Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Lyfgenia: genotox, carcinogenicity and repro: done or skipped?
lovotibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)
Genotoxicity
Insertional mutagenesis assessed: in vitro immortalization (IVIM) assay and integration site analyses; low risk
“Per the applicant, based on these data, the risk of insertional mutagenesis following BB305 transduction is low.”
Carcinogenicity
Not conducted (acceptable based on product type)
“No traditional carcinogenicity studies were conducted with lovo-cel which is acceptable based on the product type.”
Instead of carcinogenicity
In vitro immortalization assay showing low mutagenic potential of BB305 LVV versus positive control vectors, with integration site analysis
“The risk of insertional mutagenesis of BB305 LVV as evaluated using an in vitro immortalization (IVIM) assay performed with BB305 LVV-transduced mBMCs showed low mutagenic potential of BB305 LVV compared to positive control vectors , which are known to cause insertional transformation. Integration site analysis of CD34+ HSCs obtained from healthy donors showed no enrichment for LVV integration in or near known oncogenes.”
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 applicable: ex vivo HSC product, no vector administered to patients
Reproductive & developmental
Not conducted (no reproductive tissue findings in mouse studies; busulfan risk addressed in label)
“Per the applicant, developmental and reproductive toxicology studies were not conducted because there were no adverse findings in the male and female reproductive tissues of mice administered mBMCs transduced with BB305 LVV”
Safety pharmacology
Not conducted
“No safety pharmacology studies with lovo-cel were conducted.”
Genotox: Ames
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.
Genotox: in vitro mammalian
In vitro immortalization (IVIM) assay in transduced mouse marrow cells: low mutagenic potential vs positive control vectors
“The risk of insertional mutagenesis of BB305 LVV as evaluated using an in vitro immortalization (IVIM) assay performed with BB305 LVV-transduced mBMCs showed low mutagenic potential of BB305 LVV compared to positive control vectors”
Genotox: in vivo
Integration site analysis of transduced mouse marrow from transplant studies: no evidence of insertional mutagenesis
“There was no evidence of insertional mutagenesis.”
Carcinogenicity model
No carcinogenicity study; secondary-transplant mouse study: T-cell lymphoma/leukemia within radiation-associated background (15.7-25.3%), considered incidental
“The observed incidence of T-cell lymphoma and/or leukemia was within the reported range (15.7-25.3%) for radiation-associated lymphoma in C57BL/6 mice (E. Will et al. (2007) Mol Ther 15:782-91) and was considered incidental.”
Carcinogenicity timing
Not required (not warranted given product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with LYFGENIA™. These studies are not warranted based on the product characteristics and safety profile.”
hERG / QT
Not conducted (no safety pharmacology studies)
“No safety pharmacology studies with lovo-cel were conducted.”
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)
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)