For subretinal injection only.

2.1 Dose

• The recommended dose of LUXTURNA for each eye is 1.5 x 1011 vector genomes (vg), administered by subretinal injection in a total volume of 0.3 mL.
• Perform subretinal administration of LUXTURNA to each eye on separate days within a close interval, but no fewer than 6 days apart.
• Recommend systemic oral corticosteroids equivalent to prednisone at 1 mg/kg/day (maximum of 40 mg/day) for a total of 7 days (starting 3 days before administration of LUXTURNA to the first eye), and followed by tapering the dose during the following 10 days. The same corticosteroid dosing regimen applies for the administration of LUXTURNA to the second eye. If the corticosteroid taper following LUXTURNA administration to the first eye is not complete three days prior to the planned LUXTURNA administration to the second eye, then the corticosteroid regimen for the second eye replaces the taper for the first eye.

2.2 Preparation

Prepare LUXTURNA within 4 hours of administration using sterile technique under aseptic conditions in a Class II vertical laminar flow biological safety cabinet (BSC). Below is the list of items required for dilution and administration syringe preparation:

• One single-dose vial of LUXTURNA
• Two vials of Diluent
• One 3-mL sterile syringe
• One 20G 1-inch sterile needle
• Three 1-mL sterile syringes
• Three 27G ½-inch sterile needles
• Two sterile syringe caps
• One 10-mL sterile empty glass vial
• One sterile utility drape
• One sterile plastic bag
• Two sterile labels for administration syringes
• One sterile plain label
• One sterile skin marker

Dilution of LUXTURNA

1. Thaw one single-dose vial of LUXTURNA and two vials of Diluent at room temperature.
2. Mix the contents of the thawed Diluent vials by gently inverting them approximately 5 times.
3. Inspect the Diluent vials. If particulates, cloudiness, or discoloration are visible, do not use the vial(s); new vial(s) of Diluent should be used.
4. Obtain a 3-mL sterile syringe, a 20G 1-inch sterile needle, and a 10-mL sterile empty glass vial.
5. Using the 3-mL syringe with 20G 1-inch needle, transfer 2.7 mL of Diluent to the 10-mL glass vial. Dispose of the needle and syringe in an appropriate container.
6. Mix the contents of the thawed LUXTURNA single-dose vial by gently inverting approximately 5 times.
7. Inspect the LUXTURNA single-dose vial. If particulates, cloudiness, or discoloration are visible, do not use the vial; a new single-dose vial of LUXTURNA should be used.
8. Draw 0.3 mL of LUXTURNA into a 1-mL sterile syringe with a 27G ½-inch sterile needle. (Figure 1)

Figure 1. Syringe with 0.3 mL LUXTURNA

         9. Transfer 0.3 mL of LUXTURNA to the glass vial containing 2.7 mL of Diluent from Step 5. Gently invert the 10-mL glass vial approximately 5 times to mix the contents.

         10. Using the sterile plain label and sterile skin marker, label the 10-mL glass vial containing the diluted LUXTURNA as follows: "Diluted LUXTURNA".

         11. Remove all items from the BSC except the glass vial labeled 'Diluted LUXTURNA' and the sterile skin marker.

         12. Re-sanitize the BSC prior to the next steps and place the glass vial and the sterile marker to the left side in the BSC.

Preparation of LUXTURNA for Injection

To keep the syringes sterile, two operators are required for transfer of the contents of the 10-mL glass vial labeled 'Diluted LUXTURNA' into each of two sterile 1-mL syringes.

         13. Place a sterile utility drape, a sterile plastic bag, and two sterile labels into the BSC.

         14. Place the sterile drape near the Primary Operator on the right side of the sanitized BSC surface, away from the diluted LUXTURNA.

         15. The Secondary Operator unwraps two 1-mL syringes, two 27G ½-inch needles, and two syringe caps in the BSC, ensuring that the Primary Operator touches only sterile surfaces while transferring the items onto the sterile drape.

         16. The Secondary Operator changes to a new pair of sterile gloves and stands or sits to the left of the Primary Operator. The Secondary Operator holds the 10-mL glass vial containing the diluted LUXTURNA (Figure 2a).

Figure 2a. First Position of the Operators During Preparation of LUXTURNA Syringes

         17. The Primary Operator withdraws 0.8 mL of the diluted LUXTURNA into a sterile 1-mL syringe using a 27G ½-inch sterile needle while the secondary operator holds the 10-mL glass vial. After the insertion of the needle, the Secondary Operator inverts the 10-mL glass vial enabling the Primary          Operator to withdraw 0.8 mL without touching the 10-mL glass vial (Figure 2b).

Figure 2b. Second Position of the Operators During Preparation of LUXTURNA Syringes

         18. The Primary Operator removes the needle and affixes a sterile cap to the sterile syringe, disposes of the needle in an appropriate container, and attaches a sterile label to the administration syringe.

         19. The Primary Operator repeats Steps 17 and 18 to prepare a total of two administration syringes. Label the first syringe "Diluted LUXTURNA" and label the second syringe "Back-up Diluted LUXTURNA" using the sterile skin marker. The second syringe will serve as a backup for the surgeon    performing the subretinal administration procedure. Discard the back-up syringe after surgery if not used.

         20. Inspect both syringes. If particulates, cloudiness, or discoloration are visible, do not use the syringe.

         21. Place the syringes into the sterile plastic bag after visual inspection and seal the bag.

         22. Place the sterile plastic bag with syringes containing diluted LUXTURNA into an appropriate secondary container (e.g., hard plastic cooler) for delivery to the surgical suite at room temperature.

2.3 Administration

LUXTURNA should be administered in the surgical suite under controlled aseptic conditions by a surgeon experienced in performing intraocular surgery. In addition to the syringe containing the diluted LUXTURNA, the following items are required for administration:

• Subretinal injection cannula with a polyamide micro tip with an inner diameter of 41gauge.
• Extension tube made of polyvinyl chloride no longer than 6" (15.2 cm) in length and with an inner diameter no greater than 1.4mm.

Figure 3. Injection Apparatus Assembly

Follow the steps below for subretinal injection:

1. After confirming the availability of LUXTURNA, dilate the eye and give adequate anesthesia to the patient.
2. Administer a topical broad spectrum microbiocide to the conjunctiva, cornea and eyelids prior to surgery.
3. Inspect LUXTURNA prior to administration. If particulates, cloudiness, or discoloration are visible, do not use the product.
4. Connect the syringe containing the diluted LUXTURNA to the extension tube and subretinal injection cannula. To avoid excess priming volume, the extension tube should not exceed 15.2 cm in length and 1.4 mm in inner diameter. Inject the product slowly through the extension tube and the subretinal injection cannula to eliminate any air bubbles.
5. Confirm the volume of product available in the syringe for injection, by aligning the plunger tip with the line that marks 0.3 mL. (Figure 4)

Figure 4. Volume of LUXTURNA for Injection

            6. After completing a vitrectomy, identify the intended site of administration. The subretinal injection cannula can be introduced via pars plana. (Figure 5a)

            7. Under direct visualization, place the tip of the subretinal injection cannula in contact with the retinal surface. The recommended site of injection is located along the superior vascular arcade, at least 2 mm distal to the center of the fovea (Figure 5b), avoiding direct contact with the retinal vasculature or    with areas of pathologic features, such as dense atrophy or intraretinal pigment migration. Inject a small amount of the product slowly until an initial subretinal bleb is observed. Then inject the remaining volume slowly until the total 0.3 mL is delivered.

Figure 5a. Subretinal Injection Cannula Introduced via Pars Plana

Figure 5b. Tip of the Subretinal Injection Cannula Placed Within the Recommended Site of Injection (Surgeon's Point of View)

            8. After completing the injection, remove the subretinal injection cannula from the eye.

            9. Following injection, discard all unused product. Dispose of the back-up syringe according to local biosafety guidelines applicable for handling and disposal of the product.

            10. Perform a fluid-air exchange, carefully avoiding fluid drainage near the retinotomy created for the subretinal injection.

            11. Initiate supine head positioning immediately in the post-operative period.

            12. Upon discharge, advise patients to rest in a supine position as much as possible for 24 hours.

5.1 Endophthalmitis

Endophthalmitis may occur following any intraocular surgical procedure or injection. Use proper aseptic injection technique when administering LUXTURNA. Following the injection, monitor patients to permit early treatment of any infection. Advise patients to report any signs or symptoms of infection or inflammation without delay.

5.2 Permanent Decline in Visual Acuity

Permanent decline in visual acuity may occur following subretinal injection of LUXTURNA. Monitor patients for visual disturbances.

5.3 Retinal Abnormalities

Retinal abnormalities may occur during or following the subretinal injection of LUXTURNA, including macular holes, foveal thinning, loss of foveal function, foveal dehiscence, chorioretinal atrophy, and retinal hemorrhage. Monitor and manage these retinal abnormalities appropriately. Do not administer LUXTURNA in the immediate vicinity of the fovea [see Dosage and Administration (2.3)].

Retinal abnormalities may occur during or following vitrectomy including retinal tears, epiretinal membrane, or retinal detachment. Monitor patients during and following the injection to permit early treatment of these retinal abnormalities. Advise patients to report any signs or symptoms of retinal tears and/or detachment without delay.

5.4 Increased Intraocular Pressure

Increased intraocular pressure may occur after subretinal injection of LUXTURNA. Monitor and manage intraocular pressure appropriately.

5.5 Expansion of Intraocular Air Bubbles

Instruct patients to avoid air travel, travel to high elevations or scuba diving until the air bubble formed following administration of LUXTURNA has completely dissipated from the eye. It may take one week or more following injection for the air bubble to dissipate. A change in altitude while the air bubble is still present can result in irreversible vision loss. Verify the dissipation of the air bubble through ophthalmic examination.

5.6 Cataract

Subretinal injection of LUXTURNA, especially vitrectomy surgery, is associated with an increased incidence of cataract development and/or progression.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of other products and may not reflect the rates observed in practice.

The safety data described in this section reflect exposure to LUXTURNA in two clinical trials consisting of 41 subjects (81 eyes) with confirmed biallelic RPE65 mutation-associated retinal dystrophy. Forty of the 41 subjects received sequential subretinal injections of LUXTURNA to each eye. One subject received LUXTURNA in only one eye. Seventy-two of the 81 eyes were exposed to the recommended dose of LUXTURNA at 1.5 x 1011 vg; 9 eyes were exposed to lower doses of LUXTURNA. Study 1 (n=12) was an open-label, dose-exploration safety study. Study 2 (n=29) was an open-label, randomized, controlled study for both efficacy and safety [see Clinical Studies (14)]. The average age of the 41 subjects was 17 years, ranging from 4 to 44 years. Of the 41 subjects, 25 (61%) were pediatric subjects under 18 years of age, and 23 (56%) were females.

Twenty-seven (27/41, 66%) subjects had ocular adverse reactions that involved 46 injected eyes (46/81, 57%). Adverse reactions among all subjects in Studies 1 and 2 are described in Table 1. Adverse reactions may have been related to voretigene neparvovec-rzyl, the subretinal injection procedure, the concomitant use of corticosteroids, or a combination of these procedures and products.

*Transient appearance of asymptomatic subretinal precipitates inferior to the retinal injection site 1-6 days after injection

Immunogenicity

At all doses of LUXTURNA evaluated in Studies 1 and 2, immune reactions and extra-ocular exposure were mild. In Study 1 (n=12), the interval between the subretinal injections into the two eyes ranged from 1.7 to 4.6 years. In Study 2, the interval between the subretinal injections into the two eyes ranged from 7 to 14 days. No subject had a clinically significant cytotoxic T-cell response to either AAV2 or RPE65.

Subjects received systemic corticosteroids before and after subretinal injection of LUXTURNA to each eye. The corticosteroids may have decreased the potential immune reaction to either vector capsid (adeno-associated virus serotype 2 [AAV2] vector) or transgene product (retinoid isomerohydrolase RPE65 [RPE65]).

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of LUXTURNA. Because these reactions are reported voluntarily, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Eye Disorders: chorioretinal atrophy (also reported as retinal degeneration, retinal depigmentation, and injection site atrophy).

8.1 Pregnancy

8.2 Lactation

Risk Summary

There is no information regarding the presence of LUXTURNA in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for LUXTURNA and any potential adverse effects on the breastfed infant from LUXTURNA.

8.3 Females and Males of Reproductive Potential

No nonclinical or clinical studies were performed to evaluate the effect of LUXTURNA on fertility.

8.4 Pediatric Use

Treatment with 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 safety and efficacy of LUXTURNA have been established in pediatric patients. Use of LUXTURNA is supported by Study 1 and Study 2 [see Clinical Studies (14)] that included 25 pediatric patients with biallelic RPE65 mutation-associated retinal dystrophy in the following age groups: 21 children (age 4 years to less than 12 years) and 4 adolescents (age 12 years to less than 17 years). There were no significant differences in safety between the different age subgroups.

8.5 Geriatric Use

The safety and effectiveness of LUXTURNA have not been established in geriatric patients. Clinical studies of LUXTURNA for this indication did not include patients age 65 years and over.

12.1 Mechanism of Action

LUXTURNA is designed to deliver a normal copy of the gene encoding the human retinoid isomerohydrolase RPE65 (RPE65) to cells of the retina in persons with reduced or absent levels of biologically active RPE65. The RPE65 is produced in the retinal pigment epithelial (RPE) cells and converts all-trans-retinol to 11-cis-retinol, which subsequently forms the chromophore, 11-cis-retinal, during the visual (retinoid) cycle. The visual cycle is critical in phototransduction, which refers to the biological conversion of a photon of light into an electrical signal in the retina. Mutations in the RPE65 gene lead to reduced or absent levels of retinoid isomerohydrolase RPE65 activity, blocking the visual cycle and resulting in impairment of vision.

12.2 Pharmacodynamics

Injection of LUXTURNA into the subretinal space results in transduction of some retinal pigment epithelial cells with a cDNA encoding normal human RPE65 protein, thus providing the potential to restore the visual cycle.

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No animal studies have been conducted to evaluate the effects of LUXTURNA on carcinogenesis, mutagenesis, and impairment of fertility.

13.2 Animal Toxicology and/or Pharmacology

Bilateral, simultaneous subretinal administration of LUXTURNA was well tolerated at dose levels up to 8.25 x 1010 vg per eye in dogs with a naturally occurring RPE-65 mutation and 7.5 x 1011 vg (5 times higher than the recommended human dose level) per eye in non-human primates (NHPs) with normal-sighted eyes. In both animal models, bilateral, sequential subretinal administrations, where the contralateral eye was injected following the first eye, were well tolerated at the recommended human dose level of 1.5 x 1011 vg per eye. In addition, dogs with the RPE-65 mutation displayed improved visual behavior and pupillary responses. Ocular histopathology showed only mild changes, which were mostly related to healing from the surgical administration procedure. Other findings observed following subretinal injection of LUXTURNA in dogs and NHPs included occasional and isolated inflammatory cells in the retina, with no apparent retinal degeneration. Dogs not previously exposed to AAV2 vectors developed antibodies to the AAV2 capsid following a single administration of LUXTURNA, whereas NHPs did not.