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.”
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