Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Cynomolgus monkey for rAd-IFN/Syn3 GLP tox; rat and monkey for excipient Syn3
Roctavian: which tox species, and why?
valoctocogene roxaparvovec · Factor VIII
Species
Mouse (CD1, Rag2-/-, hemophilia A models) and cynomolgus/rhesus monkey; all males
“As the clinical schedule foresees one unique injection of BMN 270, all non-clinical studies supporting the safety of BMN 270 are single-dose toxicity studies conducted by the IV route, in male animals, in different animal species (Rag2-/- mice, Rag2-/- x FVIII-/- mice, CD1 mice, monkeys), which is acceptable.”
Why that species
Hemophilia A (Rag2-/- x FVIII-/-) mouse model for pharmacology; no explicit species-relevance argument; males because >99% of patients male
“All animals used in the nonclinical programme to evaluate BMN 270 were males because > 99% of HA patients are male.”
Surrogate molecule
No surrogate; clinical vector tested, though one pivotal GLP mouse study used early process B material
“The first GLP toxicity study (Study BMN 270-14-030) conducted in CD1 normal male mice used a batch of BMN 270 produced according to process B, which far diverges from process D and D’ used in phase III clinical trials and commercial process.”
Species: general tox
Mouse (CD1, Rag2-/-, Rag2-/- x FVIII-/-) and monkey; single-dose IV studies in males
“As the clinical schedule foresees one unique injection of BMN 270, all non-clinical studies supporting the safety of BMN 270 are single-dose toxicity studies conducted by the IV route, in male animals, in different animal species (Rag2-/- mice, Rag2-/- x FVIII-/- mice, CD1 mice, monkeys), which is acceptable.”
Species: DART
Not conducted (>99% of patients male); male mouse germline transmission/mating studies only
“As concerns fertility, dedicated fertility studies/embryofoetal studies have not been performed; the applicant argued that males comprise the majority (>99%) of the patient population to be treated with BMN 270”
Species: carcinogenicity
Not conducted
“As regards carcinogenicity: no carcinogenicity studies were performed with BMN 270.”
Surrogate used in
No surrogate used; BMN 270 tested directly (one pivotal CD1 mouse study used early process B material)
“The first GLP toxicity study (Study BMN 270-14-030) conducted in CD1 normal male mice used a batch of BMN 270 produced according to process B, which far diverges from process D and D’ used in phase III clinical trials and commercial process.”
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
Lenmeldy
atidarsagene autotemcel · ARSA (LVV, ex vivo HSC)Mouse (As2-/- MLD model, murine ARSA-LV HSPCs) for pivotal GLP; immunodeficient mice for human-cell biodistribution
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
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