Medical Policy

Policy Num:      11.003.103
Policy Name:    Gene Therapy for Inherited Retinal Dystrophy
Policy ID:          [11.003.103]  [Ac / B / M+ / P+]  [2.04.144]

Last Review:     February 19, 2025
Next Review:     February 20, 2026

Related Policies:  09.003.002 Retinal Prosthesis

Gene Therapy for Inherited Retinal Dystrophy

Summary

Description

Inherited retinal dystrophy can be caused by recessive variants in the RPE65 gene. Patients with biallelic variants have difficulty seeing in dim light and experience progressive loss of vision. These disorders are rare and have traditionally been considered untreatable. Gene therapy with an adeno-associated virus vector expressing RPE65 has been proposed as a treatment to improve visual function.

Summary of Evidence

For individuals who have vision loss due to biallelic RPE65 variant-associated retinal dystrophy who receive gene therapy, the evidence includes systematic reviews, randomized controlled trials (RCTs), 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. It is recognized that there will be particular challenges in generating evidence for this condition, including recruitment for adequately powered RCTs, validation of novel outcome measures, and obtaining longer-term data on safety and durability. While gene therapy with voretigene neparvovec is approved by the U.S. FDA, there are no other approved pharmacologic treatments for this condition. A recent systematic review found statistically significant improvements in full-field stimulus threshold test (FST) and Multi-Luminance Mobility Test (MLMT) from gene therapy for RPE65-mediated retinal dystrophies; the most common adverse events included ocular hypertension/intraocular pressure increase and ocular pain/discomfort. Another systematic review on gene therapy for RPE65-associated Leber congenital amaurosis (LCA) found an improvement in FST, but not in mobility, visual acuity (VA), or central retinal thickness, while a third systematic review that included the same studies found an improvement of VA and FST for up to 2 years after treatment. One RCT (N=31) comparing voretigene neparvovec with a control demonstrated greater improvements on the MLMT, 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 and the long-term efficacy and safety are unknown. Based on a small number of patients from both early and phase 3 studies, voretigene neparvovec appears to have durable effects to at least 4 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 an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to determine whether gene augmentation therapy improves the net health outcome for patients with vision loss due to biallelic RPE65 variant-associated retinal dystrophy.

Policy Statements

Adeno-associated virus vector-based gene therapy via subretinal injection with voretigene neparvovec is considered medically necessary for individuals with vision loss due to biallelic RPE65 variant-associated retinal dystrophy if they meet all of the following criteria:

• Are adults (age <65 years) or children (age ≥3 years)

• Documentation of the following:

  • Genetic testing confirming presence of biallelic RPE65 pathogenic variant(s) or likely pathogenic variants (see Policy Guidelines for additional details)

    • Single RPE65 pathogenic variant or likely pathogenic variant found in the homozygous state

    • Two RPE65 pathogenic variants or likely pathogenic variants found in the trans configuration (compound heterozygous state) by segregation analysis

  • 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:

  • Pregnancy in females.

  • Breastfeeding.

  • 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.

  • Prior intraocular surgery within 6 months.

  • Preexisting eye conditions or complicating systemic diseases that would preclude the planned surgery or interfere with the interpretation of the 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).

Other applications of voretigene neparvovec are considered investigational.

Policy Guidelines

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) are 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.

Diagnosis of Biallelic RPE65-Mediated Inherited Retinal Dystrophies

Genetic testing is required to detect the presence of pathogenic or likely pathogenic variants in the RPE65 gene in individuals with documented vision loss. By definition, pathogenic or likely pathogenic variant(s) must be present in both copies of the RPE65 gene to establish a diagnosis of biallelic RPE65-mediated inherited retinal dystrophy.

A single RPE65 pathogenic or likely pathogenic variant found in the homozygous state (eg, the presence of the same pathogenic or likely pathogenic variant in both copies of the RPE65 gene) establishes a diagnosis of biallelic RPE65-mediated dystrophinopathy.

However, if 2 different RPE65 pathogenic or likely pathogenic variants are detected (eg, compound heterozygous state), confirmatory testing such as segregation analysis by family studies may be required to determine the trans versus cis configuration (eg, whether the 2 different pathogenic or likely pathogenic variants are found in different copies or in the same copy of the RPE65 gene). The presence of 2 different RPE65 pathogenic or likely pathogenic variants in separate copies of the RPE65 gene (trans configuration) establishes a diagnosis of biallelic RPE65-mediated dystrophinopathy. The presence of 2 different RPE65 pathogenic or likely pathogenic variants in only 1 copy of the RPE65 gene (cis configuration) is not considered a biallelic RPE65-mediated dystrophinopathy.

Next-generation sequencing and Sanger sequencing typically cannot resolve the phase (eg, trans vs.cis configuration) when 2 RPE65 pathogenic or likely pathogenic variants are detected. In this scenario, additional documentation of the trans configuration is required to establish a diagnosis of biallelic RPE65-mediated inherited retinal dystrophy. Table PG1 provides a visual representation of the genetic status requirements to establish a diagnosis of RPE65-mediated inherited retinal dystrophy.

Table PG1. Genetic Diagnosis of RPE65-Mediated Inherited Retinal Dystrophy

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG2). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG3 shows the recommended standard terminology - “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign” - to describe variants identified that cause Mendelian disorders.

Table PG2. Nomenclature to Report on Variants Found in DNA

Table PG3. ACMG-AMP Standards and Guidelines for Variant Classification

   ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

Genetic Counseling

Genetic counseling is primarily aimed at individuals who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual's family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Inherited Retinal Dystrophies

Inherited retinal dystrophies are a diverse group of disorders with overlapping phenotypes characterized by progressive degeneration and dysfunction of the retina.^1, The most common subgroup is retinitis pigmentosa (RP), which is characterized by a loss of retinal photoreceptors, both cones and rods.^2,1, The hallmark of the condition is night blindness (nyctalopia) and loss of peripheral vision. These losses lead to difficulties in performing visually dependent activities of daily living such as orientation and navigation in dimly lit areas. Visual acuity may be maintained longer than peripheral vision, though eventually, most individuals progress to vision loss.

RPE65 Gene

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 RPE65 protein which is an all-trans-retinal isomerase, a key enzyme expressed in the retinal pigment epithelium (RPE) that is responsible for regeneration of 11-cis-retinol in the visual cycle.^3, The RPE65 gene is located on the short (p) arm of chromosome 1 at position 31.3 (1p31.3). Individuals with biallelic variations in RPE65 lack the RPE65 enzyme; this lack leads to build-up of toxic precursors and damage to RPE cells, loss of photoreceptors, and eventually complete blindness.^4,

Epidemiology

RPE65-associated inherited retinal dystrophy is rare. The prevalence of LCA has been estimated to be between 1 in 33,000 and 1 in 81,000 individuals in the United States.^5,6, LCA subtype 2 (RPE65-associated LCA) accounts for between 5% and 16% of cases of LCA.^5,7,8,9, The prevalence of RP in the United States is approximately 1 in 4000 ^2, with approximately 1% of patients with RP having RPE65 variants.^10, Table 1 summarizes the estimated pooled prevalence of RPE-associated inherited retinal dystrophy and the range of estimated cases based on the estimated 2017 United States population.

Table 1. Estimated Pooled Prevalence of RPE65-Associated Inherited Retinal Dystrophy and Estimated Number of Patients

LCA type 2: Leber congenital amaurosis type 2; RP: retinitis pigmentosa.

Gene Therapy

Gene therapies are treatments that change the expression of genes to treat disease, for example, by replacing or inactivating a gene that is not functioning properly or by introducing a new gene. Genes may be introduced into human cells through a vector, usually a virus. Adeno-associated viruses (AAV) are frequently used due to their unique biology and simple structure. These viruses are in the parvovirus family and are dependent on coinfection with other viruses, usually adenoviruses, to replicate. AAVs are poorly immunogenic compared with other viruses but can still trigger an immune response making it a challenge to deliver an effective dose without triggering an immune response that might render the gene therapy ineffective or harm the patient.^4, There are over 100 different AAVs, and 12 serotypes have been identified so far, labeled AAV1 to AAV12; of these, AAV2, AAV5, and AAV8 have been most extensively studied in ocular gene therapies.^11, The recombinant AAV2 is the most commonly used AAV serotype in gene therapy.^12,

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 AAV vectors to transfect cells with a functioning copy of RPE65 in the RPE cells has been investigated.

Regulatory Status

On December 19, 2017, the AAV2 gene therapy vector voretigene neparvovec-rzyl (Luxturna™; Spark Therapeutics) was approved by the U.S. Food and Drug Administration for use in patients with vision loss due to confirmed biallelic RPE65 variant-associated retinal dystrophy.^13, Spark Therapeutics received breakthrough therapy designation, rare pediatric disease designation, and orphan drug designation.

Rationale

This evidence review was created in January 2018 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through December 5, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function—including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. Randomized control trials (RCTs) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

Gene Therapy for RPE65 Variant-Associated Retinal Dystrophy

Clinical Context and Therapy Purpose

The purpose of gene therapy in individuals who have retinal dystrophies caused by RPE65 variants is to restore the visual cycle so that vision is improved and individuals can function more independently in their daily activities.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest is individuals with biallelic RPE65 variant-associated retinal dystrophy who have vision loss. Individuals 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-rzyl (Luxturna) is an U.S. Food and Drug Administration (FDA) approved adeno-associated viral serotype 2 (AAV2) gene therapy vector that supplies a functional copy of the RPE65 gene within retinal pigment epithelium (RPE) cells.

Comparators

There are no other FDA-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. Relevant outcomes measures are listed in Table 2 below.

Table 2. Health Outcome Measures Relevant to Retinal Dystrophy

ETDRS: Early Treatment of Diabetic Retinopathy Study; log10 (cd.s/m2): logarithm of candela second per meter squared; logMAR: logarithm of the minimum angle of resolution; NEI: National Eye Institute; VFQ: Visual Function Questionnaire.

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 (see examples in Table 3). 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 in 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,

Table 3. Light Levels for Multi-Luminance Mobility Test^21,

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.

Study Selection Criteria

In addition to the PICO selection criteria, additional selection criteria for studies to assess a therapy are listed below:

1. To assess efficacy outcomes, seek comparative controlled prospective trials, with preference for randomized controlled trials.

2. In the absence of such trials, seek comparative observational studies, with preference for prospective studies.

3. To assess longer term outcomes and adverse effects, also seek single-arm studies that capture longer periods of follow up and/or larger populations.

4. Consistent with the ‘best available evidence approach’, within each category of study design, prefer larger sample size studies and longer duration studies.

5. Seek to exclude studies with duplicative or overlapping populations.

Review of Evidence

Systematic Reviews

Britten-Jones et al (2022) published a systematic review that summarized gene therapies for monogenic retinal and optic nerve diseases.^22, A total of 151 reports on gene therapies for 16 different genetic variants were included, of which 54 reports concerned gene therapies using AAV-based vectors targeting the RPE65 variant. Seven of the 54 reports were published clinical trials: 1 phase 3 RCT by Russell et al (2017)^14, and 6 single-arm, open-label, phase 1/2 trials in which the untreated eye served as the comparator.^{23,24,25,26,27,28,} These trials are all summarized in the following sections. Statistically significant improvements were found in 2 major outcomes, full-field stimulus threshold (FST) test and mobility evaluation assessed using MLMT. Five of the 7 published trials reported adverse events; the most common adverse events were ocular hypertension/increase in intraocular pressure (16 of 79 patients), ocular pain/discomfort (12 of 79 patients), and the development or worsening of cataracts (7 of 79 patients). The systematic review by Wang et al (2020), summarized below, was also included in the review.^29,Due to significant heterogeneity in the included studies, a pooled meta-analysis was not performed; rather, a visual summary of the outcomes of different trials was presented.

Tuohy et al (2021) conducted a systematic review and meta-analysis that assessed the efficacy of gene therapies for inherited retinal degenerations.^30, Six studies on AAV2-mediated gene therapy in patients with RPE65-associated Leber congenital amaurosis (LCA) were included, by Jacobson et al (2012), Testa et al (2013), Bainbridge et al (2015), Weleber et al (2016), Russell et al (2017), and Le Meur et al (2018); these studies are all summarized in the following sections.^{24,31,27,28,14,23,}FST showed significant improvements with red light (risk ratio [RR], 1.89, treated vs. untreated eye; p=.04) and blue light (RR, 2.01, treated vs. untreated eye; p=.001). Modest (although not statistically significant) improvements were found in VA (weighted mean difference [WMD], -0.06 logMAR improvement over treated vs. untreated eye; 95% confidence interval [CI], -0.14 to 0.02; p=.16), ambulatory navigation/mobility (RR, 1.35; 95% CI,0.78 to 2.35; p=.29), and central retinal thickness (RR, 1.15; 95% CI, 0.45 to 3.00; p=.77). Limitations of the meta-analysis included insufficient number of RCTs (only 1 available) and variability in vector design/amount delivered across trials.

Wang et al (2020) also conducted a systematic review that assessed the association between changes in visual function and application of gene therapy in patients with RPE65-associated LCA.^29, The same 6 studies included in the systematic review by Tuohy et al (2021) were included in this study. A significant improvement in change in VA in the treated eye relative to the untreated eye was found at 1 year (-0.10 logMAR; 95% CI, -0.17 to -0.04; p=.002), but not at 2 to 3 years (WMD, 0.01; 95% CI, -0.00 to 0.02; p=.15) after treatment. At 1 year after treatment, FST sensitivity to blue flashes also improved by 1.60 log (95% CI, 0.66 to 2.55; p=.0009); however, the difference was not statistically significant for red flashes (WMD, 0.86; 95% CI, -0.29 to 2.01; p=.14). Central retinal thickness was, on average, 19.21 μm lower in treated eyes than in untreated eyes (95% CI, -34.22 to -4.20; p=.01) at 2 to 3 years after treatment.

Section Summary: Systematic Reviews

A recent systematic review (N=151 total records) summarized efficacy and safety outcomes from studies on gene therapies for monogenic diseases of the retina and optic nerve. For RPE65-mediated retinal dystrophies, gene therapy showed statistically significant improvements in FST and MLMT, while the most common adverse events were ocular hypertension/increase in intraocular pressure, ocular discomfort/pain, and the development or worsening of cataracts. Another systematic review found an improvement in FST, but not in VA, mobility, or central retinal thickness, with gene therapy treatment for RPE65-associated LCA. A third systematic review found that RPE65-gene therapy for LCA is associated with an improvement of VA and FST in up to 2 years after treatment. Most studies included in these 3 systematic reviews were nonrandomized studies in which the untreated eye served as the comparator.

Randomized Controlled Trials

One gene therapy (voretigene neparvovec) for patients with biallelic RPE65 variant-associated retinal dystrophy has RCT evidence. The pivotal RCT, titled "The efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy" (NCT00999609), 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^o in any meridian, with sufficient viable retinal cells.^14, 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 [SD], 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, and 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 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 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 (range, 4 to 44 ) 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 versus 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 (ITT) population included all randomized patients.

The efficacy outcome results at year 1 for the ITT population are shown in Table 4. 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 participants in 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% CI , 0.1 to 14.6 letters). No patients in the control group 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.

Table 4. Efficacy Outcomes Results at Year 1 in the Pivotal Phase 3 Trial of Gene Therapy for RPE65 Variant-Associated Retinal Dystrophy

CI: confidence interval; FST: full-field light sensitivity threshold; MLMT: Multi-Luminance Mobility Test; NR: not reported; SD: standard deviation; VA: visual acuity; VF: visual field.
^a Corresponds to mean improvement of about 8 letters (ie, »1.5 lines).
^b Corresponds to mean loss of about 1 letter.

The manufacturer briefing document reports results out to 2 years of follow-up.^32, 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; SD, 1.6) and FST (change, -2.86; SD, 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 (1 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.

Maguire et al (2019) published the results of the open-label follow-on phase 1 study at year 4 and the phase 3 study at year 2.^26, Mean (SD) MLMT lux score change was 2.4 (1.3) at 4 years compared with 2.6 (1.6) at 1 year after administration in phase 1 follow-on subjects (n=8). Mean (SD) MLMT lux score change was 1.9 (1.0) at 2 years and 1.9 (1.0) at 1-year post-administration in the original intervention group (n=20). The mean (SD) MLMT lux score change was 2.1 (1.6) at 1-year post-administration in control subjects (n=9). Therefore, durability for up to 4 years has been reported, with observation ongoing.

In 2021, Maguire et al published phase 3 trial results at 3 and 4 years.^33, Mean (SD) MLMT score change at year 4 for patients who received the original intervention (n=21) was 1.7 (1.1) compared to 1.8 (1.0) at year 3. For patients who received delayed intervention after serving as controls for year 1 (n=10), mean (SD) MLMT score change at year 3 was 2.4 (1.5). Therefore, durability of treatment for up to 4 years continues to be reported, with observation ongoing. Overall, 71% of patients with a year 3 visit were able to pass MLMT at the lowest light level. One patient in the original intervention group experienced retinal detachment at year 4.

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 biased assessment of other outcomes. The modified VFQ is not validated, so effects on quality of life remain uncertain. Durability of treatment with respect to MLMT change score has been observed for up to 4 years.

Early Phase Trials

Based on preclinical studies performed in animals, early phase studies of gene augmentation therapy for RPE65-associated LCA 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. Characteristics of the studies are shown in Table 5. 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 cohort.

Table 5. Characteristics of Phase 1/2 studies of Gene Therapy for RPE65 Variant-Associated Retinal Dystrophy

AAV: adeno-associated viruses; CHOP: Children’s Hospital of Pennsylvania; vg: vector genomes; LCA: Leber congenital amaurosis; NCT: national clinical trial; SECORD: severe early-childhood onset retinal degeneration; VA: visual acuity; vg: vector genomes.

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.^{34,25,35,36,37,31,38,39,40,} Early results showed improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, ambulatory behavior).^25,35,36, 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 5 of the first injected eyes (in patients from Italy) was reported.^31, There was a statistically significant improvement in VA between baseline and 3 years (p<.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.^39, 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 FDA briefing documents.^53, 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 tended to occur early and diminish and resolve over time. While all patients experienced at least 1 adverse event, 85% of the adverse events reported were of mild or moderate intensity. Fourteen serious adverse events were reported by 9 patients, but none were assessed as related to the product; 1 was assessed as related to the administration procedure (retinal disorder) and another as related to a periocular steroid injection (increased intraocular pressure). Ocular adverse events that were assessed as related to treatment, required clinical management or impacted the benefit-risk profile occurred in 81 eyes (41 patients): macular disorders (9 eyes, 7 patients), increased intraocular pressure (10 eyes, 8 patients), retinal tear (4 eyes, 4 patients), infections/inflammation (5 eyes, 3 patients), and cataracts (16 eyes, 9 patients). Nine eyes in 7 patients had a 15-letter or more loss in VA. Four of the eyes had VA loss within a month of surgery, and the other 5 eyes 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.^41,42,27,43, 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.^{44,45,46,47,24,48,49,50,} 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.^51, In that patient, there was an increase in vision as early as 15 days after treatment.

Casey/UMass Cohort

Two publications have reported results for the Casey/UMass cohort.^28,52, In 9 of 12 patients, there was improvement in 1 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. National Eye Institute VFQ-25 scores improved in 11 of 12 patients. Subconjunctival hemorrhage occurred in 8 patients, and ocular hyperemia occurred in 5 patients.

Results at 5 years following treatment were available for 11 of 12 patients, with 1 patient lost to follow-up.^52, Improvements in VA and static perimetry persisted during years 3 to 5 in all 4 pediatric patients, with no consistent changes in kinetic perimetry. In 2 of these patients, VA in the untreated eye also improved in years 3 to 5. Most adult subjects had no consistent changes in VA or static perimetry. In 4 of 5 adult subjects with poor baseline VA, progressive loss of vision in 1 or both eyes was noted during years 3 to 5. No significant adverse safety events were observed with results, providing further evidence that treatment at an early age promotes improved outcomes.

Nantes Cohort

One publication has described results of the Nantes cohort.^23, 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, 4 continued to have improvements in VF.

Section Summary: Early Phase Trials

Voretigene neparvovec appears to have durable effects to at least 4 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 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 were 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.

For individuals who have vision loss due to biallelic RPE65 variant-associated retinal dystrophy who receive gene therapy, the evidence includes systematic reviews, randomized controlled trials (RCTs), 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. It is recognized that there will be particular challenges in generating evidence for this condition, including recruitment for adequately powered RCTs, validation of novel outcome measures, and obtaining longer-term data on safety and durability. While gene therapy with voretigene neparvovec is approved by the U.S. FDA, there are no other approved pharmacologic treatments for this condition. A recent systematic review found statistically significant improvements in full-field stimulus threshold test (FST) and Multi-Luminance Mobility Test (MLMT) from gene therapy for RPE65-mediated retinal dystrophies; the most common adverse events included ocular hypertension/intraocular pressure increase and ocular pain/discomfort. Another systematic review on gene therapy for RPE65-associated Leber congenital amaurosis (LCA) found an improvement in FST, but not in mobility, visual acuity (VA), or central retinal thickness, while a third systematic review that included the same studies found an improvement of VA and FST for up to 2 years after treatment. One RCT (N=31) comparing voretigene neparvovec with a control demonstrated greater improvements on the MLMT, 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 and the long-term efficacy and safety are unknown. Based on a small number of patients from both early and phase 3 studies, voretigene neparvovec appears to have durable effects to at least 4 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 an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Institute for Health and Care Excellence

In 2019, NICE published guidance for the use of voretigene neparvovec (Luxturna) in the treatment of inherited retinal dystrophies caused by RPE65 gene mutations.^55, The treatment is recommended for individuals with vision loss caused by inherited retinal dystrophy from confirmed biallelic RPE65 mutations who have sufficient viable retinal cells. Despite uncertainty surrounding long-term durability, the committee felt this intervention is likely to provide important clinical benefits for individuals afflicted with inherited retinal dystrophies.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Interest in gene therapy for inherited retinal dystrophies has grown enormously in recent years; numerous gene therapy treatments (with various targets) are now in different stages of clinical development. Some currently ongoing and unpublished trials that might influence this review are listed in Table 6.

Table 6. Summary of Key Trials

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Policy History