Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Casgevy: genotox, carcinogenicity and repro: done or skipped?
exagamglogene autotemcel · BCL11A enhancer (CRISPR-Cas9, ex vivo HSC)
Genotoxicity
No conventional studies; specialized on-/off-target editing (GUIDE-seq, in silico, hybrid capture) and chromosomal aberration assessments
“No evidence of off-target editing was observed for in-silico and GUIDE-seq identified candidate off-target sites which were assessed by hybrid capture sequencing analyses.”
Carcinogenicity
Not conducted (tumorigenicity evaluated in 20-week NSG study; no tumors)
“No carcinogenicity studies were conducted with CTX001.”
Instead of carcinogenicity
Combined GLP toxicity and tumorigenicity study of 20 weeks in NSG mice plus specialized genotoxicity assessments of off-target editing and translocations
“The toxicity of exa-cel has been evaluated in an in vivo combined GLP toxicity and tumorigenicity study with a duration of 20 weeks in NSG mice. In addition, a battery of specialized genotoxicity studies consisting of in silico and in vitro safety assessments were conducted to evaluate the potential risks associated with off-target editing and chromosomal translocations.”
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 organ findings, low gonadal distribution, non-integrating editing)
“No DART studies were conducted with CTX001.”
Safety pharmacology
No separate studies; selected parameters assessed in GLP toxicity study with no effects
“However, selected safety pharmacology parameters, were investigated in the GLP toxicity study and no effects on CNS, cardiac, respiratory, renal or gastrointestinal systems were observed.”
Genotox: Ames
Not conducted (conventional mutagenicity studies not done)
“Conventional mutagenicity and carcinogenicity studies have not been conducted for CASGEVY.”
Genotox: in vitro mammalian
Specialized in vitro assays in edited CD34+ cells: no off-target editing (GUIDE-seq, hybrid capture) and no chromosomal aberrations (karyotyping, LR-PCR)
“No evidence of off-target editing was observed for in-silico and GUIDE-seq identified candidate off-target sites which were assessed by hybrid capture sequencing analyses. No chromosomal aberrations for SPY101-RNP edited CD34+ hHSPCs from healthy donors were observed based on karyotyping, long-range PCR sequencing, and hybrid capture sequencing analyses.”
Genotox: in vivo
In vivo indel percentage and editing spectrum in spleen and bone marrow of engrafted mice at Weeks 8 and 20: no differences versus input cells
“In addition to the % chimerism, also the average indel percentage and the editing spectrum were evaluated in spleen and BM samples of the recipient mice at Week 8 and Week 20 post-engraftment. The average indel percentage revealed no significant differences between the input cells and the samples collected from the recipient mice after 8 and 20 weeks of engraftment, respectively.”
Carcinogenicity model
Tumorigenicity in irradiated NSG mice, single IV dose followed 20 weeks: no tumor formation
“Mice received single IV administration of 1 x 106 cells/mouse and were followed for 20 weeks. There were no significant adverse findings or tumor formation.”
Carcinogenicity timing
Not conducted: not warranted (product characteristics and safety profile)
“Developmental and reproductive toxicity studies and carcinogenicity studies were not conducted with CASGEVY. These studies are not warranted based on the characteristics and safety profile of the product.”
hERG / QT
No safety pharmacology studies conducted
“There were no safety pharmacology studies conducted with CASGEVY.”
Same question, other gene therapies
Beqvez
fidanacogene elaparvovec · Factor IXNot conducted (classical); vector integration site analysis in dog and NHP liver instead
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)
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)