Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Luxturna: genotox, carcinogenicity and repro: done or skipped?
voretigene neparvovec · RPE65
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.”
Instead of genotoxicity
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.
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.”
Same question, other gene therapies
Beqvez
fidanacogene elaparvovec · Factor IXNot conducted (classical); vector integration site analysis in dog and NHP liver instead
Casgevy
exagamglogene autotemcel · BCL11A enhancer (CRISPR-Cas9, ex vivo HSC)No conventional studies; specialized on-/off-target editing (GUIDE-seq, in silico, hybrid capture) and chromosomal aberration assessments
Elevidys
delandistrogene moxeparvovec · Micro-dystrophinNot conducted (low-frequency random AAV integration per literature)
Fayuvi
rebisufligene etisparvovec · SGSH (AAV9)Not conducted; weight-of-evidence risk assessment used
Genglycos
pariglasgene brecaparvovec · G6PC (AAV8)Not conducted (low AAV integration risk); vector integration assessed in germline transmission study
Glybera
alipogene tiparvovec · LPL (AAV1)Not conducted (standard tests not relevant); integration studies (LAM-PCR, nrLAM-PCR) instead
Hemgenix
etranacogene dezaparvovec · Factor IXNot conducted as standard battery; integration site analysis (LAM-PCR) in mouse and NHP liver showed low random integration
Imlygic
talimogene laherparepvec · GM-CSF (oncolytic HSV-1)Not conducted (ICH S6(R1))
Itvisma
onasemnogene abeparvovec (intrathecal) · SMN1 (AAV9, intrathecal)Not conducted (single administration, known product characteristics, class safety profile)
Kebilidi
eladocagene exuparvovec · AADCNot conducted (agreed with CHMP; low integration risk in post-mitotic neurons)
Kresladi
marnetegragene autotemcel · ITGB2 (LVV, ex vivo HSC)Integration site analyses only (mouse and human transduced cells); no standard genotoxicity battery
Lenmeldy
atidarsagene autotemcel · ARSA (LVV, ex vivo HSC)Conducted: integration site analysis, in vitro immortalization assay, tumor-prone Cdkn2a-/- mouse; no insertional transformation
Lyfgenia
lovotibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)Insertional mutagenesis assessed: in vitro immortalization (IVIM) assay and integration site analyses; low risk
Otarmeni
lunsotogene parvec · OTOF (AAV, intracochlear)Not conducted (low AAV insertional mutagenesis risk; limited distribution beyond inner ear)
Papzimeos
zopapogene imadenovec · HPV6/11 antigens (gorilla adenovirus)Not conducted (non-integrating, replication-incompetent adenovector; no insertional mutagenesis)
Roctavian
valoctocogene roxaparvovec · Factor VIIINot conducted (literature on AAV); NHP liver integration site analysis: 1.55x10^-3 IS/cell, no clonal expansion
Skysona
elivaldogene autotemcel · ABCD1 (LVV, ex vivo HSC)Standard genotox not relevant; insertional mutagenesis assessed by in vitro immortalization assay and integration site analysis
Strimvelis
autologous CD34+ cells transduced with ADA (no INN) · ADA (gamma-retroviral, ex vivo HSC)Not conducted (conventional assays cannot detect insertional events)
Tudriqev
vusolimogene oderparepvec · GALV-GP + GM-CSF (oncolytic HSV-1)Not conducted (not warranted based on product characteristics and safety profile)
Vyjuvek
beremagene geperpavec · COL7A1 (HSV-1, topical)Not conducted (HSV-1 does not integrate; negligible insertional mutagenesis)
Waskyra
etuvetidigene autotemcel · WAS (LVV, ex vivo HSC)Conventional mutagenicity not conducted; IVIM assay, vector insertion site analysis and VITA performed, no genotoxic potential
Zevaskyn
prademagene zamikeracel · COL7A1 (RV-modified keratinocyte sheets)Not conducted (integration site analysis in transduced RDEB keratinocytes instead; no clonality or oncogene preference)
Zolgensma
onasemnogene abeparvovec · SMN1Not conducted (low random rAAV integration per literature)
Zynteglo
betibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)Insertional mutagenesis assessed instead of standard genotox: in vitro immortalization assay (low potential) and integration site analysis (no clonal dominance)