Gene therapy in RPE65 trial offers promise for improved vision


The first randomized, controlled phase III gene therapy trial that is investigating treatment with adeno-associated viral vector delivery of human RPE65 in patients with RPE65 mutation-associated inherited retinal dystrophies is discussed.

Take-home: The first randomized, controlled phase III gene therapy trial that is investigating treatment with adeno-associated viral vector delivery of human RPE65 in patients with RPE65 mutation-associated inherited retinal dystrophies met its primary efficacy endpoint at 1 year.

Reviewed by Stephen Richard Russell, MD

Iowa City, IA—Gene therapy with an adeno-associated viral vector delivering human RPE65 (voretigene neparvovec, Spark Therapeutics) improved functional vision and visual function in patients with RPE65, mutation-associated inherited retinal dystrophies, according to topline results from a phase III trial.

The study randomized 31 patients 2:1 to bilateral, sequential subretinal administration of voretigene neparvovec (formerly known as AAV2-hRPE65v2 or SPK-RPE65; 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.

At 1 year, patients receiving gene therapy benefited with a highly statistically significant improvement in mobility-test performance (primary outcome measure) and full-field light sensitivity (secondary-outcome measure). Both outcomes were essentially unchanged in the control group, and the between-group differences were also highly, statistically significant, reported Stephen R. Russell, MD, the Dina J. Schrage Professor of Macular Degeneration Research, professor of ophthalmology and visual sciences, University of Iowa Carver College of Medicine, Iowa City.

Of equal importance, there were no product-related serious adverse events or immune responses to the gene therapy, he said.

“This is the first randomized, controlled phase III gene therapy trial completed for a genetic disease,” Dr. Russell said. “The results suggest there will become a greater need for genetic screening of selected populations to identify inherited retinal disease patients who may benefit from genetic therapies.”

Two study sites

The study was conducted at two sites—the University of Iowa and Children’s Hospital of Philadelphia. Eligible patients had to be at least 3 years of age, have visual acuity < 20/60 and/or visual field < 20° in any meridian, and be within the mobility-test passing range at baseline that would allow a measurable improvement.

Dr. Russell noted that the power and sample size calculations for the trial were based on the promising results of the phase I and phase I follow-on studies investigating the gene therapy.

“The early studies also assessed efficacy with mobility testing, but in order for this novel endpoint to be used in a phase III trial, the mobility test was rigorously defined and improved,” he said. “Although 3-year-olds were eligible for the phase III study, the youngest children enrolled were 4 years because younger children could not perform the mobility testing.”

At screening, the enrolled patients had a mean age of 16 years. Patients were also stratified at entry by age (< 10 years and ≥ 10 years) and baseline mobility light level passing score (< 125 lux and ≥ 125 lux). The intervention and control arms were well balanced at baseline for demographics and the 2 stratification variables.

Patients were videotaped while performing the mobility test at 7 different lux levels (range 1 to 400). The videos were graded at an independent reading center, which were masked to study and treatment group. A passing grade required completion of the mobility test within 3 minutes with fewer than 4 errors.

Rapid improvement

Data from serial follow-up visits showed patients in the intervention arm achieved rapid improvement in mobility-test performance that was sustained during follow-up to 1 year; the difference in mean change from baseline comparing the intervention and control arms was 1.6 light levels (P = 0.004).

“At 1 year, 65% of the 20 patients in the gene therapy group passed the bilateral mobility test at 1 lux, which was the minimum light level measured,: Dr. Russell said. “This suggests the improvement achieved in the intervention arm, which was 1.9 light levels, may have been limited by a ceiling effect. None of the controls were able to pass the mobility test at 1 lux at 1 year.”

Similarly, patients receiving gene therapy achieved rapid and sustained improvements in bilateral, full-field, light sensitivity testing. Their mean improvement from baseline at 1 year was about 2.1 log units, representing about a 100-fold change. Again, there was essentially no change in the control arms, and the between-group difference was highly statistically significant (P = 0.001)

The safety review showed 2 subjects in the intervention group had serious adverse events that were unrelated to study participation. Ocular adverse events were mild and related to the procedure. The most common ocular adverse events were elevated intraocular pressure, cataract, intraoperative retinal tear (treated successfully with laser), and transient mild ocular inflammation.

Rapid improvement



“Often, the first question people ask is: ‘What is the durability of the effect?,’” Dr. Russell said.

Although data from the phase III trial is incomplete beyond 1 year, longer-term data are available from patients participating in the phase I follow-on. Mobility-test scores and full-field light sensitivity for the 8 enrolled subjects who would have met the entry criteria for the phase III trial suggest durability of at least 3 years, and observation is ongoing, Dr. Russell reported.


Stephen R. Russell, MD


This article is based on a presentation given by Dr. Russell at AAO2015.

Dr. Russell receives research grants from Spark Therapeutics and is a consultant to the company.

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