Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Hemgenix: genotox, carcinogenicity and repro: done or skipped?
etranacogene dezaparvovec · Factor IX
Genotoxicity
Not conducted as standard battery; integration site analysis (LAM-PCR) in mouse and NHP liver showed low random integration
“For both species, the majority of the identified vector DNA sequences represented episomal forms that were not integrated into the host DNA.”
Carcinogenicity
Not conducted (not warranted based on nonclinical safety profile)
“Studies to evaluate the carcinogenicity/tumorigenicity of HEMGENIX were not conducted. These studies are not warranted based on the nonclinical safety profile.”
Instead of carcinogenicity
Liver integration site analysis in mice at 180 days and NHPs at 26 weeks given the predecessor vector
“Integration site analysis was performed on host genomic DNA isolated from liver tissue collected at 180 days (healthy mice) and 26 weeks (NHPs) following IV administration of the HEMGENIX predecessor.”
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
Dorsal root ganglia toxicity not included in the histopathological analyses
“The applicant confirmed that dorsal root ganglia toxicity was not included in histopathological analyses.”
Reproductive & developmental
Paternal germline transmission/fertility study in male mice only; no transmission, no fertility effects; EFD/PPND not required
“However, there were no adverse effects on mating rates or fertility indices.”
Safety pharmacology
Incorporated into NHP toxicity studies (ECG); no test article effects
“With regard to ECG readings no effects related to the test article were observed with AMT-060.”
Genotox: Ames
Not conducted (traditional mutagenicity studies not indicated)
“No traditional nonclinical carcinogenicity or mutagenicity studies were conducted with HEMGENIX; such studies were not indicated.”
Genotox: in vitro mammalian
Not conducted (traditional mutagenicity studies not indicated)
“No traditional nonclinical carcinogenicity or mutagenicity studies were conducted with HEMGENIX; such studies were not indicated.”
Genotox: in vivo
Not conducted (traditional mutagenicity studies not indicated)
“No traditional nonclinical carcinogenicity or mutagenicity studies were conducted with HEMGENIX; such studies were not indicated.”
Carcinogenicity model
Not conducted; replaced by liver integration-site analysis: low-level integration with no predilection for specific or cancer-associated sites
“A low level of integrated vector DNA was distributed throughout the host genome with no predilection to specific integration sites, including in genes associated with malignant transformation in humans.”
Carcinogenicity timing
Not conducted: not warranted based on the nonclinical safety profile
“Studies to evaluate the carcinogenicity/tumorigenicity of HEMGENIX were not conducted. These studies are not warranted based on the nonclinical safety profile.”
hERG / QT
No hERG assay; no test article-related ECG effects in monkey toxicity studies
“With regard to ECG readings no effects related to the test article were observed with AMT-060.”
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
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)