Luxturna
voretigene neparvovec
Sources:FDA pharmacology/toxicology review ↗EMA assessment report ↗US prescribing information ↗FDA summary basis for approval ↗
Species
MonkeyDog
Longest study
31 wk
Genotox
Not conducted Not conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Dog (normal-sighted and RPE65-mutant Briard) and non-human primate
“Single dose and repeat dose toxicology studies were conducted in normal-sighted dogs, RPE65 mutant dogs, and normal-sighted non-human primates (NHPs).”
Why that species
RPE65-/- Briard dog is a natural large-animal disease model; eye size makes dog more relevant than mouse
“The applicant noted that relative transduction efficiency of AAV2 in RPE cells across species is not known but that, given the sizes of eye in dog and mouse, the studies in Briard dogs are more relevant to human effects than those in mice”
Surrogate molecule
Yes: precursor vector AAV2-hRPE65v1 (low RPE65 expression) used in GLP dog studies; clinical vector in NHP and re-dosing studies
“Thus, any potential toxicity due to the RPE65 protein cannot be adequately assessed using this vector construct.”
Species: general tox
Dog (normal-sighted and RPE65-mutant) and non-human primate
“Single dose and repeat dose toxicology studies were conducted in normal-sighted dogs, RPE65 mutant dogs, and normal-sighted non-human primates (NHPs).”
Species: DART
Not conducted
“Animal reproductive studies have not been conducted with LUXTURNA.”
Species: carcinogenicity
Not conducted
“No animal studies have been conducted to evaluate the effects of LUXTURNA on carcinogenesis, mutagenesis, and impairment of fertility.”
Surrogate used in
Yes: early dog efficacy studies used a vector encoding canine RPE65; later studies used the human RPE65 vector
“In some of the early studies in dogs, the virus used encoded for canine RPE65 and not human RPE65; however, latterly, virus encoding human RPE65 (hRPE65) was also used in mice and dogs.”
Study lengthopen answer page →
Longest pivotal study
31 weeks
“Scheduled Sacrifice Time Points Days 190 (two animals) and 217 (two animals)”
Pivotal GLP studies
Subretinal single-dose GLP dog 3-week/3-month; NHP 3-month; bilateral sequential and re-administration studies in dogs and NHP
“In these studies, virus was injected subretinally either once only, or once into each eye, and twice into the same eye.”
Route in tox
Subretinal (clinical route); intravitreal also tested in dog studies
“To determine the acute toxicity of AAV2-hRPE65v1 when administered to dogs via single subretinal or intravitreal injection”
Skipped studiesopen answer page →
Genotoxicity
Not conducted (AAV low integration frequency; limited systemic exposure)
“studies to evaluate safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity were not conducted for AAV2-hRPE65v2.”
Carcinogenicity
Not conducted (post-mitotic retinal target; low insertional mutagenesis risk)
“Thus, the risk for AAV vector-induced insertional mutagenesis/carcinogenesis, particularly in post-mitotic cells such as retinal cells, is considered low.”
Instead of carcinogenicity
Argument from vector biology: administration to post-mitotic retinal tissue and AAV reliance on cellular factors to integrate
“AAV2-hRPE65v2 is administered to post-mitotic retinal tissue. AAV vectors do not encode proteins that catalyze integration, but rather rely on cellular factors to integrate into pre-existing chromosomal breaks11.”
DRG histopathology
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reproductive & developmental
Not conducted (limited systemic distribution; no vector DNA in gonads of dogs/NHPs)
“The presence of AAV2-hRPE65v2 was not detected by qPCR in the gonads of healthy NHPs following subretinal administration.”
Safety pharmacology
Not conducted (not considered necessary)
“No safety pharmacology studies were conducted.”
Genotox: Ames
Not conducted
“No animal studies have been conducted to evaluate the effects of LUXTURNA on carcinogenesis, mutagenesis, and impairment of fertility.”
Genotox: in vitro mammalian
Not conducted
“No animal studies have been conducted to evaluate the effects of LUXTURNA on carcinogenesis, mutagenesis, and impairment of fertility.”
Genotox: in vivo
Not conducted
“No animal studies have been conducted to evaluate the effects of LUXTURNA on carcinogenesis, mutagenesis, and impairment of fertility.”
Carcinogenicity model
Not conducted; insertional mutagenesis risk considered low for AAV in post-mitotic retinal cells
“Thus, the risk for AAV vector-induced insertional mutagenesis/carcinogenesis, particularly in post-mitotic cells such as retinal cells, is considered low.”
Carcinogenicity timing
Not required (CHMP advised 2-year rodent studies would not be meaningful)
“CHMP also advised that in vivo testing in 2-year carcinogenicity studies in mice or rats would not contribute meaningful data to assessing the risk of carcinogenicity.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies were conducted.”
First doseopen answer page →
First-in-human starting dose
FIH start dose basis not stated; clinical dose chosen over broad efficacious range using safety data (NHP NOAEL 5x clinical dose)
“Because the pharmacology data indicated that efficacy could be achieved over a broad dose range, the determination of the optimal therapeutic dose also relied on safety data.”
NOAEL / key findings
NHP NOAEL 7.5e11 vg/eye (5x clinical); ocular inflammation/retinal degeneration in dogs at 1.5e12 vg/eye; no systemic toxicity
“The no-observed-adverse-effect-level (NOAEL) in NHPs was 7.5 x 1011vg/eye, which is 5-fold higher than the proposed clinical dose level”
Risksopen answer page →
Immune & cytokine safety
Anti-AAV2 capsid antibodies (dogs, pre-exposed NHPs); minimal T-cell responses; mild ocular inflammation on re-administration
“There were no pro-inflammatory T cell responses (IFN-γ) to the AAV2 capsid, except for one NHP previously exposed to AAV2 vector that developed a CD4+ T cell response.”
Biodistribution & persistence
Vector DNA mainly in intraocular fluids; low in optic nerve, spleen, liver; none in gonads; shedding not studied in animals
“The highest levels of vector DNA were detected primarily in the intraocular fluids (anterior chamber fluid and vitreous) of vector-injected eyes.”
Modality-specific risk
Immune-mediated ocular inflammation and retinal degeneration at high vector dose; surgical procedure trauma; re-administration immunity
“Subretinal injection of 1.5 x 1012 vg/eye of a precursor AAV2-hRPE65v2 vector product in normal-sighted dogs resulted in ocular inflammation and retinal degeneration histologically in regions exposed to the vector.”
Anti-drug antibodies: animals
Anti-AAV2 capsid antibodies in dogs and AAV2-pre-exposed NHPs (not naive NHPs); transient anti-RPE65 antibodies in isolated cases
“Antibodies to the AAV2 capsid were present in the anterior chamber fluid and/or serum of normal-sighted and RPE65 mutant dogs. Antibodies to the AAV2 capsid were not detected in naïve NHPs, but were detected in NHPs previously exposed to AAV2 vector.”
Anti-drug antibodies: patients
Immune reactions mild; no clinically significant cytotoxic T-cell response to AAV2 or RPE65 (with corticosteroid cover)
“No subject had a clinically significant cytotoxic T-cell response to either AAV2 or RPE65. Subjects received systemic corticosteroids before and after subretinal injection of LUXTURNA to each eye.”
Label warnings
- Endophthalmitis
- Permanent Decline in Visual Acuity
- Retinal Abnormalities
- Increased Intraocular Pressure
- Expansion of Intraocular Air Bubbles
- Cataract
Ocular toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Repeat-dose tox before first-in-human
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
First-in-human starting dose
FIH start dose basis not stated; clinical dose chosen over broad efficacious range using safety data (NHP NOAEL 5x clinical dose)
“Because the pharmacology data indicated that efficacy could be achieved over a broad dose range, the determination of the optimal therapeutic dose also relied on safety data.”
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
Non-GLP monkey subretinal re-administration study (first eye, then contralateral eye), sacrificed at Days 190 and 217; no recovery phase defined. GLP studies were single-dose (dog)
“Scheduled Sacrifice Time Points Days 190 (two animals) and 217 (two animals)”
Pivotal GLP studies
Subretinal single-dose GLP dog 3-week/3-month; NHP 3-month; bilateral sequential and re-administration studies in dogs and NHP
“In these studies, virus was injected subretinally either once only, or once into each eye, and twice into the same eye.”
DART package
Species: DART
Not conducted
“Animal reproductive studies have not been conducted with LUXTURNA.”
Reproductive & developmental
Not conducted (limited systemic distribution; no vector DNA in gonads of dogs/NHPs)
“The presence of AAV2-hRPE65v2 was not detected by qPCR in the gonads of healthy NHPs following subretinal administration.”
PPND / ePPND: when
Not conducted or required, based on product attributes, publications and pharmacology/toxicology data
“studies to evaluate safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity were not conducted or required for AAV2-hRPE65v2.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“No animal studies have been conducted to evaluate the effects of LUXTURNA on carcinogenesis, mutagenesis, and impairment of fertility.”
Carcinogenicity model
Not conducted; insertional mutagenesis risk considered low for AAV in post-mitotic retinal cells
“Thus, the risk for AAV vector-induced insertional mutagenesis/carcinogenesis, particularly in post-mitotic cells such as retinal cells, is considered low.”
Carcinogenicity timing
Not required (CHMP advised 2-year rodent studies would not be meaningful)
“CHMP also advised that in vivo testing in 2-year carcinogenicity studies in mice or rats would not contribute meaningful data to assessing the risk of carcinogenicity.”
Safety marginopen answer page →
Safety margin at NOAEL
NHP NOAEL (vg/eye) is 5-fold the proposed clinical dose
“The no-observed-adverse-effect-level (NOAEL) in NHPs was 7.5 x 1011vg/eye, which is 5-fold higher than the proposed clinical dose level specified in the applicant’s ‘Dosage and Administration’ section of the label.”
NOAEL / key findings
NHP NOAEL 7.5e11 vg/eye (5x clinical); ocular inflammation/retinal degeneration in dogs at 1.5e12 vg/eye; no systemic toxicity
“The no-observed-adverse-effect-level (NOAEL) in NHPs was 7.5 x 1011vg/eye, which is 5-fold higher than the proposed clinical dose level”
Efficacy evidenceopen answer page →
Efficacy evidence
RPE65-mutant dogs: improved pupillary responses, ERGs and visual behavior, reduced nystagmus
“Subretinal delivery (bilateral, simultaneous administration) of AAV2-hRPE65v2 vector (8.25 x 1010 vg/dog eye) into RPE65 mutant dogs resulted in improved pupillary responses, ERGs, and visual behavior, and reduced nystagmus.”
Why that model
Naturally occurring RPE65-null Briard dog is an established large-animal disease model
“Briard dogs have a naturally occurring mutation (four base-pair deletion) in canine RPE65 that results in absence of RPE65 protein expression and these dogs have been subject to study over decades”
Reviewer's view of the efficacy data
EMA: sufficient proof of concept; no further animal studies required
“The applicant presented sufficient proof of concept to support use of voretigene neparvovec in patients and no further studies in animals are required.”
Test articleopen answer page →
Test article vs clinical lot
A precursor AAV2-hRPE65v2 vector product was used in normal-sighted dog studies at 1.5 x 1012 vg/eye. Bridging: Commercial lot shown comparable to the clinical material by lot release data and side-by-side comparability testing
“Subretinal injection of 1.5 x 1012 vg/eye of a precursor AAV2-hRPE65v2 vector product in normal-sighted dogs resulted in ocular inflammation and retinal degeneration histologically in regions exposed to the vector.”
Vector and route
AAV2-hRPE65v2 vector given by subretinal administration
“Following single or repeat subretinal administration of AAV2-hRPE65v2 in dogs and NHPs, no toxicity was observed in non-ocular tissues.”
First approval
2017 (FDA)
“Summary Basis for Regulatory Action Date: December 18, 2017”
Flexibilityopen answer page →
Flexibility accepted
DARTCriticised but acceptedBeyond the letter
No reproductive toxicity studies; gonadal biodistribution in dogs and primates used instead
Why: No vector in gonads of dogs and primates; limited systemic distribution after subretinal dosing · Weight of evidence
“The CHMP previously gave scientific advice that such studies would not be needed if ‘biodistribution data in two species and two sexes demonstrate lack of vector distribution to the gonads’. The applicant considers its dataset to be in line with this advice from CHMP.”
“Ultimately, no explanation for these errors was identified, but gonadal tissues from 18 animals (dogs and primates) were examined with no positive results, which is reassuring.”
GenotoxicityAcceptedBeyond the letter
No genotoxicity studies; literature-based discussion of AAV integration instead
Why: Integration expected at random sites; retinal pigment epithelium post-mitotic, so insertional mutagenesis risk limited · Pharmacology or kinetics · Weight of evidence
“The position at the conclusion of these was that the applicant need provide no experimental data with voretigene neparvovec and that a discussion could suffice, if judged adequate.”
“AAV integration requires the cells to be dividing and as a consequence, the risk of insertional mutagenesis seems limited: it would not be further understood by requiring experimental work with voretigene neparvovec.”
CarcinogenicityAcceptedBeyond the letter
No carcinogenicity or tumorigenicity studies
Why: Two-year rodent studies would not contribute meaningful data; vector administered to post-mitotic retinal tissue · Pharmacology or kinetics
“CHMP also advised that in vivo testing in 2-year carcinogenicity studies in mice or rats would not contribute meaningful data to assessing the risk of carcinogenicity.”
Safety pharmacologyAcceptedBeyond the letter
No safety pharmacology studies
“Separate safety pharmacology studies were not conducted and are not deemed to be necessary.”
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