Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Papzimeos: genotox, carcinogenicity and repro: done or skipped?
zopapogene imadenovec · HPV6/11 antigens (gorilla adenovirus)
Genotoxicity
Not conducted (non-integrating, replication-incompetent adenovector; no insertional mutagenesis)
“PRGN-2012 does not rely on host cell genome integration for expression of the transgene, thus, it has a reduced genotoxic risk and will not result in insertional mutagenesis or position-effect variation.”
Carcinogenicity
Not conducted (non-integrating adenovector; no significant human tumorigenicity history)
“Per the applicant, studies were not conducted to evaluate carcinogenicity as adenovectors are non-integrating. Therefore, the risk for insertional mutagenesis is not a major concern.”
Instead of carcinogenicity
Rationale that adenovectors are non-integrating, plus prior data showing no significant adenovirus tumorigenicity risk in humans
“Per the applicant, studies were not conducted to evaluate carcinogenicity as adenovectors are non-integrating. Therefore, the risk for insertional mutagenesis is not a major concern. In addition, previous data indicates adenovirus has not demonstrated a significant risk for tumorigenicity in humans.”
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 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.
Reproductive & developmental
Not conducted (predictable local adenovector biodistribution, species C-like vector); reviewer agreed
“This reviewer agrees with the rationale provided by the applicant for not conducting developmental and reproductive toxicology studies.”
Safety pharmacology
Not conducted
“Safety Pharmacology studies were not conducted.”
Genotox: Ames
Not conducted (not warranted given product characteristics)
“No biodistribution (BD), genotoxicity, carcinogenicity, reproductive and developmental toxicity, juvenile, nor dedicated local tolerance studies of PRGN-2012 were conducted. These studies are not warranted based on the product characteristics and nonclinical safety profile of PRGN-2012.”
Genotox: in vitro mammalian
Not conducted (not warranted given product characteristics)
“No biodistribution (BD), genotoxicity, carcinogenicity, reproductive and developmental toxicity, juvenile, nor dedicated local tolerance studies of PRGN-2012 were conducted. These studies are not warranted based on the product characteristics and nonclinical safety profile of PRGN-2012.”
Genotox: in vivo
Not conducted (not warranted given product characteristics)
“No biodistribution (BD), genotoxicity, carcinogenicity, reproductive and developmental toxicity, juvenile, nor dedicated local tolerance studies of PRGN-2012 were conducted. These studies are not warranted based on the product characteristics and nonclinical safety profile of PRGN-2012.”
Carcinogenicity model
Not conducted (adenovectors non-integrating; insertional mutagenesis not a major concern)
“Per the applicant, studies were not conducted to evaluate carcinogenicity as adenovectors are non-integrating. Therefore, the risk for insertional mutagenesis is not a major concern.”
Carcinogenicity timing
Not required; reviewer agreed with rationale for not conducting
“This reviewer agrees with the rationale provided by the applicant for not conducting carcinogenicity/tumorigenicity studies.”
hERG / QT
Not conducted; no safety pharmacology studies
“Safety Pharmacology studies were not 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)
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)