Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Zynteglo: genotox, carcinogenicity and repro: done or skipped?
betibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)
Genotoxicity
Insertional mutagenesis assessed instead of standard genotox: in vitro immortalization assay (low potential) and integration site analysis (no clonal dominance)
“Results from an in vitro immortalization (IVIM) assay performed with BB305 LVV-transduced murine BMCs showed low mutagenic potential of BB305 LVV.”
Carcinogenicity
Not conducted (not warranted; insertional mutagenesis risk assessed by IVIM/ISA)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel.”
Instead of carcinogenicity
In vitro immortalization assay showing low mutagenic potential and integration site analysis showing no clonal dominance or oncogene enrichment
“Results from an in vitro immortalization (IVIM) assay performed with BB305 LVV-transduced murine BMCs showed low mutagenic potential of BB305 LVV. Integration site analysis (ISA) of beti-cel ZYNTEGLO showed no clonal dominance or enrichment for LVV integration in or near known oncogenes.”
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 adverse findings in reproductive tissues of mice given murine product
“No developmental and/or reproductive toxicity (DART) studies were submitted to support the use of Zynteglo for the treatment of TDT.”
Safety pharmacology
Not conducted; no adverse circulatory, respiratory, neurologic or digestive effects in in vivo studies
“No safety pharmacology studies with beti-cel or with murine beti-cel were conducted.”
Genotox: Ames
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.
Genotox: in vitro mammalian
In vitro immortalization (IVIM) assay with BB305 LVV-transduced murine BMCs: low mutagenic potential
“Results from an in vitro immortalization (IVIM) assay performed with BB305 LVV-transduced murine BMCs showed low mutagenic potential of BB305 LVV.”
Genotox: in vivo
Integration site analysis of transplanted β-thalassaemic mouse BMCs (months 4 or 6): no preferred integration in MDS1-EVI1, LMO2 or HMGA2
“In the nonclinical studies conducted, ISA profiles of BB305 LVV-transduced β-thalassaemic mouse BMCs at Months 4 or 6 post-transplantation suggested that there was no preferred integration in the MDS1-EVI1 (MECOM), LMO2 or HMGA2 genes.”
Carcinogenicity model
Not conducted; no tumorigenicity or insertional oncogenesis in studies with transduced β-thalassaemic mouse BMCs or human HSCs
“No tumorigenicity and no evidence of an oncogenesis event related to insertional mutagenesis were observed in the nonclinical studies using BB305 LVV-transduced β-thalassaemic mouse BMCs or human healthy donor HSCs.”
Carcinogenicity timing
Not required (not warranted based on product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with beti-cel. These studies are not warranted based on the product characteristics and safety profile.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies with beti-cel or with murine beti-cel 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
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)
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)