Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Roctavian: genotox, carcinogenicity and repro: done or skipped?
valoctocogene roxaparvovec · Factor VIII
Genotoxicity
Not conducted (literature on AAV); NHP liver integration site analysis: 1.55x10^-3 IS/cell, no clonal expansion
“In terms of genotoxicity, no studies were performed with BMN 270.”
Carcinogenicity
Not conducted (product characteristics, tox results, population)
“As regards carcinogenicity: no carcinogenicity studies were performed with BMN 270.”
Instead of carcinogenicity
NHP liver integration analysis: integration in 0.48% of vector sequences, average 1.55 × 10-3 integration sites per cell
“Vector integration events were observed at low frequencies (0.48% of vector sequences) with an overall average of 1.55 × 10-3 integration sites per cell (IS/cell), with the ten most abundant IS with sequence counts ranging between 2 and 7 reads or a relative frequency of less than 1.62%.”
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
No evidence of abnormalities in the dorsal root ganglia in 8 monkeys treated at 6.1012 or 2.1013 vg/Kg
“For 8 animals (Rhesus or Cynomolgus) treated at 6.1012 or 2.1013 vg/Kg, there was no evidence for abnormalities in the dorsal root ganglia, nor in the spinal cord area, at the time of euthanasia.”
Reproductive & developmental
Not conducted (DART); male mouse germline transmission/mating studies showed no F1 transmission or fertility effects
“There were no ROCTAVIAN-related adverse changes on mating rates, maternal behavior, and fertility indices.”
Safety pharmacology
Not conducted; no CNS/respiratory/CV/renal findings in toxicity studies
“Safety pharmacology studies were not performed because BMN 270 components (capsid, vector DNA, corresponding RNA and hFVIII-SQ protein) are not expected to impact major organ systems’ (central nervous system, cardiovascular, renal or respiratory) function.”
Genotox: Ames
Not conducted (literature-based argument of low AAV genotoxicity risk)
“In terms of genotoxicity, no studies were performed with BMN 270.”
Genotox: in vitro mammalian
Not conducted
“In terms of genotoxicity, no studies were performed with BMN 270.”
Genotox: in vivo
Not conducted (vector integration site analysis in monkey liver instead)
“In terms of genotoxicity, no studies were performed with BMN 270.”
Carcinogenicity model
No carcinogenicity study; monkey liver vector integration analysis plus mouse/monkey toxicology showed no clonal expansion, preferential integration or tumors
“In summary, the vector integration data in nonhuman primates and toxicology data obtained in mice and nonhuman primates (e.g., BMN270-16-045 and BMN270-16-046) indicate no evidence of BMN 270-related clonal expansion, preferential vector integration site(s), or tumor formation.”
Carcinogenicity timing
Not warranted (product characteristics, toxicology results, target population)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, carcinogenicity/tumorigenicity of ROCTAVIAN were not conducted. These studies were not warranted based on the product characteristics, results from the toxicology studies, and target patient population.”
hERG / QT
Not conducted; no CNS, respiratory, cardiovascular or renal findings in toxicity studies
“Safety pharmacology studies were not performed because BMN 270 components (capsid, vector DNA, corresponding RNA and hFVIII-SQ protein) are not expected to impact major organ systems’ (central nervous system, cardiovascular, renal or respiratory) function.”
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)
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)