Amondys 45
casimersen · DMD exon 45 (PMO)Adult male mouse and cynomolgus monkey; juvenile male rat
Tryngolza: which tox species, and why?
olezarsen · APOC3 (ASO)
Species
Mouse (with surrogate) and cynomolgus monkey
“The general toxicity of olezarsen has been characterized in repeat-dose toxicity studies in CD-1 mice and cynomolgus monkeys in studies of up to 26- and 39-weeks duration, respectively, with once-weekly SC injections.”
Why that species
Full sequence complementarity to human and cynomolgus apoC-III mRNA; mouse sequence diverges
“Olezarsen exhibits full complementarity to the apoC-III mRNA transcript of humans and cynomolgus monkeys.”
Surrogate molecule
Yes: mouse-specific GalNAc3 ASO ISIS 838707 in mouse pharmacology and 26-week mouse tox
“In wild-type mice, a mouse-specific apoC-III surrogate ASO was used (ISIS 838707, a murine”
Species: general tox
CD-1 mouse and cynomolgus monkey
“The general toxicity of olezarsen has been characterized in repeat-dose toxicity studies in CD-1 mice and cynomolgus monkeys in studies of up to 26- and 39-weeks duration, respectively, with once-weekly SC injections.”
Species: DART
Mice and/or rabbits for EFD and pre-/postnatal studies with the unconjugated ASO (volanesorsen)
“The Agency agreed that embryofetal development and pre-/postnatal development evaluations conducted with the unconjugated active ASO component of olezarsen in mice and/or rabbits were adequate to support a marketing application.”
Species: carcinogenicity
Mouse and rat lifetime studies with unconjugated volanesorsen; none with olezarsen
“Carcinogenicity studies were not conducted with olezarsen, but lifetime carcinogenicity studies were conducted for the active unconjugated ASO, volanesorsen, in both mice and rats.”
Surrogate used in
Yes: mouse-specific apoC-III surrogate ASO for mouse pharmacology and repeat-dose toxicity
“Non-clinical studies were mainly conducted in monkeys, except for some cases where a mouse specific surrogate inhibitor of apoC-III mRNA was used for pharmacodynamic (PD) and repeated-dose toxicity studies in mouse.”
Same question, other oligonucleotides
Amvuttra
vutrisiran · TTR (siRNA)Rat and cynomolgus monkey (monkey only pharmacologically active; rat for off-target/class tox); rabbit EFD
Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Mouse (CD-1) and cynomolgus monkey
Defitelio
defibrotide · Fragmented DNA oligonucleotidesRat and dog
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)
Hibsago
bepirovirsen · HBV RNA (ASO)Mouse and rabbit in labeled studies (carcinogenicity, reproduction); general-toxicity species not stated
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
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