Regulatory Decision Summary for Luxturna

Inherited retinal dystrophy (IRD) caused by biallelic RPE65 mutations includes a heterogeneous group of serious and sight-threatening genetic retinal diseases with various clinical presentations. It is a very rare genetic condition and it is estimated that there are a maximum of 300 patients in Canada. Currently, there are no pharmacological treatments for the condition.

Luxturna (voretigene neparvovec) is a gene transfer vector that employs an adeno-associated viral vector serotype 2 (AAV2) capsid as a delivery vehicle for a normal copy of RPE65 complimentary DNA (cDNA) to the retina. Injection of voretigene neparvovec underneath the retina results in transduction of the retinal pigment epithelial (RPE) cells with a normal copy of RPE65 cDNA, and thus enables restoration of the visual cycle.

The authorization of Luxturna was based on one Phase 3 study, two Phase 1 studies and other supportive studies. The Phase 3 study was an open label, randomized, controlled study investigating the efficacy and safety of voretigene neparvovec. Subjects with IRD caused by confirmed biallelic RPE65 mutations were enrolled to receive voretigene neparvovec (1.5 x 10¹¹ vector genomes in 0.3 mL solution per eye) in both eyes (the treatment group, n = 21) or no treatment (the control group, n = 10).

The primary endpoint was bilateral multi-luminance mobility testing (MLMT) that was developed to measure functional vision of the IRD patients with vision impairment. The clinical efficacy was assessed by measuring the change from baseline to one year in a subjects ability to navigate an obstacle course at various light levels. A median difference in bilateral MLMT change score from baseline of 2 was considered statistically significant and clinically meaningful. A similar improvement in bilateral MLMT 1 year from the injection was also observed in subjects from the cross-over group. Based on the available annual updates, the treatment effect was largely maintained.

Safety analysis was based on the data from Phase 1 and Phase 3 studies with a total of 41 subjects who received voretigene neparvovec injections in 81 eyes (all but 1 subject received injection in both eyes). There were no deaths or discontinuations due to AEs in any of the clinical studies. No drug-related, clinically meaningful adverse reactions were reported. A total of 30 (73%) subjects in the clinical studies reported ocular adverse events that were related to the administration procedure. The most common adverse reactions (incidence ≥5%) related to the administration procedure were: conjunctival hyperaemia; cataract; increased intraocular pressure; retinal tear; dellen (thinning of the corneal stroma); macular hole; retinal deposits; eye inflammation; eye irritation; eye pain; and maculopathy (wrinkling on the surface of the macula). Three (3) subjects experienced an ocular serious adverse event which were considered related or possibly related to the administration procedure: foveal thinning/loss of foveal function; increased intraocular pressure; and retinal detachment.

No subject had a clinically significant immune reactions to the gene therapy product. Following the injection, vector shedding detected in tears or peripheral blood was transient in nature, occurring between one and three days after vector administration. Vector DNA was not detected in any peripheral blood (white blood cell) samples during the Phase 1 and Phase 3 studies.

The safety and efficacy of Luxturna in all treated subjects in the clinical Phase 1 and 3 trials will be continuously monitored in an on-going, 15-year follow-up study. The annual updates have been provided for up to 7 years.

The benefit-risk balance for voretigene neparvovec is favourable in the treatment of adult and pediatric patients with vision loss due to IRD caused by confirmed biallelic RPE65 mutations who have sufficient viable retinal cells.

The recommended dose of voretigene neparvovec is a single injection of 1.5 x 10¹¹ vector genomes given a total volume of 0.3 mL into the subretinal space of each eye. The individual administration procedure to each eye is performed on separate days within a close interval, but no fewer than 6 days apart. View the Canadian product monograph (PM) for details.