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Atlas/Gene therapy/Lenmeldy/Skipped studies

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

atidarsagene autotemcel · ARSA (LVV, ex vivo HSC)
Check my plan vs. these
Genotoxicity
Conducted: integration site analysis, in vitro immortalization assay, tumor-prone Cdkn2a-/- mouse; no insertional transformation
“Genotoxicity risk was assessed in vitro using hHSPCs derived from healthy donors and MLD patients and showed no effects of LVV transduction or ARSA overexpression on the proliferation or differentiation of hHSPCs.”
✓ VerifiedFDA summary basis for approval, p. 15Source ↗
Carcinogenicity
Not conducted (not warranted); tumorigenicity assessed within GLP mouse study
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200.”
✓ VerifiedFDA pharmacology/toxicology review, p. 3Source ↗
Reproductive & developmental
Not conducted (ex vivo transduction; germline transduction risk very limited)
“No dedicated reproductive and developmental studies are undertaken.”
✓ VerifiedEMA assessment report, p. 40Source ↗
Safety pharmacology
Not conducted; no CNS, cardiovascular or respiratory toxicity seen in animal studies
“No dedicated safety pharmacology studies have been performed with human or murine HSPCs transduced with ARSA-LV.”
✓ VerifiedEMA assessment report, p. 34Source ↗

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)

Kebilidi

eladocagene exuparvovec · AADC
Not 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

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 →