Amondys 45
casimersen · DMD exon 45 (PMO)Conducted; negative (Ames, CHO chromosomal aberration, mouse micronucleus)
Waylivra: genotox, carcinogenicity and repro: done or skipped?
volanesorsen · APOC3 (ASO)
Genotoxicity
Conducted: bacterial reverse mutation, mouse lymphoma TK, mouse bone-marrow micronucleus; all negative
“Taking into account the lack of a genotoxic effect of volanesorsen”
Carcinogenicity
Conducted: 2-year SC studies in mouse and rat; tumours above historical controls, considered secondary to chronic inflammation
“The carcinogenic potential of volanesorsen was assessed in 2-yr repeated dose studies in mice (Study No. 304801-AS15) and rats (Study No. 304801-AS16).”
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
Conducted: mouse fertility/EFD (Seg I/II) and peri-postnatal, rabbit EFD (Seg II); no untoward effects attributed to apoC-III reduction
“Reproductive and developmental toxicity studies were conducted in mice (Segment I/II/III), and rabbits (Segment II)”
Safety pharmacology
Dedicated: hERG assay, monkey ECG/BP (IV and SC), mouse Irwin CNS and respiratory studies; no relevant effects at tested doses
“There was no significant inhibition of the hERG current by ISIS 304801 at the concentrations tested (89.5 and 251 µM) and therefore an IC50 value could not be determined.”
Genotox: Ames
Negative (Salmonella)
“304801-IS02/Gene mutations in bacteria/GLP Salmonella strains 1.5-5000µg/plate, - S9 Negative”
Genotox: in vitro mammalian
Mouse lymphoma L5178Y/TK+/- assay: negative
“L5178Y/TK+/- 100-500µg/ml +/- S9 Negative”
Genotox: in vivo
Mouse bone marrow micronucleus: negative
“Mouse, micronuclei in bone marrow 1000-2000 mg/kg Negative”
Carcinogenicity model
2-year mouse and rat
“The carcinogenic potential of volanesorsen was assessed in 2-yr repeated dose studies in mice (Study No. 304801-AS15) and rats (Study No. 304801-AS16).”
Carcinogenicity timing
2-year mouse and rat studies completed before the marketing application
“Two-year carcinogenicity studies were conducted in mice and rats. Test article-related neoplastic findings were above the historical control ranges, and it is likely that the neoplasms are secondary to chronic inflammation.”
hERG / QT
Negative: no significant hERG inhibition at 89.5 and 251 µM (IC50 not determinable)
“There was no significant inhibition of the hERG current by ISIS 304801 at the concentrations tested (89.5 and 251 µM) and therefore an IC50 value could not be determined.”
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
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)
Zanvastro
zilganersen · GFAP (ASO)Conducted: Ames, in vitro chromosomal aberration, mouse micronucleus; all negative