Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Skysona: genotox, carcinogenicity and repro: done or skipped?
elivaldogene autotemcel · ABCD1 (LVV, ex vivo HSC)
Genotoxicity
Standard genotox not relevant; insertional mutagenesis assessed by in vitro immortalization assay and integration site analysis
“Lenti-D is an autologous human cellular product, therefore, standard genotoxicity studies are not considered relevant.”
Carcinogenicity
Not conducted (traditional studies unsuitable for product); ISA on engrafted marrow instead
“Traditional carcinogenicity studies were not conducted as they are not suitable for assessing this product type.”
Instead of carcinogenicity
Integration site analysis on pre-transplant human CD34+ HSCs and post-transplant engrafted mouse bone marrow instead of traditional carcinogenicity studies
“Traditional carcinogenicity studies were not conducted for eli-cel. However, integration site analysis (ISA) was performed on Lenti-D transduced pre-transplant human CD34+ HSCs and post-transplant engrafted bone marrow cells (BMCs) from animals in the GLP toxicology study harvested at 29 and 92 days.”
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 applicable: ex vivo HSC product, no vector administered to patients
Reproductive & developmental
Not conducted; no findings in reproductive tissues in mouse GLP study
“Studies were not conducted to evaluate this safety endpoint based on the product type and due to the lack of findings in reproductive tissues in Study #10.”
Safety pharmacology
Not conducted; no overt CNS, CV or respiratory toxicity in two animal studies
“No dedicated safety pharmacology studies have been carried out.”
Genotox: Ames
Not conducted (standard genotoxicity not relevant for autologous cell product)
“Lenti-D is an autologous human cellular product, therefore, standard genotoxicity studies are not considered relevant.”
Genotox: in vitro mammalian
In vitro immortalization (IVIM) assay in murine Lin- bone marrow cells: reduced immortalization potential vs positive control vectors
“An in vitro immortalization (IVIM) assay was conducted with mouse lineage-depleted (hematopoietic non-lineage committed; Lin-) BMCs (the murine equivalent of human CD34+ HSCs) transduced with Lenti-D. There was a reduced potential for immortalization induced by insertional mutagenesis of the clinical vector, Lenti-D, compared to positive control vectors.”
Genotox: in vivo
Integration site analysis (pre-transplant HSCs and engrafted mouse bone marrow): expected SIN-lentiviral profile, no transcriptional start site preference
“Lenti-D transduced HSCs demonstrated the expected integration profile for self-inactivating lentiviral vectors, with preferred integration in gene-coding regions across the whole genome, no preference for integration in transcriptional start sites, and no bias for the 5’ or 3’ end of genes.”
Carcinogenicity model
Not conducted (traditional studies not suitable for this product type)
“Traditional carcinogenicity studies were not conducted as they are not suitable for assessing this product type.”
Carcinogenicity timing
Not required; omission acceptable given nature of product
“No repeat-dose toxicology, dedicated carcinogenicity, juvenile or developmental and reproductive toxicology studies were performed, and their omission is acceptable considering the nature of the product.”
hERG / QT
Not conducted; no safety pharmacology studies
“Safety pharmacology studies were not conducted for this product.”
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
Luxturna
voretigene neparvovec · RPE65Not conducted (AAV low integration frequency; limited systemic exposure)
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
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)