Summary Basis of Decision for Luxturna

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Luxturna is located below.

Recent Activity for Luxturna

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

The following table describes post-authorization activity for Luxturna, a product which contains the medicinal ingredient voretigene neparvovec. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.

For additional information about the drug submission process, refer to the AnchorAnchorManagement of Drug Submissions and Applications Guidance.

Updated: 2023-10-12

Drug Identification Number (DIN):

DIN 02505851 – 5 × 1012 vector genomes (vg) voretigene neparvovec per mL, solution, subretinal administration

Post-Authorization Activity Table (PAAT)

Activity/Submission Type, Control Number

Date Submitted

Decision and Date

Summary of Activities

NC # 266442

2022-07-26

Issued NOL 2022-09-29

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug substance release or shelf-life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.

NC # 264618

2022-05-26

Issued NOL 2022-08-24

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for changes to the drug substance and drug product release or shelf-life specifications. The submission was reviewed and considered acceptable, and an NOL was issued.

SNDS # 259137

2021-11-29

Issued NOC 2022-04-21

Submission filed as Level II – Supplement (Safety) to update the PM with new safety information and migrate it to the 2020 format. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the Adverse Reactions section of the PM, and corresponding changes were made to Part III: Patient Medication Information and package insert. An NOC was issued.

Drug product (DIN 02505851) market notification

Not applicable

Date of first sale: 2022-03-14

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.

NC # 255433

2021-07-29

Issued NOL 2021-10-14

Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) for a change in the drug product manufacturing process. The submission was reviewed and considered acceptable, and an NOL was issued.

NDS # 233097

2019-10-31

Issued NOC 2020-10-13

NOC issued for New Drug Submission.

 

Summary Basis of Decision (SBD) for Luxturna

Date SBD issued: 2021-05-17

The following information relates to the New Drug Submission for Luxturna.

Voretigene neparvovec

Drug Identification Number (DIN):

  • DIN 02505851 ‑ 5 × 1012 vector genomes (vg) voretigene neparvovec per mL, solution, subretinal administration

Novartis Pharmaceuticals Canada Inc.

New Drug Submission Control Number: 233097

 

On October 13, 2020, Health Canada issued a Notice of Compliance to Novartis Pharmaceuticals Canada Inc. for the drug product Luxturna.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit‑risk profile of Luxturna is favourable for the treatment of adult and pediatric patients with vision loss due to inherited retinal dystrophy caused by confirmed biallelic mutations in the gene encoding retinoid isomerohydrolase (originally identified as retinal pigment epithelium‑specific 65 kDa protein [RPE65]), and who have sufficient viable retinal cells.

Disease‑causing biallelic RPE65 mutations should be confirmed by an accredited laboratory using validated assay methods.

 

1 What was approved?

 

Luxturna, an ophthalmological gene therapy, was authorized for the treatment of adult and pediatric patients with vision loss due to inherited retinal dystrophy caused by confirmed biallelic mutations in the gene encoding retinoid isomerohydrolase (originally identified as retinal pigment epithelium‑specific 65 kDa protein [RPE65]) and who have sufficient viable retinal cells.

Disease-causing biallelic RPE65 mutations should be confirmed by an accredited laboratory using validated assay methods.

Based on the data submitted to and reviewed by Health Canada, the safety and efficacy of Luxturna in pediatric patients under 4 years of age have not been established. Therefore, Health Canada has not authorized an indication for pediatric patients younger than 4 years of age.

No data are available to Health Canada regarding the use of Luxturna in geriatric patients (65 years of age and older). Therefore, Health Canada has not authorized an indication for geriatric use.

Luxturna is contraindicated in patients who are hypersensitive to voretigene neparvovec or to any ingredient in the formulation, including any non‑medicinal ingredients, or components of the container.

Luxturna is also contraindicated in patients with:

  • ocular or periocular infection
  • active intraocular inflammation.

Luxturna was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Luxturna (5 × 1012 vector genomes [vg] of voretigene neparvovec per mL) is presented as a concentrated solution. Two vials of diluent are also supplied. In addition to the medicinal ingredient, the solution contains disodium hydrogen phosphate dihydrate (for pH adjustment), sodium chloride, sodium dihydrogen phosphate monohydrate (for pH adjustment), poloxamer 188, and water for injections. The diluent provided along with Luxturna contains only the non‑medicinal ingredients. Luxturna contains no preservatives. The solution for administration is prepared aseptically as a 1:10 dilution of voretigene neparvovec concentrate in diluent.

For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Luxturna Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Luxturna approved?

 

Health Canada considers that the benefit‑risk profile of Luxturna is favourable for the treatment of adult and pediatric patients with vision loss due to inherited retinal dystrophy caused by confirmed biallelic mutations in the gene encoding retinoid isomerohydrolase (originally identified as retinal pigment epithelium‑specific 65 kDa protein [RPE65]) and who have sufficient viable retinal cells.

Disease-causing biallelic RPE65 mutations should be confirmed by an accredited laboratory using validated assay methods.

Inherited retinal dystrophies are a broad group of genetic retinal disorders that are caused by mutations in any one of over 270 different genes. Among these is the gene encoding the retinoid isomerohydrolase 65 kDa protein (RPE65), which plays a key role in the visual cycle. Mutations in RPE65 lead to reduced or absent levels of retinoid isomerohydrolase, resulting in impairment of vision, and ultimately, complete blindness. Biallelic RPE65 mutation‑associated retinal dystrophy is a very rare genetic condition, with an estimated prevalence of 1 in 200,000 individuals. At the time of authorization of Luxturna, no pharmacological treatments were available in Canada for biallelic RPE65 mutation‑associated retinal dystrophy.

Luxturna (voretigene neparvovec) is an adeno‑associated virus serotype 2 (AAV2) gene therapy vector designed to deliver a normal copy of human RPE65 to retinal cells. Injection of Luxturna into the subretinal space results in the transduction of retinal pigment epithelium (RPE) cells with complementary deoxyribonucleic acid (cDNA) encoding normal human retinoid isomerohydrolase. The expression of normal retinoid isomerohydrolase in these cells enables restoration of the visual cycle.

The clinical efficacy and safety of Luxturna were demonstrated primarily through Study 301; an open‑label, randomized, controlled, Phase III pivotal study in pediatric and adult patients with confirmed biallelic RPE65 mutations. The efficacy and safety were supported by data from patients in the control group who crossed over to receive Luxturna after one year of observation and available annual follow‑up observations of all study subjects. Data from two non‑pivotal Phase I studies, Study 101 and Study 102, were also provided.

Study 301 evaluated the efficacy and safety of Luxturna one year after a single subretinal injection in each eye. Patients randomized to the intervention group received injections of Luxturna in two separate procedures, 6 to 18 days apart. Patients randomized to the control group received no subretinal injection during the first year from baseline.

The primary efficacy endpoint of Study 301 was the change in bilateral multiluminance mobility test (MLMT) scores between baseline and Year 1. The MLMT is a novel endpoint designed and validated to measure functional vision by assessing the ability to navigate an obstacle course across a range of light levels in subjects with inherited retinal dystrophies, such as those with confirmed biallelic RPE65 mutations. The MLMTs were videotaped and assessed by independent graders. Scores were determined based on the lowest level of light at which patients were able to complete the MLMT. A positive change in the score from baseline to Year 1 indicated that the patient was able to complete the MLMT at a lower level of light at the Year 1 visit.

A clinically relevant and statistically significant treatment effect was observed, based on the bilateral MLMT score changes between the two groups. The median (minimum, maximum) score changes were 2 (0, 4) for the intervention group and 0 (‑1, 2) for the control group, resulting in a difference in median of 2 between the two groups (p = 0.001). At Year 1, 11 out of 21 patients (52%) in the intervention group and 1 out of 10 patients (10%) in the control group had a bilateral MLMT score change of 2 or greater compared to baseline.

After one year of observation, nine patients from the control group crossed over to receive treatment with Luxturna and were thereafter known as the control/intervention group. The MLMT score changes observed in the control/intervention group from the crossover to one year after the treatment were comparable to those observed in the intervention group.

All patients in the control/intervention and intervention groups were enrolled in a long‑term follow‑up study. A median bilateral MLMT score change of 2 was observed for treated subjects at all available annual follow‑up visits.

Study 101 was a dose escalation study in which the safety and tolerability of Luxturna were the primary endpoints. Twelve patients (8 to 44 years of age) with RPE65 mutations and sufficient viable retinal cells were enrolled. The retina of each patient was injected with one of three doses of Luxturna. No dose‑dependent effects were observed. The highest dose (1.5 × 1011 vector genomes [vg] per eye) was considered safe and was administered to all patients who participated in Study 102 and the pivotal Phase III study, Study 301. Study 102 involved administering Luxturna to the contralateral, previously uninjected eye of 11 of the 12 patients who participated in Study 101, with safety and tolerability as the primary endpoints. Based on observations from Studies 101 and 102, the parameters of the specialized MLMT course were modified prior to use in subsequent studies.

The clinical safety package submitted included several years of data collected from patients in the Phase I and Phase III studies. Collectively, the data indicated that the benefit‑risk profile of Luxturna is favourable for the intended patient population. Bilateral sequential subretinal administrations of Luxturna were generally well tolerated. The majority of treatment‑emergent adverse events (TEAEs) that were determined to be related to the administration procedure or to the vector were mild or moderate in severity, and occurred during the first year after exposure.

All 41 patients who received Luxturna reported at least one TEAE. The most commonly reported TEAEs (in >30% of patients) were headache, leukocytosis, pyrexia, nasopharyngitis, nausea, cough, and vomiting.

Ocular TEAEs were reported in 30 patients (73%). The most common adverse reactions (in ≥5% of patients) related to the administration procedure were conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), macular hole, retinal deposits, eye inflammation, eye irritation, eye pain, and maculopathy (wrinkling on the surface of the macula). Serious ocular adverse events of foveal thinning/loss of foveal function, increased intraocular pressure, and retinal detachment were reported in three patients, and were considered related or possibly related to the administration procedure. Additionally, adverse events of retinal deposit (subretinal precipitate) were reported in three patients. These were transient and asymptomatic fundoscopic findings, not considered serious, and resolved spontaneously without sequelae.

Vector shedding (detected in tears or serum samples) was transient and mostly occurred between one and three days after administration. Vector DNA was not detected in any whole blood samples during the Phase I and Phase III studies.

A Risk Management Plan (RMP) for Luxturna was submitted by Novartis Pharmaceuticals Canada Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Luxturna Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look‑alike Sound‑alike brand name assessment was performed and the proposed name Luxturna was accepted.

Luxturna has an acceptable safety profile based on the non‑clinical and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Luxturna Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Luxturna?

 

Submission Milestones: Luxturna

Submission Milestone Date
Pre-submission meeting 2019-07-10
Submission filed 2019-10-31
Screening  
Screening Acceptance Letter issued 2019-12-18
Review  
Review of Risk Management Plan complete 2020-08-20
Quality Evaluation complete 2020-10-07
Clinical/Medical Evaluation complete 2020-10-09
Labelling Review complete 2020-10-09
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate 2020-10-13

 

The Canadian regulatory decision on the review of Luxturna was based on a critical assessment of the data package submitted to Health Canada. The foreign reviews completed by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were used as added references.

For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

5 What post-authorization activity has taken place for Luxturna?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product life cycle.

The PAAT for Luxturna is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision

 

Clinical Pharmacology

Luxturna (voretigene neparvovec) is designed to deliver a normal copy of the gene encoding the human retinoid isomerohydrolase (originally identified as retinal pigment epithelium-specific 65 kDa protein [RPE65]) to cells of the retina in persons with reduced, inactive, or absent levels of biologically active retinoid isomerohydrolase. The retinoid isomerohydrolase protein is produced in retinal pigment epithelium (RPE) cells and plays an important role in the visual cycle. Reduced, inactive or absent levels of retinoid isomerohydrolase lead to the impairment of vision, and ultimately, complete blindness.

Formal pharmacokinetic studies of voretigene neparvovec were not conducted. Systemic exposure is expected to be minimal, as Luxturna is administered via subretinal injection.

Biodistribution and vector shedding were evaluated by measuring voretigene neparvovec vector deoxyribonucleic acid (DNA) levels in various tissues and secretions using a quantitative polymerase chain reaction (qPCR) assay. In the pivotal study (Study 301, described in the Clinical Efficacy section), vector DNA levels were measured in tears from both eyes, serum, and whole blood.

Vector DNA was shed transiently and at low levels in tears from the injected eye in 45% of the subjects, and occasionally (7%) from the uninjected eye until Day 3 post-injection. Out of 29 patients who received bilateral injections, vector DNA was present in tear samples of 13 patients (45%). Peak levels of vector DNA were detected on Day 1 post-injection. In the majority of patients (8 out of 13), no vector DNA was detected after this point. Vector DNA was present in the tear samples of three patients (10%) until Day 3 post-injection, and in the tear samples of two patients (7%) for approximately two weeks post-injection.

Vector DNA was detected in serum samples in 3 out of 29 patients (10%), including two patients in whom vector DNA was also present in tear samples up to Day 3 following each injection.

Overall, transient and low levels of voretigene neparvovec vector DNA were found in tear samples and occasional serum samples from 14 out of 29 patients (48%) in the pivotal study.

For further details, please refer to the Luxturna Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Evidence of the clinical efficacy of Luxturna was provided primarily through Study 301; an open-label, randomized, controlled, Phase III pivotal study in pediatric and adult patients with confirmed biallelic RPE65 mutations. It was supported by data from patients in the control group who crossed over to receive Luxturna after one year of observation and available annual follow-up observations of all study subjects. Data from two non-pivotal Phase I studies, Study 101 and Study 102, were also provided.

Pivotal study (Study 301)

The primary objective of Study 301 was to investigate the efficacy of Luxturna one year after a single subretinal injection in each eye of subjects in the intervention group. Patients were randomized in a 2:1 ratio to either the intervention group (21 patients) or the control group (10 patients). One patient in each group discontinued from the study, leaving 20 patients in the intervention group and nine patients in the control group. Patients randomized to the intervention group received a subretinal injection of Luxturna (voretigene neparvovec, 1.5 × 1011 vector genomes [vg] in 0.3 mL solution) to each eye in two separate procedures, six to 18 days apart. Patients randomized to the control group received no subretinal injection.

The primary efficacy endpoint of Study 301 was the change in bilateral multiluminance mobility test (MLMT) scores between baseline and Year 1. The MLMT is a novel endpoint designed and validated to measure functional vision by assessing the ability to navigate an obstacle course across a range of luminance levels in subjects with inherited retinal dystrophies, such as those with confirmed biallelic RPE65 mutations. Each level was assigned a score code, in which a higher score indicates that the patient passed the MLMT at a lower level of light. The MLMTs were videotaped and assessed by independent graders. Scores were determined based on the lowest level of light at which patients were able to complete the MLMT. A positive change in the score from baseline to Year 1 indicated that the patient was able to complete the MLMT at a lower level of light at the Year 1 visit.

A clinically relevant and statistically significant treatment effect was observed, based on an analysis of the bilateral MLMT score changes between the two groups. The median (minimum, maximum) score changes were 2 (0, 4) for the intervention group and 0 (-1, 2) for the control group, resulting in a difference in medians of 2 between the two groups (p = 0.001). At Year 1, 11 out of 21 patients (52%) in the intervention group and 1 out of 10 patients (10%) in the control group had a bilateral MLMT score change of 2 or greater compared to baseline.

Secondary endpoints included the MLMT score change for the first assigned eye, full-field light sensitivity threshold (FST), and visual acuity (VA). The MLMT score changes for the first assigned eye were similar to the bilateral MLMT score changes (the primary endpoint). The median (minimum, maximum) values were 2 (0, 4) for the intervention group and 0 (1, 1) for the control group. The difference in medians between the two groups was 2 (p = 0.003). A clinically meaningful difference was observed with respect to the change in FST between the intervention and control groups from baseline to Year 1 (mean difference [95% confidence interval]: -2.11 [-3.19, -1.04] log10 [cd.s/m2], p <0.001). Although an improvement in VA was observed, it was not statistically significant.

After one year of observation, the nine patients from the control group crossed over to receive treatment with Luxturna and were thereafter known as the control/intervention group. The MLMT score changes observed in the control/intervention group from the crossover to one year after the treatment were comparable to those observed in the intervention group.

All 29 treated patients (20 patients in the intervention group and nine patients in the control/intervention group) were enrolled in a long-term follow-up study. At the time of filing of this submission, 20 patients in the intervention group had completed the study visit at Year 4, and eight patients in the control/intervention group had completed the study visit at Year 3. A median bilateral MLMT score change of 2 was observed for treated subjects at all available annual follow-up visits. The observed improvements in the secondary endpoints were largely maintained over this period.

Non-pivotal studies (Studies 101 and 102)

Study 101 was a dose escalation study in which the safety and tolerability of Luxturna were the primary endpoints. Twelve patients (8 to 44 years of age) with confirmed biallelic RPE65 mutations and sufficient viable retinal cells were enrolled in the study. The worse eye of each patient was injected with one of three doses of Luxturna: 1.5 × 1010 vg/eye (3 patients), 4.8 × 1010 vg/eye (6 patients), and 1.5 × 1011 vg/eye (3 patients). No dose-dependent effects were observed. The highest dose was considered safe, and was administered to all patients who participated in Study 102 and the pivotal Phase III study, Study 301.

Study 102 involved administering Luxturna into the contralateral, previously uninjected eye of 11 of the 12 patients who participated in Study 101, with safety and tolerability as the primary endpoints. The interval between the two injections varied from 1.7 to 4.6 years.

In Studies 101 and 102, various methods were considered for evaluating the efficacy of Luxturna. In both studies, there were consistent changes in FST and in the mobility testing. Based on these findings, the parameters of the specialized MLMT course were modified prior to use in subsequent studies.

All study participants are enrolled in a 15-year long term follow-up study, which requires annual visits with complete ophthalmological examinations and mobility testing. The study is currently ongoing and at the time of authorization of Luxturna, improved functional vision (as measured by MLMT) and overall retinal function (as measured by FST) have been maintained in the majority of patients.

Indication

Health Canada approved the following indication:

  • Luxturna (voretigene neparvovec) is indicated for the treatment of adult and pediatric patients with vision loss due to inherited retinal dystrophy caused by confirmed biallelic RPE65 mutations and who have sufficient viable retinal cells.
     
  • Disease-causing biallelic RPE65 mutations should be confirmed by an accredited laboratory using validated assay methods.

The initially proposed indication was revised to specify that RPE65 mutations should be confirmed, thereby reflecting the patient population in the pivotal study. The RPE65 protein was originally identified as the retinal pigment epithelium-specific 65 kDa protein, and has since been renamed retinoid isomerohydrolase.

For more information, refer to the Luxturna Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Luxturna was evaluated based on data from 41 patients enrolled in the Phase III and Phase I studies, which are described in the Clinical Efficacy section. The dataset from Study 301 included at least four years of data from patients in the intervention group and three years of data from patients in the intervention/control group. Additionally, the dataset included at least seven years of cumulative data from Studies 101 and 102, with at least four years of data following administration to the second eye in Study 102 for all patients. Patients ranged from 4 to 44 years of age, with an average age of 17 years. Pediatric patients (<18 years of age) accounted for 61% of the patient population (25 patients). All but one patient received an injection in both eyes. The authorised dose was administered to 72 eyes, and lower doses were administered to nine eyes.

Bilateral sequential subretinal administrations of Luxturna were generally well tolerated. There were no deaths or discontinuations due to adverse events in any of the clinical studies. The majority of treatment emergent adverse events (TEAEs) were not related to either Luxturna or to the administration procedure. The majority of TEAEs that were determined to be related to the administration procedure or to the vector were mild or moderate in severity and occurred during the first year after exposure.

All 41 (100%) patients who received Luxturna reported at least one TEAE. The most commonly reported TEAEs (in >30% of patients) were headache (51%), leukocytosis (41%), pyrexia (41%), nasopharyngitis (39%), nausea (34%), cough (32%), and vomiting (32%).

Ocular TEAEs were reported in 30 patients (73%). The most common adverse reactions (in ≥5% of patients) related to the administration procedure were conjunctival hyperemia (22%), cataract (22%), increased intraocular pressure (15%), retinal tear (10%), dellen (thinning of the corneal stroma; 7%), macular hole (7%), retinal deposits (7%), eye inflammation (5%), eye irritation (5%), eye pain (5%), and maculopathy (wrinkling on the surface of the macula; 5%). Serious ocular adverse events of foveal thinning/loss of foveal function, increased intraocular pressure, and retinal detachment were reported in three patients, and were considered related or possibly related to the administration procedure. Additionally, adverse events of retinal deposit (subretinal precipitate) were reported in three patients (7%). These were transient and asymptomatic fundoscopic findings, not considered serious, and resolved spontaneously without sequelae.

Immune reactions were mild in severity, and extraocular exposure was limited. No subject had a clinically significant cytotoxic T-cell response to either the adeno-associated virus serotype 2 (AAV2) vector capsid or the retinoid isomerohydrolase protein. The potential immune reaction to either the vector capsid (AAV2) or the transgene product (RPE65) may have been decreased by the systemic administration of corticosteroids before and after subretinal injection of Luxturna in each eye.

Vector shedding (detected in tears or serum samples) was transient and mostly occurred between one and three days after administration. Vector DNA was not detected in any whole blood samples during the Phase I and Phase III studies.

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Luxturna and to support its safe and effective use. Overall, the benefit-risk profile of Luxturna is favourable for the approved indication.

For more information, refer to the Luxturna Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non‑clinical studies on voretigene neparvovec, the medicinal ingredient in Luxturna, support the use of Luxturna for the specified indication.

Transduction of retinal pigment epithelium (RPE) cells with voretigene neparvovec resulted in transgene expression in vitro and in vivo, in RPE65‑deficient models. Subretinal injection of voretigene neparvovec in RPE65‑deficient mouse and dog models resulted in improved visual function.

The biodistribution of voretigene neparvovec was evaluated in normal cynomolgus monkeys three months after subretinal injection. The vector was administered at 3.0 × 1011 vector genomes (vg)/eye in each eye or 7.5 × 1011 vg/eye in one or both eyes. The detected levels of vector DNA were highest in intraocular fluids (vitreous and aqueous humours) of injected eyes. Low levels were also detected in the optic nerve of injected eyes, optic chiasm, spleen, liver, and lymph nodes. In one animal who received a dose of 7.5 × 1011 vg in one eye, low levels of vector DNA were additionally found in the ocular fluids/tissues of the uninjected contralateral eye, and in the stomach, colon, duodenum, and trachea.

Toxicology studies demonstrated that bilateral, simultaneous administration of voretigene neparvovec was well tolerated at a dose of 8.25 × 1010 vg/eye in dogs with a naturally occurring RPE65 mutation and at doses up to 7.5 × 1011 vg/eye (5 times higher than the recommended human dose) in normal‑sighted cynomolgus monkeys. Additionally, bilateral, sequential administration was well tolerated at 1.5 × 1011 vg/eye (the recommended human dose) in RPE65‑deficient dogs and normal‑sighted cynomolgus and rhesus monkeys.

Mild changes were observed in the ocular tissues of dogs and monkeys exposed to voretigene neparvovec, mainly related to surgical trauma. Mild inflammatory responses were also observed in both eyes in dogs and monkeys following bilateral, sequential administrations. Occasional and isolated inflammatory cells were also detected in the retina, with no apparent retinal degeneration. Antibodies to the adeno‑associated virus serotype 2 (AAV2) vector capsid were detected in dogs following a single subretinal administration.

Carcinogenicity and genotoxicity studies were not conducted in connection with this drug submission. Studies evaluating the potential risk of vector integration within the human genome were also not conducted. The Risk Management Plan for Luxturna includes monitoring patients for the onset or exacerbation of cancer.

Reproductive and developmental toxicity studies were not conducted, and the potential for voretigene neparvovec to integrate into the germline has not been evaluated. However, vector DNA sequences were not detected in the ovaries of normal cynomolgus monkeys following subretinal administration. In addition, vector DNA sequences of a similar AAV2 vector were not detected in the ovaries and testes of normal dogs following subretinal administration.

The results of the non‑clinical studies as well as the potential risks to humans have been included in the Luxturna Product Monograph. Appropriate warnings and precautionary measures are in place in the Luxturna Product Monograph to address the identified safety concerns. Considering the intended use of Luxturna, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

For more information, refer to the Luxturna Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

Characterization of the Drug Substance

Voretigene neparvovec, the drug substance, is a recombinant non‑replicating viral vector derived from adeno‑associated virus serotype 2 (AAV2) and designed to deliver the gene encoding the retinoid isomerohydrolase protein (originally identified as retinal pigment epithelium‑specific 65 kDa protein [RPE65]) to retinal pigment epithelium (RPE) cells.

Voretigene neparvovec comprises a single‑stranded DNA genome packed in a non‑enveloped icosahedral capsid consisting of 60 proteins, including VP1, VP2, and VP3 present at a ratio of approximately 1:1:8. The voretigene neparvovec genome encodes the therapeutic gene RPE65 and retains short regions of adeno‑associated virus (AAV) DNA containing inverted terminal repeats (ITRs). These regions are required for packaging of the genome into capsid particles during vector production, and for expression of the therapeutic gene in vivo. Adeno‑associated virus cap and rep genes, respectively encoding capsid proteins and proteins involved in DNA replication, are not a part of voretigene neparvovec. Rather, these genes, and adenovirus type 2 genes required for AAV replication in the host cells, are supplied during voretigene neparvovec manufacture by transient co‑transfection of the host cells with appropriate packaging and helper plasmids.

The structural, physicochemical, and functional characteristics of voretigene neparvovec were analyzed and found to be satisfactory. The vector sequence covering the full therapeutic gene expression cassette was verified.

Process‑derived impurities and product related impurities were identified, and are adequately controlled through the combination of validated clearance by the manufacturing process, in‑process monitoring of appropriate vector substance intermediates, and/or vector product release specification.

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

Voretigene neparvovec bulk (drug substance) and voretigene neparvovec vials (drug product) are manufactured at distinct manufacturing facilities. Voretigene neparvovec and diluent vials are manufactured at the same manufacturing facility. Long term storage and transportation of voretigene neparvovec takes place at ≤‑65°C.

The manufacture of each drug substance lot begins with thawed contents of a qualified cell bank of human embryonic kidney (HEK) 293 cells. The cells undergo expansion, and are propagated in a seed train to provide host cells for multiple product sub‑lots. For each sub‑lot, the cells are co‑transfected with plasmids encoding the necessary viral vector components. The transfected cells are harvested, lysed to release the viral vector, and the resulting cell lysate is clarified by filtration.

Capsid particles are purified from the clarified cell lysate by a process that includes density gradient centrifugation and column chromatography. Sub‑lots of the purified capsid particles are pooled, adjusted for concentration, filtered, dispensed into primary packaging, and shipped to the drug product manufacturing site.

At the drug product manufacturing site, the drug substance is thawed, pooled, filtered, and aseptically dispensed into primary packaging within a controlled environment isolator. The drug product is visually inspected, labelled, and shipped to the finished product manufacturing site.

The diluent that is supplied with Luxturna is formulated, filtered, and aseptically dispensed into primary packaging at the same manufacturing facility as the drug product, using the same equipment and techniques. Vials containing the diluent are visually inspected, labelled, and shipped to the finished product manufacturing site.

At the finished product manufacturing site, one vial of voretigene neparvovec drug product and two vials of the diluent are packaged in a carton, and shipped to the long‑term storage and distribution site.

The operating parameters associated with individual manufacturing steps were described, including the respective set points and control ranges that were appropriately justified. The process execution is monitored at key process intermediates by testing of applicable performance parameters against justified control ranges. Designated critical operations of the manufacturing processes were appropriately validated or characterized. The consistency of the manufacturing processes was confirmed through the execution of process performance qualification (PPQ) runs under nominal manufacturing conditions. Continued process verification was initiated after completion of the PPQ.

The critical starting materials for voretigene neparvovec include the host cell banks that are of human origin and plasmids that are of bacterial origin. Both were adequately described regarding the development, manufacture, and qualification. The routine manufacturing process involves only one raw material of animal origin, fetal bovine serum (FBS). The remaining raw materials are either of synthetic or recombinant bacterial origin.

All non‑medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of voretigene neparvovec with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

The required quality of voretigene neparvovec drug substance and drug product is defined in the provided specification. The specification is a list of tests for product characteristics, indicative of its identity, purity, potency and dosage form properties, with the associated analytical methods and acceptance criteria that were appropriately justified.

Batch analysis data indicate that the drug substance and drug product manufacturing processes operate consistently, and yield product that meets the respective proposed specifications. Overall, the control strategies for the manufacturing processes of the drug substance and drug product were found to be acceptable.

Luxturna is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

No laboratory testing of consistency samples was planned due to the nature of the therapeutic product (viral vector for gene therapy). A request to waive the requirement to provide consistency samples was granted during the pre‑submission meeting.

Stability of the Drug Substance and Drug Product

The proposed shelf‑life and storage conditions for the drug substance, drug product, and diluent were adequately supported by the submitted stability data. Therefore, the proposed shelf‑life of 12 months for the drug substance, and 24 months for the drug product and diluent is acceptable. The drug substance, drug product, and diluent must be stored frozen at ≤‑65°C.

Luxturna should be used immediately following thawing of the vials. If necessary, it may be stored at room temperature (15 °C to 25 °C) for up to four hours prior to administration. The vials should not be refrozen. Additional storage and special handling instructions are included in the Luxturna Product Monograph.

Facilities and Equipment

Based on risk assessment scores determined by Health Canada, an on‑site evaluation (OSE) was recommended for the drug substance manufacturing facility. However, reports from a recent Pre‑Approval Inspection (PAI) of the facility conducted by the United States Food and Drug Administration (US FDA), provided in the submission, addressed all major areas of interest and adequately mitigated the concerns identified in the risk assessment. An OSE was not recommended for the drug product manufacturing facility, based on the formal risk assessment. Therefore, OSEs were not conducted in connection with this drug submission.

Adventitious Agents Safety Evaluation

The master cell bank used in the manufacture of Luxturna was extensively characterized and found to be free from viral contaminants and other adventitious agents. The plasmid cell banks were also characterized and qualified, and detailed histories were provided.

The pre‑harvest cell culture fluid and end‑of‑production cells are tested to ensure freedom from adventitious microorganisms (bioburden, mycoplasma, and viruses). Process‑derived and product‑related impurities are adequately controlled through validated clearance by the manufacturing process, in‑process monitoring of appropriate process intermediates, and/or product release specifications.

The biological raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy or other human pathogens.

 

Report a problem or mistake on this page
Please select all that apply:
Date modified: