Amondys 45
casimersen · DMD exon 45 (PMO)Adult male mouse and cynomolgus monkey; juvenile male rat
Zanvastro: which tox species, and why?
zilganersen · GFAP (ASO)
Species
Mouse (SC and ICV, juvenile) and juvenile monkey (intrathecal); mouse surrogate ASO arm
“The nonclinical package submitted to the NDA included general toxicology studies of up to 26 and 39 weeks' duration in mouse (subcutaneous [SC]) and monkey (intrathecal lumbar [ITL]), respectively, as well as a 13-week ICV toxicity study in mouse;”
Why that species
Single mismatch to monkey GFAP mRNA gave no knockdown in monkey; mouse surrogate used to probe on-target GFAP reduction
“No meaningful changes in GFAP mRNA levels were observed in brain or spinal cord tissues, likely due to the single mismatch between zilganersen and monkey GFAP mRNA.”
Surrogate molecule
Yes: mouse-specific surrogate ASO (ISIS 713812) dosed ICV in parallel juvenile mouse arm
“A parallel group administered the mouse surrogate ASO (ISIS 713812; 0.1 mg ICV) demonstrated locomotor hypoactivity and reductions in bone mineral content in males;”
Species: general tox
Mouse (SC and ICV) and juvenile monkey (intrathecal lumbar)
“The nonclinical package submitted to the NDA included general toxicology studies of up to 26 and 39 weeks' duration in mouse (subcutaneous [SC]) and monkey (intrathecal lumbar [ITL]), respectively, as well as a 13-week ICV toxicity study in mouse;”
Species: DART
Mouse (combined fertility and developmental toxicity study)
“The Applicant has completed a combined fertility and developmental toxicology study in the mouse model.”
Species: carcinogenicity
None conducted; 6-month Tg.rasH2 mouse and 2-year rat required as PMRs
“5053-1: Conduct a 6-month carcinogenicity study of zilganersen in Tg.rasH2 mice to assess tumorigenic potential. 5053-2: Conduct a 2-year carcinogenicity study of zilganersen in rats to assess tumorigenic potential.”
Surrogate used in
Yes: mouse surrogate ASO ISIS 713812 (ICV) in juvenile mouse toxicity study
“A parallel group administered the mouse surrogate ASO (ISIS 713812; 0.1 mg ICV) demonstrated locomotor hypoactivity and reductions in bone mineral content in males;”
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
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