Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Qalsody: genotox, carcinogenicity and repro: done or skipped?
tofersen · SOD1 (ASO)
Genotoxicity
Conducted; negative (Ames, CHL chromosomal aberration, mouse micronucleus)
“Tofersen was negative in a complete battery of genetic toxicology studies.”
Carcinogenicity
Not conducted pre-approval (severity of indication); to be assessed post-approval
“Due to the severity of the indication, the carcinogenic potential of tofersen is to be conducted post-approval.”
Instead of carcinogenicity
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Instead of genotoxicity
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
DRG histopathology
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Reproductive & developmental
Mouse fertility (seminiferous tubule degeneration, NOAEL 10 mg/kg), mouse/rabbit EFD and mouse PPND negative; pharmacologically non-relevant species
“There were no effects on embryofetal development in CD1 mouse or NZW rabbit, or on pre- and postnatal development in CD1 mouse.”
Safety pharmacology
Incorporated into single-dose IT rat (CNS) and 13-week IT monkey study (CNS, CV, respiratory); hERG in vitro
“Safety pharmacology assessments following IT administration of tofersen were incorporated into a single dose study in male and female SD rats (CNS) and a 13-week repeat (Q2W) dose toxicity study in cynomolgus monkeys (CNS, CV, and respiratory).”
Genotox: Ames
Negative
“Tofersen was negative in in vitro (bacterial reverse mutation and mammalian cell chromosomal aberration) and in vivo (mouse micronucleus) assays.”
Genotox: in vitro mammalian
Mammalian cell chromosomal aberration: negative
“Tofersen was negative in in vitro (bacterial reverse mutation and mammalian cell chromosomal aberration) and in vivo (mouse micronucleus) assays.”
Genotox: in vivo
Mouse micronucleus: negative
“Tofersen was negative in in vitro (bacterial reverse mutation and mammalian cell chromosomal aberration) and in vivo (mouse micronucleus) assays.”
Carcinogenicity model
Not conducted (severity of indication); to be assessed post-approval
“Due to the severity of the indication, the carcinogenic potential of tofersen is to be conducted post-approval.”
Carcinogenicity timing
Not conducted before approval; carcinogenicity studies to be conducted after approval given the severity of the indication
“Due to the severity of the indication, the carcinogenic potential of tofersen is to be conducted post-approval.”
hERG / QT
hERG IC50 >34 µM
“The IC50 for hERG inhibition in transfected HEK cells was greater than 34µM.”
Same question, other oligonucleotides
Amvuttra
vutrisiran · TTR (siRNA)Conducted: Ames, human lymphocyte chromosome aberration, rat micronucleus; all negative
Dawnzera
donidalorsen · Prekallikrein / KLKB1 (ASO)Conducted: in vitro Ames, CHL chromosomal aberration and in vivo mouse bone marrow micronucleus; no genotoxicity
Defitelio
defibrotide · Fragmented DNA oligonucleotidesNegative: Ames assay and in vivo rat bone marrow micronucleus assay
Exondys 51
eteplirsen · DMD exon 51 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Givlaari
givosiran · ALAS1 (siRNA)Conducted: Ames, human lymphocyte chromosome aberration, rat micronucleus; all negative
Hibsago
bepirovirsen · HBV RNA (ASO)Conducted; negative (Ames, mammalian cell chromosomal aberration, in vivo mouse micronucleus)
Izervay
avacincaptad pegol · C5 (aptamer)Conducted: Ames, chromosomal aberration in mammalian cells, mouse micronucleus; all negative
Kynamro
mipomersen · APOB (ASO)Conducted; negative (Ames, mouse lymphoma, mouse micronucleus)
Leqvio
inclisiran · PCSK9 (siRNA)Conducted: standard panel, negative
Macugen
pegaptanib · VEGF-165 (aptamer)Conducted (GLP); pegaptanib and 2'-FU/2'-FC nucleosides negative overall
Onpattro
patisiran · TTR (siRNA)Conducted: Ames, human lymphocyte chromosome aberration, mouse micronucleus; all negative
Oxlumo
lumasiran · HAO1 (siRNA)Conducted: Ames, human lymphocyte chromosome aberration, rat micronucleus; all negative
Qfitlia
fitusiran · Antithrombin / SERPINC1 (siRNA)Conducted: bacterial reverse mutation, in vitro chromosomal aberration (human lymphocytes), rat bone-marrow micronucleus; all negative
Redemplo
plozasiran · APOC3 (siRNA)Conducted: Ames, in vitro chromosomal aberration (TK6), in vivo mouse micronucleus; not genotoxic
Rivfloza
nedosiran · LDHA (siRNA)Conducted; negative (Ames, in vitro micronucleus, in vivo mouse micronucleus)
Rytelo
imetelstat · Telomerase (oligo)Conducted; negative (Ames, in vitro micronucleus, in vivo mouse micronucleus)
Spinraza
nusinersen · SMN2 (ASO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Tegsedi
inotersen · TTR (ASO)Conducted; negative (Ames, CHL chromosomal aberration, mouse micronucleus)
Tryngolza
olezarsen · APOC3 (ASO)Conducted; negative (Ames, chromosomal aberration, mouse micronucleus)
Viltepso
viltolarsen · DMD exon 53 (PMO)Conducted; negative (Ames, CHL chromosomal aberration, mouse micronucleus)
Vitravene
fomivirsen · CMV IE2 mRNA (ASO)Conducted: mutagenic potential evaluated in in vitro and in vivo assays
Vyondys 53
golodirsen · DMD exon 53 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Wainua
eplontersen · TTR (ASO)Conducted; negative (Ames, chromosomal aberration, mouse micronucleus)
Waylivra
volanesorsen · APOC3 (ASO)Conducted: bacterial reverse mutation, mouse lymphoma TK, mouse bone-marrow micronucleus; all negative
Zanvastro
zilganersen · GFAP (ASO)Conducted: Ames, in vitro chromosomal aberration, mouse micronucleus; all negative