Summary Of Evidence

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 (1.5x10¹⁰), medium (4.8x10¹⁰), or high dose (1.5x10¹¹) 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 (1.5x10¹¹ 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.  

A Phase 3 open-label, randomized, control crossover trial in 31 subjects (aged 4-44 years; 20 of which were under 18) with biallelic RPE65 LCA was conducted to assess efficacy in improving visual function. Subjects were randomized (2:1) to undergo subretinal voretigene neparvovec-rzyl (1.5x10¹¹ vector genomes) subretinal injections in both eyes versus control (Study 301) and followed for 1 year. The control group did not undergo treatment or sham injection. In total, there were 20 subjects in the bilateral treatment group and 9 subjects serving as controls; 2 subjects withdrew prior to intervention. The average age of the treatment group was 15.9 years and 15.1 years for the control group. At the end of the first year, all 9 control group patients crossed over to undergo bilateral, sequential subretinal injections of voretigene neparvovec-rzyl (Study 302) within 6 to 18 days apart in accordance with the same protocol for Study 301. This was the control/intervention group in Study 302.

The primary outcome measure was the monocular change in scored ability at 1 year to navigate an obstacle course called the multi-luminance mobility test (MLMT) under 7 standardized light levels ranging from 1 to 400 lux using both eyes. A change in MLMT score by 2 or greater is considered to be clinically meaningful. Secondary outcome measures were full-field light sensitivity threshold testing (FST) averaged over both eyes, best-corrected visual acuity (averaged over both eyes), and change in MLMT score of the first treated eye at 1 year. Exploratory endpoints included visual field testing with both Goldmann kinetic perimetry and Humphrey static microperimetry, contrast sensitivity testing, pupillary light reflex, and functional vision assessments, which included a questionnaire completed by subjects (or parents of subjects), as well as, an in-home assessment by independent orientation and mobility specialists.

At 1 year, subjects in the treatment arm of Study 301 had a significantly improved bilateral MLMT score from baseline than did those in the control arm of 1.8 (1.1) light levels vs 0.2 (1.0) light levels (95% CI 0.72-2.41, p=0.0013). FST testing was also significant between the treatment and control groups. Visual acuity changes from baseline were not statistically significant between the 2 groups, though there was a trend toward improvement in the treatment group. Changes from baseline of the other secondary endpoints were not statistically significant between the 2 groups. The self-reported questionnaire indicated an improvement in visual function in performing activities of daily living in the treatment group.  

In total, there were 81 eyes of 41 subjects that underwent treatment with voretigene neparvovec-rzyl in the Phase 1 and Phase 3 studies. Of these, ocular adverse reactions occurred in 46 eyes of 27 subjects and included conjunctival hyperemia, cataract formation, increased intraocular pressure, retinal tears, dellen, macular hole, intraocular inflammation, macular breaks, transient subretinal deposits, irritation pain, and maculopathies. There were 2 serious adverse reactions, 1 case of endophthalmitis with subsequent complications resulting in loss of vision, and 1 case of vision loss due to foveal thinning. 

Durability of response

Earlier studies by independent investigators using RPE65 gene therapies for the same indicated population found similar initial improvement in mobility testing and retinal light sensitivity testing, though the effects were not sustained beyond 3 years. The current study has reported a sustained effect for 2 years (Phase 3) and 3 years (Phase 1); however, long-term efficacy and safety are unknown. 

Analysis of Evidence

Based on the evidence from the Phase I and Phase III trials, voretigene neparvovec-rzyl has been found to clinically improve functional vision in patients with the biallelic mutations in the RPE65 gene in the inherited retinal degenerations, RP and LCA. In summary, Palmetto GBA considers a single treatment per eye, per lifetime of voretigene neparvovec-rzyl (Luxturna^®) medically reasonable and necessary for the treatment of beneficiaries with confirmed biallelic RPE65 mutation-associated subtypes of RP or LCA, who otherwise meet all of the clinical criteria as outlined in this LCD.

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 10¹¹ 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^®).