Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Cynomolgus monkey for rAd-IFN/Syn3 GLP tox; rat and monkey for excipient Syn3
Lenmeldy: which tox species, and why?
atidarsagene autotemcel · ARSA (LVV, ex vivo HSC)
Species
Mouse (As2-/- MLD model, murine ARSA-LV HSPCs) for pivotal GLP; immunodeficient mice for human-cell biodistribution
“The in vivo safety of single IV administration of ARSA LVV-transduced mHSPCs at 1x106 cells/mouse (40-50x106 cells/kg) in irradiated As2-/- mice was evaluated in a pivotal GLP study for up to 12 months post-transplant.”
Why that species
As2-/- mouse used as MLD disease model; recapitulates some pathology but milder phenotype than patients
“The applicant has used the As2-/- mouse as a disease model for MLD in children.”
Surrogate molecule
Yes: murine Lin- HSPCs from As2-/- mice transduced with ARSA LVV (plus healthy human HSPCs) used instead of patient cells
“Therefore, lineage negative (Lin-) mHSPCs (derived from the BM of As2-/- mice) and healthy hHSPCs (derived from umbilical cord blood or BM) transduced with ARSA LVV were used for the majority of the nonclinical studies.”
Species: general tox
Mouse only (irradiated As2-/- MLD mice given ARSA-LV murine HSPCs; pivotal GLP study up to 12 months)
“The in vivo safety of single IV administration of ARSA LVV-transduced mHSPCs at 1x106 cells/mouse (40-50x106 cells/kg) in irradiated As2-/- mice was evaluated in a pivotal GLP study for up to 12 months post-transplant.”
Species: DART
Not conducted (ex vivo transduction with replication-incompetent LV; germline risk very limited)
“No dedicated reproductive and developmental studies are undertaken. As the cells are transduced ex vivo with a replication-incompetent lentiviral vector, the risk for transduction of the gametes and consequently the risk from germline transduction can be regarded as very limited and rather theoretical.”
Species: carcinogenicity
Not conducted (not warranted given product characteristics and safety profile)
“Carcinogenicity and developmental and reproductive toxicity studies were not conducted with OTL-200. These studies are not warranted based on the product characteristics and safety profile.”
Surrogate used in
Yes: murine Lin- HSPCs as homologue of human CD34+ cells, transduced with LV carrying human PGK and ARSA
“For the proof-of-principle studies, the applicant has used murine Lin- HSPCs as homologue for human CD34+ cells, although the LV vector did contain human PGK and ARSA.”
Same question, other gene therapies
Beqvez
fidanacogene elaparvovec · Factor IXCynomolgus monkey and mouse (tox); hemophilia B dog and mouse (pharmacology); rabbit (shedding)
Casgevy
exagamglogene autotemcel · BCL11A enhancer (CRISPR-Cas9, ex vivo HSC)Mouse only (irradiated NSG immunodeficient xenotransplant mice)
Elevidys
delandistrogene moxeparvovec · Micro-dystrophinMouse only (wild-type C57BL/6J and mdx disease model); NHP only in non-GLP supporting studies
Fayuvi
rebisufligene etisparvovec · SGSH (AAV9)Wild-type C57BL/6 mice only (6-month and 3-month GLP studies)
Genglycos
pariglasgene brecaparvovec · G6PC (AAV8)Mouse (adult and juvenile C57BL/6N) and juvenile cynomolgus monkey; GLP single-dose studies
Glybera
alipogene tiparvovec · LPL (AAV1)Wild-type mouse only for GLP tox; PD in LPL-/- mice and LPL-deficient cats; biodistribution in cats, mice, rabbits
Hemgenix
etranacogene dezaparvovec · Factor IXMouse and cynomolgus monkey
Imlygic
talimogene laherparepvec · GM-CSF (oncolytic HSV-1)Mouse (BALB/c) for GLP tox; single-dose studies also in rats and dogs; no permissive/relevant species for human GM-CSF
Itvisma
onasemnogene abeparvovec (intrathecal) · SMN1 (AAV9, intrathecal)Cynomolgus monkey (pivotal IT tox); FVB mice for ICV safety and fertility/EFD; SMA piglet and SMN-delta7 mouse pharmacology
Kebilidi
eladocagene exuparvovec · AADCRat (pivotal GLP); cynomolgus monkey for biodistribution/excipient studies
Kresladi
marnetegragene autotemcel · ITGB2 (LVV, ex vivo HSC)Mouse only (CD18HYP/CD18KO disease models, recipient mice, NSG mice); no large-animal tox
Luxturna
voretigene neparvovec · RPE65Dog (normal-sighted and RPE65-mutant Briard) and non-human primate
Lyfgenia
lovotibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)Mouse only (beta-thalassemic and wild-type C57BL/6 transplant models; immunodeficient mice for human cells)
Otarmeni
lunsotogene parvec · OTOF (AAV, intracochlear)Mouse (Otof-Q828X hom disease model) and cynomolgus monkey
Papzimeos
zopapogene imadenovec · HPV6/11 antigens (gorilla adenovirus)Mouse only (wild-type C57BL/6); no NHP studies
Roctavian
valoctocogene roxaparvovec · Factor VIIIMouse (CD1, Rag2-/-, hemophilia A models) and cynomolgus/rhesus monkey; all males
Skysona
elivaldogene autotemcel · ABCD1 (LVV, ex vivo HSC)Mouse only: myeloablated immunodeficient NSG/NSGS mice given human CD34+ HSCs
Strimvelis
autologous CD34+ cells transduced with ADA (no INN) · ADA (gamma-retroviral, ex vivo HSC)NSG immunodeficient mouse only (xenograft of transduced human CD34+ cells)
Tudriqev
vusolimogene oderparepvec · GALV-GP + GM-CSF (oncolytic HSV-1)Tumor-bearing immunocompetent mice (TUDRIQEV, mRP1) and healthy rats (murine surrogate mRP1)
Vyjuvek
beremagene geperpavec · COL7A1 (HSV-1, topical)Mouse only (BALB/c) for GLP tox; single species
Waskyra
etuvetidigene autotemcel · WAS (LVV, ex vivo HSC)Mouse only: WAS knockout (C57BL/6 and SV129) mice with murine surrogate cells; Rag2-/-IL2rg-/- mice for human-cell fate
Zevaskyn
prademagene zamikeracel · COL7A1 (RV-modified keratinocyte sheets)Mouse only (immunodeficient mice with implanted human keratinocyte products); no relevant large-animal species
Zolgensma
onasemnogene abeparvovec · SMN1Mouse only for pivotal GLP tox (neonatal FVB); NHP only in non-GLP studies (later 6-month juvenile NHP study in label)
Zynteglo
betibeglogene autotemcel · HBB T87Q (LVV, ex vivo HSC)Mouse only (beta-thalassaemic Hbbth1/th1 and wild-type C57BL/6; immunodeficient NSG for human HSC); murine surrogate product