Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Strimvelis: genotox, carcinogenicity and repro: done or skipped?
autologous CD34+ cells transduced with ADA (no INN) · ADA (gamma-retroviral, ex vivo HSC)
Genotoxicity
Not conducted (conventional assays cannot detect insertional events)
“Conventional genotoxicity assays are inappropriate to detect insertional events and would not provide additional information to inform a quantitative risk assessment in humans and hence no studies have been conducted.”
Carcinogenicity
Not conducted (no adequate model; long-term engraftment of transduced cells in mice not achievable); relies on clinical follow-up
“Accordingly, the SmPC states that carcinogenicity studies have not been conducted as no adequate animal model was available to evaluate the tumourigenic potential of Strimvelis due to the inability to achieve long-term engraftment of transduced cells in mice.”
Instead of carcinogenicity
Tumourigenicity risk assessment based on clinical data and literature on similar vectors instead of a full tumourigenicity study
“In summary, in previous scientific advice, it was agreed that the tumourgenicity risk assessment for GSK2696273 could be based on clinical data and literature on similar vectors if tumourgenicity/general toxicity studies were unsuccessful in allowing for the determination of optimal conditions for a full tumourgenicity study.”
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; gonad histopathology in biodistribution study (busulfan-related atrophy); germline risk via clinical monitoring
“No reproductive or developmental toxicity studies were conducted with GSK2696273.”
Safety pharmacology
Not conducted (not feasible or relevant; ADA expressed at or below physiological levels)
“As per the applicant’s statement, no safety pharmacology studies were considered feasible in animals or relevant to the administration of GSK2696273 to humans.”
Genotox: Ames
Not conducted (conventional assays cannot detect insertional events)
“Conventional genotoxicity assays are inappropriate to detect insertional events and would not provide additional information to inform a quantitative risk assessment in humans and hence no studies have been conducted.”
Genotox: in vitro mammalian
Not conducted (conventional assays cannot detect insertional events)
“Conventional genotoxicity assays are inappropriate to detect insertional events and would not provide additional information to inform a quantitative risk assessment in humans and hence no studies have been conducted.”
Genotox: in vivo
Not conducted (conventional assays cannot detect insertional events)
“Conventional genotoxicity assays are inappropriate to detect insertional events and would not provide additional information to inform a quantitative risk assessment in humans and hence no studies have been conducted.”
Carcinogenicity model
Not conducted; pilot tumorigenicity studies could not achieve long-term engraftment of transduced cells in mice
“Conducted pilot studies indicate that a tumourgenicity study is not feasible since it was not possible to demonstrate long-term engraftment of transduced cells in mice.”
Carcinogenicity timing
Not required; tumorigenicity risk assessment based on clinical data and literature on similar vectors
“In summary, in previous scientific advice, it was agreed that the tumourgenicity risk assessment for GSK2696273 could be based on clinical data and literature on similar vectors if tumourgenicity/general toxicity studies were unsuccessful in allowing for the determination of optimal conditions for a full tumourgenicity study.”
hERG / QT
Not conducted; safety pharmacology not considered feasible or relevant
“As per the applicant’s statement, no safety pharmacology studies were considered feasible in animals or relevant to the administration of GSK2696273 to humans.”
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
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)