Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Defitelio: genotox, carcinogenicity and repro: done or skipped?
defibrotide · Fragmented DNA oligonucleotides
Genotoxicity
Negative: Ames assay and in vivo rat bone marrow micronucleus assay
“Defibrotide was not mutagenic in the in vitro bacterial reverse mutation assay (Ames assay) nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.”
Carcinogenicity
Not conducted by the intravenous route; oral studies inadequate to assess carcinogenic potential
“No carcinogenicity studies have been conducted with defibrotide administered by the intravenous route and the oral studies were inadequate to conduct an assessment of the potential for carcinogenicity.”
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
Rabbit embryo-fetal toxicity: fewer implantations and viable fetuses at doses about equal to the clinical dose (mg/m2)
“Exposure to defibrotide was associated with embryo-fetal toxicity (decreased number of implantations and viable fetuses compared to controls) in pregnant rabbits at doses approximately equivalent to the recommended clinical dose on a mg/m2 basis.”
Safety pharmacology
No hERG inhibition up to 500 µg/mL; ECG incorporated into 13-week dog infusion study
“Defibrotide did not reduce hERG tail current at concentrations up to 500 μg/ml. ECG examinations were performed as part of a 13 week intravenous infusion toxicity study in dogs.”
Genotox: Ames
Negative
“Defibrotide sodium was not mutagenic in vitro in a bacterial reverse mutation assay (Ames assay).”
Genotox: in vitro mammalian
Chromosomal aberration in Chinese hamster ovary cells: negative
“Defibrotide sodium was not clastogenic in an in vitro chromosomal aberrations assay in Chinese hamster ovary cells or an in vivo micronucleus assay conducted in bone marrow from rats administered defibrotide sodium by intravenous infusion.”
Genotox: in vivo
Rat bone marrow micronucleus (IV): negative
“Defibrotide sodium was not clastogenic in an in vitro chromosomal aberrations assay in Chinese hamster ovary cells or an in vivo micronucleus assay conducted in bone marrow from rats administered defibrotide sodium by intravenous infusion.”
Carcinogenicity model
No IV carcinogenicity studies; oral studies inadequate for assessment
“No carcinogenicity studies have been conducted with defibrotide administered by the intravenous route and the oral studies were inadequate to conduct an assessment of the potential for carcinogenicity.”
Carcinogenicity timing
No IV carcinogenicity studies; oral mouse and rat studies inadequate; none required for approval
“No carcinogenicity studies have been conducted with defibrotide administered by the intravenous route and the oral studies were inadequate to conduct an assessment of the potential for carcinogenicity.”
hERG / QT
Negative: no hERG tail current reduction up to 500 µg/mL
“Defibrotide did not reduce hERG tail current at concentrations up to 500 μg/ml.”
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
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
Qalsody
tofersen · SOD1 (ASO)Conducted; negative (Ames, CHL chromosomal aberration, mouse micronucleus)
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