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Atlas/Gene therapy/Kebilidi/Skipped studies

Kebilidi: genotox, carcinogenicity and repro: done or skipped?

eladocagene exuparvovec · AADC
Check my plan vs. these
Genotoxicity
Not conducted (agreed with CHMP; low integration risk in post-mitotic neurons)
“It was previously agreed with CHMP that genotoxicity, carcinogenicity and evaluation of insertional mutagenesis studies were not required (EMEA/CHMP/SAWP/236092/2018).”
✓ VerifiedEMA assessment report, p. 41Source ↗
Carcinogenicity
Not conducted (product characteristics and patient population)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, genotoxicity, and carcinogenicity/tumorigenicity of KEBLIDI were not conducted.”
✓ VerifiedFDA summary basis for approval, p. 11Source ↗
Reproductive & developmental
Not conducted (local brain delivery, no systemic exposure or gonadal distribution)
“Given the local administration of eladocagene exuparvovec to the brain and lack of systemic exposure, and the absence of biodistribution to the gonads, the risk for germline transmission is low.”
✓ VerifiedEMA assessment report, p. 41Source ↗
Safety pharmacology
CNS (FOB) endpoints incorporated into 6-month GLP rat tox study; no stand-alone studies
“Stand-alone safety pharmacology studies were not conducted with eladocagene exuparvovec. An evaluation of CNS effects was included in the 6-month GLP toxicology study.”
✓ VerifiedEMA assessment report, p. 35Source ↗

Same question, other gene therapies

Adstiladrin

nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)
Not conducted for rAd-IFN; conducted for excipient Syn3 only (Ames and chromosome aberration, negative)

Beqvez

fidanacogene elaparvovec · Factor IX
Not 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-dystrophin
Not 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 IX
Not 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)

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 · RPE65
Not 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 VIII
Not 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 · SMN1
Not 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)

Summary across all 26 gene therapies →