Amondys 45
casimersen · DMD exon 45 (PMO)Adult male mouse and cynomolgus monkey; juvenile male rat
Defitelio: which tox species, and why?
defibrotide · Fragmented DNA oligonucleotides
Species
Rat and dog
“To support the current application, single-dose and repeat-dose toxicity studies were performed in rats and dogs with intravenous infusion.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; defibrotide itself was tested in rats and dogs
“To support the current application, single-dose and repeat-dose toxicity studies were performed in rats and dogs with intravenous infusion.”
Species: general tox
Rat and dog
“To support the current application, single-dose and repeat-dose toxicity studies were performed in rats and dogs with intravenous infusion.”
Species: DART
Rat and rabbit (IV EFD; not evaluable due to maternal mortality, abortion and resorption)
“Embryo-Fetal toxicity assessment was attempted in rats and rabbits, but was not possible because of high maternal mortality, abortion, and fetal resorption at all doses.”
Species: carcinogenicity
Mouse and rat (oral route)
“Two studies in mice and rats were conducted to review the potential long-term/carcinogenicity effects of defibrotide. The studies were performed to GLP standards and used the oral route of administration.”
Surrogate used in
No surrogate used; defibrotide tested directly in rats and dogs
“To support the current application, single-dose and repeat-dose toxicity studies were performed in rats and dogs with intravenous infusion.”
Same question, other oligonucleotides
Amvuttra
vutrisiran · TTR (siRNA)Rat and cynomolgus monkey (monkey only pharmacologically active; rat for off-target/class tox); rabbit EFD
Cyfendus
anthrax vaccine adsorbed, adjuvanted · TLR9 (CpG 7909 adjuvant)Rat only
Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Mouse (CD-1) and cynomolgus monkey
Exondys 51
eteplirsen · DMD exon 51 (PMO)Cynomolgus monkey and juvenile rat (eteplirsen); mdx/C57BL mouse incl. mouse surrogate
Givlaari
givosiran · ALAS1 (siRNA)Rat and cynomolgus monkey (both pharmacologically active); rabbit inactive (EFD only)
Heplisav-B
hepatitis B vaccine (recombinant), adjuvanted · TLR9 (CpG 1018 adjuvant)Mouse, rat and cynomolgus monkey (repeat-dose); rabbit and baboon escalation studies
Izervay
avacincaptad pegol · C5 (aptamer)Rabbit and dog (IVT ocular studies); rat and cynomolgus monkey (7-day IV); monkey the only pharmacologically relevant species
Kynamro
mipomersen · APOB (ASO)Mouse, rat and cynomolgus monkey (clinical ASO plus rodent surrogates)
Leqvio
inclisiran · PCSK9 (siRNA)Rat and cynomolgus monkey (both pharmacologically active); rabbit for EFD
Macugen
pegaptanib · VEGF-165 (aptamer)Rabbit and dog (pivotal IVT); rat IV for systemic; supportive monkey, mouse
Onpattro
patisiran · TTR (siRNA)Rat and cynomolgus monkey (monkey pharmacologically active; rat off-target/LNP)
Oxlumo
lumasiran · HAO1 (siRNA)Rat and cynomolgus monkey (both pharmacologically relevant); rabbit for EFD
Qalsody
tofersen · SOD1 (ASO)Cynomolgus monkey (IT, relevant species), CD-1 mouse (SC) and rat single-dose IT
Qfitlia
fitusiran · Antithrombin / SERPINC1 (siRNA)Healthy rat and cynomolgus monkey (GLP); hemophilia A mouse, hemophilia A dog and induced-HA monkey models
Redemplo
plozasiran · APOC3 (siRNA)Rat (off-target toxicity) and cynomolgus monkey (pharmacologically relevant)
Rivfloza
nedosiran · LDHA (siRNA)Cynomolgus monkey (relevant) plus mouse (nedosiran inactive; off-target assessment)
Rytelo
imetelstat · Telomerase (oligo)Mouse and cynomolgus monkey (general tox); mouse and rabbit (EFD)
Spinraza
nusinersen · SMN2 (ASO)Juvenile cynomolgus monkey (IT) and CD-1 mouse (SC, systemic effects)
Tegsedi
inotersen · TTR (ASO)Mouse, rat and cynomolgus monkey; monkey the only pharmacologically relevant species
Tryngolza
olezarsen · APOC3 (ASO)Mouse (with surrogate) and cynomolgus monkey
Viltepso
viltolarsen · DMD exon 53 (PMO)Male CD-1 mouse and male cynomolgus monkey (plus juvenile male mouse)
Vitravene
fomivirsen · CMV IE2 mRNA (ASO)Rabbit and monkey
Vyondys 53
golodirsen · DMD exon 53 (PMO)Mouse, cynomolgus monkey (adult males) and juvenile rat
Wainua
eplontersen · TTR (ASO)Mouse and cynomolgus monkey (monkey the pharmacologically relevant species)
Waylivra
volanesorsen · APOC3 (ASO)Mouse, rat and cynomolgus monkey (rabbit for embryo-fetal); monkey most relevant
Zanvastro
zilganersen · GFAP (ASO)Mouse (SC and ICV, juvenile) and juvenile monkey (intrathecal); mouse surrogate ASO arm