Voretigene neparvovec

Voretigene neparvovec
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sonya Gelfand

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Overview

Voretigene neparvovec is a adeno-associated virus vector-based gene therapy that is FDA approved for the treatment of confirmed biallelic RPE65 mutation-associated retinal dystrophy in patients who have viable retinal cells as determined by the treating physician(s). Common adverse reactions include 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).

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Dose

• The recommended dose of voretigene neparvovec 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 voretigene neparvovec 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 voretigene neparvovec 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 voretigene neparvovec to the second eye. If the corticosteroid taper following voretigene neparvovec administration to the first eye is not complete three days prior to the planned voretigene neparvovec administration to the second eye, then the corticosteroid regimen for the second eye replaces the taper for the first eye.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding voretigene neparvovec Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding voretigene neparvovec Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

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

Dose

• The recommended dose of voretigene neparvovec 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 voretigene neparvovec 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 voretigene neparvovec 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 voretigene neparvovec to the second eye. If the corticosteroid taper following voretigene neparvovec administration to the first eye is not complete three days prior to the planned voretigene neparvovec administration to the second eye, then the corticosteroid regimen for the second eye replaces the taper for the first eye.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding voretigene neparvovec Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding voretigene neparvovec Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Contraindications

• None.

Warnings

Endophthalmitis

• Endophthalmitis may occur following any intraocular surgical procedure or injection. Use proper aseptic injection technique when administering voretigene neparvovec. 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. Monitor patients for visual disturbances.

Retinal Abnormalities

• Retinal abnormalities may occur during or following the subretinal injection of voretigene neparvovec, including macular holes, foveal thinning, loss of foveal function, foveal dehiscence, and retinal hemorrhage. Monitor and manage these retinal abnormalities appropriately. Do not administer voretigene neparvovec 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. 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 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, especially vitrectomy surgery, is associated with an increased incidence of cataract development and/or progression.

Adverse Reactions

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 voretigene neparvovec 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 voretigene neparvovec to each eye. One subject received voretigene neparvovec in only one eye. Seventy-two of the 81 eyes were exposed to the recommended dose of voretigene neparvovec at 1.5 x 10¹¹ vg; 9 eyes were exposed to lower doses of voretigene neparvovec. 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. 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.

This image is provided by the National Library of Medicine.

Immunogenicity

• At all doses of voretigene neparvovec 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 voretigene neparvovec 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 (retinal pigment epithelial 65 kDa protein [RPE65]).

Postmarketing Experience

There is limited information regarding Voretigene neparvovec Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding Voretigene neparvovec Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

Risk Summary

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

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Voretigene neparvovec in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Voretigene neparvovec during labor and delivery.

Nursing Mothers

Risk Summary

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

Pediatric Use

• Treatment with voretigene neparvovec is not recommended for patients younger than 12 months of age, because the retinal cells are still undergoing cell proliferation, and voretigene neparvovec would potentially be diluted or lost during cell proliferation.
• The safety and efficacy of voretigene neparvovec have been established in pediatric patients. Use of voretigene neparvovec is supported by Study 1 and Study 2 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.

Geriatic Use

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

Gender

There is no FDA guidance on the use of Voretigene neparvovec with respect to specific gender populations.

Race

There is no FDA guidance on the use of Voretigene neparvovec with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Voretigene neparvovec in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Voretigene neparvovec in patients with hepatic impairment.

Females of Reproductive Potential and Males

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

Immunocompromised Patients

There is no FDA guidance one the use of Voretigene neparvovec in patients who are immunocompromised.

Administration and Monitoring

Administration

Preparation

• Prepare voretigene neparvovec 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 voretigene neparvovec
• 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 Voretigene Neparvovec

• Thaw one single-dose vial of voretigene neparvovec and two vials of Diluent at room temperature.
• Mix the contents of the thawed Diluent vials by gently inverting them approximately 5 times.
• 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.
• Obtain a 3-mL sterile syringe, a 20G 1-inch sterile needle, and a 10-mL sterile empty glass vial.
• 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.
• Mix the contents of the thawed voretigene neparvovec single-dose vial by gently inverting approximately 5 times.
• Inspect the voretigene neparvovec single-dose vial. If particulates, cloudiness, or discoloration are visible, do not use the vial; a new single-dose vial of voretigene neparvovec should be used.
• Draw 0.3 mL of voretigene neparvovec into a 1-mL sterile syringe with a 27G ½-inch sterile needle. (Figure 1)

This image is provided by the National Library of Medicine.

• Transfer 0.3 mL of voretigene neparvovec 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.
• Using the sterile plain label and sterile skin marker, label the 10-mL glass vial containing the diluted voretigene neparvovec as follows: ‘Diluted Voretigene Neparvovec’.
• Remove all items from the BSC except the glass vial labeled ‘Diluted Voretigene Neparvovec’ and the sterile skin marker.
• 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 Voretigene Neparvovec for Injection

• To keep the syringes sterile, two operators are required for transfer of the contents of the 10-mL glass vial labeled ‘Diluted Voretigene Neparvovec’ into each of two sterile 1-mL syringes.
• Place a sterile utility drape, a sterile plastic bag, and two sterile labels into the BSC.
• Place the sterile drape near the Primary Operator on the right side of the sanitized BSC surface, away from the diluted voretigene neparvovec.
• 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.
• 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 voretigene neparvovec (Figure 2a).

This image is provided by the National Library of Medicine.

• The Primary Operator withdraws 0.8 mL of the diluted voretigene neparvovec 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).

This image is provided by the National Library of Medicine.

• 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.
• The Primary Operator repeats Steps 17 and 18 to prepare a total of two administration syringes. Label the first syringe “Diluted Voretigene Neparvovec” and label the second syringe “Back-up Diluted Voretigene Neparvovec” 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.
• Inspect both syringes. If particulates, cloudiness, or discoloration are visible, do not use the syringe.
• Place the syringes into the sterile plastic bag after visual inspection and seal the bag.
• Place the sterile plastic bag with syringes containing diluted voretigene neparvovec into an appropriate secondary container (e.g., hard plastic cooler) for delivery to the surgical suite at room temperature.

Administration

• Voretigene neparvovec 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 voretigene neparvovec, 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.

This image is provided by the National Library of Medicine.

• Follow the steps below for subretinal injection:
• After confirming the availability of voretigene neparvovec, dilate the eye and give adequate anesthesia to the patient.
• Administer a topical broad spectrum microbiocide to the conjunctiva, cornea and eyelids prior to surgery.
• Inspect voretigene neparvovec prior to administration. If particulates, cloudiness, or discoloration are visible, do not use the product.
• Connect the syringe containing the diluted voretigene neparvovec 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.
• 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).

This image is provided by the National Library of Medicine.

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

This image is provided by the National Library of Medicine.

This image is provided by the National Library of Medicine.

• After completing the injection, remove the subretinal injection cannula from the eye.
• 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.
• Perform a fluid-air exchange, carefully avoiding fluid drainage near the retinotomy created for the subretinal injection.
• Initiate supine head positioning immediately in the post-operative period.
• Upon discharge, advise patients to rest in a supine position as much as possible for 24 hours.

Monitoring

• Improvement in functional vision indicates efficacy.
• Dissipation of an intraocular air bubble: Via ophthalmic examination prior to air travel, travel to high elevations, or scuba diving.
• Increases in intraocular pressure.
• Retinal abnormalities: During and after injection, including macular holes, foveal thinning, loss of foveal function, foveal dehiscence, retinal hemorrhage, retinal tears, and epiretinal membrane or retinal detachment.
• Signs and symptoms of infection or inflammation.
• Visual disturbances.

IV Compatibility

There is limited information regarding the compatibility of Voretigene neparvovec and IV administrations.

Overdosage

There is limited information regarding Voretigene neparvovec overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

Voretigene neparvovec
Systematic (IUPAC) name
?
Identifiers
CAS number	?
ATC code	S01XA
PubChem	?
Chemical data
Formula	?
Mol. mass	?
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
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Therapeutic considerations
Pregnancy cat.	?(US)
Legal status	[[Prescription drug|Template:Unicode-only]](US)
Routes	subretinal injection

Mechanism of Action

• Voretigene neparvovec is designed to deliver a normal copy of the gene encoding the human retinal pigment epithelial 65 kDa protein (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 chomophore, 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 RPE65 isomerohydrolase activity, blocking the visual cycle and resulting in impairment of vision.

Structure

There is limited information regarding Voretigene neparvovec Structure in the drug label.

Pharmacodynamics

• Injection of voretigene neparvovec 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.

Pharmacokinetics

Biodistribution (within the body) and Vector Shedding (excretion/secretion)

• Voretigene neparvovec vector DNA levels in various tissues and secretions were determined using a quantitative polymerase chain reaction (qPCR) assay.

Nonclinical data

• Biodistribution of voretigene neparvovec was evaluated at three months following subretinal administration in non-human primates. The highest levels of vector DNA sequences were detected in intraocular fluids (anterior chamber fluid and vitreous) of vector-injected eyes. Low levels of vector DNA sequences were detected in the optic nerve of the vector-injected eye, optic chiasm, spleen and liver, and sporadically in the lymph nodes. Vector DNA sequences were not detected in the gonads.

Clinical data

• Voretigene neparvovec vector shedding and biodistribution were investigated in a study measuring voretigene neparvovec DNA in tears from both eyes, and from serum, and whole blood of subjects in Study 2. In summary, voretigene neparvovec vector was shed transiently and at low levels in tears from the injected eye in 45% of the subjects in Study 2, and occasionally (7%) from the uninjected eye until Day 3 post-injection.
• In 29 subjects who received bilateral administrations, voretigene neparvovec vector DNA was present in tear samples of 13 subjects (45%). Peak levels of vector DNA were detected in the tear samples on Day 1 post-injection, after which no vector DNA was detected in a majority of the subjects (8 of 13). Three subjects (10%) had vector DNA in tear samples until Day 3 post-injection, and two subjects (7%) had vector DNA in tear samples for around two weeks post-injection. In another two subjects (7%), vector DNA was detected in tear samples from the uninjected (or previously injected) eye until Day 3 post-injection. Vector DNA was detected in serum in 3/29 (10%) subjects, including two with vector DNA in tear samples up to Day 3 following each injection.

Specific Populations

• No pharmacokinetic studies with voretigene neparvovec have been conducted.

Drug Interaction Studies

• No interaction studies have been performed with voretigene neparvovec.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Animal Toxicology and/or Pharmacology

• Bilateral, simultaneous subretinal administration of voretigene neparvovec 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 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 voretigene neparvovec 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 voretigene neparvovec, whereas NHPs did not.

Clinical Studies

• The efficacy of voretigene neparvovec in pediatric and adult patients with biallelic RPE65 mutation-associated retinal dystrophy was evaluated in an open-label, two-center, randomized trial (Study 2). Of the 31 enrolled subjects, 21 subjects were randomized to receive subretinal injection of voretigene neparvovec. One subject discontinued from the study prior to treatment. Ten subjects were randomized to the control (non-intervention) group. One subject in the control group withdrew consent and was discontinued from the study. The nine subjects who were randomized to the control group were crossed over to receive subretinal injection of voretigene neparvovec after one year of observation. The average age of the 31 randomized subjects was 15 years (range 4 to 44 years), including 64% pediatric subjects (n=20, age from 4 to 17 years) and 36% adults (n=11). The 31 randomized subjects included 13 males and 18 females. Sixty-eight percent (68%) of the subjects were White, 16% were Asian, 10% were American Indian or Alaska Native, and 6% were Black or African-American. Bilateral subretinal injections of voretigene neparvovec were administered sequentially in two separate surgical procedures with an interval of 6 to 18 days.
• The efficacy of voretigene neparvovec was established on the basis of multi-luminance mobility testing (MLMT) score change from Baseline to Year 1. The MLMT was designed to measure changes in functional vision, as assessed by the ability of a subject to navigate a course accurately and at a reasonable pace at different levels of environmental illumination. The MLMT was assessed using both eyes and each eye separately at one or more of seven levels of illumination, ranging from 400 lux (corresponding to a brightly lit office) to 1 lux (corresponding to a moonless summer night). Each light level was assigned a score code ranging from 0 to 6. A higher score indicated that a subject was able to pass the MLMT at a lower light level. A score of -1 was assigned to subjects who could not pass MLMT at a light level of 400 lux. The MLMT of each subject was videotaped and assessed by independent graders. The MLMT score was determined by the lowest light level at which the subject was able to pass the MLMT. The MLMT score change was defined as the difference between the score at Baseline and the score at Year 1. A positive MLMT score change from Baseline to Year 1 visit indicated that the subject was able to complete the MLMT at a lower light level.
• Additional clinical outcomes were also evaluated, including full-field light sensitivity threshold (FST) testing, visual acuity, and visual fields.
• Table 2 summarizes the median MLMT score change from Baseline to Year 1 in the voretigene neparvovec treatment group as compared to the control group. A median MLMT score of 2 or greater was observed in the voretigene neparvovec treatment group, while a median MLMT score change of 0 was observed in the control group, when using both eyes or the first-treated eye. An MLMT score change of two or greater is considered a clinically meaningful benefit in functional vision.

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• Table 3 shows the number and percentage of subjects with different magnitudes of MLMT score change using both eyes at Year 1. Eleven of the 21 (52%) subjects in the voretigene neparvovec treatment group had an MLMT score change of two or greater, while one of the ten (10%) subjects in the control group had an MLMT score change of two.

This image is provided by the National Library of Medicine.

• Figure 6 shows MLMT performance of individual subjects using both eyes at Baseline and at Year 1.

This image is provided by the National Library of Medicine.

• Analysis of white light FST testing showed statistically significant improvement from Baseline to Year 1 in the voretigene neparvovec treatment group compared to the control group. The change in visual acuity from Baseline to Year 1 was not significantly different between the voretigene neparvovec and control groups.
• Figure 7 shows the effect of voretigene neparvovec over the two-year period in the voretigene neparvovec treatment group, as well as the effect in the control group after crossing over to receive subretinal injection of voretigene neparvovec. A median MLMT score change of two was observed for the voretigene neparvovec treatment group at Day 30, and this effect was sustained over the remaining follow-up visits throughout the two-year period. For the control group, a median MLMT score change of 0 was observed at all four follow-up visits during the first year. However, after crossing-over to receive subretinal injection of voretigene neparvovec, the subjects in the control group showed a similar response to voretigene neparvovec as compared to the subjects in the voretigene neparvovec treatment group.

This image is provided by the National Library of Medicine.

How Supplied

• Each carton of voretigene neparvovec (NDC 71394 – 415-01) contains one single-dose vial of the voretigene neparvovec (NDC 71394 – 065-01, 0.5 mL extractable volume) and two vials of Diluent (NDC 71394 – 716-01, 1.7 mL extractable volume in each vial). Voretigene neparvovec contains 5 x 10¹² vector genomes (vg) per mL, requires a 1:10 dilution prior to administration.

Storage

• Store voretigene neparvovec and Diluent frozen at ≤ -65 °C.
• Following thaw of the vials, store at room temperature. Store diluted voretigene neparvovec at room temperature.
• Voretigene neparvovec is an adeno-associated virus vector-based gene therapy. Follow universal biohazard precautions for handling.

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Patient Counseling Information

• Advise patients and/or their caregivers of the following risks.
• 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.

• Permanent decline in visual acuity

• Permanent decline in visual acuity may occur following subretinal injection of voretigene neparvovec. Advise patients to contact their healthcare provider if they exprience any change in vision.

• Retinal abnormalities

• Treatment with voretigene neparvovec 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 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.

• Increased intraocular pressure

• Treatment with voretigene neparvovec 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.

• Expansion of intraocular air bubbles

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

• Cataract

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

• Shedding of voretigene neparvovec

• Transient and low level shedding of voretigene neparvovec 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 administration.

Precautions with Alcohol

Alcohol-Voretigene neparvovec interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

• Luxturna

Look-Alike Drug Names

There is limited information regarding Voretigene neparvovec Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.