Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)
Elevidys: genotox, carcinogenicity and repro: done or skipped?
delandistrogene moxeparvovec · Micro-dystrophin
Genotoxicity
Not conducted (low-frequency random AAV integration per literature)
“Per the applicant, genotoxicity studies have not been conducted with SRP-9001 because the literature thus far, supports random integration of AAV vector into the host genome at low frequencies”
Carcinogenicity
Not conducted (no cancers in AAV clinical trials; dystrophin possible tumor suppressor)
“Based on the indication of X-linked DMD which occurs primarily in males and lack of concerning findings in the completed toxicology studies, further assessment of developmental and reproductive toxicology, carcinogenicity/tumorigenicity, and genotoxicity are not warranted at this time.”
Instead of carcinogenicity
Class data: AAV vectors studied in 162 clinical trials with no cancer reported
“AAV of various serotypes including AAV2 and AAVrh74, have been studied in 162 clinical trials; thus far, no cancer of any type has been reported.”
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
Not conducted (male population, no reproductive lesions); neonatal juvenile tox done; low germline signal in testes
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
Safety pharmacology
Not conducted
“There were no safety pharmacology studies performed with SRP-9001.”
Genotox: Ames
Not conducted (low-frequency random AAV integration per literature)
“Per the applicant, genotoxicity studies have not been conducted with SRP-9001 because the literature thus far, supports random integration of AAV vector into the host genome at low frequencies”
Genotox: in vitro mammalian
Not conducted (low-frequency random AAV integration per literature)
“Per the applicant, genotoxicity studies have not been conducted with SRP-9001 because the literature thus far, supports random integration of AAV vector into the host genome at low frequencies”
Genotox: in vivo
Not conducted (low-frequency random AAV integration per literature)
“Per the applicant, genotoxicity studies have not been conducted with SRP-9001 because the literature thus far, supports random integration of AAV vector into the host genome at low frequencies”
Carcinogenicity model
Not conducted; applicant cited no cancer reported across 162 AAV clinical trials
“AAV of various serotypes including AAV2 and AAVrh74, have been studied in 162 clinical trials; thus far, no cancer of any type has been reported.”
Carcinogenicity timing
Not conducted: acceptable given patient population and no ELEVIDYS-related adverse toxicology findings
“Animal reproductive and developmental toxicity and carcinogenicity studies were not conducted with ELEVIDYS, which is acceptable based on the patient population and lack of ELEVIDYS-related adverse findings in the toxicology studies.”
hERG / QT
No safety pharmacology studies conducted
“There were no safety pharmacology studies performed with SRP-9001.”
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
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)