Amondys 45
casimersen · DMD exon 45 (PMO)Adult male mouse and cynomolgus monkey; juvenile male rat
Redemplo: which tox species, and why?
plozasiran · APOC3 (siRNA)
Species
Rat (off-target toxicity) and cynomolgus monkey (pharmacologically relevant)
“Monkeys were deemed the most pharmacologically relevant species to evaluate on-target safety profile of plozasiran.”
Why that species
Antisense strand fully complementary to monkey and human ApoC-III mRNA, 7 mismatches to rodent; rat only suitable for off-target toxicity
“The antisense strand of plozasiran is fully complementary to monkey and human ApoC-III mRNAs, whereas plozasiran has seven sequence mismatches to the rodent ApoC-III mRNA transcript.”
Surrogate molecule
Yes: rodent-specific surrogate AD06313 used in rat embryo-fetal/repro studies; clinical molecule in general tox
“A follow-up EFD study was conducted with single dose SC administration of plozasiran or the rodent-specific surroga”
Species: general tox
Rat (24-week) and cynomolgus monkey (37-week), SC Q4W
“Q4W in rats (15, 30, and 120 mg/kg) and monkeys (30, 90, and 180 mg/kg) for durations up to 24- and 37-weeks, respectively”
Species: DART
Rat (FEED, EFD, PPND) and rabbit (EFD)
“Plozasiran was tested in a complete battery of nonclinical reproductive and developmental toxicity studies, including a fertility and early embryonic development (FEED) study in rats, embryo-fetal development (EFD) studies in rats and rabbits, and a pre/postnatal development (PPND) study in rats.”
Species: carcinogenicity
6-month transgenic mouse and 2-year rat
“Carcinogenic potential of plozasiran was tested in a 6-month transgenic mouse and a 2-year rat carcinogenicity study, the latter of which was submitted in the second round of the procedure.”
Surrogate used in
Yes: rat surrogate siRNA AD06313 in rat FEED and EFD studies
“Due to sequence mismatch between plozasiran and rat ApoC-III mRNA, animals treated with a rat surrogate anti-ApoC-III siRNA (AD06313) were included in the FEED and EFD studies to assess the on-target reproductive and developmental effects.”
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
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