LCD L37863: Voretigene Neparvovec-rzyl (Luxturna®)

This Local Coverage Determination (LCD) addresses limited indications of the gene therapy, voretigene neparvovec-rzyl (Luxturna ® ). Voretigene neparvovec-rzyl will be considered reasonable and necessary for the following inherited retinal degenerations with confirmed biallelic RPE65 mutations:

• Retinitis pigmentosa

• Leber congenital amaurosis

This limited coverage of voretigene neparvovec-rzyl (Luxturna ® ) allows for a single dose (1.5x 10 11 vector genomes) per eligible eye, per lifetime in beneficiaries who meet all of the coverage indications and documentation requirements as outlined in this LCD. Additionally, coverage is limited to manufacturer-designated Centers of Excellence with expertise in heritable retinal degenerations when performed by qualified vitreoretinal surgeons with evidence of completion of the manufacturer’s surgical and pharmacy training program for the appropriate storage, handling, and administration of voretigene neparvovec-rzyl (Luxturna ® ).

Voretigene neparvovec-rzyl (Luxturna ® ) is a gene therapy product approved by the United States (U.S.) Food and Drug Administration (FDA) on December 19, 2017 for treatment of vision loss due to certain heritable retinal dystrophies in patients with confirmed biallelic RPE65 mutations. Specifically, biallelic RPE65 mutation-associated retinal dystrophy is responsible for 2% of cases of autosomal recessive retinitis pigmentosa (RP) and 8-16% of cases of Leber congenital amaurosis (LCA), both of which are phenotypically and genotypically heterogeneous conditions associated with progressive loss of vision, typically presenting at birth or in early childhood-adolescence. The RPE65 gene codes for an enzyme expressed in the retinal pigment epithelium (RPE) that is essential to the visual cycle. The RPE65 mutation results in an inability to regenerate 11-cis retinal, a vitamin A-derived chromophore, which effectively renders rods incapable of responding to light and eventual degeneration of the RPE and photoreceptors.

Using an adeno-associated viral vector, a normal copy of the RPE65 gene is transfected to defective RPE cells by injection of voretigene neparvovec-rzyl into the subretinal space of the macula via a standard 3-port vitrectomy operation in a surgical suite under controlled aseptic conditions in the outpatient setting. The injection is followed by an air-fluid exchange. Post-operative supine head positioning is maintained as much as possible for the first 24 hours. Following treatment of the first eye, the contralateral eye is treated sequentially within a period of 6 to 18 days. A 7-day course of oral prednisone (1 mg/kg/d; max of 40 mg/d) is started 3 days prior to injection, then tapered.

A Phase 1 open-label, dose escalation study in 12 subjects (aged 8-44 years) with biallelic RPE65 mutation-associated retinal dystrophy was performed to assess safety and efficacy of voretigene neparvovec-rzyl (Study 101). Subjects underwent monocular treatment with either a low (1.5x10 10 ), medium (4.8x10 10 ), or high dose (1.5x10 11 ) vector genome of voretigene neparvovec-rzyl in a 1:2:1 ratio. No dose response effects on safety or preliminary measures of efficacy were observed.

The contralateral eye of subjects in Study 101 underwent subretinal injection of voretigene neparvovec-rzyl at the high dose (1.5x10 11 vector genomes) in a Phase I follow-on study (Study 102). The treatments occurred between 1.7 to 4.6 years following injection of the first eye in 11 of the 12 subjects; 1 subject was excluded due to elevated intraocular pressure prior to undergoing treatment. Improvements over baseline in light sensitivity, navigational ability, and visual acuity were observed in the majority of subjects.