LUXTURNA(voretigene neparvovec-rzyl)intraocular suspension forsubretinal injection(七)
ients. Use of LUXTURNA issupported by Study 1 and Study 2 [see Clinical Studies (14)] that included 25 pediatric patients with biallelicRPE65 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 safetybetween 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.
11 DESCRIPTION
LUXTURNA (voretigene neparvovec-rzyl) is a suspension of an adeno-associated virus vector-based genetherapy for subretinal injection. LUXTURNA is a live, non-replicating adeno-associated virus serotype 2 whichhas been genetically modified to express the human RPE65 gene. LUXTURNA is derived from naturallyoccurring adeno-associated virus using recombinant DNA techniques.
Each single-dose vial of LUXTURNA contains 5 x 1012 vector genomes (vg) per mL, and the excipients 180mM sodium chloride, 10 mM sodium phosphate, and 0.001% Poloxamer 188 (pH 7.3), in a 0.5-mL extractablevolume. LUXTURNA requires a 1:10 dilution prior to administration. After dilution, each dose of
LUXTURNA consists of 1.5 x 1011 vg in a deliverable volume of 0.3 mL.
The Diluent, supplied in 1.7 mL extractable volume per vial in two 2-mL vials, is composed of sterile watercontaining 180 mM sodium chloride, 10 mM sodium phosphate, and 0.001% Poloxamer 188 (pH 7.3).
LUXTURNA may also contain residual components of HEK293 cells including DNA and protein and tracequantities of fetal bovine serum.
The product contains no preservative.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
LUXTURNA is designed to deliver a normal copy of the gene encoding the human retinal pigment epithelial 65kDa protein (RPE65) to cells of the retina in persons with reduced or absent levels of biologically activeRPE65. The RPE65 is produced in the retinal pigment epithelial (RPE) cells and converts all-trans-retinol to
11-cis-retinol, which subsequently forms the chomophore, 11-cis-retinal, during the visual (retinoid) cycle. Thevisual cycle is critical in phototransduction, which refers to the biological conversion of a photon of light intoan electrical signal in the retina. Mutations in the RPE65 gene lead to reduced or absent levels of RPE65
isomerohydrolase 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
Biodistribution (within the body) and Vector Shedding (excretion/secretion)LUXTURNA vector DNA levels in various tissues and secretions were determined using a quantitativepolymerase chain reaction (qPCR) assay.
Nonclinical data
Biodistribution of LUXTURNA was eva luated at three months following subretinal administration in nonhumanprimates. The highest levels of vector DNA sequences were detected in intraocular fluids (anteriorchamber fluid and vitreous) of vector-injected eyes. Low levels of vector DNA sequences were detected in theoptic nerve of the vector-injected eye, optic chiasm, spleen and liver, and sporadically in the lymph nodes.
Vector DNA s |
