Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Waskyra: genotox, carcinogenicity and repro: done or skipped?
etuvetidigene autotemcel · WAS (LVV, ex vivo HSC)
Genotoxicity
Conventional mutagenicity not conducted; IVIM assay, vector insertion site analysis and VITA performed, no genotoxic potential
“No mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have been performed with WASKYRA”
Carcinogenicity
Not conducted (not suited to product); tumorigenicity assessed in mouse toxicity and serial transplant studies up to 16 months
“While, standard carcinogenicity studies are usually not required due to the nature of the advanced medicinal product”
Reproductive & developmental
Not conducted; no vector in testes, no treatment-related effect on reproductive organs in mouse surrogate study
“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA.”
Safety pharmacology
Not conducted (WASP expressed under WAS promoter, accidental expression in heart unlikely)
“No standalone safety pharmacology studies have been conducted.”
Genotox: Ames
Not conducted (conventional mutagenicity studies not required for gene therapy)
“Conventional mutagenicity, carcinogenicity and reproductive and developmental toxicity studies have not been conducted, which is in accordance with scientific and regulatory recommendations related to gene therapies.”
Genotox: in vitro mammalian
In vitro immortalization (IVIM) assay in wild-type mouse Lin- HSPCs: WAS LVV negative; SFFV gammaretroviral vectors positive
“In the IVIM test, Lin- HSPCs were used from untreated wild type C57BL6/J mice which lack a pre-existing transforming lesion. The positive control vector and all gammaretroviral vectors with the SFFV enhancer– promoter induced re-plating in every experiment. Only the LVV with the WAS promoter and WAS transgene was negative in the assay.”
Genotox: in vivo
In vivo integration site analysis in Rag2-/-γc-/- mice: no enrichment near cancer genes (6.3% vs 16.1% random)
“After 8 weeks from transduced cell infusion in Rag2−/−/γc−/− mice, there was no in vivo enrichment of the frequency of insertion sites in close proximity to genes involved in cancer (6.3% in both HD and WAS patients versus 16.1% in random in silico insertions dataset).”
Carcinogenicity model
Not conducted; tumorigenicity assessed by IVIM assay and in vivo integration site analysis, no evidence of tumorigenicity
“Traditional carcinogenicity studies were not conducted since they are not suitable for assessment of this drug product type. The nonclinical data provided by the applicant showed no evidence of tumorigenicity using the in vitro immortalization (IVIM) assay (U Modlich, 2009)”
Carcinogenicity timing
Not required (not warranted for this product)
“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA. These studies are not warranted based on the drug product characteristics and safety profile.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No carcinogenicity, developmental and reproductive toxicology (DART) studies, and safety pharmacology studies were conducted for WASKYRA.”
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
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)
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)