Gene Therapy for Inherited Retinal Dystrophy

POLICY NUMBER

A.2.04.144

Voretigene neparvovec-rzyl (Luxturna

TM

)

DESCRIPTION

Inherited retinal dystrophy can be caused by recessive variants in the RPE65 gene. Individuals 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.

Inherited Retinal Dystrophies

Inherited retinal dystrophies are a diverse group of disorders with overlapping phenotypes characterized by progressive degeneration and dysfunction of the retina. The most common subgroup is retinitis pigmentosa, which is characterized by a loss of retinal photoreceptors, both cones and rods. 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

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 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. 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.

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. LCA subtype 2 (RPE65-associated LCA) accounts for between 5% and 16% of cases of LCA. The prevalence of RP in the United States is approximately 1 in 4,000 with approximately 1% of patients with RP having RPE65 variants. The table below summarizes the estimated pooled prevalence of RPE-associated inherited retinal dystrophy and the range of estimated cases based on the estimated 2017 U.S. population.

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, eg, 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. 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. The recombinant AAV2 is the most commonly used AAV serotype in gene therapy.

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.

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. Spark Therapeutics received breakthrough therapy designation, rare pediatric disease designation, and orphan drug designation.

POLICY

I. Designated and Approved Providers for Immunotherapy and Gene Therapy

Benefits for Immunotherapy and Gene Therapy will not be provided unless Medically Necessary subject to Medical Policy and a treatment plan submitted by the Network Provider and approved by the Company prior to the initiation of treatment. Immunotherapy and Gene Therapy services must be received from a Network Provider designated and approved by the Company where the Company has a contract in place with the Network Provider, either directly or through BlueCard®, for the specific Immunotherapy and Gene Therapy service.

No benefits will be provided unless the Member receives prior authorization through Case Management from Blue Cross & Blue Shield of Mississippi.

II. Medically Necessary Immunotherapy and Gene Therapy

Voretigene neparvovec-rzyl (Luxturna) adeno-associated virus vector-based gene therapy via subretinal injection 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 bilallelic 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 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-rzyl (Luxturna) are considered investigational.

POLICY EXCEPTIONS

Self-Insured Groups

For Federal Employee Program (FEP) subscribers, prior approval is required for gene therapy and cellular immunotherapy.

For State and School Employee subscribers, gene therapy must be certified as medically necessary by the Plan’s Utilization Review Vendor. No benefits will be provided unless prior approval is obtained.

Hood Packaging: Gene therapy and all gene therapy related services are excluded from coverage effective 01/01/2025.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

The recommended dose of voretigene neparvovec-rzyl (Luxturna) 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 (Luxturna) 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 (Luxturna) 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 two different RPE65 pathogenic or likely pathogenic variants are detected (eg, compound heterogygous state), confirmatory testing such as segregation analysis by family studies may be required to determine the trans versus cis configuration (eg, whether the two different pathogenic or likely pathogenic variants are found in different copies or in the same copy of the RPE65 gene). The presence of two 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 two different RPE65 pathogenic or likely pathogenic variants in only one 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 two 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 1 provides a visual representation of the genetic status requirements to establish a diagnosis of RPE65-mediated inherited retinal dystrophy.

Table 1. 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 2). 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 3 shows the recommended standard terminology - “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign” - to describe variants identified that cause Mendelian disorders.

Table 2. Nomenclature to Report on Variants Found in DNA

Table 3. 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.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B. appropriate with regard to standards of good medical practice; and

C. not solely for the convenience of the Member, his or her Provider; and

D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

08/01/2019: New policy added. Approved by Medical Policy Advisory Committee.

12/09/2019: Medically necessary policy statement and policy guidelines updated to include "likely pathogenic variants" as a criteria for individuals with vision loss.

02/13/2020: Policy reviewed; no changes.

03/02/2021: Policy description updated regarding 2020 data. Policy statements unchanged. Policy Guidelines updated to remove genetics nomenclature information.

02/10/2022: Policy description updated regarding the RPE65 gene. Policy statements unchanged. Policy Guidelines updated to add genetics nomenclature and revise genetic counseling information.

02/14/2023: Policy description updated regarding gene therapy. Policy statement updated to change "patients" to individuals." Policy Guidelines updated regarding genetic counseling.

02/21/2024: Policy reviewed; no changes.

01/15/2025: Policy Exceptions updated to add the following for Hood Packaging: Gene therapy and all gene therapy related services are excluded from coverage effective 01/01/2025.

03/11/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.144

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Code

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