Coverage Policy Manual
Policy #: 2018021
Category: Pharmacy
Initiated: August 2018
Last Review: September 2023
  Gene Therapy for Inherited Retinal Dystrophy-Voretigene (e.g., Luxturna)
Description:
Inherited retinal dystrophies are a group of disorders characterized by progressive degeneration and dysfunction of the retina (Hartong, 2006). The most common subgroup is retinitis pigmentosa which is characterized by a loss of retinal photoreceptor. The hallmark of this condition is night blindness and loss of peripheral vision which leads to difficulties in performing visually dependent activities of daily living. Visual acuity may be maintained longer than peripheral vision, but most individual progress to vision loss.
 
Retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) both have subtypes related to pathogenic variants in RPE65. The RPE65 (retinal pigment epithelium-specific protein 65-kD) gene encodes the RPE54 protein is a key enzyme expressed in the retinal pigment epithelium (RPE) that is responsible for regeneration of 11-cis-retinol in the visual cycle (Jin, 2005). Individuals with biallelic variations in RPE65 lack the RPE65 enzyme which leads to build-up of toxic precursors and damage to RPE cells, loss of photoreceptors, and eventually complete blindness (Naso, 2017).
 
RPE65-associated inherited retinal dystrophy is rare. At the end of 2017, the prevalence of RPE65-associated retinal dystrophies in the United States was estimated to be between 1000 to 2500 individuals.
 
Gene therapies are treatments that change the expression of genes to treat disease by replacing or inactivating a non-functioning or malfunctioning gene or by introducing a new gene. Genes may be introduced into the human cells through a vector, usually a virus (FDA, 2017). There are over 100 different AAVs, and 12 serotypes have been identified so far, labeled AAV1 to AAV12; in particular, AAV2, AAV4, and AAV5 are specific for retinal tissues. The recombinant AAV2 is the most commonly used AAV serotype in gene therapy  (Campa, 2017).
 
The eye is a particularly appropriate target for gene therapy due to the immune privilege provided by the blood-ocular barrier and the minimal amount of vector needed, given the size of the organ. Gene therapy for RPE65 variant-associated retinal dystrophy using various adeno-associated viruses (AAV) vectors to transfect cells with a functioning copy of RPE65 in the RPE cells has been investigated.
 
Regulatory Status
 
In December 2017, the AAV2 gene therapy vector voretigene neparvovec-rzyl (e.g., Luxturna™; Spark Therapeutics) was approved by the U.S. Food and Drug Administration for use in individuals with vision loss due to confirmed biallelic RPE65 variant-associated retinal dystrophy. Spark Therapeutics received breakthrough therapy designation, rare pediatric disease designation, and orphan drug designation.
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
Effective February 15, 2023, prior approval is required for Voretigene (e.g., Luxturna).
 
Effective September 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Voretigene neparvovec-rzyl adeno-associated virus vector-based gene therapy subretinal injection for individuals with vision loss due to biallelic RPE65 variant-associated retinal dystrophy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL of the following criteria are met:
 
A.  Individual age is greater than or equal to 3 years old to less than or equal to 65 years old AND
B.  Documentation of ALL the following:
        1. Genetic testing confirming presence of biallelic RPE65 pathogenic variant(s) (FDA, 2017)
a.  Single RPE65 pathogenic variant found in the homozygous state.
b.  Two RPE65 pathogenic variants found in the trans configuration (compound heterozygous state) by segregation analysis AND
2.  Presence of viable retinal cells (FDA, 2017) s determined by treating physicians as assessed by optical coherence tomography imaging and/or ophthalmoscopy:
a.  An area of retina within the posterior pole of >100 μm thickness shown on optical coherence tomography, OR
b.  Greater than or equal to 3-disc areas of retina without atrophy or pigmentary degeneration within the posterior pole, OR
c.  Remaining visual field within 30° of fixation as measured by III4e isopter or equivalent AND
C.  Do not have any of the following:
        1.  Pregnancy in females (FDA, 2017) OR
        2.  Breastfeeding (FDA, 2017) OR
        3.  Use of retinoid compounds or precursors that could potentially interact with the biochemical activity of the RPE65 enzyme; individuals who discontinue use of these compounds for 18 months may become eligible. (Ashtari, 2011) OR
        4.  Prior intraocular surgery within 6 months (Ashtari, 2011) OR
        5.  Pre-existing eye conditions or complicating systemic diseases that would preclude the planned surgery or interfere with the interpretation of study. Complicating systemic diseases would include those in which the disease itself, or the treatment for the disease, can alter ocular function. Examples are malignancies whose treatment could affect central nervous system function (e.g., radiotherapy of the orbit; leukemia with central nervous system/optic nerve involvement). Subjects with diabetes or sickle cell disease would be excluded if they had any manifestation of advanced retinopathy (eg, macular edema, proliferative changes). Also excluded would be subjects with immunodeficiency (acquired or congenital) because they could be susceptible to opportunistic infection (eg, cytomegalovirus retinitis) (Ashtari, 2011) OR
        6.  The individual has not had placement of a subconjunctival retinal prostheses (Argus II system) within a year AND
D.  Must be dosed in accordance with the FDA label.
 
Dosing and Administration
Dosing per FDA Guidelines
 
The recommended dose of voretigene neparvovec-rzyl for each eye is 1.5×100 billion vector genomes (vg), administered by subretinal injection in a total volume of 0.3 mL.
 
Subretinal administration of voretigene neparvovec-rzyl to each eye must be performed on separate days within a close interval, but no fewer than 6 days apart.
 
Systemic oral corticosteroids equivalent to prednisone at 1 mg/kg/d (maximum, 40 mg/day) recommended for a total of 7 days (starting 3 days before administration of voretigene neparvovec-rzyl to each eye) and followed by a tapering dose during the next 10 days.
 
Voretigene neparvovec-rzyl is available as a suspension for subretinal injection, supplied in a 0.5 mL extractable volume in a single-dose 2 mL vial for a single administration in one eye. The supplied concentration (5 X 1 trillion vg/mL) requires a 1:10 dilution prior to administration. The Diluent is supplied in two single-use 2-mL vials.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Voretigene neparvovec-rzyl for any indication or circumstance not described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, voretigene neparvovec-rzyl for any indication or circumstance not described above is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
August, 2018 to August 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Voretigene neparvovec-rzyl (Luxturna) adeno-associated virus vector-based gene therapy subretinal injection for patients with vision loss due to biallelic RPE65 variant-associated retinal dystrophy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness when all of the following criteria are met:
    • Children (age 18 years of age or less)
    • Documentation of all of the following:
        1. Genetic testing confirming presence of bilallelic RPE65 pathogenic variant(s)
§ Single RPE65 pathogenic variant found in the homozygous state
§ Two RPE65 pathogenic variants found in the trans configuration (compound heterozygous state) by segregation analysis
2.  Presence of viable retinal cells as determined by treating physicians as assessed by optical coherence tomography imaging and/or ophthalmoscopy:
§ An area of retina within the posterior pole of >100 μm thickness shown on optical   coherence tomography, OR
§ ≥3 disc areas of retina without atrophy or pigmentary degeneration within the posterior pole, OR
§ Remaining visual field within 30° of fixation as measured by III4e isopter or equivalent.
 
    • Do not have any of the following:
        1. Pregnancy in females
        2. Breastfeeding.
        3. Use of retinoid compounds or precursors that could potentially interact with the biochemical activity of the RPE65 enzyme; individuals who discontinue use of these compounds for 18 months may become eligible.
        4. Prior intraocular surgery within 6 months.
        5. Pre-existing eye conditions or complicating systemic diseases that would preclude the planned surgery or interfere with the interpretation of study. Complicating systemic diseases would include those in which the disease itself, or the treatment for the disease, can alter ocular function. Examples are malignancies whose treatment could affect central nervous system function (eg, radiotherapy of the orbit; leukemia with central nervous system/optic nerve involvement). Subjects with diabetes or sickle cell disease would be excluded if they had any manifestation of advanced retinopathy (eg, macular edema, proliferative changes). Also excluded would be subjects with immunodeficiency (acquired or congenital) because they could be susceptible to opportunistic infection (eg, cytomegalovirus retinitis).
        6. The patient has not had placement of a subconjunctival retinal prostheses (Argus II system) within a year.
 
Dosing:
 
The recommended dose of voretigene neparvovec-rzyl for each eye is 1.5×1011 vector genomes (vg), administered by subretinal injection in a total volume of 0.3 mL.
 
Subretinal administration of voretigene neparvovec-rzyl to each eye must be performed on separate days within a close interval, but no fewer than 6 days apart.
 
Systemic oral corticosteroids equivalent to prednisone at 1 mg/kg/d (maximum, 40 mg/d) recommended for a total of 7 days (starting 3 days before administration of voretigene neparvovec-rzyl to each eye), and followed by a tapering dose during the next 10 days.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Voretigene neparvovec-rzyl (Luxturna) for any other indication other than those listed above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, voretigene neparvovec-rzyl (Luxturna) for any other indication other than those listed above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
GENE THERAPY FOR RPE65 VARIANT-ASSOCIATED RETINAL DYSTROPHY
 
Clinical Context and Test Purpose
The purpose of gene therapy in patients who have retinal dystrophies caused by RPE65 variants is to restore the visual cycle so that vision is improved and patients can function more independently in their daily activities. The question addressed in this evidence review is: Does gene augmentation therapy improve the net health outcome for patients with vision loss due to biallelic RPE65 variant-associated retinal dystrophy?
 
The following PICOTS were used to select literature to inform this review.
 
Patients
The relevant population of interest is patients with biallelic RPE65 variant-associated retinal dystrophy who have vision loss. Patients must still have sufficient, viable retinal cells to respond to the missing protein and restore visual function.
 
Interventions
The treatment being considered is gene augmentation therapy.
 
Voretigene neparvovec (Luxturna) is a Food and Drug Administration-approved adeno-associated viral serotype 2 (AAV2) gene therapy vector that supplies a functional copy of the RPE65 gene within the retinal pigment epithelium (RPE) cells.
 
Comparators
There are no other Food and Drug Administration-approved pharmacologic treatments for RPE65 variant-associated retinal dystrophy. Supportive care such as correction of refractive error and visual aids and assistive devices may aid in performing daily activities.
 
Outcomes
Outcomes related to both how the eyes function and how an individual functions in vision-related activities of daily living are important for evaluating the efficacy of gene therapy for the treatment of retinal dystrophy.
 
Because the hallmark of the disease is nyctalopia, the manufacturer developed a novel outcome measure that assesses functional vision by evaluating the effects of illumination on speed and accuracy of navigation. The measure incorporates features of visual acuity (VA), visual field (VF), and light sensitivity. The Multi-Luminance Mobility Test (MLMT) grades individuals navigating a marked path while avoiding obstacles through various courses at 7 standardized levels of illumination, ranging from 1 to 400 lux. Graders monitoring the navigation assign each course either a “pass” or “fail” score, depending on whether the individual navigates the course within 180 seconds with 3 or fewer errors. The lowest light level passed corresponds to an MLMT lux score, which ranges from 0 (400 lux) to 6 (1 lux). The score change is the difference between the MLMT lux score at year 1 and baseline. A positive score change corresponds to passing the MLMT at a lower light level. The reliability and content validity of the MLMT were evaluated in 60 (29 normal sighted, 31 visually impaired) individuals who navigated MLMT courses 3 times over 1 year.20
 
Timing
Improvements in vision and function over a period of a year would demonstrate treatment efficacy. Evidence of durability of these effects over a period of several years or more is also needed given the progressive nature of the disease process.
 
Setting
 
Gene therapy is administered at highly specialized facilities with an active ophthalmology practice treating individuals with retinal dystrophies. Access is needed to medical retina specialists, vitreoretinal surgery expertise, and specialty pharmacies. Training programs for surgeons and pharmacists will likely be necessary.
 
Randomized Controlled Trials
One gene therapy (voretigene neparvovec) for patients with biallelic RPE65 variant-associated retinal dystrophy has RCT evidence. The pivotal RCT (NCT00999609) for voretigene neparvovec was an open-label trial of patients ages 3 or older with biallelic RPE65 variants, VA worse than 20/60, and/or a VF less than 20 degrees in any meridian, with sufficient viable retinal cells (Russell, 2017; Spark Therapeutics, 2017). Those patients meeting these criteria were randomized 2:1 to intervention (n=21) or control (n=10). The trial was conducted at a children’s hospital and university medical center. Patients were enrolled between 2012 and 2013. The intervention treatment group received sequential injections of 1.5E11 vg AAV2-hRPE65v2 (voretigene neparvovec) to each eye no more than 18 days apart (target, 12 days; standard deviation, 6 days). The injections were delivered in a total subretinal volume of 0.3 mL under general anesthesia. The control treatment group received voretigene neparvovec 1 year after the baseline evaluation. Patients received prednisone 1 mg/kg/d (max, 40 mg/d) for 7 days starting 3 days before injection in the first eye and tapered until 3 days before injection of the second eye at which point the steroid regimen was repeated. During the first year, follow-up visits occurred at 30, 90, 180 days, and 1 year. Extended follow-up is planned for 15 years. The efficacy outcomes were compared at 1 year. The primary outcome was the difference in mean bilateral MLMT score change. MLMT graders were masked to treatment group. The trial was powered to have greater than 90% power to detect a difference of 1 light level in the MLMT score at a 2-sided type I error rate of 5%. Secondary outcomes were hierarchically ranked: (1) difference in change in full-field light sensitivity threshold (FST) testing averaged over both eyes for white light; (2) difference in change in monocular (first eye) MLMT score change; (3) difference in change in VA averaged over both eyes. Patient-reported vision-related activities of daily living (ADLs) using a Visual Function Questionnaire (VFQ) and VF testing (Humphrey and Goldmann) were also reported. The VFQ has not been validated.
 
At baseline, the mean age was about 15 years old (range, 4-44 years) and approximately 42% of the participants were male. The MLMT passing level differed between the groups at baseline; about 60% passed at less than 125 lux in the intervention group vs 40% in the control group. The mean baseline VA was not reported but appears to have been between approximately 20/200 and 20/250 based on a figure in the manufacturer briefing document. One patient in each treatment group withdrew before the year 1 visit; neither received voretigene neparvovec. The remaining 20 patients in the intervention treatment and 9 patients in the control treatment groups completed the year 1 study visit. The intention-to-treat population included all randomized patients.
 
In summary, the differences in change in MLMT and FST scores were statistically significant. No patients in the intervention group had worsening MLMT scores at 1 year compared with 3 patients in the control group. Almost two-thirds of the intervention arm showed maximal improvement in MLMT scores (passing at 1 lux) while no participants in the control arm were able to do so. Significant improvements were also observed in Goldmann III4e and Humphrey static perimetry macular threshold VF exams. The difference in change in VA was not statistically significant although the changes correspond to an improvement of about 8 letters in the intervention group and a loss of 1 letter in the control group. The original VA analysis used the Holladay method to assign values to off-chart results. Using, instead the Lange method for off-chart results, the treatment effect estimate was similar, but variability estimates were reduced (difference in change, 7.4 letters; 95% confidence interval [CI], 0.1 to 14.6 letters). No control patients experienced a gain of 15 or more letters (≤0.3 logMAR) at year 1 while 6 of 20 patients in the intervention group gained 15 or more letters in the first eye and 4 patients also experienced this improvement in the second eye. Contrast sensitivity data were collected but were not reported.
 
The manufacturer briefing document reports results out to 2 years of follow-up (Spark Therapeutics). In the intervention group, both functional vision and visual function improvements were observed for at least 2 years. At year 1, all 9 control patients received bilateral injections of voretigene neparvovec. After receiving treatment, the control group experienced improvement in MLMT (change score, 2.1; standard deviation, 1.6) and FST (change, -2.86; standard deviation, 1.49). VA in the control group improved an average of 4.5 letters between years 1 and 2. Overall, 72% (21/29) of all treated patients achieved the maximum possible MLMT improvement at 1 year following injection.
 
Two patients (one in each group) experienced serious adverse events; both were unrelated to study participation. The most common ocular adverse events in the 20 patients treated with voretigene neparvovec were mild to moderate: elevated intraocular pressure, 4 (20%) patients; cataract, 3 (15%) patients; retinal tear, 2 (10%) patients; and eye inflammation, 2 (10%) patients. Several ocular adverse events occurred only in 1 patient each: conjunctival cyst, conjunctivitis, eye irritation, eye pain, eye pruritus, eye swelling, foreign body sensation, iritis, macular hold, maculopathy, pseudopapilledema, and retinal hemorrhage. One patient experienced a loss of VA (2.05 logMAR) in the first eye injected with voretigene neparvovec; the eye was profoundly impaired at 1.95 logMAR (approximately 20/1783 on a Snellen chart) at baseline.
 
Section Summary: Randomized Controlled Trials
In the pivotal RCT, patients in the voretigene neparvovec group demonstrated greater improvements on the MLMT, which measures the ability to navigate in dim lighting conditions, compared with patients in the control group. The difference in mean improvement was both statistically significant and larger than the a priori defined clinically meaningful difference. Most other measures of visual function were also significantly improved in the voretigene neparvovec group compared with the control group, except VA. Improvements seemed durable over a period of 2 years. The adverse events were mostly mild to moderate; however, 1 patient lost 2.05 logMAR in the first eye treated with voretigene neparvovec by the 1 year visit. There are limitations in the evidence. There is limited follow-up available. Therefore, long-term efficacy and safety are unknown. The primary outcome measure has not been used previously in RCTs and has limited data to support its use. Only the MLMT assessors were blinded to treatment assignment, which could have introduced bias assessment of other outcomes. The modified VFQ is not validated, so effects on quality of life remain uncertain.
 
Early Phase Trials
Based on preclinical studies performed in animals, early phase studies of gene augmentation therapy for RPE65-associated Leber congenital amaurosis were initiated in 2007 by several independent groups of investigators. The initial reports of the results of these studies began to be published in 2008. The studies did not have an untreated control group, but several used a patient’s untreated eye as a control. Most cohorts included in the studies have been followed in several publications. The baseline visual function, gene constructs, vector formulations, and surgical approaches used by different investigators have varied. Voretigene neparvovec was administered to the Children’s Hospital of Pennsylvania (CHOP) cohort.
 
Voretigene Neparvovec
CHOP Cohort
Several publications have described various outcomes and subgroups of the cohort included in the phase 1/2 studies of voretigene neparvovec. Early results showed improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, ambulatory behavior) (Maguire, 2009; Simonelli, 2010; Ashtari, 2011). Although the samples were too small for subgroups analyses, the investigators noted that the greatest improvement appeared to be in children. Three-year follow-up of five of the first injected eyes (in patients from Italy) was reported (Testa, 2013). There was a statistically significant improvement in VA between baseline and 3 years (p<0.001). All patients maintained increased VF and a reduction of the nystagmus frequency compared with baseline. Three-year follow-up is also available for both the originally injected eye and contralateral eye in 11 patients (Bennett, 2016). Statistically significant improvements in mean mobility and full-field light sensitivity persisted to year 3. The changes in VA were not significant. Ocular adverse events were mostly mild (dellen formation in 3 patients and cataracts in 2 patients). One patient developed bacterial endophthalmitis.
 
Long-term follow-up for safety was reported in the manufacturer’s Food and Drug Administration briefing documents (Spark Therapeutics, 2017). This follow-up included the 12 patients in the phase 1 study as well as the 29 patients in the phase 3 study. Two phase 2 patients had 9 years of follow-up, 8 patients had 8 years of follow-up, and all 12 patients had at least 7 years of follow-up. Four phase 3 patients had 4 years of follow-up and the remaining patients had between 2 and 3 years of follow-up. No deaths occurred. The adverse events had VA loss at or after the first year. No deleterious immune responses were observed in any patients.
 
Other Gene Therapies
 
London Cohort
At least 4 publications following the London cohort are available (Bainbridge, 2008; Stieger, 2010; Bainbridge, 2015; Ripamonti, 2015). Preliminary results showed increased retinal sensitivity in 1 of 3 participants. After 3 years of follow-up in all 12 patients, 2 patients had substantial improvements (10 to 100 times as high) in rod sensitivity that peaked around 12 months after treatment and then declined. There was no consistent improvement overall in VA. A decline in VA of 15 letters or more occurred in 2 patients. Intraocular inflammation and/or immune responses occurred in 5 of the 8 patients who received the higher dose and in 1 of 4 patients who received the lower dose. The immune response was deleterious in 1 patient.
 
Scheie/Shands Cohort
Results for patients in the Scheie/Shands cohort have also been reported in many publications (Hauswirth, 2008; Cideciyan, 2008; Cideciyan, 2009; Cideciyan, 2009; Jacobson, 2012; Cideciyan, 2013; Cideciyan, 2014; Jacobson, 2015). Visual function was reported to have improved in all patients. Dark-adapted FST showed highly significant increases from baseline in the treated eye and no change in the control eye. Cone and rod sensitivities improved significantly in the treated regions of the retina at 3 months, and these improvements were sustained through 3 years. Small improvements in VA were reported, and the improvement appeared to be largest in eyes with the lowest baseline acuities. Retinal detachment and persistent choroidal effusions were reported in 1 patient each; both were related to surgery. However, at a mean follow-up of 4.6 years, the investigators noted that while improvements in vision were maintained overall, the photoreceptors showed progressive degeneration. In 3 patients followed for 5 to 6 years, improvements in vision appeared to peak between 1 and 3 years after which there was a decline in the area of improved sensitivity in all 3 patients.
 
Israel Cohort
Although the registration for this study indicates that 10 patients were enrolled and followed for 3 years, only the short-term results of 1 patient have been reported (Banin, 2010). In that patient, there was an increase in vision as early as 15 days after treatment.
 
Casey/UMass Cohort
One publication has reported results for the Casey/UMass cohort (Weleber, 2016). In 9 of 12 patients, there was improvement in one or more measures of visual function. VA increased in 5 patients, 30° VF hill of vision increased in 6 patients, total VF hill of vision increased in 5 patients, and kinetic VF area increased in 3 patients. The improvements persisted to 2 years in most patients. NEI VFQ-25 scores improved in 11 of 12 patients. Subconjunctival hemorrhage occurred in 8 patients, and ocular hyperemia occurred in 5 patients.
 
Nantes Cohort
One publication has described results of the Nantes cohort (LeMeur, 2018). In 8 of 9 patients, there was an improvement in VA of more than 2.5 letters at 1 year after injection; improvements were greatest for patients with a baseline VA between 7 and 31 letters and those with nystagmus. After 2 years of follow-up, the surface area of the VF had increased in 6 patients, decreased in 2 patients, and was the same in 1 patient. For the 6 patients with 3 years of follow-up, four continued to have improvements in VF.
 
Section Summary: Early Phase Trials
Voretigene neparvovec appears to have durable effects to at least 3 years in a small number of patients with follow-up.
 
Other gene therapies tested in early phase trials have shown improvements in retinal function but the variable durability of effect; some patients from 2 cohorts who initially experienced improvements have subsequently experienced declines after 1 to 3 years.
 
Adverse events of gene therapy tended to occur early; most are mild to moderate and diminished over time. Seven of 41 patients treated with voretigene neparvovec have had a loss of 15 letters or more in at least 1 eye. Most studies have reported minimal immune response.
 
SUMMARY OF EVIDENCE
For individuals who have vision loss due to biallelic RPE65 variant-associated retinal dystrophy who receive gene therapy, the evidence includes randomized controlled trials and uncontrolled trials. Relevant outcomes are symptoms, morbid events, functional outcomes, quality of life, and treatment-related morbidity. Biallelic RPE65 variant-associated retinal dystrophy is a rare condition and, as such, it is recognized that there will be particular challenges in generating evidence, including recruitment for adequately powered randomized controlled trials, validation of novel outcome measures, and obtaining long‐term data on safety and durability. There are no other Food and Drug Administration-approved pharmacologic treatments for this condition. One randomized controlled trial (N=31) comparing voretigene neparvovec with a control demonstrated greater improvements on the Multi-Luminance Mobility Test, which measures the ability to navigate in dim lighting conditions. Most other measures of visual function were also significantly improved in the voretigene neparvovec group compared with the control group. Adverse events were mostly mild to moderate. However, there is limited follow-up available. Therefore, the long-term efficacy and safety are unknown. Based on a small number of patients from early phase studies, voretigene neparvovec appears to have durable effects to at least 3 years. Other gene therapies tested in early phase trials have shown improvements in retinal function but variable durability of effect; some patients from 2 cohorts who initially experienced improvements have subsequently experienced declines after 1 to 3 years. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.
 
ONGOING AND UNPUBLISHED CLINICAL TRIALS
The following is a list of currently unpublished trials that might influence this review:
 
NCT02781480a   An Open-label, Multi-centre, Phase I/II Dose Escalation Trial of an Adeno Associated
                            Virus Vector for Gene Therapy of Adults And Children With Retinal Dystrophy
                            Associated With Defects in RPE65 (LCA)  
 
  Planned Enrollment: 27   Completion Date: Oct 2018
 
a Denotes industry-sponsored or cosponsored trial.
 
NCT02946879    Long-term Follow-up Study of Participants Following an Open Label, Multi-centre, Phase
                            I/II Dose Escalation Trial of an Adeno-associated Virus Vector (AAV2/5-OPTIRPE65) for
                            Gene Therapy of Adults and Children With Retinal Dystrophy Owing to Defects in
                            RPE65 (LCA2)
 
  Planned Enrollment: 27 Completion Date: Apr 2023
 
2019 Update
A literature search conducted through September 2019 did not reveal any new information that would prompt a change in the coverage statement.
 
2020 Update
Maguire AM, Russell S, Wellman JA, et al. (2019), reported the durability of voretigene neparvovec-rzyl (VN) adeno-associated viral vector–based gene therapy for RPE65 mutation–associated inherited retinal dystrophy (IRD), including results of a phase 1 follow-on study at year 4 and phase 3 study at year 2.
Forty subjects who received 1.5×1011 vector genomes (vg) of VN per eye in at least 1 eye during the trials, including 11 phase 1 follow-on subjects and 29 phase 3 subjects (20 original intervention [OI] and 9 control/intervention.
End points common to the phase 1 and phase 3 studies included change in performance on the Multi-Luminance Mobility Test (MLMT) within the illuminance range evaluated, full-field light sensitivity threshold (FST) testing, and best-corrected visual acuity (BCVA). Safety end points included adverse event reporting, ophthalmic examination, physical examination, and laboratory testing.
Mean (standard deviation) MLMT lux score change was 2.4 at 4 years compared with 2.6 at 1 year after administration in phase 1 follow-on subjects, 1.9 at 2 years, and 1.9 at 1 year post-administration in OI subjects, and 2.1 at 1 year post-administration in CI subjects. All 3 groups maintained an average improvement in FST, reflecting more than a 2 log10(cd.s/m2) improvement in light sensitivity at 1 year and subsequent available follow-up visits. The safety profile was consistent with vitrectomy and the subretinal injection procedure, and no deleterious immune responses occurred.
After VN gene augmentation therapy, there was a favorable benefit-to-risk profile with similar improvement demonstrated in navigational ability and light sensitivity among 3 groups of subjects with RPE65 mutation–associated IRD, a degenerative disease that progresses to complete blindness. The safety profile is consistent with the administration procedure. These data suggest that this effect, which is nearly maximal by 30 days after VN administration, is durable for 4 years, with observation ongoing.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
67299Unlisted procedure, posterior segment
C9399Unclassified drugs or biologicals
J3398Injection, voretigene neparvovec rzyl, 1 billion vector genomes
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Ashtari M, Nikonova ES, Marshall KA, et al.(2017) The role of the human visual cortex in assessment of the long-term durability of retinal gene therapy in follow-on RPE65 clinical trial patients. Ophthalmology. Jun 2017;124(6):873-883. PMID 28237426

Ashtari M, Zhang H, Cook PA, et al.(2015) Plasticity of the human visual system after retinal gene therapy in patients with Leber's congenital amaurosis. Sci Transl Med. Jul 15 2015;7(296):296ra110. PMID 26180100

Astuti GD, Bertelsen M, Preising MN, et al.(2016) Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark. Eur J Hum Genet. Jul 2016;24(7):1071-1079. PMID 26626312

Bainbridge JW, Mehat MS, Sundaram V, et al.(2015) Long-term effect of gene therapy on Leber's congenital amaurosis. N Engl J Med. May 14 2015;372(20):1887-1897. PMID 25938638

Bainbridge JW, Smith AJ, Barker SS, et al. (2008) Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. May 22 2008;358(21):2231-2239. PMID 18441371

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