Amondys 45
casimersen · DMD exon 45 (PMO)Adult male mouse and cynomolgus monkey; juvenile male rat
Rivfloza: which tox species, and why?
nedosiran · LDHA (siRNA)
Species
Cynomolgus monkey (relevant) plus mouse (nedosiran inactive; off-target assessment)
“Nedosiran is inactive in the mouse because the LDHA mRNA sequence is different from humans, and hence, the toxicology of nedosiran was studied in the mouse to assess off-target hybridization effects.”
Why that species
LDHA mRNA target sequence 100% homologous in monkey; not conserved in mouse
“The monkey is considered a pharmacologically relevant model because the LDHA mRNA target sequence has 100% homology with humans.”
Surrogate molecule
Yes: mouse-active analog DCR-m355 used in pharmacology and mouse reproductive studies
“The effects of knockdown of LDHA mRNA were also assessed in genetically or chemically induced mouse models of PH using the pharmacologically active mouse-specific analog DCR-m355.”
Species: general tox
Mouse (juvenile, off-target) and cynomolgus monkey (juvenile and adult)
“Repeat dose toxicology studies were conducted in mice for up to 26 weeks and monkeys for up to 39 weeks.”
Species: DART
Mouse (fertility, EFD, PPND; plus mouse-active analog) and rabbit (EFD)
“In an embryo-fetal development study in mice, no maternal or developmental toxicities were observed with nedosiran at doses up to 2000 mg/kg/dose (58x the maximum recommended human dose (MRHD) or with the mouse active analog DCR-m355.”
Species: carcinogenicity
Not conducted pre-approval; 2-year study in one rodent species required postmarketing
“Complete a long-term (2-year) GLP carcinogenicity study of nedosiran by subcutaneous injection in one rodent species.”
Surrogate used in
Yes: mouse-specific analog DCR-m355 in mouse PH disease models, fertility, EFD and PPND studies
“The effects of knockdown of LDHA mRNA were also assessed in genetically or chemically induced mouse models of PH using the pharmacologically active mouse-specific analog DCR-m355.”
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)
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