Interim Results from a Multicenter Observational Safety Study of Patients Treated with Voretigene Neparvovec-Rzyl in the United States.

OBJECTIVE

To assess long-term safety and exploratory ophthalmic outcomes with voretigene neparvovec-rzyl (VN) in US clinical practice.

DESIGN

Prospective, multicenter, observational postauthorization safety study.

PARTICIPANTS

Eighty-seven patients (169 eyes) receiving VN at 10 ocular gene therapy treatment centers.

METHODS

Patients ≥12 months old with viable retinal photoreceptors received VN in ≥1 eye. Subretinal delivery followed a 3-port pars plana vitrectomy modified at surgeons' discretion (e.g., automated foot pedal delivery, prebleb injection, cannula cut, and use of dye for visualization).

MAIN OUTCOME MEASURES: Safety outcomes included treatment-emergent adverse events (TEAEs) and occurrence of chorioretinal atrophy (CRA). Exploratory assessments included changes in best-corrected visual acuity (BCVA) and full-field stimulus threshold (FST). Outcomes were analyzed descriptively; relative risk (RR) was estimated for subgroup comparisons.

RESULTS

With a median of 3.7 years of follow up (range, 2.9-4.9), most patients (95%) reported ≥1 TEAE (387 events); 67% procedure related, 9% attributed to VN, and 82% mild. Chorioretinal atrophy, including related terms retinal degeneration and retinal depigmentation, occurred in 24 patients (27%; 45 eyes), typically within 1 year, and was mild (80%) or moderate (20%). The area of CRA was mostly localized to the retinotomy or bleb area, with 40% of eyes with CRA having atrophy outside the bleb area, and highly correlated between fellow eyes (r = 0.97; P < 0.0001). Chorioretinal atrophy risk was higher with automated foot pedal administration of VN (RR, 5.33; 95% confidence interval [CI], 1.27-22.40) and in patients with myopia (RR, 8.40; 95% CI, 1.16-60.69). At 3 years, treated eyes showed sustained improvements in BCVA (-0.13 logarithm of the minimum angle of resolution) and FST (-1.68 log10 cd·s/m2). Best-corrected visual acuity and FST were comparable between CRA and non-CRA eyes, although a subset of CRA eyes showed greater FST improvement at most timepoints up to year 3.

CONCLUSIONS

This interim analysis supports the long-term safety of VN in a US cohort, consistent with clinical trial results. Chorioretinal atrophy did not seem to diminish sustained functional and anatomical benefits over minimum 3-year follow up. Ongoing data collection will further clarify the occurrence, impact, and risk factors for CRA while continuing to monitor VN safety in clinical practice.

FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.