Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Imlygic: genotox, carcinogenicity and repro: done or skipped?
talimogene laherparepvec · GM-CSF (oncolytic HSV-1)
Genotoxicity
Not conducted (ICH S6(R1))
“In accordance with ICH S6(R1) guideline, genotoxicity studies were not conducted.”
Carcinogenicity
Not conducted; literature review of HSV-1 epidemiology provided
“No carcinogenicity studies have been conducted (see non-clinical discussion).”
Instead of carcinogenicity
Review of available HSV-1 epidemiological data; wild-type HSV-1 does not integrate into the host genome
“Because wild-type HSV-1 does not integrate into the host genome, the risk of insertional mutagenesis with talimogene laherparepvec is negligible (SmPC section 5.3). In accordance with the ICH S9 guideline, no carcinogenicity studies have been conducted. The carcinogenic potential for an HSV-1-based therapy was evaluated by review of the available epidemiological data.”
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
Mouse embryo-fetal study (IV, up to 4e8 PFU/kg) no effects; adult reproductive tissues unaffected; no fertility/PPND studies
“No effects on embryo-foetal development were observed when talimogene laherparepvec was administered during organogenesis to pregnant mice at doses up to 4 x 108 (400 million) PFU/kg”
Safety pharmacology
Not conducted (no specific safety pharmacology studies)
“The applicant did not submit specific safety pharmacology studies (see non-clinical discussion).”
Genotox: Ames
Not conducted (ICH S6(R1)); HSV-1 forms episomes and does not integrate into host DNA
“In accordance with ICH S6(R1) guideline, genotoxicity studies were not conducted. Talimogene laherparepvec is a genetically-modified HSV-1 virus, which is an enveloped, double-stranded DNA virus that forms stable, circular episomes and does not integrate with host DNA.”
Genotox: in vitro mammalian
Not conducted (ICH S6(R1)); HSV-1 forms episomes and does not integrate into host DNA
“In accordance with ICH S6(R1) guideline, genotoxicity studies were not conducted. Talimogene laherparepvec is a genetically-modified HSV-1 virus, which is an enveloped, double-stranded DNA virus that forms stable, circular episomes and does not integrate with host DNA.”
Genotox: in vivo
Not conducted (ICH S6(R1)); HSV-1 forms episomes and does not integrate into host DNA
“In accordance with ICH S6(R1) guideline, genotoxicity studies were not conducted. Talimogene laherparepvec is a genetically-modified HSV-1 virus, which is an enveloped, double-stranded DNA virus that forms stable, circular episomes and does not integrate with host DNA.”
Carcinogenicity model
Not conducted; carcinogenic potential assessed by review of HSV-1 epidemiological data
“The carcinogenic potential for an HSV-1-based therapy was evaluated by review of the available epidemiological data.”
Carcinogenicity timing
Not conducted: not required per ICH S9; carcinogenic potential assessed from HSV-1 epidemiological data
“In accordance with the ICH S9 guideline, no carcinogenicity studies have been conducted. The carcinogenic potential for an HSV-1-based therapy was evaluated by review of the available epidemiological data.”
hERG / QT
Not conducted (no specific safety pharmacology studies)
“The applicant did not submit specific safety pharmacology studies (see non-clinical discussion).”
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
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)