Voretigene Neparvovec-rzyl (Ophthalmic) (Monograph)

Brand name: Luxturna
Drug class: Gene Therapy

Introduction

Voretigene neparvovec-rzyl is a recombinant adeno-associated virus serotype 2 (AAV2) vector-based gene therapy that expresses the human RPE65 gene.

Uses for Voretigene Neparvovec-rzyl (Ophthalmic)

Voretigene neparvovec-rzyl has the following uses:

Voretigene neparvovec-rzyl 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). Voretigene neparvovec-rzyl is designated an orphan drug by FDA for this use.

Biallelic RPE65 mutation-associated retinal dystrophy is an autosomal recessive disorder that impairs the visual cycle and causes degeneration of retinal cells. Voretigene neparvovec-rzyl injections into the subretinal space can potentially restore the visual cycle by delivering a functional gene to retinal cells; such therapy has been shown to improve functional vision.

Efficacy of voretigene neparvovec-rzyl was established in an open-label phase 3 randomized trial which randomized 21 patients to subretinal injections of voretigene neparvovec-rzyl and 10 patients to control (no intervention). Bilateral subretinal injections of voretigene neparvovec-rzyl were administered sequentially in two separate surgical procedures with an interval of 6 to 18 days. The primary end point was the change in multi-luminance mobility testing (MLMT) score, a measure of functional vision, from baseline to 1 year after treatment. A median MLMT score change of 2 was observed in the voretigene neparvovec-rzyl group compared to a median MLMT score change of 0 in the control group; the difference was considered clinically meaningful. Voretigene neparvovec-rzyl also has been evaluated in a phase 1 open-label dose-escalation study; data from the phase 1 and phase 3 studies were used to support the efficacy and safety of voretigene neparvovec-rzyl in the pediatric population.

Voretigene Neparvovec-rzyl (Ophthalmic) Dosage and Administration

General

Voretigene neparvovec-rzyl is available in the following dosage form(s) and strength(s):

Voretigene neparvovec-rzyl 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 10¹²vector genome [vg]/mL) requires a 1:10 dilution prior to administration. The Diluent is supplied in two single-use 2-mL vials.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

For subretinal injection only.

• Perform subretinal administration of voretigene neparvovec-rzyl to each eye on separate days within a close interval, but no fewer than 6 days apart.

• The manufacturer recommends administration of 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 voretigene neparvovec-rzyl to each eye), followed by a tapering dose during the next 10 days. The same corticosteroid dosing regimen applies for the administration of voretigene neparvovec-rzyl to the second eye. If the corticosteroid taper following voretigene neparvovec-rzyl administration to the first eye is not complete three days prior to the planned voretigene neparvovec-rzyl administration to the second eye, then the corticosteroid regimen for the second eye replaces the taper for the first eye.

• Dilute voretigene neparvovec-rzyl with the supplied Diluent prior to use. Prepare voretigene neparvovec-rzyl within 4 hours of administration using sterile technique under aseptic conditions in a Class II vertical laminar flow biological safety cabinet (BSC).

• Voretigene neparvovec-rzyl should be administered in the surgical suite under controlled aseptic conditions by a surgeon experienced in performing intraocular surgery.

• For additional details on preparation and administration, consult the Full Prescribing Information.

Pediatric Patients

Dosage

The recommended dose of voretigene neparvovec-rzyl for each eye is 1.5 x 10¹¹ vg, administered by subretinal injection in a total volume of 0.3 mL. Use in pediatric patients younger than 12 months of age is not recommended because of potential dilution or loss of voretigene neparvovec-rzyl after administration due to the active retinal cell proliferation occurring in this age group.

Adults

Dosage

The recommended dose of voretigene neparvovec-rzyl for each eye is 1.5 x 10¹¹ vg, administered by subretinal injection in a total volume of 0.3 mL.

Cautions for Voretigene Neparvovec-rzyl (Ophthalmic)

Contraindications

None.

Warnings/Precautions

Endophthalmitis

Endophthalmitis may occur following any intraocular surgical procedure or injection. Use proper aseptic injection technique when administering voretigene neparvovec-rzyl. 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.

Permanent Decline in Visual Acuity

Permanent decline in visual acuity may occur following subretinal injection of voretigene neparvovec-rzyl. Monitor patients for visual disturbances.

Retinal Abnormalities

Retinal abnormalities may occur during or following the subretinal injection of voretigene neparvovec-rzyl, 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 voretigene neparvovec-rzyl in the immediate vicinity of the fovea.

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.

Increased Intraocular Pressure

Increased intraocular pressure may occur after subretinal injection of voretigene neparvovec-rzyl. Monitor and manage intraocular pressure appropriately.

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 voretigene neparvovec-rzyl 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.

Cataract

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

Specific Populations

Pregnancy

Adequate and well-controlled studies with voretigene neparvovec-rzyl have not been conducted in pregnant women. Animal reproductive studies have not been conducted with voretigene neparvovec-rzyl. 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.

Lactation

There is no information regarding the presence of voretigene neparvovec-rzyl 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 voretigene neparvovec-rzyl and any potential adverse effects on the breastfed infant from voretigene neparvovec-rzyl.

Females and Males of Reproductive Potential

No nonclinical or clinical studies were performed to evaluate the effect of voretigene neparvovec-rzyl on fertility.

Pediatric Use

Treatment with voretigene neparvovec-rzyl is not recommended for patients younger than 12 months of age, because the retinal cells are still undergoing cell proliferation, and voretigene neparvovec-rzyl would potentially be diluted or lost during cell proliferation.

The safety and efficacy of voretigene neparvovec-rzyl have been established in pediatric patients. Use of voretigene neparvovec-rzyl is supported by a phase 1 study and a phase 3 study that included a total of 25 pediatric patients with biallelic RPE65 mutation-associated retinal dystrophy in the following age groups: 21 children (4 years to less than 12 years of age) and 4 adolescents (12 years to less than 17 years of age). There were no significant differences in safety between the different age subgroups.

Geriatric Use

The safety and effectiveness of voretigene neparvovec-rzyl have not been established in geriatric patients. Clinical studies of voretigene neparvovec-rzyl for this indication did not include patients 65 years of age and older.

Common Adverse Effects

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).

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions

Mechanism of Action

Voretigene neparvovec-rzyl 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.

Advice to Patients

• Advise patients and/or their caregivers of the risks of endophthalmitis and other eye infections. Serious infection can occur inside of the eye and may lead to blindness. In such cases, there is an urgent need for management without delay. Advise patients to call their healthcare provider if they experience new floaters, eye pain, or any change in vision.

• Advise patients and/or their caregivers of the risks of permanent decline in visual acuity. This may occur following subretinal injection of voretigene neparvovec-rzyl. Advise patients to contact their healthcare provider if they experience any change in vision.

• Advise patients that treatment with voretigene neparvovec-rzyl may cause some defects in the retina such as a small tear or a hole in the area or vicinity of the injection. Treatment may cause thinning of the central retina, loss of retinal cells and the choroid (layer of blood vessels that line the back of the eye), or bleeding in the retina. Advise patients to follow up with their healthcare provider on a regular basis and report any symptoms such as decreased vision, blurred vision, flashes of light, or floaters in their vision without delay.

• Advise patients that treatment with voretigene neparvovec-rzyl may cause transient or persistent increase in intraocular pressure. If untreated, such increases in intraocular pressure may cause blindness. Advise patients to follow-up with their healthcare provider to detect and treat any increase in intraocular pressure.

• Advise patients to avoid air travel, travel to high elevations, or scuba diving until the air bubble formed following administration of voretigene neparvovec-rzyl has completely dissipated from the eye. A change in altitude while the air bubble is still present may cause irreversible damage.

• Advise patients that following treatment with voretigene neparvovec-rzyl, they may develop a new cataract, or any existing cataract may get worse.

• Advise patients that transient and low level shedding of voretigene neparvovec-rzyl may occur in patient tears. Advise patients and/or their caregivers on proper handling of waste material generated from dressing, tears, and nasal secretion, which may include storage of waste material in sealed bags prior to disposal. These handling precautions should be followed for up to 7 days following voretigene neparvovec-rzyl administration.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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