This Local Coverage Determination (LCD) addresses limited indications of the
gene therapy, [voretigene neparvovec-rzyl
(Luxturna](https://www.fda.gov/media/109906/download)). 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).

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.

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.