Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Kebilidi: genotox, carcinogenicity and repro: done or skipped?
eladocagene exuparvovec · AADC
Genotoxicity
Not conducted (agreed with CHMP; low integration risk in post-mitotic neurons)
“It was previously agreed with CHMP that genotoxicity, carcinogenicity and evaluation of insertional mutagenesis studies were not required (EMEA/CHMP/SAWP/236092/2018).”
Carcinogenicity
Not conducted (product characteristics and patient population)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted.”
Instead of carcinogenicity
Weight of evidence: episomal AAV2 biology, integration sites, clinical experience and absence of tumours in rat chronic toxicology
“Based on the weight of evidence discussed regarding episomal AAV2 vector biology, integration sites, clinical experience with recombinant AAV2 vectors, the lack of any histologic or clinical evidence for tumor formation in eladocagene exuparvovec or rAAV2-AADC chronic toxicology studies in rats, carried out by the applicant, and supportive data from nonhuman primates, there appears to be a low risk for genomic integration or tumorigenicity”
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 (local brain delivery, no systemic exposure or gonadal distribution)
“Given the local administration of eladocagene exuparvovec to the brain and lack of systemic exposure, and the absence of biodistribution to the gonads, the risk for germline transmission is low.”
Safety pharmacology
CNS (FOB) endpoints incorporated into 6-month GLP rat tox study; no stand-alone studies
“Stand-alone safety pharmacology studies were not conducted with eladocagene exuparvovec. An evaluation of CNS effects was included in the 6-month GLP toxicology study.”
Genotox: Ames
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been performed with KEBILIDI.”
Genotox: in vitro mammalian
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been performed with KEBILIDI.”
Genotox: in vivo
Not conducted
“Carcinogenicity, genotoxicity, and fertility studies have not been performed with KEBILIDI.”
Carcinogenicity model
Not conducted; weight-of-evidence (episomal AAV2, no tumors in rat chronic studies) indicates low integration/tumorigenicity risk in post-mitotic neurons
“The applicant has provided a discussion on the risk of insertional mutagenesis and carcinogenic potential. Based on the weight of evidence discussed there appears to be a low risk for genomic integration or tumorigenicity in postmitotic neuronal cells.”
Carcinogenicity timing
Not required; not warranted given product characteristics and target patient population
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted. These studies were not warranted based on the product characteristics and target patient population.”
hERG / QT
Not conducted (no safety pharmacology studies)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI 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)
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)
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)