Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Otarmeni: genotox, carcinogenicity and repro: done or skipped?
lunsotogene parvec · OTOF (AAV, intracochlear)
Genotoxicity
Not conducted (low AAV insertional mutagenesis risk; limited distribution beyond inner ear)
“No genotoxicity studies have been conducted with DB-OTO. The risk of insertional mutagenesis with recombinant AAV vectors is considered to be low.”
Carcinogenicity
Not conducted (local distribution, no clinical AAV carcinogenesis evidence)
“No carcinogenicity studies have been conducted with DB-OTO.”
Instead of carcinogenicity
Review of animal toxicology and local biodistribution data, and lack of clinical evidence of AAV carcinogenesis
“These were considered not warranted based on a review of the animal toxicology studies, data from biodistribution studies showing limited DB-OTO vector distribution beyond the local compartment of the inner ear, and a lack of clinical evidence of carcinogenesis attributable to recombinant AAV vectors.”
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; gonadal biodistribution/expression assessed in tox studies (negligible, no findings)
“Across these nonclinical studies, there was negligible biodistribution of DB-OTO vector to the gonads, no expression of hOTOF mRNA in the gonads, and no gross or microscopic findings in the gonads, suggesting a low reproductive and germline integration risk.”
Safety pharmacology
No standalone studies; endpoints (Irwin/FOB, neuro exams) incorporated into toxicology studies
“No standalone safety pharmacology studies were conducted with DB-OTO. However, the toxicology studies included some safety pharmacology endpoints and are reviewed in the ‘Toxicology Studies’ section.”
Genotox: Ames
Not conducted (AAV insertional mutagenesis risk considered low)
“No genotoxicity studies have been conducted with DB-OTO. The risk of insertional mutagenesis with recombinant AAV vectors is considered to be low.”
Genotox: in vitro mammalian
Not conducted (AAV insertional mutagenesis risk considered low)
“No genotoxicity studies have been conducted with DB-OTO. The risk of insertional mutagenesis with recombinant AAV vectors is considered to be low.”
Genotox: in vivo
Not conducted (AAV insertional mutagenesis risk considered low)
“No genotoxicity studies have been conducted with DB-OTO. The risk of insertional mutagenesis with recombinant AAV vectors is considered to be low.”
Carcinogenicity model
Not conducted (limited vector distribution beyond inner ear; no clinical evidence of AAV carcinogenesis)
“No carcinogenicity studies have been conducted with DB-OTO. These were considered not warranted based on a review of the animal toxicology studies, data from biodistribution studies showing limited DB-OTO vector distribution beyond the local compartment of the inner ear, and a lack of clinical evidence of carcinogenesis attributable to recombinant AAV vectors.”
Carcinogenicity timing
Not warranted (intracochlear route, limited systemic exposure)
“Developmental and reproductive toxicity, genotoxicity, and carcinogenicity studies were not conducted with DB-OTO. These studies were not warranted based on the IC route of administration, limited systemic exposure, target patient population, and absence of safety concerns in the toxicology studies.”
hERG / QT
Not conducted; no standalone safety pharmacology (endpoints in toxicology studies)
“No standalone safety pharmacology studies were conducted with DB-OTO. However, the toxicology studies included some safety pharmacology endpoints and are reviewed in the ‘Toxicology Studies’ section.”
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
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)