Beqvez
fidanacogene elaparvovec · Factor IXNot conducted (classical); vector integration site analysis in dog and NHP liver instead
Adstiladrin: genotox, carcinogenicity and repro: done or skipped?
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)
Genotoxicity
Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
“Safety pharmacology, pharmacokinetics, toxicology, and genotoxicity studies were also conducted for the exicipient Syn3.”
Carcinogenicity
Not conducted (not warranted by product characteristics, tox results, target population)
“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd”
Reproductive & developmental
Not conducted (not warranted by product characteristics, tox results, target population)
“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd”
Safety pharmacology
No dedicated vector study; excipient Syn3 in vitro hERG and in vivo CNS/CV/respiratory studies showed no risk up to 5 mg/kg
“Safety pharmacology studies do not indicate a risk for Syn3NODA in the in vivo studies evaluating CNS, cardiovascular and respiratory systems up to a concentration of 5 mg/kg.”
Genotox: Ames
Excipient Syn3: Ames negative
“The genotoxicity of Syn3NODA was evaluated in vitro in an Ames test for bacterial mutagenicity and in a chromosome aberration study in human lymphocytes for potential for clastogenicity. Overall, these studies indicate that Syn3NODA is not genotoxic in vitro.”
Genotox: in vitro mammalian
Excipient Syn3: chromosome aberration assay in human lymphocytes negative
“The genotoxicity of Syn3NODA was evaluated in vitro in an Ames test for bacterial mutagenicity and in a chromosome aberration study in human lymphocytes for potential for clastogenicity. Overall, these studies indicate that Syn3NODA is not genotoxic in vitro.”
Genotox: in vivo
Excipient Syn3: rat bone marrow micronucleus negative up to 25 mg/kg/day
“In the main study, male rats (n=5/group) dosed up to 25 mg/kg/day did not show an increase in the mean frequency of micronucleated polychromatic erythrocytes in bone marrow compared to control animals.”
Carcinogenicity model
Not conducted
“No carcinogenicity studies were conducted with Adstiladrin.”
Carcinogenicity timing
Not conducted: not warranted (product characteristics, toxicology results, target population)
“Carcinogenicity and reproductive and developmental toxicity studies were not performed for rAd-IFN/Syn3. These studies are not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”
hERG / QT
Excipient Syn3: no hERG tail-current effect up to 4.53 µM (GLP); hERG inhibition not expected clinically
“In a GLP compliant hERG test for SYN3NODA, 4.53 µM (nominally 10 µM) is considered the highest tested concentration of Syn3NODA with no statistically significant effect on hERG tail current, thereby confirming that hERG inhibition by SYN3NODA will not occur upon clinical treatment.”
Same question, other gene therapies
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)
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)