Medical Policies - Prescription Drugs


Voretigene Neparvovec (Luxturna)

Number:RX501.098

Effective Date:06-01-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by the FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

Voretigene neparvovec (Luxturna™) may be considered medically necessary for the treatment of inherited retinal dystrophies (IRD) caused by mutations in the retinal pigment epithelium-specific protein 65kDa (RPE65) gene in patients who meet ALL the following criteria:

Patient is greater than 12 months of age; and

Diagnosis of a confirmed biallelic RPE65 mutation-associated retinal dystrophy (e.g. Leber’s congenital amaurosis [LCA], retinitis pigmentosa [RP] early onset severe retinal dystrophy [EOSRD], etc.); and

Genetic testing documenting biallelic mutations of the RPE65 gene; and

Sufficient viable retinal cells as determined by optical coherence tomography (OCT) confirming an area of retina within the posterior pole of >100 μm thickness; and

Prescribed and administered by ophthalmologist or retinal surgeon with experience providing sub-retinal injections; and

Patient has not previously received RPE65 gene therapy in intended eye.

Voretigene neparvovec (Luxturna™) is considered experimental, investigational, and/or unproven for all other indications.

Description:

Gene therapy is a technique that seeks to prevent or treat genetic conditions by addressing their root cause. There are several approaches to gene therapy such as replacing or inactivating dysfunctional genes or introducing new genes to counteract mutated genes. The new genes create functional proteins that are necessary to restore health. Because the risks of gene therapy are not completely understood, the approach is currently being researched in conditions that have no alternative treatments. Multiple genetic mutations causing inherited retinal dystrophy (IRD) are currently under investigation. (1)

Vector identification is an essential element of gene therapy. Viruses can be used as vectors because they can deliver the new gene and integrate it into the host’s genetic material. The vectors could be administered by injection or intravenously. Voretigene Neparvovec uses the adeno-associated virus (AVV) as a vector to deliver a human derived Retinal Pigment Epithelium 65 (RPE65) gene into retinal cells. These vectors have been studied for over 2 decades and have shown to have an acceptable safety profile. (1, 2)

Gene Therapy for RPE65 IRD

IRDs include a group of rare heritable diseases that cause progressively impaired vision. (2) There are more than 220 known genes that are implicated in IRD. (3) Biallelic RPE65-mediated IRD can be diagnosed as Leber congenital amaurosis (LCA) or retinal pigmentosa (RP). (2) LCA is one of the most severe types of IRD that often presents at birth. RPE65 encodes the enzyme, all-trans-retinyl isomerase, present in photoreceptors that is an essential component for the completion of the visual cycle. In patients with a biallelic mutation in RPE65 this cycle is broken and the toxic precursors for all-trans-retinyl isomerase damage the photoreceptors. By introducing a wildtype copy of the RPE65 gene, the all-trans-retinyl isomerase can be generated so that the visual cycle may be completed. (2, 4)

There are at least 125 identified mutations affecting the RPE65 gene. Most of them have an autosomal recessive pattern of inheritance. Therefore, 2 carriers of the mutated gene would have a 25% chance of having offspring with biallelic RPE65-mediated IRD. (2) Spark Therapeutics predicted that there are approximately 6000 people in the U.S., Europe, Asia/Pacific and other select American markets that have the RPE65 mutation. (5) In the U.S., the prevalence of LCA is 1 in 81,000. The disease is often identified at infancy, though sometimes it does not get discovered until children go to school. Severe and progressive retinal and visual deterioration occurs and almost all patients proceed to total blindness. (2)

Clinical features of this IRD include substantially reduced electroretinogram (ERG), poor visual acuity often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia, and keratoconus. A characteristic finding is Franceschetti's oculo-digital sign, comprising eye poking, pressing, and rubbing. The appearance of the fundus is extremely variable. While the retina may initially appear normal, a pigmentary retinopathy reminiscent of retinitis pigmentosa is frequently observed later in childhood. (6)

Treatment with voretigene neparvovec works through gene augmentation by providing a functional gene to express the normal, functional RPE65 protein in affected cells of the retina. For therapy to be effective, patients must have sufficient viable retinal cells and a genetically confirmed diagnosis. Under general anesthesia, the drug is administered through subretinal injections with a dose of 1.5E11vg/0.3mL. The second eye must be treated between 1 to 18 days after the first eye. (2)

Regulatory Status

On December 19, 2017, voretigene neparvovec (Luxturna™) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with viable retinal cells and confirmed biallelic RPE65 mutation-associated retinal dystrophy.

Per the FDA label, treatment with Voretigene neparvovec (Luxturna™) is not recommended for patients younger than 12 months of age, because the retinal cells are still undergoing cell proliferation, and Luxturna would potentially be diluted or lost during cell proliferation. The subretinal administration of Luxturna to each eye should be performed on separate days, but no less than 6 days apart. (7)

Rationale:

This policy was created in January 2018 based on the United States (U.S.) Food and Drug Administration (FDA) approved labeled indications for Voretigene neparvovec (Luxturna™). Following is the key literature to date.

The safety and efficacy of Luxturna™ was established with 3 open-label studies (2 phase 1 and 1 phase 3). (2)

In the phase 1 studies, Luxturna was evaluated in 12 subjects with biallelic RPE65-mediated IRD. (2) The subjects were predominantly white (92%) and male (58%) with an age range of 8 to 44 years. They received the Luxturna injection in 1 eye and were followed for 1 year prior to getting the injection into their second eye. These studies allowed for dose selection, established a safety profile, and created clear-cut endpoints for the phase 3 trial.

The phase 3 trial was an open-label, randomized controlled study of patients with confirmed biallelic RPE65 mutations. Subjects were randomized 2:1 to voretigene neparvovec or control for 1 year. Subjects were included in the study if they were at least 3 years old, had visual acuity worse than or equal to 20/60 for both eyes and/or a visual field less than 20 degrees in any median. They also had to have sufficient viable retinal cells (area of retina within posterior pole > 100 microns thickness), the ability to comprehend the Multi-Luminance Mobility Test (MLMT), and had an MLMT score worse than 1 lux and accuracy of less than or equal to 1 at 400 lux. (2)

The MLMT, which is an obstacle course, was the tool used to determine efficacy of the treatment. Throughout the study, subjects had to navigate the MLMT independently and accurately under differing light conditions with a 3-minute time limit and a maximum allowance of 3 errors. The MLMT was completed with one eye patched, another MLMT was completed with the other eye patched, and a third MLMT was completed with both eyes open. These attempts were videotaped and scored on a pass/fail basis by 2 masked independent graders. There were 12 different courses with the same number of turns and obstacles. They were conducted at 12 different light levels from 1 lux (moonless summer night) to 400 lux (office environment or food court). (2)

The mean age of the subjects was 15 years with a range of 4 to 44 years. Most of them were white and 40% were male. The clinical presentation at baseline ranged from mild to severe vision impairment. All subjects initially presented with nystagmus and retinal abnormalities. The primary endpoint of the study was a change from baseline at Year 1 in MLMT performance of the intervention group compared to the control group. An improvement of even 1 light level would significantly impact activities of daily living. For instance, is somebody who progressed from 50 lux to 125 lux would gain the ability to safely navigate a bus or train car during an independent commute. The phase 3 study demonstrated a mean difference of MLMT performance score increase of 1.6 levels (p=0.001). These improvements were early as day 30 and were sustained for over 1 year. One year after treatment, 13 of the 20 subjects (65%) in the active group were able to complete the MLMT at the lowest light level of 1 lux; none of the subjects in the control group were able to do this. Overall, 21 of 29 subjects achieved the maximum possible MLMT improvement over 1 year and over 2 years in the original intervention group. (2)

The most common adverse events noted in the clinical trials were conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), macular hole, subretinal deposits, eye inflammation, eye irritation, eye pain, and maculopathy (wrinkling on the surface of the macula). (7)

The authors of the phase 3 clinical trial concluded that treatment with voretigene neparvovec improved light sensitivity, visual fields, and navigational ability under dim light in patients who have no treatment alternatives. (8)

Summary of Evidence

The use of Voretigene neparvovec (Luxturna™) is supported by the United States Food and Drug Administration (FDA) approval status, and clinical trials which demonstrate improved light sensitivity, visual fields, and navigational ability under dim light situations. Additional randomized controlled trials with sufficiently large sample sizes are needed to identify the safety and efficacy for the use of Voretigene neparvovec (Luxturna™) outside of the FDA labeled indication.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

C9032, J3398, J3490

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Genetics Home Reference. United States National Library of Medicine. November 28, 2017. Available at <https://ghr.nlm.nih.gov> (accessed January 2, 2018).

2. Luxturna™. FDA Advisory Committee Briefing Document. Spark Therapeutics. October 12, 2017. Available at <https://www.fda.gov> (accessed January 2, 2018).

3. Press Release: Spark Therapeutics’ Biologics License Application for Investigational Voretigene Neparvovec Accepted for Filing By FDA. Spark Therapeutics. July 17, 2017. Available at <http://ir.sparktx.com> (accessed January 2, 2018).

4. Sundaram V, Moore AT, Ali RR, et al. Retinal dystrophies and gene therapy. Eur J Pediatr. 2012; 171(5):757-65. PMID 22080959

5. Spark Therapeutics. FDA Approves Spark Therapeutics’ Luxturna™ (voretigene neparvovec-rzyl), a One-time Gene Therapy for Patients with Confirmed Biallelic RPE65 Mutation-associated Retinal Dystrophy. December 19, 2017. Available at <http://ir.sparktx.com> (accessed January 3, 2018)

6. Weleber R, Francis P, Trzupek K, et al. Leber Congenital Amaurosis. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; July 2004 (updated May 2, 2013). PMID 20301475.

7. Prescribing Label: Luxturna (voretigene neparvovec-rzyl). United States Food and Drug Administration (2017). Available at <http://www.accessdata.fda.gov> (accessed January 3, 2018)

8. Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017; 390(10097):849-860. PMID 28712537

Policy History:

Date Reason
6/1/2018 New medical document. Voretigene neparvovec (Luxturna™) may be considered medically necessary for the treatment of inherited retinal dystrophies (IRD) caused by mutations in the retinal pigment epithelium-specific protein 65kDa (RPE65) gene in patients who meet ALL the following criteria: Patient is greater than 12 months of age; Diagnosis of a confirmed biallelic RPE65 mutation-associated retinal dystrophy (e.g. Leber’s congenital amaurosis [LCA], retinitis pigmentosa [RP] early onset severe retinal dystrophy [EOSRD], etc.); Genetic testing documenting biallelic mutations of the RPE65 gene; Sufficient viable retinal cells as determined by optical coherence tomography (OCT) confirming an area of retina within the posterior pole of >100 μm thickness; Prescribed and administered by ophthalmologist or retinal surgeon with experience providing sub-retinal injections; Patient has not previously received RPE65 gene therapy in intended eye. Voretigene neparvovec (Luxturna™) is considered experimental, investigational, and/or unproven for all other indications.
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