Amondys 45
casimersen · DMD exon 45 (PMO)Adult male mouse and cynomolgus monkey; juvenile male rat
Macugen: which tox species, and why?
pegaptanib · VEGF-165 (aptamer)
Species
Rabbit and dog (pivotal IVT); rat IV for systemic; supportive monkey, mouse
“From the total of studies performed, the 6-month rabbit and 9-month dog studies are considered pivotal.”
Why that species
VEGF highly conserved; identical binding sequence in rabbit and dog as in humans
“VEGF seems highly conserved between species and has an identical binding sequence in the pivotal toxicity species (rabbit and dog) as in humans.”
Surrogate molecule
No surrogate; clinical aptamer tested; nucleoside metabolites (2'-FU, 2'-FC) tested separately
“The two pegaptanib component modified nucleotides (2’-FU and 2’-FC) were evaluated in 90-day IV toxicity studies in woodchucks and rats.”
Species: general tox
Rabbit and dog (pivotal 6-month and 9-month intravitreal studies)
“From the total of studies performed, the 6-month rabbit and 9-month dog studies are considered pivotal.”
Species: DART
Mouse (definitive IV EFD) and rabbit (IVT range-finding EFD only)
“The reproductive toxicology program included range-finding embryo-foetal development studies in rabbit and mouse and a final embryo-foetal development study in the mouse.”
Species: carcinogenicity
Not conducted
“Carcinogenicity studies were not conducted.”
Surrogate used in
No surrogate used; VEGF binding sequence identical in rabbit, dog and human
“VEGF seems highly conserved between species and has an identical binding sequence in the pivotal toxicity species (rabbit and dog) as in humans.”
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
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