Luxturna
voretigene neparvovec
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.”
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.”
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.”
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.”