Gene therapy benefits for retinal dystrophies persist through trial


Results from 3 years of follow-up in the phase III trial investigating treatment with adeno-associated viral vector delivery of human RPE65 (voretigene neparvovec, Spark Therapeutics) show this gene therapy has an acceptable safety profile.

Results from 3 years of follow-up in the phase III trial investigating treatment with adeno-associated viral vector delivery of human RPE65 (voretigene neparvovec, Spark Therapeutics) show this gene therapy has an acceptable safety profile. Also, it provided rapid and durable improvements in functional vision and visual function for patients with RPE65 mutation-associated inherited retinal dystrophies.

The data were reported by Albert M. Maguire, MD, professor of ophthalmology, Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, at Retina 2017.

The phase III trial was conducted at the Children’s Hospital of Philadelphia and the University of Iowa, Iowa City, where Stephen R. Russell, MD, was principal investigator.

To be eligible for participation, patients had to be at least 3 years of age, have a confirmed diagnosis of biallelic mutations in the RPE65 gene, visual acuity <20/60 and/or visual field <20° in any meridian, sufficient viable retinal cells, and be able to perform the standardized multi-luminance mobility test (MLMT), within the evaluated luminance range, but unable to pass at 1 lux.


Dr. Maguire explained that the MLMT test was developed to measure functional, ambulatory vision at light levels encountered during activities of daily living. In the test, subjects are tasked to complete a mobility course by following guidance arrows and avoiding obstacles. Their performance is graded as pass or fail, taking into account speed and accuracy.

The test is done under seven standard lux light levels that are analogous to those encountered in various situations found in daily levels. The light levels ranged from 1 lux, which is similar to a moonless summer night, to 400 lux, which reflects a typical office setting.

“There are 12 different courses with the same number of turns and obstacles in order to reduce the potential for learning effect,” Dr. Maguire said.

“The ability to do the MLMT at dimmer light levels indicates the potential to perform visually dependent activities of daily living over a wider range of environmental light levels, thus potentially improving quality of life and independence,” he said.

The study randomly assigned 31 patients 2:1 to bilateral, sequential subretinal administration of voretigene neparvovec (1.5E11 vector genomes per eye/300 μL) after vitrectomy or observation. Second eye surgeries in the intervention arm were performed within 18 days of the first procedure.

When the randomized, controlled study period ended at 1 year, patients randomly assigned to observation were allowed to crossover to gene therapy.
One patient in each arm withdrew consent before intervention. All remaining patients (20 randomly assigned to original intervention and 9 who received delayed intervention after crossover) were evaluated at the 3-year visit.


The primary endpoint was change in functional vision as measured by performance in the MLMT at 1 year postinjection, and the secondary endpoint was change in visual function measured by white light full-field sensitivity.

Additional visual function endpoints included change in visual field and change in best-corrected visual acuity (BCVA).

In the analysis of mean bilateral change score in MLMT, both the original intervention arm and the crossover patients who received delayed intervention showed statistically improvements in performance when first evaluated 30 days after receiving the gene therapy. Mean bilateral change score in MLMT was stable throughout continued follow-up for both groups.

At 3 years after treatment, the original intervention patients had a mean bilateral change score in MLMT of 1.8 levels. The delayed intervention cohort gained 2.1 levels when evaluated at 2 years following treatment.

“Sixty-nine percent of all subjects and 89% of the delayed intervention subjects were able to pass the MLMT at the lowest light level,” Dr. Maguire said.


The same temporal pattern of rapid improvement and stability of benefit over time was seen in analyses of mean change in white light full-field sensitivity and mean change in visual field (Goldman III4e) in both the original and delayed intervention groups. With data for each patient averaged over both eyes, mean change in white light sensitivity was >2 log10 units for the original intervention group.

At 2 years after voretigene neparvovec treatment, the delayed intervention group had a mean change of about 2.7 log10 units.

These values represent an approximate 100-fold improvement in light sensitivity in the original intervention group and a near 500-fold increase in the delayed intervention group, Dr. Maguire noted.

Compared with baseline, Goldmann visual field III4e improved by a mean of 282.2 sum total degrees at year 3 in the original intervention group.

The visual field declined during the first 3 months after randomization in the observation arm and then was relatively stable for the next 9 months. At 2 years after being crossed over to treatment with voretigene neparvovec, the delayed intervention patients had a mean improvement of 182.6 sum total degrees.

At the end of the 1-year randomized controlled study period, the mean change in BCVA averaged over both eyes was not significantly different between the treated patients and the controls, and BCVA remained stable in both groups during the rest of the study.

Dr. Maguire noted that the BCVA outcomes were not unexpected considering that the disease is rod-mediated.


No serious safety signals

Voretigene neparvovec was well tolerated, and its safety profile was consistent with the delivery procedure, which involved vitrectomy and subretinal injection. A single ocular serious adverse event was recorded-foveal thinning with modest loss of visual acuity-but it was judged to be related to the administration procedure rather than the product. There was no evidence of deleterious immune responses to voretigene neparvovec.

The most common ocular treatment-emergent adverse events were increased IOP and cataract, each occurring in 5 patients (17%) followed by retinal tear and retinal deposits, each of occurring in 3 patients (10%). The retinal deposits were subretinal precipitates that were asymptomatic and self-limited.

Dr. Maguire is a consultant to and receives grant support from Spark Therapeutics.


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