LUXTURNA, Voretigene Neparvovec-rzyl Form

Voretigene neparvovec-rzyl (Luxturna™) is an adeno-associated virus vector-based gene therapy. FDA Approved Indication(s) Luxturna is indicated for the treatment of patients with confirmed biallelic RPE65 mutation- associated retinal dystrophy. Patients must have viable retinal cells as determined by the treating physician(s). Policy/Criteria Provider must submit documentation (including such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. All requests reviewed under this policy require medical director review. It is the policy of health plans affiliated with Centene Corporation® that Luxturna is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Retinal Dystrophy (must meet all):

1. Diagnosis of retinal dystrophy confirmed by genetic diagnosis of biallelic RPE65 gene mutations;
2. Prescribed by or in consultation with an ophthalmologist;
   3. Age ≥ 3 years;
   4. Member has not previously been treated with Luxturna in the requested treatment eye(s);
3. Sufficient viable retinal cells as evidenced by both of the following (a and b): a. Retinal thickness on spectral domain optical coherence tomography (i.e., areas of retina with thickness measurements > 100 microns within the posterior pole); b. Fundus photography (i.e., presence of neural retina);
4. Significant vision loss as evidenced by at least one of the following (a or b): a. Visual acuity of 20/60 or worse in both eyes (see Appendix D); b. Visual field less than 20 degrees in any meridian (see Appendix D);
5. Member has not received intraocular surgery within prior 6 months;
   8. Full-field stimulus testing (FST) for blue and red light baseline score of > -2.00 log10(cd/m2) (e.g., + 1.00 log10(cd/m2));

6. Dose does not exceed 1.5 x 1011 vector genomes (vg) per eye. Approval duration: 4 weeks (1 lifetime dose per eye)
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   CLINICAL POLICY Voretigene Neparvovec-rzyl B. Other diagnoses/indications (must meet 1 or 2):

7. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or
8. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
   II. Continued Therapy A. Retinal Dystrophy (must meet all):
9. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
10. Greater than 6 days but no more than 18 days have passed since treatment of the first eye;
11. Request is not for a repeat treatment of a previously treated eye (see Appendix D);
    4. Dose does not exceed 1.5 x 1011 vg per eye. Approval duration: 4 weeks (1 lifetime dose per eye) B. Other diagnoses/indications (must meet 1 or 2):

12. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or Page 2 of 8

    CLINICAL POLICY Voretigene Neparvovec-rzyl

13. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
    III. Diagnoses/Indications for which coverage is NOT authorized:
    A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents.
    IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key FDA: Food and Drug Administration FST: full-field stimulus testing MLMT: multi-luminance mobility testing Appendix B: Therapeutic Alternatives
    Not applicable
    Appendix C: Contraindications/Boxed Warnings None reported RP: retinitis pigmentosa VA: visual acuity vg: vector genomes Appendix D: General Information • No clinical data are available on repeat administration of Luxturna to treat an individual eye.
    • Due to significant safety concerns associated with immunogenicity against the vector and/or expressed protein, treatment of the second eye should be within 18 days of treatment of the first eye, but no fewer than 6 days apart. • Due to the safety concerns related to subretinal injection procedure, as well as lack of evidence of clinical benefit in patients with greater baseline visual function than specified in the criteria, only patients with significant vision loss in both eyes are candidates for treatment at this time. • Patients who did not show any viable retinal cells were excluded from the clinical studies of Luxturna and may not benefit from treatment based on its mechanism of action. Viable retinal cells can be determined by the following: o Fundus photography documents the retina, the neurosensory tissue in our eyes through a specialized low power microscope with an attached camera.
    o Optical coherence tomography is a noninvasive imaging test that uses light waves to take cross-section pictures of the retina to visualize the retina’s distinctive layers. • Retinitis pigmentosa (RP) refers to a group of hereditary retinopathies or retinal dystrophies that affects about 2.5 million people worldwide. Mutations in human RPE65 cause Leber congenital amaurosis and other forms of autosomal recessive RP, which are Page 3 of 8

    CLINICAL POLICY Voretigene Neparvovec-rzyl characterized by early-onset blindness. Leber congenital amaurosis occurs in 2 to 3 per 100,000 newborns and it is one of the most common causes of blindness in children.
    • Multi-Luminance Mobility Testing (MLMT) description:
    o The MLMT is a task that challenges a subject to navigate a course independently and accurately under differing light conditions within a time limit. The test is conducted at seven different light levels, from 1 lux to 400 lux, which span a wide range of environmental lighting conditions commonly encountered during the course of everyday activities. o The inclusion criteria in the clinical trial of Luxturna (Study 301) required that the eligible patient be able to perform a standardized MLMT test within the luminance range evaluated, but unable to pass the MLMT at 1 lux, the lowest luminance level tested. Light Level MLMT Lux Score 1 lux 4 lux 10 lux 50 lux 125 lux 250 lux 400 lux 6 5 4 3 2 1 0 • Significant vision loss as evidenced by visual acuity (VA) description: o Visual acuity of 20/60 or worse in both eyes:  Visual acuity can be measured by a Snellen eye test chart or a LogMAR chart.  The Snellen chart has optotypes arranged 5 by 5 on a grid to indicate the letter size. VA is determined by the line that the person can recognize, and if that line is twice as large as the reference standard (20/20), that person’s Magnification Requirement (MAR) is 2x. If the MAR is 2x, the VA is 1/2 (20/40), and would need 2x the magnification. Similarly if the MAR is 3x, the VA is 1/3 (20/60), and would need 3x magnification.
     The LogMAR chart comprises of rows of letters and is used to estimate a more accurate visual acuity than other more commonly used charts (e.g., the Snellen chart). Each letter in the LogMAR chart has a score value of 0.02 log units. Since there are 5 letters per line, the total score for a line on the LogMAR chart represents a change in 0.1 log units. The formula used in calculating the score is: [LogMAR VA = 0.1 + LogMAR value of the best line read – 0.02 X (number of letters read)]. Zero LogMAR indicates standard vision, while zero VA indicates blindness.  The World Health Organization established criteria for low vision using the LogMAR scale, which is defined as a best-corrected visual acuity worse than 0.5 LogMAR but equal or better than 1.3 LogMAR in the better eye. Blindness is defined as a best-corrected visual acuity worse than 1.3 LogMAR. o Visual field less than 20 degrees in any meridian:  Visual field is another distinct measurable function of the eye. It represents the visual area that is perceived simultaneously by a fixating eye. Page 4 of 8

    CLINICAL POLICY Voretigene Neparvovec-rzyl  The field of vision is that portion of space in which objects are visible at the same moment during steady fixation of gaze in one direction. The normal limits of the visual field consists of central vision, which includes the inner 30 degrees of vision and central fixation, and the peripheral visual field, which extends 100 degrees laterally, 60 degrees medially, 60 degrees upward, and 75 degrees downward.  Visual field can be measured by a Goldmann Perimetry Test. • Perimetry measures all areas of eyesight, including side, or peripheral, vision. Goldmann perimetry testing is the most widely used instrument for manual perimetry (meridian). It uses a specific background luminance and a bowl with a specific radius with a dotted stimuli that is used to plot an isopter, which is denoted by: o Roman numerals = 0 to V (size) o Number = 1 to 5 (Luminance) use of filter o Alphabet = a to e use of filter Isopter: The line connecting all points in the visual field with the same threshold for a given test spot; boundary between area of visibility of the area of non-visibility for a particular stimulus. • • Expected findings for normal isopters for those under 50 years of age are: o Peripheral: I-4e o Intermediate: I-3e o Central: I-2e • The visual field is considered abnormal if the threshold values are significantly brighter than the expected values. • Patients with a visual field less than 20 degrees in any meridian as measured by a III4e isopter or equivalent in both eyes show significant vision loss for treatment with Luxturna. • Full-field Light Sensitivity Testing (FST) threshold: o FST is a method to quantify extremely abnormal visual perception, and it tests the patient’s light sensitivity of the entire retina by measuring the patient’s perception of different luminance levels. A light flashes inside of a dome accompanied by a beeping sound, and each time a beep sounds, the patient must indicate whether or not they saw a light by pressing a yes or no button. And this is repeated at different intensities and an algorithm identifies the minimum luminance at which the patient reliably perceives light. o The lower or more negative the FST score, the better the eye light sensitivity, and vice versa.
    o In the Luxturna pivotal trial, all of the patients enrolled and treated had a baseline FST score of -2.00 or higher. According to Klen M. and the Retina Foundation of the Southwest, the median FST threshold of eyes of normal subjects tested were around - 4.8 or lower, while a median threshold value of 0.9 +/- 1.4 log10 (cd/m2) has been reported for patients with severe retinal degenerative disease with light perception. Page 5 of 8

    CLINICAL POLICY Voretigene Neparvovec-rzyl V. Dosage and Administration
    Indication Biallelic RPE65 mutation- associated retinal dystrophy Dosing Regimen 1.5 x 1011 vg administered one time by subretinal injection in a total volume of 0.3 mL per eye Maximum Dose 1.5 x 1011 vg/eye VI. Product Availability
    Single-dose vial: 5 x 1012 AAV2-hRPE65v2 vg/mL VII.