Adstiladrin
nadofaragene firadenovec · IFN-alpha2b (adenovirus, intravesical)Cynomolgus monkey for rAd-IFN/Syn3 GLP tox; rat and monkey for excipient Syn3
Beqvez: which tox species, and why?
fidanacogene elaparvovec · Factor IX
Species
Cynomolgus monkey and mouse (tox); hemophilia B dog and mouse (pharmacology); rabbit (shedding)
“A toxicology study was also conducted evaluating IV administration of AAVRh74var Padua in nonhuman primates (NHP) at dose levels ranging from 1 x 1012 vg/kg to 5 x 1012 vg/kg.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For biologics, ICH S6(R1) asks for species in which the product is pharmacologically active (target binding and activity), usually a cynomolgus monkey.
“A relevant species is one in which the test material is pharmacologically active due to the expression of the receptor or an epitope (in the case of monoclonal antibodies).”
✓ VerifiedICH 2011: ICH S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived…, p. 7Source ↗
Surrogate molecule
Yes: canine FIX surrogate vector for dog pharmacology; tox used closely related predecessor vector
“In vivo pharmacology was evaluated using a surrogate BEQVEZ product, AAVRh74var-cFIX-R338L, which expresses a transgene encoding canine factor IX, in a juvenile hemophilia B dog model.”
Species: general tox
Nonhuman primate and mouse
“The biodistribution (BD) profile following administration of BEQVEZ in mice and NHPs was evaluated in toxicology Study Nos. 12 and 14 and within a select panel of tissues in Study No. 16.”
Species: DART
Not conducted (hemophilia B almost exclusively male; not intended for women)
“Per applicant, hemophilia B is almost exclusively limited to male subjects, and BEQVEZ is not intended for administration in women.”
Species: carcinogenicity
Not conducted (not warranted given product characteristics, BD/toxicology results, patient population)
“Studies to evaluate the safety pharmacology, developmental and reproductive toxicity, and carcinogenicity/tumorigenicity of BEQVEZ were not conducted. These studies are not warranted based on the product characteristics, results from the biodistribution and toxicology studies, and patient population.”
Surrogate used in
Yes: canine FIX surrogate vector (AAVRh74var-cFIX-R338L) for in vivo pharmacology in hemophilia B dogs
“In vivo pharmacology was evaluated using a surrogate BEQVEZ product, AAVRh74var-cFIX-R338L, which expresses a transgene encoding canine factor IX, in a juvenile hemophilia B dog model.”
Same question, other gene therapies
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
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