Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation-Associated Inherited Retinal Dystrophy: Results of Phase 1 and 3 Trials

Written by: Rehan M. Hussain, MD

November 2019

Maguire, AM, Russell S, Wellman JA. Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation-Associated Inherited Retinal Dystrophy: Results of Phase 1 and 3 Trials. Ophthalmology 2019 Sep;126(9):1273-1285.  doi: 10.1016/j.ophtha.2019.06.017. Published online Jun 22, 2019.

Voretigene neparvovec (VN) is a non-replicating adeno-associated virus (AAV), which has been genetically modified to express the human RPE65 transgene. In 2017, the FDA approved VN (Luxturna, Spark Therapeutics, Philadelphia, PA, USA) for the one-time treatment of confirmed biallelic RPE65 mutation-associated retinal dystrophies (ie. certain types of Leber’s congenital amaurosis and retinitis pigmentosa), which previously had no treatment options. VN is administered by subretinal injection during pars plana vitrectomy and is the first available gene therapy for a genetic disease.

The efficacy of VN was established on the basis of multi-luminance mobility testing (MLMT) score change from baseline to Year 1. The MLMT was designed to measure changes in functional vision, as assessed by the ability of a subject to navigate an obstacle course at different levels of environmental illumination. The development and validation of novel functional visual endpoints, such as the MLMT, have served as a more useful measure of the beneficial effects of VN compared to the traditional method of measuring VA, which is a more appropriate marker for diseases that predominantly impair cone functionality.

Maguire et al. recently published updated results from the phase 1 and phase 3 studies that paved the way for its FDA approval. All patients in this analysis received the same dose of 1.5 x 1011 vector genomes per eye in at least one eye.  The open-label phase 1 patients had been followed for four years and the phase 3 patients for two years. Of the phase 3 patients, 20 patients were in the original intervention (OI) group, while 9 were in the control/intervention (CI) group that received VN after 1 year without treatment.

The results indicated that VN’s positive impact on MLMT performance was nearly maximal by 30 days after administration and was durable for up to four years. For context, an MLMT score change of two or greater is considered a clinically meaningful benefit in functional vision. Mean MLMT lux score change was 2.4 at four years compared with 2.6 at 1 year after administration in phase 1 follow-on subjects (n=8). For the phase 3 subjects, mean MLMT lux score change remained stable at 1.9 between the first and second year post-administration in OI subjects (n=20), and was 2.1 at 1 year post-administration in CI subjects (n=9).

All 3 groups maintained a mean improvement in full-field light sensitivity testing (FST), reflecting more than a 2 log10(cd.s/m2) improvement in light sensitivity at 1 year and subsequent available follow-up visits. In contrast to the average yearly VF loss of approximately 25 sum total degrees on Goldmann VF III4e in the natural history of patients with RPE65 mutation-associated IRD, phase 3 subjects had a mean change of +267 sum total degrees at 1 year post-treatment, and OI subjects maintained this increase at 2 years. This denotes an expanded area of retinal sensitivity caused by improved photoreceptor function, which translates into greater light sensitivity and peripheral vision.

The safety profile was consistent with vitrectomy and the subretinal injection procedure, and no adverse immune responses occurred. The cohort of 40 patients is notable in a rare disease such as RPE65 mutation associated IRD. This study does not provide data on subjects aged less than 4 years or subjects whose baseline visual function or functional vision were better than the inclusion criteria of these trials. Ethical concerns led these to be open-label trials, potentially introducing biases, although graders for the MLMT, the primary phase 3 end point, were masked to treatment group.

In summary, the results of this study support the continued efficacy, safety and durability of VN to improve functional outcomes of patients with previously untreatable RPE65 mutation-associated inherited retinal degenerations. Routine implementation of genetic testing in patients with suspected IRDs is critical to ensure that patients who qualify for genetic therapies will be identified and managed appropriately.