Voretigene Neparvovec

LUXTURNA (voretigene neparvovec-rzyl) is an adeno-associated virus vector-based gene therapy 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). LUXTURNA is an adeno-associated virus vector-based gene therapy 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). ( 1 )

LUXTURNA is a suspension for subretinal injection, supplied in a 0.5-mL extractable volume in a 2-mL single-dose vial; the supplied concentration (5 x 10 12 vg/mL) requires a 1:10 dilution prior to administration. The Diluent is supplied in two single-use 2 mL vials. LUXTURNA is a suspension for subretinal injection, supplied in a 0.5 mL extractable volume in a single-dose 2 mL vial for a single administration in one eye. The supplied concentration (5 x 10 12 vg/mL) requires a 1:10 dilution prior to administration. The Diluent is supplied in two single-use 2-mL vials. ( 3 )

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Endophthalmitis: Use proper aseptic injection technique and monitor for signs and symptoms of infection. ( 5.1 ) Permanent decline in visual acuity: Monitor for visual disturbances. ( 5.2 ) Retinal abnormalities: Monitor for macular abnormalities, retinal tears or breaks and chorioretinal atrophy. Do not inject in the immediate vicinity of the fovea. ( 5.3 ) Increased intraocular pressure: Monitor and manage intraocular pressure elevations. ( 5.4 ) Expansion of intraocular air bubbles: Air travel and/or scuba diving is not recommended until any intraocular air bubbles have been absorbed. ( 5.5 ) Cataract: Subretinal injection of LUXTURNA may result in cataract formation or increase in the rate of cataract progression. ( 5.6 )

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.

The most common adverse reactions (incidence ≥ 5%) 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). The most common adverse reactions (incidence ≥ 5%) 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). ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Spark Therapeutics, Inc. at 1-855-SPARKTX, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 10 11 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. Table 1. Ocular Adverse Reactions Following Treatment with LUXTURNA (N=41) Adverse Reactions Subjects n=41 Treated Eyes n=81 Any ocular adverse reaction 27 (66%) 46 (57%) Conjunctival hyperemia 9 (22%) 9 (11%) Cataract 8 (20%) 15 (19%) Increased intraocular pressure 6 (15%) 8 (10%) Retinal tear 4 (10%) 4 (5%) Dellen (thinning of the corneal stroma) 3 (7%) 3 (4%) Macular hole 3 (7%) 3 (4%) Subretinal deposits* 3 (7%) 3 (4%) Eye inflammation 2 (5%) 4 (5%) Eye irritation 2 (5%) 2 (2%) Eye pain 2 (5%) 2 (2%) Maculopathy (wrinkling on the surface of the macula) 2 (5%) 3 (4%) Foveal thinning and loss of foveal function 1 (2%) 2 (2%) Endophthalmitis 1 (2%) 1 (1%) Foveal dehiscence (separation of the retinal layers in the center of the macula) 1 (2%) 1 (1%) Retinal hemorrhage 1 (2%) 1 (1%) *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).

Pediatric use: Use in infants under 12 months of age is not recommended because of potential dilution or loss of LUXTURNA after administration due to the active retinal cell proliferation occurring in this age group. ( 8.4 )

8.1 Pregnancy Risk Summary Adequate and well-controlled studies with LUXTURNA have not been conducted in pregnant women. Animal reproductive studies have not been conducted with LUXTURNA. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

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.

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.