Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Lenmeldy: genotox, carcinogenicity and repro: done or skipped?
atidarsagene autotemcel · ARSA (LVV, ex vivo HSC)
Genotoxicity
Conducted: integration site analysis, in vitro immortalization assay, tumor-prone Cdkn2a-/- mouse; no insertional transformation
“Genotoxicity risk was assessed in vitro using hHSPCs derived from healthy donors and MLD patients and showed no effects of LVV transduction or ARSA overexpression on the proliferation or differentiation of hHSPCs.”
Carcinogenicity
Not conducted (not warranted); tumorigenicity assessed within GLP mouse study
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200.”
Instead of carcinogenicity
In vitro immortalization assay and a tumor-prone mouse model with a GFP LVV sharing the ARSA LVV backbone, instead of carcinogenicity studies
“No evidence of insertional mutagenesis of the LVV backbone in an in vitro immortalization (IVIM) assay and no increase in tumorigenesis in vivo in a tumor-prone mouse model were demonstrated using a LVV expressing GFP, which shares the same LVV backbone as that of ARSA LVV. Carcinogenicity and developmental and reproductive toxicity studies were not conducted with”
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 (ex vivo transduction; germline transduction risk very limited)
“No dedicated reproductive and developmental studies are undertaken.”
Safety pharmacology
Not conducted; no CNS, cardiovascular or respiratory toxicity seen in animal studies
“No dedicated safety pharmacology studies have been performed with human or murine HSPCs transduced with ARSA-LV.”
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 same-backbone GFP-LV: no insertional mutagenesis
“No evidence of insertional mutagenesis of the LVV backbone in an in vitro immortalization (IVIM) assay and no increase in tumorigenesis in vivo in a tumor-prone mouse model were demonstrated using a LVV expressing GFP, which shares the same LVV backbone as that of ARSA LVV.”
Genotox: in vivo
Tumor-prone mouse model with same-backbone GFP-LV: no increase in tumorigenesis
“No evidence of insertional mutagenesis of the LVV backbone in an in vitro immortalization (IVIM) assay and no increase in tumorigenesis in vivo in a tumor-prone mouse model were demonstrated using a LVV expressing GFP, which shares the same LVV backbone as that of ARSA LVV.”
Carcinogenicity model
No carcinogenicity study; 12-month GLP tumorigenicity study in As2-/- mice: 2 hepatocellular neoplasms (1 ARSA-LV, 1 mock-LV)
“During the observation period of 12 months after transplantation, only 2 hepatocellular neoplasms were found (1 in ARSA-LV group, 1 in mock-LV group).”
Carcinogenicity timing
Not required (not warranted given product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. These studies are not warranted based on the product characteristics and safety profile.”
hERG / QT
Not conducted (no dedicated safety pharmacology studies)
“No dedicated safety pharmacology studies have been performed with human or murine HSPCs transduced with ARSA-LV.”
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
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)
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)