitivity experience difficulty navigating through unfamiliar environments. [Graefes Arch Clin Exp Ophthalmol 2005;243:417-426; Vision Res 2005;45:3117-3132; Invest Ophthalmol Vis Sci 2006;47:5295-5302]

“Strengths of the [present] VN phase III trial include the optimized vector, surgical procedure, and perioperative immunomodulatory regimen. The 4-year study period demonstrates durability of treatment effect and continuing safety, with ongoing observation planned,” the investigators noted, adding that they will continue to monitor the patients for up to 15 years.