Voretigene neparvovec demonstrated sustained improvements in vision for patients with biallelic RPE65-mutation–associated inherited retinal disease.
Stephen Russell, MD
Treatment with voretigene neparvovec (Luxturna) demonstrated sustained improvements in vision for patients with biallelic RPE65-mutation—associated inherited retinal disease (IRD), both in the original treatment group and for those who crossed over from the control arm after 1 year, according to an updated phase 3 assessment presented at the 2018 ARVO annual meeting.
The mean change in multi-luminance mobility test (MLMT) scores at 3 years was 1.8 (±1.0) in the original intervention (OI) arm of voretigene neparvovec, for an overall Lux score around 5 out of 6. In the delayed intervention (DI) group at 2 years, the mean change in MLMT score was 2.1 (±1.6), with 89% of patients in the DI group able to pass the lowest light test (1 lux).
Across both groups, there was an impressive improvement in light sensitivity by full-field light sensitivity threshold (FST) testing. The mean change in white light FST testing for both eyes was -2.04 log10 cd.s/m2 (±1.43) at 3 years for those in the OI group and -2.69 log10 cd.s/m2 (±1.41) at 2 years for the DI arm, which represented a 500-fold increase in light sensitivity from baseline.
“I am delighted that the duration of effect of voretigene neparvovec appears to be unchanged over 3 years in the originally treated group with RPE65-associated Leber's congenital amaurosis,” lead study author Stephen Russell, MD, Schrage Professor of Ophthalmology, The University of Iowa, told MD Magazine. “It is also reassuring to see that the visual improvements in MLMT and light sensitivity as measured by the FST appears unchanged over 2 years in the original control subjects that were allowed to cross over and receive treatment at 1 year.”
In December 2017, voretigene neparvovec became the first adeno-associated virus (AAV) vector gene therapy approved by the FDA. The one-time gene therapy is indicated for the treatment of adults and children with confirmed biallelic RPE65 mutation-associated IRD, which includes Leber’s congenital amaurosis and retinitis pigmentosa. The approval followed a breakthrough therapy designation and priority review from the FDA.
Data from two studies led to the FDA approval of voretigene neparvovec. In the first trial, there was a mean bilateral change in MLMT from baseline of 2 with voretigene neparvovec compared with 0 in the control group (P = .001). In the second trial, which was the basis for the 3-year assessment at the ARVO annual meeting, 52% of patients had a score change in MLMT of 2 to 4 at 1 year with the gene therapy compared with just 10% having a change of 2 in the control arm.
The trial enrolled 31 patients with IRD to receive the a bilateral subretinal injection of the gene therapy (n = 21) or control (n = 10). Patients in the trial had visual acuity worse than 20/60 and/or a visual field of less than 20 degrees in any meridian. The average age was 15 years (range, 4-44).
One patient discontinued at baseline in the gene therapy group and 1 withdrew following screening in the control arm, leaving 29 eligible patients for assessment. By the time of the 3-year analysis, all 29 patients had received voretigene neparvovec, which is injected in two separate procedures that are 6 to 18 days apart.
Consistent changes were seen in visual acuity across both groups of patients. There was an 8-letter improvement in visual acuity in the OI group at 3 years and a 3-letter increase in the DI group at 2 years’ post treatment. This was equivalent to -0.16 (±0.35) and -0.06 (±0.23) on the Holladay scale, respectively.
The mean change in Goldmann visual field (VF) III4e was 282.2 sum total degrees (±256.5) in the OI group at 3 years and 182.6 (±309.9) for the DI arm at 2 years. In the DI group, there was an initial loss of 100 sum total degrees during the 1 year initial stage. There was a mean change in the Humphrey VF macular threshold of 6.50 dB (±5.77) in the OI group and a change of 7.06 dB (±7.23) in the DI arm.
Adverse events observed in the study were consistent with vitrectomy and subretinal injection. The most common treatment-emergent adverse events were intraocular pressure increase (17%), cataracts (17%), retinal tear (10%), and retinal deposits (10%). There were 3 serious adverse events in the OI group and 1 in the DI arm. There were no treatment-related serious adverse events.
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