Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Zolgensma: genotox, carcinogenicity and repro: done or skipped?
onasemnogene abeparvovec · SMN1
Genotoxicity
Not conducted (low random rAAV integration per literature)
“Recent scientific literature supports low random integration frequencies of recombinant AAV (rAAV) vectors1,2 and lack of hepatic genotoxicity in rAAV2/5 genome integration in NHP and human liver samples.”
Carcinogenicity
Not conducted (no tumors in clinical trials since 2013)
“Ongoing clinical trials (under IND #15699) since September 2013 have shown no evidence of tumor formation clinically in any subject administered with AVXS-101.”
Instead of carcinogenicity
Clinical trial experience since September 2013 with no tumour formation in any treated subject
“Ongoing clinical trials (under IND #15699) since September 2013 have shown no evidence of tumor formation clinically in any subject administered with AVXS-101.”
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
DRG microscopic findings in juvenile NHP after single IV dose of 1.1e14 vg/kg (6-month study)
“In a 6-month toxicology study conducted in juvenile non-human primates, single IV administration of onasemnogene abeparvovec at the recommended clinical dose level of 1.1 × 10 14 vg/kg, with or without corticosteroid treatment, resulted in microscopic findings in the dorsal root ganglia (DRG), trigeminal ganglia (TG), spinal cord, brainstem, and liver.”
Reproductive & developmental
Not conducted (infants sexually immature, low gonadal vector); label later reports mouse fertility study without effects
“The target patient population for AVXS-101 with infantile-onset SMA are typically less than 1 year of age and sexually immature.”
Safety pharmacology
Not conducted
“No safety pharmacology studies were performed with AVXS-101.”
Genotox: Ames
Not conducted (not warranted)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, carcinogenicity/tumorigenicity of AVXS-101 were not conducted for AVXS-101.”
Genotox: in vitro mammalian
Not conducted (not warranted)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, carcinogenicity/tumorigenicity of AVXS-101 were not conducted for AVXS-101.”
Genotox: in vivo
Not conducted (not warranted)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, carcinogenicity/tumorigenicity of AVXS-101 were not conducted for AVXS-101.”
Carcinogenicity model
Not conducted; applicant cited absence of tumors in clinical trials since September 2013
“Ongoing clinical trials (under IND #15699) since September 2013 have shown no evidence of tumor formation clinically in any subject administered with AVXS-101.”
Carcinogenicity timing
Not required (not warranted by product characteristics, toxicology results and patient population)
“These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies were performed with AVXS-101.”
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)
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)