Amondys 45
casimersen · DMD exon 45 (PMO)Adult male mouse and cynomolgus monkey; juvenile male rat
Exondys 51: which tox species, and why?
eteplirsen · DMD exon 51 (PMO)
Species
Cynomolgus monkey and juvenile rat (eteplirsen); mdx/C57BL mouse incl. mouse surrogate
“The pivotal toxicity studies were conducted in mdx or C57BL mice (12-week, 3-month, and 26-week), cynomolgus monkey (12- and 39-week), and juvenile Sprague-Dawley rat (10-week).”
Why that species
Human-sequence-specific PMO; no pharmacologically relevant species, monkey used for exposure/exon-skipping, mdx mouse needs exon 23 surrogate
“For mdx mouse, the pharmacological activity of the human product cannot be tested because of differences in the dystrophin gene mutation, requiring use of a mouse-specific PMO, exon 23 skipping AON and, therefore, resulting in a different truncated dystrophin.”
Surrogate molecule
Yes: mouse-specific exon 23 PMO (AVI-4225) used in 3-month and 26-week mdx/C57BL mouse studies
“In the 3-month and 26-week studies, the mouse surrogate, AVI-4225, was administered to mdx and C57BL mice according to the same study design.”
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
Givlaari
givosiran · ALAS1 (siRNA)Rat and cynomolgus monkey (both pharmacologically active); rabbit inactive (EFD only)
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)
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